A Single-center, Randomized, Controlled, Open-label Study in Smoking Healthy Subjects to Investigate the Nicotine Pharmacokinetic Profiles Following Single Use of Tobacco Heating System (THS) With a Regular or a Menthol Stick, Compared to Smoking of a Single Combustible Cigarette (CIG)
Phase: NA
Conditions: Smoking, Tobacco
Sponsor: Philip Morris Products S.A.

 
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Data and information contained in this document are considered to constitute trade secrets 
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Clinical Study Protocol 
 
Study Number: 
P1-PK-12 
Study Title: 
A single-center, randomized, controlled, open-label 
study in smoking healthy subjects to investigate the 
nicotine pharmacokinetic profiles following single 
use of Tobacco Heating System (THS) with a regular 
or a menthol stick, compared to smoking of a single 
combustible cigarette (CIG) 
Short title: 
Nicotine pharmacokinetics of THS single use of a 
regular or a menthol stick compared to CIG 
Product Name: 
Tobacco Heating System (THS) Induction device 
and regular or menthol sticks 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 3 
2000 Neuchâtel, Switzerland 
Version: 
2.0, 
Approved 
Date: 
06 Feb 2023 
Authors: 
 
, PhD, Clinical Scientist 
, PhD, Biostatistician 
, MD, Medical Safety Officer 
 
 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P1-PK-12 
2.0, Approved 
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Document ID: VV-TMF-11280 
 
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law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
Version History 
Version 
Date 
Protocol 
Update/Amendment 
Original Document 1.0 
22 Nov 2022 
Not applicable 
2.0 
Refer to electronic 
signature date 
Non-substantial 
Amendment 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
The main purpose of this non-substantial amendment is the correction of typing errors, and 
the clarification of terms.  
For identification of the significant changes, the previous and the amended texts are 
provided. The new text has been highlighted in bold (e.g. new text) and deleted text has 
been crossed out (e.g. deleted text). 
Section 
Changes 
 
General 
The version number and the revision date were 
updated accordingly to the most current version and 
date. The double date for Version 01 was deleted. 
Synopsis 
Figure 1 
As there was red underline of the term “period”, a 
clean figure without the red underline. 
Synopsis 
Study Design 
Parenthesis added to describe “…prior to admission 
(on Baseline (Day -1)…” 
Section 4.1 
Figure 2 
As there was red underline of the term “period”, a 
clean figure without the red underline. 
Section 8.5 
Reporting and 
Follow-Up of 
Pregnancies 
Any pregnancy detected after enrollment must be 
reported by the Investigator to Sponsor within 24 
hours of first awareness.  
Section 9.2 
Table 4 
Body weight and height 
Section 10.4 
Risk 
Management 
In addition, at the end of study, the Sponsor will 
describe in the CSR the quality management 
approach implemented in the study. 
Section 12.7.1 
Blinding 
A certain level of blinding, for study statisticians and 
study scientists (CRO personnelalls which will be 
author of the body SAP)… 
 

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Synopsis 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 3 
2000 Neuchâtel 
Switzerland 
Name of Product: 
Tobacco Heating System (THS) Induction device and regular or menthol sticks 
Study Title: 
A single-center, randomized, controlled, open-label study in smoking healthy subjects to 
investigate the nicotine pharmacokinetic profiles following single use of Tobacco 
Heating System (THS) with a regular or a menthol stick, compared to smoking of a single 
combustible cigarette (CIG) 
Study Number: 
P1-PK-12 
Short Title: 
Nicotine pharmacokinetics following single use of THS with a regular or a menthol stick 
compared to CIG 
Main Objective and Endpoints: 
1. To describe the plasma concentration-time profile of nicotine and derived 
pharmacokinetic (PK) parameters of a single use of THS with either a regular or a 
menthol stick or of a single CIG. 
Endpoints (Day 1 to Day 3) 
Plasma nicotine concentration-time PK parameters (THS regular stick, THS menthol 
stick, and CIG separately): 
• Maximum nicotine plasma concentration [Cmax] 
• Time to the maximum nicotine plasma concentration [Tmax] 
• Area under the curve of nicotine plasma concentration-time computed from T0 to 
T=24 hours [AUC0-24h]  
• Area under the curve of nicotine plasma concentration-time computed from T0 to 
the subject-specific time of maximum nicotine concentration [AUC0-t’] 

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Secondary Objectives and Endpoints: 
1. To evaluate pharmacodynamic (PD) effects (subjective effects) of a single use of a 
THS with either a regular or a menthol stick or of a single CIG. Endpoints are by 
investigational product (IP). 
Endpoints (Day 1 to Day 3) 
• Score of CIG craving by the visual analogue scale (VAS) Craving assessment  
• Score of IP liking by the VAS Liking assessment 
• Score of intention to use the IP again by the VAS Intention to Use Again 
assessment 
2. To evaluate the safety of test products during the study. 
Endpoints 
• Incidence of adverse events (AEs) and serious adverse events (SAEs)  
• Incidence of product events  
• Changes in electrocardiogram (ECG) from baseline (heart rate, PR, QRS, QT, 
QTcF interval) 
• Changes in vital signs from baseline (systolic and diastolic blood pressure, pulse 
rate and respiratory rate) 
• Concomitant medication 
• Changes in standard spirometry from baseline (FEV1, FEV1 % predicted, FVC, 
FVC % predicted, FEV1/FVC) 
• Changes from baseline in clinical chemistry, hematology, and urine analysis 
safety panel 
Study Hypothesis: 
There is no pre-specified hypothesis to be tested in this study. This study aims to obtain 
PK profiles of the tested products. 
Study Design: 
This is a single-center, randomized, controlled, open-label, cross-over study in healthy 
subjects. The study will be conducted with 3 periods and 6 sequences in a cross-over 
design. 

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Abbreviations: CIG = combustible cigarette; P1M = menthol taste; P1R = regular taste  
Figure 1 
Study Design 
A Screening visit will be conducted within 27 days (Day -28 to Day -2) prior to admission 
(on Baseline Day -1) to the investigational site (Figure 1) to check and document the 
eligibility of the subjects. Investigational site staff will demonstrate the THS (without 
product use) during the Screening visit. The brand of subjects’ cigarettes will be 
recorded. 
Qualified subjects will return to the investigational site for Baseline on Day -1. Subjects 
will have fasted for at least 6 hours prior to the safety laboratory assessments. After 
confirmation of eligibility, subjects can be randomized. All subjects who will not be 
randomized will be documented as screen failures. 
Thirty subjects will be randomized to one of 6 possible full crossover sequences of 
investigational product (IP) use (THS with either regular or menthol stick, and CIG) on 
Day 1 to Day 3 (see Figure 1). After admission on Baseline Day -1 in the morning, 
nicotine wash-out will start, and the use of any other tobacco and/or nicotine containing 
products (TNP) different from the IP assigned for use on Day 1 to Day 3, will not be 

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law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
allowed. Use of TNP will not be restricted after the subject has been discharged from the 
investigational site on Day 3. 
On Day 1 to Day 3, after at least 23 hours of abstinence from any TNP on Day 1, and 
after at least 24 hrs of former IP use on Day2 and Day 3 (nicotine wash-out), subjects 
will smoke a single CIG or perform a single use of a THS either with a regular or a 
menthol stick, according to randomized product use sequence.  
The start of IP use will be defined as T0. T0 on Day 1 to Day 3 should be at approximately 
the same time in the morning. Venous blood samples will be obtained according to the 
standard operating procedures (SOPs) at the investigational site. Subjects will report their 
cigarette craving, IP liking, and intention to use again by performing VAS assessments.  
After Discharge on Day 3 or after Early termination following product exposure, the 
subjects will enter a 3-day Safety follow-up period (SFU period) during which AE/SAEs 
reported by the subjects will be collected and the follow-up of AEs/SAEs will be 
conducted, concluded per a telephone contact by the investigational site on the last day 
of the SFU period.  
Blood sample collection 
On Day 1, fourteen blood samples will be collected for determination of nicotine 
concentration at the following time points in relation to T0 with a time window as 
indicated in brackets: 
Before T0: 
• TB0 5 minutes before IP use (± 2 minutes) 
After T0: 
• TB1 after 4 minutes (± 1 minute) 
• TB2 after 6 minutes (± 1 minute) 
• TB3 after 8 minutes (± 1 minute) 
• TB4 after 10 minutes (± 1 minute) 
• TB5 after 12 minutes (± 1 minutes) 
• TB6 after 15 minutes (± 2 minutes) 
• TB7 after 30 minutes (± 5 minutes) 
• TB8 after 1 hour (± 5 minutes) 
• TB9 after 2 hours (± 5 minutes) 
• TB10 after 4 hours (± 5 minutes) 
• TB11 after 10 hours (± 5 minutes) 
• TB12 after 14 hours (± 5 minutes) 

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• TB13 after 24 hours (± 10 minutes) 
On Day 2, thirteen blood samples will be collected for determination of nicotine PK after 
allocated product use at the same time points (without timepoint TB0). The sample TB13 
of Day 1 will also be used to determine the nicotine baseline concentration prior to T0 
on Day 2 and similarly, TB13 of Day 2 for determination of nicotine baseline 
concentration prior to T0 on Day 3.  
On Day 3, eleven blood samples (TB1 to TB11) will be collected for determination of 
nicotine PK after allocated product use. The samples TB12 and TB13 will not be collected. 
Questionnaire completion 
On Day 1 to Day 3, product liking, cigarette craving, and intention to use the product 
again will be assessed using a VAS (100 mm going from “strong disliking” to “strong 
liking” for VAS Liking; from “no craving” to “strong craving” for VAS Craving; and 
“very unlikely” to “very likely” for VAS Intention to Use Again) at the following time 
points in relation to T0 with a time window as indicated in brackets: 
Prior to T0 (for VAS Craving assessment) 
• TV0: within 15 minutes prior to T0  
After T0 (for VAS Craving assessment) 
• TV1 after 4 minutes (± 2 minutes) 
• TV2 after 10 minutes (± 2 minutes) 
• TV3 after 15 minutes (± 2 minutes) 
• TV4 after 30 minutes (± 2 minutes) 
• TV5 after 10 hours (± 5 minutes) 
After T0 (for VAS Liking and VAS Intention to Use Again assessments) 
• Tv3 after 15 minutes (± 1 minute) 

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law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
Study Population and Main Criteria for Inclusion/Exclusion: 
An adequate number of healthy adult female and male smokers who meet all the 
following eligibility criteria will be screened to ensure that 30 subjects will be 
randomized. 
Inclusion Criteria 
Screening 
Day -1 
1. Subject has signed the ICF and is able to understand the 
information provided in the ICF.  
X  
  
2. Subject is male or female and between 21 and 65 years 
old (inclusive).  
X 
  
3. Subject has been a smoker for ≥3 years prior to the 
screening visit (smoking cessation attempts during this 
period, if any, did not last > 6 months in total).  
X 
 
4. Subject has continuously smoked on average ≥10 
commercially available regular CIG/day over the last 4 
weeksa. Smoking status will be verified based on a 
urinary cotinine test (cotinine ≥200 ng/mL).  
X 
X 
5. Subject is healthy as judged by the Investigator based on 
available assessments from the screening period (e.g., 
safety laboratory, spirometry, vital signs, physical 
examination, ECG, and medical history).  
X 
X 
6. Subject does not plan to quit smoking within the next 
three months. 
X 
X 
a. 
Regular users of other TNP in addition to CIG smoking may be enrolled into the study if they agree to limit 
themselves to stick use/CIG smoking (according to their randomization) during the Exposure period 
Subjects who meet any of the following exclusion criteria must not be randomized into 
the study: 

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secrets and confidential information are hereby claimed under the provisions of applicable 
law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
Exclusion Criteria 
Screening  Day -1 
1. As per the Investigator’s judgment, the subject cannot 
participate in the study for any reason other than 
medical (e.g., psychological, social reason).   
X 
X 
2. Subject is legally incompetent, or physically or 
mentally incapable of giving consent (e.g., in 
emergency situations, under guardianship, prisoners).  
X 
 
3. Subject has a clinically relevant disease which requires 
medication 
(including 
but 
not 
limited 
to 
gastrointestinal, 
renal, 
hepatic, 
neurological, 
hematological, endocrine, oncological, urological, 
immunological, 
pulmonary, 
and 
cardiovascular 
disease) or any other medical condition (including 
safety laboratory), which as per the judgment of the 
Investigator would jeopardize the safety of the subject.  
X 
 
4. Subject experienced within 30 days prior to 
screening/admission a body temperature >37.5°C or an 
acute illness (e.g., upper respiratory-tract infection, 
viral infection, etc.) or the subject has a confirmed or 
suspected active COVID-19 infection (based on the 
signs and symptoms observed at the time of 
assessment)  
X 
X 
5. As per the Investigator’s judgment, the subject has 
medical conditions which do or will require a medical 
intervention 
(e.g., 
start 
of 
treatment, 
surgery, 
hospitalization) during the study participation, which 
may interfere with the study participation and/or study 
results.   
X 
 
6. Subject has relevant history of, or current asthma 
condition or COPD condition, and/or clinically 
significant findings.   
X 
 
7. Subject has donated blood or received whole blood or 
blood products within 3 months.   
X 
 
8. BMI < 18.5 kg/m2 or ≥ 32.0 kg/m2.   
X 
 
9. Positive serology test for HIV 1/2, HBV, or HCV a.   
X 
 

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10. Subject has a positive alcohol breath test and/or has a 
history of alcohol disorder that could interfere with 
their participation in the study.    
X 
X 
11. The subject has a positive urine drug test.   
X 
X 
12. Subject or one of their family membersb is a current or 
former employee of the tobacco or e-cigarette industry.  
X 
 
13. Subject or one of their family membersb is an employee 
of the investigational site or of any other parties 
involved in the study.   
X 
 
14. Subject has participated in another clinical study within 
3 months.   
X 
 
15. Subject has been previously screened or enrolled in this 
study.   
X 
 
16. Subject is pregnant (does not have negative pregnancy 
tests at Screening and at Baseline) or is breastfeeding.  
X 
X 
17. For women of childbearing potential only:c subject does 
not agree to use an acceptable method of effective 
contraceptiond . 
X 
 
Abbreviations:  
BMI = body mass index; COVID-19 = Corona virus infection disease; COPD = chronic obstructive pulmonary disease 
a. 
Human immunodeficiency virus, hepatitis B virus, hepatitis C virus 
b. 
As defined by FDA guidance on Human Subject Protection (21 CFR 50.3(l), (m), 50.24(a)(6), (a)(7)(v), b)): 
"Family member” means among other things “parent”, “spouse”, “brothers, sisters, and spouses of brothers 
and sisters”, and “any individual related by affinity…whose close association with the subject is equivalent 
of a family relationship”.  
c. 
Women who are not of childbearing potential meet at least one of the following criteria:   
• Have undergone hysterectomy or bilateral tubal ligation, 
• Have medically confirmed ovarian failure, or 
• Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive 
months with no alternative pathological or physiological cause).  
d. 
Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with 
spermicidal foam/gel/film/suppository, hormonal contraception, vasectomized partner(s), or true abstinence 
(periodic abstinence and withdrawal are not effective methods) from Screening until the end of the Safety 
follow-up period.   
Sample Size: 
The sample size is empirically based as there are no considerations for statistical 
hypotheses. A total of 30 subjects is expected to be sufficient to obtain a precision of 0.2 
or lower on the THS / CIG Cmax ratios. 

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Investigational Product: 
Test product: The THS induction device, and regular and menthol sticks, will be provided 
by the Sponsor. The following two stick variants will be investigated:  
Name in the study 
Flavor  
P1R stick 
Regular 
P1M stick 
Menthol 
Comparator product: The subjects will bring their own supply of commercially available 
single brand CIG for the study duration. 
Duration of Study: 
The entire study per subject will last up to 34 days. This will include a screening period 
of up to 27 days prior to Baseline (Day -28 to Day -2), 4 days of confinement (from the 
subjects’ admission on Day -1 to time of Discharge on Day 3, including 3 overnight 
stays), and a 3-day Safety follow-up (SFU) period (from time of Discharge on Day 3 or 
Early termination plus three days). The end of the study (EOS) for a subject is defined as 
the end of the SFU period. The end of the whole study corresponds to the individual EOS 
of the last subject. 
Statistical Methods:  
Demographics and baseline characteristics will be analyzed on the randomized and PK 
populations. 
PK and PD endpoints will be analyzed on the randomized and the PK population.  
Safety will be analyzed using the safety population.  
Nicotine PK endpoints will be derived from the plasma nicotine concentrations. Nicotine 
PK parameters will be derived from plasma nicotine concentration versus time data using 
a non-compartmental analysis (NCA) technique. 
All data will be presented in listings, ordered by subject, study visit, IP and time point, 
unless otherwise specified.  
All endpoints will be summarized with descriptive statistics including number of subjects 
(n), number and percentage of subjects with missing data, arithmetic means, and standard 
deviations (mean and SD), median, first and third quartiles, minimum and maximum.  
For log normally distributed endpoints (AUC0-24h, Cmax, and AUC0-t’), geometric mean, 
geometric CV and geometric CI will be presented in addition.  

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Categorical variables will be summarized by frequency statistics (number and 
percentage).  
For endpoints relating to sampling times (e.g., Tmax), only median, first and third 
quartiles, and minimum and maximum will be presented. 
All analyses and summaries will be performed by product. 
A mixed-model analysis of variance (ANOVA) will be conducted on Cmax, AUC0-t’, and 
AUC0-24h endpoints in the natural logarithmic scale. The results of this analysis will be 
presented in terms of geometric least square mean ratios and 95% confidence intervals 
(95% CI) for the THS / CIG ratio for both variants of sticks.  
The analysis of Tmax will be conducted using non-parametric tests and Hodges-Lehmann 
estimates of median difference with its derived 95% CI. 
 
 
 

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Table of Contents 
Version History ....................................................................................................................2 
Synopsis ...............................................................................................................................3 
Abbreviations and Definitions of Terms ............................................................................19 
1. 
Ethics and Regulations ...............................................................................................22 
1.1 
Independent Ethics Committee (IEC) Approval ..................................................22 
1.2 
Ethical Conduct of the Study ...............................................................................23 
1.3 
Subject Information and Consent ........................................................................23 
1.3.1 
Informed Consent Form for Study Participation ......................................... 23 
1.3.2 
Amendment to the Informed Consent Form ................................................ 24 
1.4 
Good Clinical Practice and Regulatory Requirements ........................................24 
2 
Introduction ................................................................................................................25 
2.1 
Background ..........................................................................................................25 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy .......................... 25 
2.1.2 
Description of the Product and Scientific Findings ..................................... 25 
2.2 
Purpose of the Study ............................................................................................25 
2.3 
Anticipated Benefits and Risks ............................................................................26 
2.3.1 
Anticipated Benefits..................................................................................... 26 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures ............................. 26 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Products .................. 26 
2.3.4 
Unforeseeable Risks..................................................................................... 27 
3 
Study Objectives ........................................................................................................28 
3.1 
Primary Objective(s) ............................................................................................28 
3.2 
Secondary objective .............................................................................................28 
3.3 
Success Criteria ...................................................................................................29 
4 
Investigational Plan ....................................................................................................30 
4.1 
Overall Study Design and Plan ............................................................................30 
4.2 
Rationale for Study Design ..................................................................................33 
4.3 
Appropriateness of Measurements ......................................................................33 
4.4 
Study Duration .....................................................................................................33 
5 
Study Population ........................................................................................................34 
5.1 
Selection of Study Population .............................................................................34 
5.1.1 
Inclusion Criteria ......................................................................................... 34 

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5.1.2 
Exclusion Criteria ........................................................................................ 35 
5.2 
Discontinuation of Subjects from the Study ........................................................36 
5.3 
Lost to Follow-up ................................................................................................38 
5.4 
Violation of Selection Criteria .............................................................................38 
6 
Investigational Products .............................................................................................39 
6.1 
Description of Investigational Products ...............................................................39 
6.1.1 
Test Product: Tobacco Heating System ....................................................... 39 
6.1.2 
Comparator Product ..................................................................................... 39 
6.1.3 
Packaging and Labeling ............................................................................... 39 
6.2 
Use of Investigational Product(s) ........................................................................40 
6.2.1 
Screening Visit (Day -28 to Day -2) ............................................................ 40 
6.2.2 
Baseline Visit (Day -1) ................................................................................ 40 
6.2.3 
Exposure Period (Day 1 to Day 3) ............................................................... 40 
6.2.4 
Discharge (Day 3) ........................................................................................ 40 
6.2.5 
Safety Follow-up Period .............................................................................. 40 
6.2.6 
Stopping Rules for Investigational Product ................................................. 40 
6.3 
Method for Assigning Subjects to Product Sequences ........................................41 
6.4 
Blinding ...............................................................................................................41 
6.5 
Investigational Product Accountability and Compliance ....................................41 
6.5.1 
Dispensing Investigational Product ............................................................. 41 
6.5.2 
Storage and Accountability .......................................................................... 41 
6.5.3 
Investigational Product Retention ................................................................ 42 
6.5.4 
Compliance to Investigational Products ...................................................... 42 
6.6 
Restrictions ..........................................................................................................42 
6.6.1 
Smoking Restrictions ................................................................................... 42 
6.6.2 
Dietary Restrictions ..................................................................................... 42 
6.7 
Concomitant Medication .....................................................................................43 
7 
Study Procedures .......................................................................................................44 
7.1 
Informed Consent ................................................................................................44 
7.2 
Information on the Risk of Smoking, Smoking Cessation Advice, and THS 
Briefing ..........................................................................................................................44 
7.3 
Support During Abstinence from any Tobacco and Nicotine Containing Products
 
44 

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7.4 
Clinical Assessments ...........................................................................................45 
7.4.1 
Demographic Data ....................................................................................... 45 
7.4.2 
Medical History, Concomitant Disease, Previous and Concomitant 
Medications ................................................................................................................ 45 
7.4.3 
Physical Examination................................................................................... 45 
7.4.4 
Body Height and Weight ............................................................................. 46 
7.4.5 
Vital Signs .................................................................................................... 46 
7.4.6 
Spirometry.................................................................................................... 46 
7.4.7 
Electrocardiogram ........................................................................................ 47 
7.5 
Laboratory Assessments ......................................................................................47 
7.5.1 
Clinical Chemistry, Hematology, and Urine Analysis for Safety Panel ...... 47 
7.5.2 
Serology ....................................................................................................... 48 
7.5.3 
Urine Drug Screening .................................................................................. 48 
7.5.4 
Urine Cotinine Screening ............................................................................. 49 
7.5.5 
Alcohol BreathTest ...................................................................................... 49 
7.5.6 
Urine Pregnancy Test ................................................................................... 49 
7.6 
Sample Handling, Storage, and Shipment ...........................................................49 
7.6.1 
Urine samples............................................................................................... 49 
7.6.2 
Blood Samples ............................................................................................. 50 
7.7 
Other Study Procedures .......................................................................................50 
7.7.1 
Investigational Product Demonstration ........................................................ 50 
7.8 
Questionnaires .....................................................................................................50 
7.8.1 
Fagerström Test for Nicotine Dependence (Revised Version) .................... 50 
7.8.2 
Tobacco/Nicotine Product Use History ....................................................... 51 
7.8.3 
VAS Craving Assessment ............................................................................ 51 
7.8.4 
VAS Liking Assessment .............................................................................. 51 
7.8.5 
VAS Intention to Use Again Assessment .................................................... 51 
8 
Adverse Events ..........................................................................................................52 
8.1 
Definitions ...........................................................................................................52 
8.1.1 
Adverse Events ............................................................................................ 52 
8.1.2 
Serious Adverse Events ............................................................................... 52 
8.1.3 
Conditions Existent Before the Start of the Period of Collection (ICF 
signature).................................................................................................................... 52 

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8.2 
Collection and Reporting of Adverse Events ......................................................53 
8.2.1 
Collection of Information ............................................................................ 53 
8.2.2 
Period of Collection ..................................................................................... 53 
8.2.3 
Intensity of Adverse Event........................................................................... 53 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures .................................................................................................................. 54 
8.2.5 
Expectedness ................................................................................................ 54 
8.2.6 
Follow-up of Non-serious and Serious Adverse Events .............................. 54 
8.3 
Reporting Serious Adverse Events ......................................................................55 
8.4 
Reporting of Other Abnormal Findings ...............................................................55 
8.5 
Reporting and Follow-Up of Pregnancies ...........................................................55 
8.5.1 Period of Collection and Follow-up .................................................................. 55 
8.5.2 Reporting of Pregnancies .................................................................................. 56 
8.6 
Adverse Events Leading to Discontinuation .......................................................56 
8.7 
Device Malfunction, Product Complaints and Misuse ........................................56 
9 
Study Activities ..........................................................................................................57 
9.1 
Screening Visit (Day -28 to Day -2) ....................................................................57 
9.2 
Baseline Visit Day -1 ...........................................................................................58 
9.3 
Day 1 ....................................................................................................................59 
9.4 
Day 2 ....................................................................................................................61 
9.5 
Day 3 ....................................................................................................................62 
9.6 
Safety Follow-up Period ......................................................................................63 
9.7 
Early Termination Procedures .............................................................................64 
10 Quality Control and Quality Assurance .....................................................................65 
10.1 Monitoring ...........................................................................................................65 
10.2 Training of Staff ..................................................................................................65 
10.3 Audits and Inspections .........................................................................................66 
10.4 Risk Management ................................................................................................66 
11 Data Management Activities......................................................................................67 
11.1 Data Capture ........................................................................................................67 
11.1.1 Case Report Forms and Study Records ....................................................... 67 
11.1.2 Protocol Deviations ...................................................................................... 67 

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11.1.3 Data Handling .............................................................................................. 69 
12 Planned Statistical Methods .......................................................................................70 
12.1 General Considerations ........................................................................................70 
12.1.1 Stratification Criteria ................................................................................... 70 
12.1.2 Definitions for Statistical Data Analysis...................................................... 70 
12.1.3 Handling of Missing Values and of Values outside the Detection Limits ... 71 
12.1.4 Significance Level for Inferential Analysis ................................................. 72 
12.2 Analysis Sets ........................................................................................................72 
12.2.1 Screened Population..................................................................................... 72 
12.2.2 Safety Set (SAF) .......................................................................................... 72 
12.2.3 Randomized Population ............................................................................... 72 
12.2.4 Pharmacokinetics Population ....................................................................... 72 
12.3 Demographics and Baseline Characteristics ........................................................72 
12.4 Main Objective ....................................................................................................73 
12.4.1 Main Estimand Analysis .............................................................................. 73 
12.5 Secondary Objectives ..........................................................................................75 
12.5.1 Secondary Objective 1 ................................................................................. 75 
12.5.2 Secondary Objective 2 ................................................................................. 75 
12.6 Interim Analysis ...................................................................................................76 
12.7 Measures to Control Bias .....................................................................................76 
12.7.1 Blinding........................................................................................................ 76 
12.7.2 Multiple Testing Procedures ........................................................................ 76 
12.7.3 Determination of Sample Size and Power Consideration ............................ 76 
12.7.3.1 Assumptions ................................................................................................. 76 
12.7.3.2 Method ......................................................................................................... 77 
13 Administrative Considerations...................................................................................78 
13.1 Study Administrative Structure ...........................................................................78 
13.1.1 Sponsor ........................................................................................................ 78 
13.1.2 List of Principal Investigators and Sites ...................................................... 78 
13.2 Subject Confidentiality ........................................................................................78 
13.3 Access to Source Documents ...............................................................................78 
13.4 Record Retention .................................................................................................79 

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law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
13.5 Clinical Study Report ..........................................................................................80 
13.6 Financial Disclosure ............................................................................................81 
13.7 Publication and Disclosure Policy .......................................................................81 
13.8 Insurance ..............................................................................................................81 
14 Reference List ............................................................................................................82 
 
List of In-Text Tables 
Table 1 
Clinical Laboratory Parameters for Safety Panel ........................... 48 
Table 2 
Intensity of Adverse Events ........................................................... 53 
Table 3 
Time Schedule – Screening Visit ................................................... 57 
Table 4 
Time Schedule – Baseline Visit ..................................................... 59 
Table 5 
Time Schedule – Day 1 .................................................................. 59 
Table 6 
Time Schedule – Day 2 .................................................................. 61 
Table 7 
Time Schedule – Day 3 .................................................................. 62 
Table 8 
Early Termination .......................................................................... 64 
Table 11 
Blinding Scheme ............................................................................ 76 
 
List of In-Text Figures 
Figure 1 
Study Design .................................................................................... 5 
Figure 2 
Study Design .................................................................................. 30 
 
List of Appendices 
Appendix A 
Schedule of Events ......................................................................... 85 
Appendix B 
Participating Laboratories .............................................................. 87 
Appendix C 
FTND Scoring Manual .................................................................. 88 
Appendix D 
Questionnaire scoring rules ............................................................ 89 
 

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Abbreviations and Definitions of Terms 
Abbreviations  
AE 
Adverse event 
ANOVA 
Analysis of variants 
AUC 
Area under the curve 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
CIG 
Combustible cigarette(s) 
CI 
Confidence interval 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTMS 
Clinical trial management system 
DMP 
Data management plan 
ECG 
Electrocardiogram 
EOS 
End of study 
FAS 
Full analysis set 
FDA 
Food and Drug Administration  
FEV1  
Forced expiratory volume in 1 second 
FTND 
Fagerström test for nicotine dependence (revised version) 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GCV 
Geometric coefficient of variation 
GeoM 
Geometric means 
GSD 
Geometric standard deviation 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
IEC 
Independent Ethics Committee 
ICH 
International Conference on Harmonization  
IP 
Investigational product 

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IxRS 
Interactive web/voice response system 
LLN 
Lower limit of the normal range 
LLOQ 
Lower limit of quantification 
MAR 
Missing at random 
MedDRA 
Medical dictionary for regulatory activities 
MRTP 
Modified risk tobacco product 
PMP 
Philip Morris Products S.A. 
SAE 
Serious adverse event 
SAF 
Safety population 
SAP 
Statistical analysis plan 
SEM 
Standard error of the mean 
SFU 
Safety follow-up 
SOP 
Standard operating procedure 
SRO 
Subject reported outcome(s) 
T0 
Timepoint of start of investigational product use 
TBX 
Timepoint of blood collection 
THS 
Tobacco heating system 
TNP 
Tobacco and/or nicotine containing product 
TVX 
Timepoint of VAS completion 
ULN 
Upper limit of the normal range 
ULOQ 
Upper limit of quantification 
VAS 
Visual analogue scale 
WBC 
White blood cell 
WHO 
World Health Organization 
 

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Explanation of Terms 
The following special terms are used in this protocol:  
Alternate subjects 
Subjects who have signed the ICF, have met the eligibility 
criteria at Screening visit and Baseline Day -1, and have 
not been randomized due to an adequate number of 
subjects available for randomization at that time. 
An alternate subject may join the following group if their 
28-day Screening period has not exceeded. The alternate 
subject will have to repeat the Baseline Day -1 to re-
confirm eligibility. 
Cigarette(s) (CIG) 
The term ‘cigarette’ refers to commercially available 
combustible cigarettes (manufactured and hand-rolled) 
and 
excludes 
cigars, 
pipes, 
bidis, 
and 
other 
nicotine-containing products. 
Early termination (ET)  
Premature termination of exposure to the IP after the start 
of the Exposure period in the confinement setting 
End of study (EOS) 
The EOS for a subject is defined as Discharge on Day 3 or 
the date of Early termination of the subject plus the 3 days 
for the SFU period. The EOS of the entire study is the end 
of the SFU period for the last subject. 
Investigational product (IP) The IP of this study comprises both the test product, the 
Tobacco Heating System (THS), and the comparator 
product, the combustible cigarette (CIG). 
Randomization  
Allocation of a subject to a particular sequence of IP use.  
Screening failure 
All subjects who underwent at least one screening 
procedure and are not randomized (except alternate 
subjects) will be considered as screen failures. Re-
screening of subjects who did not meet any entry criteria 
will not be permitted. 
Stick 
Induction tobacco stick, either regular or menthol variant, 
designed to be used with the THS induction device. 
Tobacco Heating System 
(THS) 
Tobacco Heating System (THS) device with Induction 
technology (device with Induction stick Holder for 
Induction stick use and separate Charger). 

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1. Ethics and Regulations 
1.1 
Independent Ethics Committee (IEC) Approval 
Prior to the start of the study, the clinical study protocol, together with its associated 
documents (informed consent form [ICF] including the subject information sheet, subject 
recruitment procedures [e.g., advertisements], written information to be provided to the 
subjects, Investigator’s brochure [IB], available safety information, curriculum vitae of the 
Principal Investigator(s) (PI(s)) and designee(s) and/or other evidence of qualifications and 
any other documents requested by an Independent Ethics Committee [IEC]), will be 
submitted for review and approval to the relevant IEC according to the appropriate 
provisions found in 21 Code of Federal Regulations (CFR) part 50 (“Informed Consent of 
Human Subjects”) and 21 CFR part 56 (“Institutional Review Boards”). The IEC shall be 
appropriately constituted and perform its functions in accordance with the International 
Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) Guidance for Good Clinical Practice (GCP) [1] and local requirements, as applicable. 
In accordance with GCP and 21 CFR part 56, a written confirmation of the IEC approval 
will be provided to the Sponsor. This should identify the study (name of the PI(s) and 
designee(s), study number, and title) and the documents that have been approved by the 
IEC, with dates and version numbers, as well as the date of approval. The composition of 
the IEC, including the name and occupation of the chairperson, will be supplied to the 
Sponsor together with a GCP compliance statement. 
The written approval from the IEC will be filed in the Principal Investigator’s file, and a 
copy will be filed in the study master file at the Sponsor or designated organization. The 
study must not start at a site before the Sponsor has obtained written confirmation of 
favorable opinion/approval from the concerned IEC. 
Any substantial change or addition to this protocol will require a written protocol 
amendment that must be approved by the Sponsor and the PI(s). All amendments will be 
submitted to the IEC, and substantial amendments will only be implemented after approval 
by the IEC. 
These requirements for approval should in no way prevent any action from being taken by 
the PI(s) or designee(s) or by the Sponsor to eliminate immediate hazards to the subjects. 
If such a change to the protocol is felt to be necessary by the PI(s) or designee(s), and is 
implemented for safety reasons, the Sponsor and the IEC should be informed immediately. 
The PI(s) is(are) responsible for local reporting (e.g., to the IEC) of serious adverse events 
(SAEs) that occur during the study, according to local regulations. 

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Relevant safety information will be submitted to the IEC during the study in accordance 
with national regulations and requirements. Medically qualified study personnel will be 
available during the study. 
1.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki [2] and are consistent with ICH/GCP [1] applicable regulatory 
principles. 
The PI(s) or designee(s) agree(s) to conduct the clinical study in compliance with the 
protocol agreed with the Sponsor and approved by the IEC. The PI(s) and the Sponsor must 
sign the protocol (and protocol amendments, if applicable) to confirm this agreement. A 
copy of the Declaration of Helsinki will be filed in the Investigator site file. 
1.3 
Subject Information and Consent 
1.3.1 
Informed Consent Form for Study Participation 
Before or at the Screening visit, the PI(s) or designee(s) will ensure that each subject is 
given full and adequate oral and written information about the nature, purpose, possible 
risks and benefits of the study, and the PI(s) or the designee(s) will answer all questions the 
subject might have to his/her full satisfaction. The subject will have sufficient time for 
consideration of his/her participation in the study and will be notified that he/she is free to 
withdraw his/her participation at any time. 
Once the subject has received all the necessary information, and if she/he agrees to 
participate in the study, the subject and the person who conducted the informed consent 
discussion during Screening visit will both sign, date, and time the ICF. The ICF includes 
both the subject information sheet and informed consent. No study-specific procedures will 
be performed before the ICF has been signed (including date and time). 
The original, dated and signed ICF(s) must be kept by the PI(s) and filed in the Principal 
Investigator’s file at the site or with the subject’s files and a copy must be given to the 
subject. 
The subject will be informed that if she/he withdraws from the study, the data collected 
until the point of withdrawal will be maintained as part of the study data and the samples 
collected prior to withdrawal will be analyzed unless she/he disagrees. The subject will be 
informed that additional data analyses not mentioned in the protocol or in the statistical 
analysis plan (SAP) might be performed with the collected data at a later time point. Any 
additional analysis performed will be covered by data confidentiality, as for the main 
analysis described in this protocol. 

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1.3.2 
Amendment to the Informed Consent Form 
If a protocol amendment is required, or if any new information regarding the risk profile of 
the IP becomes available for any other reason deemed necessary, an amendment to the ICF 
may be required. If a revision of the ICF is necessary, the PI(s) or designee will, with the 
support of the Sponsor, ensure that the documents have been reviewed and approved by a 
relevant IEC before subjects are required to re-sign the ICF (including date and time). If 
new and important safety information is received, subjects who already completed or are 
discontinued from the study will be informed by letter, e-mail or phone call. 
1.4 
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation, 
and documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, PI(s) or designee(s) abide by the principles of the ICH guidelines on GCP 
[1]. These guidelines apply specifically to pharmaceutical development, but nevertheless 
provide a robust and ethical framework for conducting clinical studies of tobacco products 
following the United States Food and Drug Administration (FDA) guidelines on modified 
risk tobacco product (MRTP) [3]. The study will also be conducted in accordance with the 
general ethical principles outlined in the Declaration of Helsinki [2]. 
In addition, the PI(s) or designee(s) will carry out the clinical study in accordance with 
applicable national and local laws of the pertinent regulatory authorities. 

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2 
Introduction 
2.1 
Background 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy 
Cigarette (CIG) smoking causes pulmonary, cardiovascular and other serious diseases in 
smokers [4]. The best option for smokers to reduce the adverse health consequences of 
smoking is to quit. Despite the risks that are attributable to smoking, some smokers decide 
to continue smoking. The development of novel tobacco and/or nicotine containing 
products (TNP) with the potential to be less harmful as potential alternatives to CIG 
smoking represents an approach to reduce cigarette-related deaths and diseases among 
smokers [5]. 
Philip Morris Products S.A. (PMP) is developing such alternative products that have the 
potential to reduce individual risk and population harm in comparison to smoking CIG. 
These products aim to substantially reduce or eliminate the exposure to harmful and 
potentially harmful constituents of CIG smoke (except nicotine), thus providing an 
acceptable substitute for CIG smoking and lowering the health risk. When developing new 
products such as Tobacco Heating Systems (THS), appropriate assessment including 
comprehensive understanding of product characterization, its safety, and related impact of 
product use in humans is critical.  
2.1.2 
Description of the Product and Scientific Findings 
PMP has developed a Tobacco Heating System (THS) with Induction heating technology 
(marketed under the name of ILUMA™). The THS device consists of a charging unit and 
a separate stick holder used to heat a tobacco stick. Several taste variants of tobacco sticks 
are available, e.g., regular, menthol. The temperature of the stick heating is controlled 
during the use to avoid burning (= combustion) of the tobacco. Further details are provided 
in the Investigator’s Brochure [6].   
2.2 
Purpose of the Study 
The purpose of this study is to describe the nicotine pharmacokinetic (PK) profile during 
and after single use of THS (Induction heating technology, with either a regular or menthol 
stick) compared to singular CIG smoking in healthy adult subjects. In addition, 
pharmacodynamic effects (subjective effects) will be evaluated to provide further insights 
on product acceptance and likelihood to use the THS again. Safety will be assessed 
throughout the study. 

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2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
Information on health risks associated with smoking and smoking cessation advice will be 
provided at the Screening visit, the Baseline visit on Day -1, and at Discharge on Day 3. 
The advice will follow the recommendations of the World Health Organization (WHO) 
“Evidence based Recommendations on the Treatment of Tobacco Dependence” [7]. 
Subjects who are motivated to quit smoking during the study will be encouraged to do so 
and will be referred to appropriate medical services for necessary support and counselling. 
Subjects who participate in this study will also benefit from repeated and detailed health 
check-ups. 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures 
The potential risk of scheduled procedures in the present study (e.g., blood samples) are 
deemed to be on par with procedures routinely performed during normal or extended health 
examinations by the subject’s healthcare professional. The total volume of blood to be 
drawn is approximately 275 mL and does not exceed the levels for a standard blood 
donation. The risks related to blood sampling include, for example: excessive bleeding, 
fainting, hematoma, paresthesia, or infection, and those related to the total amount of blood 
taken over a time span such as weakness, dizziness, or anemia. 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Products  
An adult smoker using a THS device or CIG may experience: 
• Transient nicotine withdrawal symptoms (e.g., urge to smoke, irritability, anxiety, 
restlessness, and difficulty to concentrate) similar to cravings observed during smoking 
cessation 
• Transient symptoms suggesting mild nicotine overdose such as stimulatory effects on 
sympathetic tone (increased blood pressure, increased heart rate), central nervous 
system (tremor, blunting of emotions, and decreased ability to concentrate), gastric acid 
secretion, and vomiting. Individuals who experience adverse events (AEs) (suggesting 
excessive stimulant effects) should be instructed to reduce their intensity of product use 
by decreasing the number of puffs and/or the intensity of puffing 
• Change in smoking habits due to study requirements and related concomitant 
symptoms, e.g., craving. 
Medical supervision of all study subjects with follow-up of those who have experienced 
adverse events/serious adverse events (AEs/SAEs) will be ensured. 

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2.3.4 
Unforeseeable Risks 
The possibility of unforeseeable events/risks will be explained in detail to study 
participants. Unexpected malfunction of any of the THS devices may lead to unforeseeable 
risk. Risk mitigation will include close monitoring and medical supervision to detect any 
unforeseeable risk or safety signals at the earliest time possible. 

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3 
Study Objectives 
3.1 
Primary Objective(s)  
The main objective of this study is: 
1. To describe the plasma concentration-time profile of nicotine and derived 
pharmacokinetic (PK) parameters of the single use of THS with either a regular or a 
menthol stick or of a single CIG. 
Endpoints (Day 1 to Day 3) 
Plasma nicotine concentration-time PK parameters (THS regular stick, THS menthol stick, 
and CIG separately): 
• Maximum nicotine plasma concentration [Cmax] 
• Time to the maximum nicotine plasma concentration [Tmax] 
• Area under the curve of nicotine plasma concentration-time computed from T0 to 
T=24 hours [AUC0-24h]  
• Area under the curve of nicotine plasma concentration-time computed from T0 to 
the subject-specific time of maximum nicotine concentration [AUC0-t’] 
3.2 
Secondary objective 
1. To evaluate pharmacodynamic (PD) effects (subjective effects) of a single use of a THS 
with either a regular or a menthol stick or of a single CIG. Endpoints are by 
investigational product (IP). 
Endpoints (Day 1 to Day 3) 
• Score of CIG craving by the visual analogue scale (VAS) Craving assessment  
• Score of IP liking by the VAS Liking assessment 
• Score of intention to use the IP again by the VAS Intention to Use Again assessment 
2. To evaluate the safety of test products during the study. 
Endpoints 
• Incidence of adverse events (AEs) and serious adverse events (SAEs)  
• Incidence of product events  
• Changes in electrocardiogram (ECG) from baseline (heart rate, PR, QRS, QT, 
QTcF interval) 

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• Changes in vital signs from baseline (systolic and diastolic blood pressure, pulse 
rate and respiratory rate) 
• Concomitant medication 
• Changes in standard spirometry from baseline (FEV1, FEV1 % predicted, FVC, 
FVC % predicted, FEV1/FVC) 
• Changes from baseline in clinical chemistry, hematology, and urine analysis safety 
panel 
3.3 
Success Criteria 
Not applicable. 

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4 
Investigational Plan 
4.1 
Overall Study Design and Plan 
This is a single-center, randomized, controlled, open-label, cross-over study in healthy 
subjects. The study will be conducted with 3 periods and 6 sequences in a full cross-over 
design. 
Abbreviations: CIG = combustible cigarette; P1M = menthol taste; P1R = regular taste  
Figure 2 
Study Design 
A Screening visit will be conducted within 27 days (Day -28 to Day -2) prior to Baseline 
(Day -1) to check and document the eligibility of the subjects. A demonstration of the THS 
(without product use) will be done by the investigational site staff during the Screening 
visit. The brand of subjects’ cigarettes will be recorded. 
Qualified subjects will return to the investigational site for Baseline on Day -1. Subjects 
will have fasted for at least 6 hours prior to the safety laboratory assessments and will start 
abstinence of TNP. After confirmation of eligibility, subjects can be randomized. All 

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subjects who will not be randomized during their individual Screening period will be 
documented as screen failures. 
Provided that the 28-day Screening period is not exceeded, alternate subjects (not yet 
randomized) will repeat the Baseline visit of the following group to re-confirm their 
eligibility for randomization. 
Thirty subjects will be randomized to one of 6 possible full crossover sequences of product 
use (THS with either regular or menthol stick, and CIG) on Day 1 to Day 3. After admission 
at Baseline Day -1, nicotine wash-out will start, and the use of any other TNP (different 
from IP assigned for use on Day 1 to Day 3) will not be allowed during confinement at the 
site. Use of TNP will not be restricted after the subject has been discharged from the 
investigational site on Day 3. 
On Day 1 to Day 3, after at least 23 hours of abstinence from any TNP on Day 1, and at 
least 24 hours after former IP use on Day 2 and on Day 3 (nicotine wash-out), subjects will 
smoke a CIG or use the THS either with a regular or a menthol stick according to 
randomized product use sequence.  
The start of use of IP will be defined as T0. T0 on Day 1 to Day 3 should be at approximately 
the same time in the morning. Venous blood samples will be obtained according to the 
standard operating procedures (SOPs) at the investigational site. Subjects will report their 
cigarette craving, IP liking, and intention to use the IP again by completing VAS 
assessments.  
After Discharge on Day 3 or after an Early termination following product exposure, the 
subjects will enter a 3-day Safety follow-up (SFU) period during which AE/SAEs reported 
by the subjects will be collected and the follow-up of AEs/SAEs will be conducted, 
concluded per a telephone contact by the investigational site on the last day of the SFU 
period.  
Blood sample collection 
On Day 1, fourteen blood samples will be collected for determination of nicotine 
concentration at the following time points in relation to T0 with a time window as indicated 
in brackets: 
Before T0: 
• TB0 5 minutes before IP use (± 2 minutes) 
After T0: 
• TB1 after 4 minutes (± 1 minute) 
• TB2 after 6 minutes (± 1 minute) 
• TB3 after 8 minutes (± 1 minute) 

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• TB4 after 10 minutes (± 1 minute) 
• TB5 after 12 minutes (± 1 minutes) 
• TB6 after 15 minutes (± 2 minutes) 
• TB7 after 30 minutes (± 5 minutes) 
• TB8 after 1 hour (± 5 minutes) 
• TB9 after 2 hours (± 5 minutes) 
• TB10 after 4 hours (± 5 minutes) 
• TB11 after 10 hours (± 5 minutes) 
• TB12 after 14 hours (± 5 minutes) 
• TB13 after 24 hours (± 10 minutes) 
On Day 2, thirteen blood samples will be collected for determination of nicotine PK after 
allocated product use at the same time points (without timepoint TB0). The sample TB13 of 
Day 1 will also be used to determine the nicotine baseline concentration prior to T0 on Day 
2 and similarly, TB13 of Day 2 for determination of nicotine baseline concentration prior 
to T0 on Day 3.  
On Day 3, eleven blood samples (TB1 to TB11) will be collected for determination of 
nicotine PK after allocated product use. The samples TB12 and TB13 will not be collected. 
Questionnaire completion 
On Day 1 to Day 3, product liking, cigarette craving, and intention to use the product again 
will be assessed using a VAS (100 mm going from “strong disliking” to “strong liking” for 
VAS Liking; from “no craving” to “strong craving” for VAS Craving; and “very unlikely” 
to “very likely” for VAS Intention to Use Again) at the following time points in relation to 
T0 with a time window as indicated in brackets: 
Prior to T0 (for VAS Craving assessment) 
• TV0: within 15 minutes prior to T0  
After T0 (for VAS Craving assessment) 
• TV1 after 4 minutes (± 2 minutes) 
• TV2 after 10 minutes (± 2 minutes) 
• TV3 after 15 minutes (± 2 minutes) 
• TV4 after 30 minutes (± 2 minutes) 
• TV5 after 10 hours (± 5 minutes) 
After T0 (for VAS Liking and VAS Intention to Use Again assessment) 
• Tv3 after 15 minutes (± 1 minute) 

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4.2 
Rationale for Study Design  
The single use of a THS with either a regular or menthol stick or of a single CIG will allow 
appropriate comparison between THS usage and CIG smoking, as well as comparison to 
published data [8-11].  
Sampling time points for determination of nicotine concentrations were selected to ensure 
reliable estimation of PK parameters. Frequent sampling during the first 15 minutes from 
T0 will be performed to reliably assess Cmax, Tmax, and AUC. 
4.3 
Appropriateness of Measurements 
All laboratory measures utilized for this study are validated and are appropriate for the 
study assessments.  
The Fagerström Test for Nicotine Dependence (FTND) [12, 13] and the visual analogue 
scale (VAS) assessments of craving, liking, and intention to use the IP again [14-16] used 
in this study are validated and previously published or adapted versions of validated 
questionnaires. 
4.4 
Study Duration 
The entire study per subject will last up to 34 days. This will include a screening period of 
up to 27 days prior to Admission (Day -28 to Day -2), 4 days of confinement (from 
admission on Day -1 to time of Discharge on Day 3 (3 overnight stays), and a 3-day SFU 
period (from time of Discharge on Day 3 or Early termination plus three days). The end of 
the study (EOS) for a subject is defined as the end of the SFU period. The end of the whole 
study corresponds to the individual EOS of the last subject. 

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5 
Study Population 
Thirty healthy female or male adult subjects who have smoked on average at least 10 
regular CIG per day for the last 4 weeks prior to Baseline Day -1 will be randomized to one 
of 6 possible full crossover sequences of IP use (THS with either regular or menthol stick, 
and CIG) on Day 1 to Day 3. Quotas will be applied to ensure that the randomized 
population contains at least 40% of both sexes (i.e., at least 12 males and 12 females in the 
study) overall. 
The subjects must have been smoking for at least 3 years prior to the Screening visit. There 
will be no brand restrictions of CIG. Smoking status will be verified with a urinary cotinine 
test (cotinine ≥200 ng/mL). 
5.1 
Selection of Study Population 
5.1.1 
Inclusion Criteria 
Subjects who meet all the following inclusion criteria can be randomized: 
Inclusion Criteria 
Screening 
Day -1 
1. Subject has signed the ICF and is able to understand the 
information provided in the ICF.  
X  
  
2. Subject is male or female and between 21 and 65 years old 
(inclusive).  
X 
  
3. Subject has been a smoker for ≥3 years prior to the screening 
visit (smoking cessation attempts during this period, if any, 
did not last > 6 months in total).  
X 
 
4. Subject has continuously smoked on average ≥10 
commercially available regular CIG/day over the last 4 
weeks.a Smoking status will be verified based on a urinary 
cotinine test (cotinine ≥200 ng/mL).  
X 
X 
5. Subject is healthy as judged by the Investigator based on 
available assessments from the screening period (e.g., safety 
laboratory, spirometry, vital signs, physical examination, 
ECG, and medical history).  
X 
X 
6. Subject does not plan to quit smoking within the next three 
months. 
X 
X 

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a. 
Users of other TNP in addition to CIG smoking may be enrolled into the study if they agree to limit themselves to 
stick use/CIG smoking (according to their randomization) as per study design 
5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be randomized: 
Exclusion Criteria 
Screening   Day -1 
1. As per the Investigator’s judgment, the subject cannot 
participate in the study for any reason other than medical 
(e.g., psychological, social reason).   
X 
X 
2. Subject is legally incompetent, or physically or mentally 
incapable of giving consent (e.g., in emergency situations, 
under guardianship, prisoners).  
X 
 
3. Subject has a clinically relevant disease which requires 
medication (including but not limited to gastrointestinal, 
renal, hepatic, neurological, hematological, endocrine, 
oncological, urological, immunological, pulmonary, and 
cardiovascular disease) or any other medical condition 
(including safety laboratory), which as per the judgment of 
the Investigator would jeopardize the safety of the subject.   
X 
 
4. Subject 
experienced 
within 
30 
days 
prior 
to 
screening/admission a body temperature >37.5°C or an 
acute illness (e.g., upper respiratory-tract infection, viral 
infection, etc.) or the subject has a confirmed or suspected 
active COVID-19 infection (based on the signs and 
symptoms observed at the time of assessment)  
X 
X 
5. As per the Investigator’s judgment, the subject has medical 
conditions which do or will require a medical intervention 
(e.g., start of treatment, surgery, hospitalization) during the 
study participation, which may interfere with the study 
participation and/or study results.   
X 
 
6. Subject has relevant history of, or current asthma condition 
or COPD condition, and/or clinically significant findings.   
X 
 
7. Subject has donated blood or received whole blood or blood 
products within 3 months.   
X 
 
8. BMI < 18.5 kg/m2 or ≥ 32.0 kg/m2.   
X 
 
9. Positive serology test for HIV 1/2, HBV, or HCV a.   
X 
 

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10. Subject has a positive alcohol breath test and/or has a 
history of alcohol disorder that could interfere with their 
participation in the study.    
X 
X 
11. The subject has a positive urine drug test.   
X 
X 
12. Subject or one of their family membersb is a current or 
former employee of the tobacco or e-cigarette industry.   
X 
 
13. Subject or one of their family membersb is an employee of 
the investigational site or of any other parties involved in 
the study.   
X 
 
14. Subject has participated in another clinical study within 3 
months.   
X 
 
15. Subject has been previously screened or enrolled in this 
study.   
X 
 
16. Subject is pregnant (does not have negative pregnancy tests 
at screening and at admission) or is breastfeeding.  
X 
X 
17. For women of childbearing potential only:c subject does not 
agree to use an acceptable method of effective 
contraceptiond.   
X 
 
Abbreviations:  
BMI = body mass index; COVID-19 = Corona virus infection disease; COPD = chronic obstructive pulmonary disease 
a. Human immunodeficiency virus, hepatitis B virus, hepatitis C virus 
b. As defined by FDA guidance on Human Subject Protection (21 CFR 50.3(l), (m), 50.24(a)(6), (a)(7)(v), b)): 
"Family member” means among other things “parent”, “spouse”, "brothers, sisters, and spouses of brothers and 
sisters" and “any individual related by affinity…whose close association with the subject is equivalent of a family 
relationship”  
c. Women who are not of childbearing potential meet at least one of the following criteria:   
• 
Have undergone hysterectomy or bilateral tubal ligation, 
• 
Have medically confirmed ovarian failure, or 
• 
Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive 
months with no alternative pathological or physiological cause).  
d. Intraunterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with 
spermicidal foam/gel/film/suppository, hormonal contraception, vasectomized partner(s), or true abstinence 
(periodic abstinence and withdrawal are not effective methods) from Screening until the end of the Safety follow-
up period.   
5.2 
Discontinuation of Subjects from the Study 
Discontinued subjects will include both subjects who withdraw from the study (subject’s 
decision) or subjects who are discontinued from the study by the decision of the Principal 
Investigator (PI). 

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Subjects will be informed that they are free to withdraw from the study at any time. Subjects 
should be questioned for the reason of withdrawal from the study, although they are not 
obliged to disclose it. 
If the subject withdraws from the study, this information will be fully documented by the 
PI or designee including: 
• 
The early termination procedures for safety assessments will be performed as defined 
in Section 9.7, unless the subject refuses to perform the assessments. 
• 
The samples collected up to the time of withdrawal that have been analyzed and data 
collected up to the time of withdrawal will be used in the analysis and report. If the 
subject refuses that non-analyzed samples and data will be used, he/she needs to 
document his/her disagreement in writing. 
Subjects must be discontinued from the study for any of the following reasons: 
• 
Withdrawal of informed consent 
• 
Non-adherence to allocated product 
• 
Subject becomes an employee of the investigational site, or any other parties involved 
in the study or their first-degree relatives (parent, sibling, and child) 
• 
Any AE or condition (including clinically significant changes in a laboratory 
parameter) which at the discretion of the PI no longer justifies the subject’s 
participation in this study 
• 
Positive pregnancy test 
• 
Discontinuation considered to be in the best interest of the subject or the other 
subjects, as judged by the PI 
• 
Subject unwilling to use the product or to comply with abstinence as required 
• 
An alternate subject that has completed the individual 28-day Screening period and 
has not been randomized 
• 
The Sponsor terminates the study, or the study terminates at the site. If the Sponsor 
decides to prematurely terminate the study, the subjects will be promptly informed. 
The PI or designee should report the fact and the reason in writing to the IEC 
• 
The PI terminates the study or suspends the trial (e.g., due to a loss of key staff 
members, change of circumstances). If the PI terminates or suspends a trial without 
prior agreement of the sponsor, the PI must inform the institution as applicable, and 

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must promptly inform in the Sponsor and the IEC in writing, including a detailed 
explanation. 
Subjects may be discontinued from the study for the following reasons: 
• 
Non-compliance to the study procedures based on the judgment of the Investigator 
• 
Violation of eligibility criteria 
Subjects who will be discontinued from the study before randomization will be replaced. 
Subjects that are discontinued after randomization will not be replaced, except if a need 
will occur to discontinue all subjects of a treatment group.  
5.3 
Lost to Follow-up 
A reasonable attempt will be made to contact all participants needing to complete or resolve 
post-study activities (e.g., on-going AEs, end of SFU period phone call). If the subject is 
not accessible, up to three contact attempts will be made via contact information provided 
by the subject (e.g., telephone number, cell phone number, email address), allowing one 
day between attempts for response. 
The PI or designee(s) will declare the subject Lost to follow-up if the investigational site 
lost contact to the subject and the subject has reached the maximum number of study days 
(34 days) without making any contact. 
5.4 
Violation of Selection Criteria 
Detected violations of eligibility criteria post enrollment may require subjects to be 
discontinued from the study based on a case-by-case decision of the PI. Any subsequent 
decision on the use of the corresponding samples will be made on a case-by-case basis by 
the PI. 

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6 
Investigational Products 
6.1 
Description of Investigational Products 
The distribution, dispensation and return of investigational products will be controlled by 
qualified and appropriately trained investigational site staff. 
6.1.1 
Test Product: Tobacco Heating System 
The investigational test product examined in this study is the THS Induction Mid device 
with regular and menthol sticks.  
The THS devices and the two variants of the sticks (i.e., regular and menthol) will be 
supplied by the Sponsor. 
The THS device provided by the Sponsor comprises the following components: Charger, 
Holder, and power supply/charging cable. 
6.1.2 
Comparator Product 
The investigational comparator product in this study will be a regular CIG. The subject’s 
preferred brand of commercially available CIG will not be provided by the Sponsor.  
All subjects eligible at Screening visit and invited for Baseline visit Day -1 will be asked 
to purchase their usual brand of CIG and to provide it to the site personnel at their admission 
on Baseline (Day -1). Every subject will bring an unopened pack of CIG which will be kept 
in secured storage room at site with access limited to authorized personnel. 
6.1.3 
Packaging and Labeling 
At Baseline visit (Day -1), all study subjects will provide a sealed pack of CIG (sufficient 
for the confinement period) to the investigational site staff. The CIG pack provided by the 
subject should not be opened and the cellophane cover should be intact.  
Each pack of CIG provided by the subject will be labeled to identify to which subject the 
CIG belong to. The investigational site staff will return all unused comparator products to 
the subjects at Discharge or Early termination. 
THS devices and packs of regular and menthol sticks will be labelled with the necessary 
information including, but not limited to, product code, expiry date, and notification of 
limiting THS devices and sticks to investigational use only. 

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6.2 
Use of Investigational Product(s) 
Subjects will not be forced to smoke CIG or use THS and will be free to stop smoking CIG/ 
using THS at any time during the study.  
During the Screening period, subjects will be allowed to smoke and use TNP according to 
their product use habits except during the procedures of the Screening visit (Section 9.1). 
6.2.1 
Screening Visit (Day -28 to Day -2)  
The subjects will be informed how to use the THS, and the site personnel will give a 
demonstration of the THS use. 
6.2.2 
Baseline Visit (Day -1)  
With the start of the Baseline visit Day -1, subjects will be required to stop smoking CIG 
and remain abstinent of any use of TNP (except the single use of IP on Day 1 to Day 3 of 
the exposure period) until completion of the discharge procedures on Day 3. 
6.2.3 
Exposure Period (Day 1 to Day 3)  
On Day 1, after at least 23 hours of abstinence from any TNP on Day 1, and after at least 
24 hours on Day 2 and Day 3, subjects will start using their allocated IP (Section 9.3). 
According to the randomized sequence, for THS use, subjects will be provided with a  fully 
charged THS holder with a regular stick or menthol stick, switched on for use, at T0 (start 
of use). 
For CIG smoking, subjects will be provided one CIG (lightened up) at T0 (start of use). 
6.2.4 
Discharge (Day 3)  
After completion of the Discharge procedures at the end of Day 3, subjects can use any 
TNP according to usual habits. 
6.2.5 
Safety Follow-up Period  
During the 3-day Safety follow-up period, subjects can use any TNP according to usual 
habits. 
6.2.6 
Stopping Rules for Investigational Product  
For safety purposes, using THS or smoking CIG should be temporarily stopped in the event 
of any signs suggesting nicotine overexposure, e.g., gastrointestinal disturbance (nausea, 
vomiting, diarrhea, stomach or abdominal pain), cold sweats, headache, dizziness and 
breathing problems, or any reasons at the discretion of the PI.  

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For subjects who are discontinued, the reason for discontinuation should be documented in 
the source documents and in the Case report form (CRF) and subjects will undertake Early 
termination procedures (Section 9.7), unless they disagree, or certain procedures have 
already been performed. 
6.3 
Method for Assigning Subjects to Product Sequences 
On Day -1, following the re-confirmation of eligibility and completion of baseline 
procedures, the subjects will be randomized to one of the six sequences of the 3-period 
cross-over design (Figure 2) by means of a permuted-block schema. Details about the 
randomization process will be documented in the randomization plan that should contain 
information about number of blocks, block sizes, block pre-allocation process, 
stratification, storage of the randomization list and study personal blinding requirements. 
The following quotas will be applied on the total number of randomized subjects: 
• At least 40% of each sex will be represented 
If an adequate number of subjects is already randomized to the study sequences, any 
additional subjects (except alternate subjects) will be discontinued from the study prior to 
randomization and will enter the 3-day Safety follow-up period (Section 9.6). 
Block size and other randomization details will be available in the randomization plan. The 
randomization scheme will be generated by an independent statistician and neither the 
Sponsor staff, nor Investigator or study subjects will have access to the randomization 
scheme during study conduct. 
6.4 
Blinding 
This is an open-label study. Therefore, the subjects, the Investigator, the PMP and CRO 
personnel will be unblinded to the subject’s sequence and product use. 
6.5 
Investigational Product Accountability and Compliance 
6.5.1 
Dispensing Investigational Product 
From Day 1 until Day 3, the THS, comprising of a fully charged device and a stick 
(according to randomized sequence), or a CIG will be dispensed by the investigational site 
staff, as per the study design. Each dispensing of IP to the subject will be recorded in a log.  
6.5.2 
Storage and Accountability  
The THS components and cigarettes will be stored in a secured storage place at the 
investigational site with access limited to the authorized personnel only. The distribution 
and return of IP will be controlled by qualified and appropriately trained investigational 

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site staff. Subjects will return the THS, comprising of the THS device and the used stick, 
immediately after the IP use to the investigational site staff for accountability.  
Smoked CIG will be documented, and CIG butts will be collected by investigational site 
staff for accountability. 
6.5.3 
Investigational Product Retention 
Used and unused THS devices and sticks will be destroyed or returned to the Sponsor upon 
study completion. Smoked CIG butts will be destroyed upon study completion. 
6.5.4 
Compliance to Investigational Products 
Compliance will be ensured by strict distribution and collection of any used and unused 
THS comprising of the THS device and stick, and CIG / CIG butts by designated 
investigational site staff. 
6.6 
Restrictions 
6.6.1 
 Smoking Restrictions 
During the Screening period, subjects will be allowed to use any TNP according to their 
usual habits except during the procedures of the Screening Visit (Section 9.1). Spirometry 
assessments at Screening and at Day -1 will be performed at least one hour after stopping 
smoking (Sections 9.1 and 9.2). 
From Baseline visit (Day -1) to Discharge (Day 3) or Early termination, use of any TNP 
(except IP use as per study design) will not be permitted.  
A nicotine washout period of at least 23 hours should be respected before IP use on Day 1, 
and of at least 24 hours on Day 2 and Day 3. 
6.6.2 
Dietary Restrictions 
A standard diet will be designed for the whole confinement period. For each meal, the 
caloric and fat content should be controlled to avoid a “high-fat” diet. The FDA guidance 
on food-effect studies for bioequivalence testing identifies a “high-fat” diet as a diet which 
contains “approximately 50 percent of total caloric content of the meal [from fat] and is 
high in calories (approximately 800 to 1000 calories) [17].”  
Subjects are not allowed to bring their own food or beverages to the investigational site. 
Meals will be served as described in Section 9. Additional light snacks, fruit, and raw 
vegetables can be distributed to the subjects without restrictions at any time during 
confinement (except during product use periods) if they comply with the standard diet. 
Consumption of water is allowed as desired. Consumption of quinine-containing drinks 
(e.g., tonic water) is not allowed. Subjects should refrain from ingesting foods or beverages 

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containing grapefruit or Seville-type (sour) oranges and marmalade from 7 days prior to 
Day -1 and throughout the study. The same menu and meal schedule will be administered 
uniformly for all subjects. Subjects should have fasted (black coffee or tea without sugar is 
possible) for at least 6 hours prior to safety laboratory assessments at Day -1. 
Subjects should refrain from strenuous and/or unaccustomed exercise throughout the entire 
course of the study. 
6.7 
Concomitant Medication 
All medication taken within four weeks prior to the ICF signature will be considered prior 
medication. All medication taken from Screening visit to end of the SFU period will be 
considered Concomitant medication.  
Medications will be allowed and carefully monitored during the study by the PI or designee. 
The PI(s) is(are) responsible for the medical care including medication of the subjects 
during their participation in the study. Any decisions regarding the prescription of 
medication will be taken in the best interest of the subject. The use of any concomitant 
medication must be fully documented in the source document and transcribed into the CRF. 

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7 
Study Procedures 
Investigational site staff performing or recording study assessments must have the 
appropriate and fully documented training. An overview of study assessments and time 
points is shown in the schedule of events (Appendix A). Appropriate medical advice will 
be provided to the subject in case of any medical findings requiring health care. Site 
personnel will adhere to the site’s standard operating procedures (SOPs) for study-related 
procedures. 
7.1 
Informed Consent 
Subjects will be asked to provide their written informed consent to participate in the study 
(Section 1.3). Study assessments must only start after the time of ICF signature by the 
subject. 
7.2 
Information on the Risk of Smoking, Smoking Cessation Advice, 
and THS Briefing  
At the Screening visit, on Baseline Day -1 (before randomization) and at Discharge (Day 
3), subjects will receive i) information on the risks of smoking, ii) smoking cessation 
advice, and iii) briefing on THS (e.g., that its use is not risk-free) as described in the 
Schedule of Events (Appendix A).  
The information on the risk of smoking and advice on smoking cessation will take the form 
of a brief interview according to the WHO recommendations [7]. The briefing of subjects 
on THS will address any intended or unintended beliefs that subjects may have about THS. 
The goal of the debriefing is to help ensure that subjects enter and exit the study with an 
accurate understanding of the product risks.  
Details of the sessions will be recorded in the source document file. This information will 
be given to the subjects on an individual basis during a face-to-face meeting between the 
subject and the PI or designee or may be given in a group session. 
7.3 
Support During Abstinence from any Tobacco and Nicotine 
Containing Products 
Subjects will be offered support during periods of abstinence from any TNP during the 
study from Day -1 to Discharge on Day 3 by the PI and/or investigational site staff. Support 
resources will include counselling and assistance, entertainment, monitoring of the 
subject’s behavior, AEs, and the subject’s mood, clinical tests e.g., vital signs, physical 
examination. 

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7.4 
Clinical Assessments 
Any clinically relevant medical condition detected during Screening visit assessments will 
be documented as a concomitant disease. This also applies to clinically relevant findings in 
laboratory values, vital signs, at spirometry and ECGs detected during Screening visit 
assessments. Any untoward medical occurrence in a subject detected during the study that 
was not present at the Screening visit must be documented as an Adverse Event (AE). 
Worsening of a pre-existing condition from Screening visit onwards will also be 
documented as an AE.  
7.4.1 
Demographic Data 
Sex, date of birth, and race will be recorded for each subject as described in the Schedule 
of Events (Appendix A). 
7.4.2 
Medical History, Concomitant Disease, Previous and Concomitant 
Medications 
Relevant medical history or any concomitant disease will be documented at the Screening 
Visit. Medical history is defined as any condition that started and ended prior to the ICF 
signature at the Screening visit. A concomitant disease is defined as any condition that is 
either detected or is still ongoing at the time of ICF signature. The final status of any 
concomitant disease (i.e., stop date or ongoing) should be verified at each visit. 
Prior medication taken within 4 weeks prior to the Screening visit and any concomitant 
medication will be documented. Any medication started prior to the Screening visit and 
still being taken by the subject will be considered concomitant medication. Medication 
initiated after the Screening visit will also be referred to as concomitant medication. The 
definition of concomitant medication applies to both prescribed and over-the-counter 
products. 
Records of medication taken should include the drug name (preferably both generic and 
trade name), route of administration (e.g., oral, intravenous), dose and frequency (expressed 
in metric units, e.g., mg, mL, or IU), indication, start date and, if applicable, stop date (day, 
month, and year). Therapy changes (including changes of regimen) during the study will 
be documented. If a concomitant medication is still being taken by the subject at the end of 
the study, this will be recorded in the CRF. 
7.4.3 
Physical Examination 
Physical examinations will be conducted as described in the Schedule of Events; the 
examination will include review of general appearance, hair and skin, head, eyes, ears, nose 
and throat, neck, thyroid gland, chest, lungs, back, abdomen, dentition, gastrointestinal, 

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cardiovascular, musculoskeletal, and neurological systems. The physical examination is to 
be conducted by the PI or designated fully trained representative. 
7.4.4 
Body Height and Weight   
Body height and weight will be recorded at the Screening Visit and body-mass-index (BMI) 
will be calculated using the following formula:  
BMI = weight in kilograms
height in meters2
= 𝑘𝑔
𝑚2 
The BMI will be used to assess eligibility for enrolment. 
7.4.5 
Vital Signs 
The vital signs (systolic and diastolic blood pressure, respiratory rate, and pulse rate) will 
be measured as described in the Schedule of Events (Appendix A). On Day 1 to Day 3, 
vital signs will be assessed prior to T0. 
All parameters will be recorded in supine position after the subject has rested for at least 5 
minutes. Subjects should have abstained from using any TNP for at least 15 minutes prior 
to assessment of vital signs. 
The PI will define vital sign ranges to determine normal or abnormal results. For those 
results outside of the normal range, the PI will determine appropriate follow-up including 
reporting of any AEs. 
7.4.6 
Spirometry 
Spirometry (without bronchodilator) will be performed at the Screening visit, Baseline Day 
-1 and at Discharge (Day 3) or Early termination in accordance with the 2019 guideline of 
the American Thoracic Society (ATS)/European Respiratory Society (ERS) Joint Task 
Force on the standardization of spirometry [18, 19]. Spirometry predicted values will be 
standardized to the National Health and Nutrition Examination Survey III predicted set 
[20]. 
Assessed parameters will include: FEV1, FEV1 % predicted, FVC, FVC % predicted and 
FEV1/FVC. 
All personnel performing spirometry testing should have the appropriate training and 
quality control measures should be put into place and be properly documented. The testing 
will be performed in sitting position at rest for at least 15 minutes and at least one hour after 
CIG smoking (Screening visit). 

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The Investigator will define Spirometry ranges to determine normal or abnormal results. 
For those results outside of the normal range, the Investigator will determine appropriate 
follow-up including reporting of any AEs. 
Any printouts of Spirometry on thermo-sensitive paper must be photocopied and stapled 
together for inclusion in the source documents. 
7.4.7 
Electrocardiogram 
At the Screening visit, Baseline Day -1 and at Discharge (Day 3) or Early termination, a 
standard 12-lead ECG will be recorded after the subject has rested for at least 10 minutes 
in supine position as described in the Schedule of Events.  
All ECGs will be reviewed on an ongoing basis by the PI or designee. The following 
parameters will be documented: heart rate, PR interval, QRS interval, QT interval, and QTc 
interval corrected according to Fridericia’s formula.  
The Investigator will define ECG ranges to determine normal or abnormal results. For those 
results outside of the normal range, the Investigator will determine appropriate follow-up 
including reporting of any AEs.  
Any printouts of ECGs on thermo-sensitive paper must be photocopied and stapled together 
for inclusion in the source documents. 
7.5 
Laboratory Assessments 
7.5.1 
Clinical Chemistry, Hematology, and Urine Analysis for Safety Panel 
Hematology and clinical chemistry analysis will be assessed as per Schedule of Events. 
Subjects should have fasted for at least 6 hours prior to safety laboratory assessments, 
except at Discharge and Early termination where non-fasting samples can be used. Tests 
will be conducted at a local laboratory (Appendix B). If during the Screening visit a blood 
sample is not suitable for analysis (e.g., blood clotting) a re-test should be performed for 
the specific parameters which are not available. Safety urine analysis will be assessed at 
Screening, Baseline and at Discharge or at Early termination.  
Parameters to be tested are listed in Table 1. 

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Table 1 
Clinical Laboratory Parameters for Safety Panel 
Hematology 
Clinical Chemistry 
Urine analysis 
• 
Hematocrit 
• 
Hemoglobin 
• 
Mean corpuscular 
hemoglobin 
• 
Mean corpuscular 
hemoglobin concentration 
• 
Mean corpuscular volume 
• 
Platelet count 
• 
Red blood cell count 
• 
White blood cell count 
• 
Differential* WBC count: 
- 
Neutrophils 
- 
Basophils 
- 
Eosinophils 
- 
Lymphocytes 
- 
Monocytes 
• Albumin 
• Total protein 
• Alkaline phosphatase 
• Alanine aminotransferase 
• Aspartate aminotransferase 
• Blood urea nitrogen 
• Creatinine 
• Gamma-glutamyl transferase 
• Glucose 
• Lactate dehydrogenase 
• Potassium 
• Sodium 
• Total bilirubin 
• Direct bilirubin 
• Total cholesterol 
• Triglycerides 
• pH 
• Bilirubin 
• Glucose 
• Nitrite 
• Red blood cell 
traces 
• Protein 
• Specific gravity 
*Differential WBC count both percentage and absolute 
7.5.2 
Serology  
Tests for hepatitis B virus (HbsAg), hepatitis C virus (HCV antibody) and human 
immunodeficiency virus (anti-HIV1/2) will be performed at the Screening visit. In case of 
positive results, the subject will be referred to appropriate medical care. 
7.5.3 
Urine Drug Screening 
A urine drug screen including testing for alcohol will be performed at the site at the 
Screening Visit and at Baseline Day -1. The urine will be screened for:  
• amphetamine type substances  
• barbiturates 
• benzodiazepines 
• cannabinoids 
• cocaine 
• opiates 
• methadone. 

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In case of a positive urine drug test, a re-test will not be allowed to evaluate eligibility. In 
case of an inconclusive test, a re-test can be performed but this needs to be done 
immediately after the inconclusive test.  
7.5.4 
Urine Cotinine Screening  
A urine cotinine test will be performed to confirm the TNP use status as described in the 
Schedule of Events. 
The test must detect cotinine with a threshold of ≥ 200 ng/mL. In case of a negative cotinine 
test, a re-test will not be allowed to evaluate eligibility. In case of an inconclusive test, a 
re-test can be performed but this needs to be done immediately after the inconclusive test. 
7.5.5 
Alcohol BreathTest  
An alcohol breath test will be performed in all subjects as described in the Schedule of 
Events. 
7.5.6 
Urine Pregnancy Test  
A urine pregnancy test will be performed for all female subjects as per Schedule of Events. 
Subjects with a positive urine pregnancy test or unclear results (from two repetitions) before 
randomization will be considered as screen failures.  
In case of any positive pregnancy test, the PI or designee will inform the subject about the 
risks associated with smoking during pregnancy and subjects will be referred to a health 
care facility/health care provider for pregnancy follow-up. 
All pregnancies detected during the study must be reported and handled as described in 
Section 8.5. Pregnancies detected after randomization will lead to discontinuation from the 
study Section 5.2). 
7.6 
Sample Handling, Storage, and Shipment 
7.6.1 
Urine samples 
Urine drug test including testing for alcohol, urine pregnancy tests and urine cotinine tests 
will be done by the site personnel at the site. All other blood and urine samples will be 
managed by the laboratory designated in Appendix B. 
Detailed procedures for handling of samples are described in a separate document. Safety 
laboratory samples will be destroyed as per laboratory local regulations. All other samples 
will be destroyed post database lock or post finalization of the bioanalytical reports, 
whichever occurs last. The facility/-ies at which the samples are stored will be informed in 
writing by the Sponsor when destruction of the samples shall be performed. 

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7.6.2 
Blood Samples  
Venous blood samples will be drawn by qualified and trained site personnel and according 
to the standard operating procedures (SOPs) at the investigational site. 
Since the test for nicotine concentration is highly sensitive, precautions should be taken 
during blood sampling and processing to prevent the contamination of samples with 
environmental nicotine.  
In total, approximately 275 mL of blood will be collected for this study including samples 
for determination of plasma nicotine concentrations (approximately 190 mL), serology (5 
mL) and safety laboratory (approximately 60 mL, or 80 ml for alternate subjects). This 
calculation is based on an individual volume of each sample of 5.0 mL for nicotine PK, 
5 mL for serology, and 20 mL per safety laboratory assessments. The total volume of blood 
drawn will not exceed the levels for a standard blood donation.  
Details on the procedures for collection, labeling, handling and shipment of samples are 
described in the laboratory manual. 
7.7 
Other Study Procedures  
7.7.1 
Investigational Product Demonstration 
All subjects will have a demonstration of the THS by the investigational site staff at the 
Screening visit without product use.  
7.8 
Questionnaires  
The questionnaires will be completed by the subject as described in Section 9, and the 
Schedule of Events (Appendix A). Completion at later time points will be considered as a 
protocol deviation. All subject-reported outcome as well as instructions will be provided in 
the subject’s local language. Details of the assessments are provided in Appendix C and in 
Appendix D. 
7.8.1 
Fagerström Test for Nicotine Dependence (Revised Version) 
At the Screening visit, potential nicotine dependence will be assessed as per Schedule of 
Event using the FTND in its revised version as updated in 2012 [21]. 
The questionnaire consists of six questions which are to be answered by the subjects 
themselves. The scores obtained on the test will permit the classification of nicotine 
dependence into three levels: Mild (0 to 3 points); Moderate (4 to 6 points); Severe (7-10 
points) [21]. 

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7.8.2 
Tobacco/Nicotine Product Use History 
At Screening visit and Baseline visit Day -1, subjects will be asked questions about their 
TNP use history. The questions will capture frequency and quantity of TNP use over the 
past four weeks, the flavor of CIG the subjects do smoke, the number of continuous years 
of CIG smoking, the duration of cessation attempts over the past three years, and the 
intention to quit smoking within the next 3 months. This information will be used as 
characteristics of the study subjects, to assess their eligibility to participate in the study, 
and to serve as baseline values. 
7.8.3 
VAS Craving Assessment 
At the time points specified in Section 4.1, craving for CIG will be evaluated using a one-
item self-reported VAS Craving assessment [14], asking subjects to rate craving for CIG 
(How strong is your craving for cigarettes?), on a 100 mm unipolar scale, ranging from 0 
(no craving) to 100 (strong craving). 
7.8.4 
VAS Liking Assessment 
Product liking for the THS or the CIG used and smoked as part of the study will be 
evaluated using a one-item self-reported VAS Liking assessment, asking subjects to rate 
liking for the product (Overall, my liking for this product is:) on a 100 mm bipolar scale, 
ranging from 0 (strong disliking) to 100 (strong liking), with a neutral middle point, as 
recommended in the FDA guidance for industry on abuse liability assessment [15]. 
7.8.5 
VAS Intention to Use Again Assessment 
The intention to use the THS or the CIG again will be evaluated using a one-item self-
reported VAS Intention to Use Again assessment, asking subjects to rate their intention to 
use the IP again (How likely are you to use this product again?) on a 100 mm bipolar scale, 
ranging from 0 (very unlikely) to 100 (very likely) [16] . 

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8 
Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Events 
An adverse event (AE) is defined as any health-related event which is adverse or 
unfavorable and which either starts after ICF signature or represents a worsening of a 
health–related condition that existed at the time of that signature. Careful medical judgment 
is required to establish whether a clinical finding (including an abnormal laboratory result) 
is a true AE or just a manifestation of a preexisting health–related condition. An AE may 
or may not have a causal relationship with the study procedures or with the use of IP. 
8.1.2 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an AE that: 
• Results in death 
• Is life-threatening  
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity  
• Is a congenital anomaly/birth defect or 
• Is an important medical event. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate Investigator’s 
medical judgment, they may jeopardize the subject, or the subject may require medical or 
surgical intervention to prevent one of the outcomes listed in the above definitions. 
"Life-threatening" means that the subject was at immediate risk of death from the event. It 
might have caused death if it had occurred in a more serious form. 
8.1.3 
Conditions Existent Before the Start of the Period of Collection (ICF 
signature) 
Concomitant diseases whose severity is increasing after the Screening visit are to be 
captured as AE or SAE, depending on if any seriousness criterion is met.  
Therapies or surgical interventions including admissions to hospital that were planned 
before the ICF signature should not be considered AEs/SAEs. 

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8.2 
Collection and Reporting of Adverse Events 
8.2.1 
Collection of Information 
AEs should be collected mainly via face-to-face interview with the subject by the use of 
consistent, open, non-directive questions from the investigator(s) or designee(s) (e.g., 
“How have you been feeling since you were last asked?”). 
Any non-serious AE occurrence during the study must be documented in the subject’s 
medical records in accordance with the Investigator’s normal clinical practice and on the 
AE page of the CRF. SAEs that occur during the study must be documented in the subject’s 
medical record, on the AE CRF, and on the SAE form for recording into safety database. 
Information recorded for AEs/SAEs will include verbatim description, start and stop dates, 
seriousness, severity (intensity), causal relationship with IP and study procedures, 
expectedness, action taken with IP (e.g., reduced, not changed), other action taken (e.g., 
treatment administered, if led to the subject’s discontinuation from the study), and outcome 
(e.g., resolved, stabilized).  
Whenever a medically meaningful diagnosis is available to comprise a set of reported signs 
and/or symptoms, it should be preferentially provided as the AE or SAE term, rather than 
the individual signs and/or symptoms. 
8.2.2 
Period of Collection 
AEs (including SAEs) will be collected from the time of ICF signature until the individual 
EOS for each participant. 
Any AEs which occur during the Screening period will be captured by the investigational 
site staff and assessed by the Investigator or designee(s) to establish relationship to study 
procedures. 
During a 3-day SFU period new AEs/SAEs will be recorded and ongoing AEs/SAEs will 
be followed-up by the study site, as described in Section 8.2.6. 
8.2.3 
Intensity of Adverse Event 
The Investigator must assess the intensity of each reported AE according to the following 
grading scale: 
Table 2 
Intensity of Adverse Events 
Mild: 
Easily tolerated, not interfering with normal everyday activities 
Moderate: 
Interferes with normal everyday activities, but the subject is still able to 
function 

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Severe: 
Incapacitating and requiring medical intervention 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures 
The Investigator must assess the causal relationship between the exposure to the IP (THS 
or CIG) and each of the reported AEs, using the classification system and the criteria 
described below. The same assessment must be made separately to assess the causal 
relationship between the study procedures and each of the reported AEs:  
Not related: The temporal relationship of the adverse event to IP administration or study 
procedure(s) makes a causal relationship unlikely, or concomitant 
medication, therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event.  
Related: 
The temporal relationship of the adverse event to IP or study procedure(s) 
makes a causal relationship possible, and concomitant medication, 
therapeutic interventions, or underlying conditions do not provide a 
sufficient explanation for the observed event. 
8.2.5 
Expectedness 
Any AE assessed as related to the IP (THS or CIG) will be assessed for its expectedness. 
An AE will be regarded as “unexpected” if its nature or severity is not consistent with 
information already recorded in Section 6.7 of the current Investigator’s Brochure [6]. 
8.2.6 
Follow-up of Non-serious and Serious Adverse Events 
Any non-serious AE that is ongoing at the time of Discharge or early termination will be 
followed-up by the Investigator during the Safety follow-up (SFU) period until it has been 
resolved, stabilized (i.e., no worsening of the condition), or an acceptable explanation has 
been found (e.g., a chronic condition). The follow-up of the ongoing non-serious AEs will 
be done via a phone call performed at the end of the SFU period. If the subject does not 
respond at the first phone call, two additional attempts will be made, then subject will be 
declared lost to follow-up.  
At the end of the 3-day SFU period, all ongoing non-serious AEs will have the outcome 
documented as “unknown” and will not be followed-up by the Investigator. At the 
discretion of the Investigator, the subject will be referred to his General Practitioner to have 
his/her ongoing AEs addressed accordingly. 
All SAEs will be followed up by the Investigator or designee after the end of the SFU 
period, until their resolution, stabilization (i.e., no worsening of the condition), or an 
acceptable explanation has been found (e.g., a chronic condition). In case the subject cannot 

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be reached for additional information related to SAE(s), a total 3 attempts should be 
performed before the subject will be declared as lost to follow-up. 
8.3 
Reporting Serious Adverse Events 
Any SAE observed during the period of collection in this study must be reported within 24 
hours of first awareness to Sponsor, via email, having the SAE form attached. 
Follow-up information should be reported on a new SAE report form, marked as a follow-
up report and submitted to Sponsor according to the same timelines as described above. 
The follow-up SAE report form must include the minimum information required for form 
completion and only changed/new information needs to be specified. Information provided 
in the follow-up SAE report form supersedes any information that was initially reported.  
The Investigator or designee is responsible for submitting the relevant reports of SAEs that 
occur during the study to the IEC, according to local regulations. 
8.4 
Reporting of Other Abnormal Findings 
The other abnormal findings discovered during different clinical assessments (e.g., ECG, 
spirometry, vital signs, body weight) should be evaluated for the clinical significance by 
the Investigator/designee based on his/her medical judgement. All abnormal clinically 
significant test results or clinical examination findings can, at the discretion of the 
Investigator, be reported as AEs and handled according to the directions from Section 8.2. 
8.5 
Reporting and Follow-Up of Pregnancies 
8.5.1 Period of Collection and Follow-up 
Pregnancies detected between the time of signature of the ICF and the time before first 
exposure to the IP will be considered a reason for screen failure. No pregnancy form will 
be filled in for that case, however the diagnosed pregnancy must be captured in the screen 
failure page of the CRF. 
Any pregnancy detected after enrollment must be reported by the Investigator to Sponsor 
within 24 hours of first awareness. This also includes pregnancies spontaneously reported 
to the Investigator after the end of the study for a subject. A dedicated pregnancy form will 
be used to report reportable cases of pregnancy. 
Any pregnancy that was potentially associated with exposure to IP (THS and CIG) will be 
followed-up until an outcome is reached (e.g., normal delivery, spontaneous abortion, or 
voluntary termination), and until 8 weeks after delivery. Any pregnancy complication, 
adverse pregnancy outcome or maternal complications will be recorded as an AE 
accordingly. 

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The procedure outlined in Section 8.3 should be followed to collect pregnancy reports and 
provide any additional/follow-up information to Sponsor. 
8.5.2 Reporting of Pregnancies 
The Investigator is responsible for informing the responsible IEC of any pregnancy case 
that was reported during the study, as determined by local regulations. 
8.6 
Adverse Events Leading to Discontinuation 
Subjects who are discontinued from the study because of an AE will undergo the Early 
termination (Section 9.6), as soon as practical after discontinuation and will enter the 3-day 
SFU period.  
Any AEs or SAEs that are ongoing at the end of the SFU period will be managed as 
described in Section 8.2.6. 
8.7 
Device Malfunction, Product Complaints and Misuse 
Any occurrence of a test product (THS) device malfunction, product complaints, or misuse 
(use not in accordance with its instructions) by a subject will be documented by the PI. 
Information regarding any test product (THS) events should be actively collected during 
the study and assessed for severity as Minor or Major: 
Minor – Can be resolved easily. 
Major – Cannot be resolved. 
Any occurrences of a test product (THS) device malfunction (e.g., holder does not charge 
when inserted into the charger), product complains (e.g., stick filter fall off) or misuse by a 
subject (e.g., use not in accordance with its label and instructions), will be documented by 
the PI or designee using a device issue log, and recorded.   
Any test product misuse may result in use-related hazards (Section 2.3.3). 
Furthermore, any malfunction or misuse of the test product (THS) that leads to an AE/SAE 
will follow the same processes as described above. 

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9 
Study Activities 
A detailed schedule of assessments can be found in Appendix A. Measurements not 
conducted at the exact timepoint but conducted within the given time window (if 
applicable) do not constitute a protocol deviation but an accepted variability for the given 
timepoint. 
In general, if no start time for the procedures is provided, then the procedure can be 
performed at any time during the day. 
The main objective for this study is the evaluation of the plasma concentration-time profile 
of nicotine and derived PK parameters. Therefore, the collection of blood samples for 
determination of plasma nicotine concentration should be as close to the schedule time as 
possible and should take precedence over any other assessments required at the same time. 
9.1 
Screening Visit (Day -28 to Day -2) 
The Screening visit will be performed ≤27 days prior to potential randomization at Baseline 
Day -1. First, the Informed consent form (ICF) along with study information will be given 
to the subject. Prior to being asked to sign the consent form, subjects will be given time to 
review the study information and ask any questions. When/if the ICF is signed and dated 
and timed, the screening procedures (Table 3) can be performed in the order deemed most 
practical. While it is recommended to complete as many screening procedures as possible 
in one day, it is permissible to complete those over more than one day. Smoking is allowed 
at the Screening visit. 
If the inclusion and exclusion criteria are satisfactorily met after Screening visit (including 
negative pregnancy test for female), the site staff will call the subject to arrange the Baseline 
visit (Day -1) to the site. 
Table 3 
Time Schedule – Screening Visit 
Time 
Procedures 
Additional Information 
Prior to any other 
study procedure 
Informed consent process and 
signature of ICF 
 
During the Visit 
Information on smoking risks, 
advice on smoking cessation  
Incl. THS briefing 
 
Demographics 
 
 
Medical History   
Incl. concomitant diseases 
 
Concomitant medication  
Incl. during ≤4 weeks 
 
Body weight and height 
BMI 
 
FTND questionnaire 
Nicotine dependence 
 
TNP Use History questionnaire 
Smoking history 

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Physical examination 
 
 
Vital signs 
≥5 min supine rest 
≥15 min TNP abstinence 
 
ECG 
≥10 min supine rest 
 
Spirometry 
≥15 min sitting rest 
≥1 hr TNP abstinence 
 
Serology 
HBV, HCV, and HIV 
 
Venous blood sample 
- Safety panel 
(hematology and clinical 
chemistry) 
 
Spot urine sample  
 
- Safety panel 
- Drug test  
- Cotinine test 
- Pregnancy test (female) 
 
Alcohol breath test 
 
 
THS demonstration 
Without product use 
 
Identification of current CIG 
brand 
Explain CIG provision for 
confinement period by 
subject 
 
AE/SAE recording 
 
 
Review of eligibility criteria 
Incl. subject’s willingness 
to comply with study 
procedures, particularly 
periods of TNP abstinence 
Abbreviations:  
AE = Adverse event; BMI = Body mass index; ECG = electrocardiogram; CIG = combustible cigarette; HBV = hepatitis 
B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; hr = hour; ICF = informed consent form; Incl. 
= including; min = minute; SAE = Serious adverse event; THS = tobacco heating system; TNP = tobacco and/or nicotine 
containing product. 
9.2 
Baseline Visit Day -1 
At the Baseline visit Day -1, if the subject’s eligibility will be confirmed 1 by the procedures 
shown in Table 4. The subject eligible for randomization must abstain from any TNP, to 
ensure at least 23 hours of nicotine wash-out ahead of the IP exposure on Day 1.  
                                                 
1 Alternate subjects will have to repeat the Baseline visit Day -1 to qualify for randomization. The data of that 
repeated visit will be captured in the database as “Baseline visit Day -1 – Second occurrence”. 

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Table 4 
Time Schedule – Baseline Visit 
Time 
Procedures 
Additional Information 
Start of the Visit 
Stop of TNP use 
To ensure ≥23 hours of 
nicotine wash-out  
During the Visit 
TNP Use History questionnaire 
Smoking history 
 
Information on smoking risks, 
advice on smoking cessation 
Incl. THS briefing 
 
Concomitant disease / 
concomitant medication  
Since Screening visit 
 
Body weight 
BMI 
 
Vital signs 
≥5 min supine rest 
≥15 min TNP abstinence 
 
ECG 
≥10 min supine rest 
 
Spirometry 
≥15 min sitting rest 
≥1 hr TNP abstinence 
 
Venous blood sample 
- Safety panel 
(hematology and clinical 
chemistry) 
 
Spot urine sample  
 
- Safety panel 
- Drug test  
- Cotinine test 
- Pregnancy test (female) 
 
Alcohol breath test 
 
 
Review of eligibility criteria  
Incl. subject’s willingness 
to comply with study 
procedures 
 
Randomization 
 
 
AE/SAE recording 
 
Abbreviations:  
AE = Adverse event; ECG = electrocardiogram; hr = hour; Incl. = including; min = minute; SAE = Serious adverse event; 
TNP = tobacco and/or nicotine containing product. 
9.3 
Day 1 
The study procedures performed on Day 1 are listed in Table 5. 
Table 5 
Time Schedule – Day 1 
Time 
Procedures 
Additional Information 
Prior to T0 
Vital signs 
≥5 min supine rest 
Prior to T0 
VAS Craving TV0 
≤15 min prior to T0 

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Prior to T0 
Blood sample TB0 
≤5 min (±2 min) prior to T0 
Just before T0 
Switch-on of THS (with stick) 
or lighting of CIG  
Performed by investigational 
site staff 
T0 
Start of IP use 
 
During / after IP use 
Blood sampling (nicotine PK) 
Post-T0 time points: 
TB1 after 4 minutes (± 1 min) 
TB2 after 6 min (± 1 min) 
TB3 after 8 min (± 1 min) 
TB4 after 10 min (± 1 min) 
TB5 after 12 min (± 1 min) 
TB6 after 15 min (± 2 min) 
TB7 after 30 min (± 5 min) 
TB8 after 1 hr (± 5 min) 
TB9 after 2 hrs (± 5 min) 
TB10 after 4 hrs (± 5 min) 
TB11 after 10 hrs (± 5 min) 
TB12 after 14 hrs (± 5 min) 
TB13 after 24 hrs (± 10 min) 
 
VAS Craving  
Post-T0 time points 
TV1 after 4 min (± 2 min) 
TV2 after 10 min (± 2 min) 
TV3 after 15 min (± 2 min) 
TV4 after 30 min (± 2 min) 
TV5 after 10 hrs (± 5 min) 
 
VAS Liking and 
VAS Intention to Use Again 
TV3 after 15 min (± 1 min) 
≤2 hours after T0 
Breakfast 
 
≥4 hours after T0 
Lunch 
 
Ongoing 
Nicotine wash-out 
Optional: snacks and water 
 
Support during TNP 
abstinence period 
 
 
Concomitant disease / 
concomitant medication  
 
 
AE/SAE recording 
 
 
Product events 
Malfunction / misuse 
Abbreviations:  
AE = Adverse event; CIG = combustible cigarette; hr(s) = hours; min = minute(s); IP = investigational product; PK = 
Pharmacokinetic; SAE = Serious adverse event; T0 = start of IP use; TBX = time point blood sampling; TVX = time point 
VAS assessment; THS = Tobacco Heating System; VAS = Visual analogue scale 

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9.4 
Day 2 
The study activities performed on Day 2 are listed in Table 6:  
Table 6 
Time Schedule – Day 2 
Time 
Procedures 
Additional Information 
Prior to T0 
Vital signs 
≥5 min supine rest 
Prior to T0 
VAS Craving TV0 
≤15 min prior to T0 
≤5 min prior to T0 
Blood sample TB14 
Day 1 sample TB13 (24 hrs 
±10 min) = TB0 of Day 2 
Just before T0 
Switch-on of THS (with stick) 
or lighting of CIG  
Performed by investigational 
site staff 
T0 
Start of IP use 
 
During / after IP use 
Blood sampling (nicotine PK) 
Post-T0 time points: 
TB1 after 4 minutes (± 1 min) 
TB2 after 6 min (± 1 min) 
TB3 after 8 min (± 1 min) 
TB4 after 10 min (± 1 min) 
TB5 after 12 min (± 1 min) 
TB6 after 15 min (± 2 min) 
TB7 after 30 min (± 5 min) 
TB8 after 1 hr (± 5 min) 
TB9 after 2 hrs (± 5 min) 
TB10 after 4 hrs (± 5 min) 
TB11 after 10 hrs (± 5 min) 
TB12 after 14 hrs (± 5 min) 
TB13 after 24 hrs (± 10 min) 
 
VAS Craving  
Post-T0 time points 
TV1 after 4 min (± 2 min) 
TV2 after 10 min (± 2 min) 
TV3 after 15 min (± 2 min) 
TV4 after 30 min (± 2 min) 
TV5 after 10 hrs (± 5 min) 
 
VAS Liking and 
VAS Intention to Use Again 
TV3 after 15 min (± 1 min) 
≤2 hours after T0 
Breakfast 
 
≥4 hours after T0 
Lunch 
 

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Ongoing 
Nicotine wash-out 
Optional: snacks and water 
 
Support during TNP 
abstinence period 
 
 
Concomitant disease / 
concomitant medication  
 
 
AE/SAE recording 
 
 
Product events 
Malfunction / misuse 
Abbreviations:  
AE = Adverse event; CIG = combustible cigarette; hr(s) = hours; min = minute(s); IP = investigational product; PK = 
Pharmacokinetic; SAE = Serious adverse event; T0 = start of IP use; TBX = time point blood sampling; TVX = time point 
VAS assessment; THS = Tobacco Heating System; VAS = Visual analogue scale 
9.5 
Day 3 
The study activities performed on Day 3 before and during IP exposure, and prior to the 
time of discharge are presented in Table 7.  
Table 7 
Time Schedule – Day 3 
Time 
Procedures 
Additional Information 
Prior to T0 
Vital signs 
≥5 min supine rest 
Prior to T0 
VAS Craving TV0 
≤15 min prior to T0 
≤5 min prior to T0 
Blood sample TB14 
Day 2 sample TB13 (24 hrs 
±10 min)  TB0 of Day 3 
Just before T0 
Switch-on of THS (with stick) 
or lighting of CIG  
Performed by investigational 
site staff 
T0 
Start of IP use 
 
During / after IP use 
Blood sampling (nicotine PK) 
Post-T0 time points: 
TB1 after 4 minutes (± 1 min) 
TB2 after 6 min (± 1 min) 
TB3 after 8 min (± 1 min) 
TB4 after 10 min (± 1 min) 
TB5 after 12 min (± 1 min) 
TB6 after 15 min (± 2 min) 
TB7 after 30 min (± 5 min) 
TB8 after 1 hr (± 5 min) 
TB9 after 2 hrs (± 5 min) 
TB10 after 4 hrs (± 5 min) 
TB11 after 10 hrs (± 5 min) 

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VAS Craving  
Post-T0 time points 
TV1 after 4 min (± 2 min) 
TV2 after 10 min (± 2 min) 
TV3 after 15 min (± 2 min) 
TV4 after 30 min (± 2 min) 
TV5 after 10 hrs (± 5 min) 
 
VAS Liking and 
VAS Intention to Use Again 
TV3 after 15 min (± 1 min) 
Ongoing 
Support during TNP 
abstinence period 
 
≤2 hours after T0 
Breakfast 
 
 
ECG 
≥10 min supine rest 
 
Spirometry 
≥15 min sitting rest 
 
Venous blood sample 
- Safety panel hematology 
and clinical chemistry 
 
Spot urine sample  
 
- Safety panel 
- Pregnancy test (female) 
≥4 hours after T0 
Lunch 
 
 
Vital signs 
≥5 min supine rest 
 
Concomitant disease / 
concomitant medication  
 
 
AE/SAE recording 
 
 
Product events 
Malfunction / misuse 
 
Information on smoking risks, 
advice on smoking cessation  
Incl. THS briefing 
 
Discharge 
Stop of TNP abstinence 
Abbreviations:  
AE = Adverse event; CIG = combustible cigarette; ECG = electrocardiogram; hr(s) = hours; IP = investigational product; 
min = minute(s); PK = Pharmacokinetic; SAE = Serious adverse event; T0 = start of IP use; TBX = time point blood 
sampling; TVX = time point VAS assessment; THS = Tobacco Heating System; TNP = tobacco and/or nicotine containing 
product; VAS = Visual analogue scale 
9.6 
Safety Follow-up Period 
All subjects participating in the Baseline visit will enter a 3-day Safety follow-up (SFU) 
period at the time of Discontinuation from the study, even if they are not randomized into 
the study, unless they are Lost to follow-up. 
After Discharge on Day 3, or after Early termination, the subject will enter a 3-day SFU 
period. During this 3-day period, there will be spontaneous reporting by the subject of new 
AEs and new SAEs. Any ongoing AEs/SAEs will be actively followed-up by the site. The 
SFU period is concluded by a phone contact to the subject on the last day of the SFU period. 

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Any AEs or SAEs that are ongoing at the end of the 3-day Safety Follow-up period will be 
managed as described in Section 8.2.6. 
9.7 
Early Termination Procedures 
When a subject is discontinued from the study, all early termination procedures as listed in 
Table 8 are performed unless the subject refuses to perform the assessments or the 
procedures have already been performed during that study day.  
Table 8 
Early Termination 
Procedures 
Additional Information 
Venous blood sample 
- Safety panel hematology and clinical 
chemistry 
Spot urine sample  
 
- Safety panel 
- Pregnancy test (female) 
Vital signs  
After ≥5 min in supine position 
ECG  
After ≥10 min in supine position 
Spirometry 
After ≥15 min in sitting position 
Risks of smoking/advice on smoking 
cessation / THS briefing 
 
Concomitant disease/ concomitant 
medication 
 
AE/SAE 
 
IP events/ malfunctions/ misuse 
If applicable 
Discharge  
 
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; SAE = Serious adverse event 

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10 Quality Control and Quality Assurance 
10.1 Monitoring 
The Clinical Research Associate (“Monitor”) of the contract research organization (CRO) 
will be responsible for the monitoring of the study. Monitoring will be performed according 
to CRO’s SOPs and as per the agreed monitoring plan with the Sponsor. 
The PI(s) or designee(s) shall permit the Monitor to review study data as frequently as 
considered necessary to ensure that data are being recorded in an adequate manner and that 
protocol adherence is satisfactory met. 
The PI or designee(s) shall access medical records for the Monitor in order that entries in 
the CRFs may be verified. As part of his/her(their) responsibilities, the PI or designee(s) 
is(are) expected to ensure that the study adheres to GCP requirements [22]. 
An Investigator’s meeting will be held prior to or in conjunction with the Site Initiation 
visit. During this meeting, the general training of the study procedures and specific training 
on selected procedures will be completed and documented. 
In conjunction with, or after, the Investigator’s meeting, and before the first subject is 
screened into the study, the Site Initiation visit will be conducted by the Monitor and, if 
necessary, together with the Sponsor or its authorized representative. The purpose of the 
Site Initiation visit is described in the Monitoring Plan. 
During the study, the Monitor will have regular contact with the study site, including 
interim monitoring visits. The purpose of these visits is described in the Monitoring Plan. 
Communication by telephone, mail, and e-mail may be used as needed to supplement site 
visits. The PI and study personnel will cooperate with the Monitor, provide all appropriate 
documentation, and will be available to discuss the study. 
The Monitor and the Sponsor’s personnel will be available between visits should the PI or 
other staff at the sites need information and advice. 
Site visits will be made at regular intervals during the study. The frequency of the 
monitoring visits will be defined in the Monitoring Plan. 
The PI or designee(s) must be available during the monitoring visit to review the data, 
resolve any queries and to allow direct access to the subject’s records for source data 
verification. 
10.2 Training of Staff 
A formal meeting (Investigator’s meeting) will be conducted prior to or in conjunction with 
the Site Initiation visit. During this meeting, the requirements of the clinical study protocol 
and related documents will be discussed, and training to the relevant systems and other 

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study-specific procedures will be provided. The activities of this meeting will be described 
in the Monitoring Plan. 
Further to the Investigator meeting, the PI or designee(s) will ensure that appropriate 
training relevant to the study is provided to all staff involved in the study, and that any new 
information relevant to the performance of this study is forwarded in a timely manner to 
the staff involved. The PI or designee(s) will maintain a record of all individuals involved 
in the study. 
10.3 Audits and Inspections 
Good Clinical Practice (GCP) regulations require that there are independent inspections of 
clinical program activities. Such inspections may be performed at any time before, during 
and/or after the study. 
Authorized representatives of the Sponsor, regulatory agencies and/or an IEC may perform 
audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted and data were recorded, 
analyzed, and accurately reported according to the protocol, ICH/GCP guidelines [22], and 
any applicable regulatory requirements. The PI or designee(s) will contact the Sponsor or 
the authorized representative immediately if contacted by a regulatory agency about an 
inspection at their site. 
The PI or designee(s) is(are) responsible for maintaining a comprehensive and accurate 
filing system of all study-related documentation that will be suitable for inspection at any 
time by the Sponsor, its authorized representative, and/or regulatory agencies. In signing 
this protocol, the PI or designee(s) understand(s) and agree(s) to provide access to the 
necessary documentation and files. 
10.4 Risk Management 
According to ICH-GCP E6(R2) Section 5, the sponsor will implement a system to manage 
quality throughout all stages of the study process. Pursuant to this, a risk management 
process will be implemented including identification and scoring of risks, identification of 
critical data and processes. Risk assessment log will be periodically reviewed during 
monthly meetings with the CROs.  
This risk management approach will be described in the Risk Management Plan which will 
be developed during the set-up phase of the study and reviewed throughout all stages of the 
study.  
In addition, at the end of study, the Sponsor will describe in the CSR the quality 
management approach implemented in the study. 

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11 Data Management Activities 
All data management activities will be described in detail in the data management plan 
(DMP) and documents specified therein. The electronic systems used to collect subject data 
will be FDA 21 CFR Part 11 compliant. 
11.1 Data Capture 
11.1.1 
Case Report Forms and Study Records 
Electronic Case Report Forms (eCRFs) are produced by the CRO responsible for Data 
Management activities (DM-CRO), stored electronically, and are available to the 
designated study team members. Each eCRF is reviewed and signed by the PI. The final 
signed CRFs will be provided to the Sponsor in the format as decided upon between DM-
CRO and the Sponsor (e.g., CD, flash drive, SFTP). This will be documented in the DMP. 
The subject questionnaires will be completed directly by the subject. Trained study 
personnel will be responsible for capturing the data from the observations, tests, and 
assessments specified in the protocol in the source documents, and to transfer the data into 
the eCRF, in accordance with the CRF Completion Guidelines.  
The PI has ultimate responsibility for the collection and reporting of all data related to the 
clinical study and ensuring that the data are accurate, authentic/original, legible, timely 
(contemporaneous), enduring, and available when required. The eCRF must be signed by 
the PI to attest that the data contained in the eCRF are true and accurate. Any correction 
made to source documents must be clearly recorded, without obscuring the original values 
and be accompanied by the date of change, reason for change, and identification of the 
person making the change. The eCRF for each subject will be checked against the source 
documents at the investigational site by the Monitor. Instances of missing or unclear data 
will be discussed with the Investigator for resolution. An eCRF will be generated for all 
subjects that sign the ICF.  
11.1.2 
Protocol Deviations 
Protocol deviations are considered as deviations from the study procedures as defined in 
this document, including but not limited to, as any violation of inclusion/exclusion criteria, 
mis-randomizations, assessments not performed or performed outside the scheduled time 
windows, or use of drugs that are known to affect components of the “smokers’ health 
profile”. 
All protocol deviations will be documented in the clinical trial management system 
(CTMS) or another approved format following site monitoring and other manual review. 
Information from the source documents will represent the primary source of protocol 
deviations. Information following site monitoring and other manual reviews will be 
documented in the site visit reports, follow-up letters, audit documentation, or other manual 

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review and will be recorded and tracked in the CTMS or other approved format. 
Telecommunications and other verbal communications regarding deviations will be 
considered and handled as important communication, documented and tracked as protocol 
deviations, as necessary. 
The protocol deviations from the CTMS (or other approved format) will be reviewed 
against the individual data points in the CRF database. The overall procedure for managing 
protocol deviations is described in the SOPs and/or documented in the DMP. 
Subjects with major protocol deviations will be identified to determine whether they will 
be excluded from any of the analysis populations.  
Major protocol deviations are a subset of protocol deviations that may significantly impact 
the completeness, accuracy, and/or reliability of the study data or that may significantly 
affect a subject's rights, safety, or well-being. 
The categories for the major and minor deviations will include, but are not limited to the 
deviations presented in Table 9 and Table 10.  
Table 9 Definition of Major Protocol Deviations Categories 
Sub-Category  
Description  
Protocol violation  
Violation 
of 
inclusion/exclusion 
criteria. 
Or 
missing 
documentation of any of the inclusion/exclusion criteria at time 
enrollment. 
Procedural deviation 
Deviation to any study procedures. 
Mis-randomization  
Misclassification of subject’s sex at randomization. Or incorrect 
product administered according to randomized sequence.  
Use of TNP not allowed  Use of any nicotine or tobacco–containing product other than the 
assigned product during the exposure period, or use of any 
nicotine tobacco-containing product during at least 23 hours of 
abstinence from any nicotine/tobacco containing products 
(nicotine wash-out). 
 

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Table 10 Definition of Minor Protocol Deviations Categories 
Sub-Category  
Description  
Procedural deviation 
Deviation to any study procedures. 
Time deviation (Plasma 
nicotine PK sample) 
Assessments not taken at the correct time or within the allowed 
time window or date/time is missing (see Section 4.1) 
Time deviation (other 
assessment) 
Assessments not taken at the correct time or within the allowed 
time window or date/time is missing (see Section 4.1) 
Assessment missing (Plasma 
nicotine PK sample) 
Assessment is missing 
Assessment missing (other 
assessment) 
Assessment is missing 
11.1.3 
Data Handling 
All study data will be managed by the data management team at the CRO responsible for 
this study. The overall procedures for quality assurance of clinical study data are described 
in the SOPs of the CRO data management team. The data management team at the CRO 
will prepare a DMP, prior to the start of data entry. This document will describe, in details, 
the data management-related procedures and processes. 
Data of all subjects who sign the ICF, including screen failures, will be captured in the 
source documents. 
All data of all subjects that are enrolled will be captured and stored in the study database. 
For screen failures, only the following information should be captured: date/time of ICF 
signature, date of birth, sex, race, AEs, date, and reason for screen failure. 
All data collected during the study in the database is declared property of the Sponsor, 
irrespective of the location of the database and the data management CRO. 
Additional details are covered in the DMP. 

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12 Planned Statistical Methods 
12.1 General Considerations 
Full details of the statistical analysis will be provided in the Statistical Analysis Plan (SAP). 
The following statistical analyses will not be performed prior to the finalization of the SAP. 
Any changes to the planned statistical methods from the SAP will be documented in the 
clinical study report (CSR). The statistical evaluation will be performed using SAS®, 
version 9.2 or later. 
12.1.1 
 Stratification Criteria 
The sample randomization will enforce at least 40% of each sex (i.e., a minimum of 12 
females and 12 males), therefore analyses will be stratified by sex (male and female), as 
well as unstratified, as detailed in the SAP.  
12.1.2 
Definitions for Statistical Data Analysis 
For PK and PD analyses, baseline will be defined as the last assessment prior to T0 (5 
minutes prior to T0 for blood sampling and 15 minutes for VAS questionnaires) for each 
study day of exposure. 
Nicotine PK parameters (Tmax, Cmax, AUC0-24h and AUC0-t’) will be derived from measured 
plasma nicotine concentrations-time data. Nicotine PK parameters will be derived from 
plasma nicotine concentration versus time data using a non-compartmental analysis (NCA) 
technique. All PK parameters will be computed in measured plasma nicotine concentration-
time. Indeed, due to the study requirement of at minimum 23 hours of nicotine abstinence 
before any IP use and the typical half-life of plasma nicotine of about 2 hours [23]. Then 
after 23 hours of nicotine abstinence it is expected that a maximum of 0.05% of nicotine 
will be present. Descriptive Statistics 
All data will be presented in listings, ordered by subject, study visit, IP, and time point, 
unless otherwise specified.  
For continuous data, summary statistics will include the number of subjects (n), the number 
and percent of subjects with missing data, the arithmetic mean, arithmetic standard 
deviation (SD), 95% confidence interval (CI) of the arithmetic mean, median, first and third 
quartiles, minimum, maximum; for log-normal data, the geometric mean, geometric 
coefficient of variation (CV), and 95% CI of the geometric mean will be presented instead 
of arithmetic mean, SD, and 95% CI of the arithmetic mean, respectively.  
For log normally distributed endpoints (Cmax, AUC0-24h and AUC0-t’), geometric mean, 
geometric CV, and confidence interval will be presented additionally.  

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Nominal categorical variables will be summarized by frequency statistics (number and 
percentage), including the number of missing data as a category.  
Ordinal categorical data (e.g., Tmax) will be summarized by number of subjects (n), 
number and percent of subjects with missing data, median, first and third quartiles, and 
minimum and maximum.  
For categorical data, the number and % of subjects with missing data, frequency counts and 
percentages will be presented. 
For PK and PD endpoints, all analyses and summaries will be performed by IP. 
For safety endpoints, analyses and summaries will be performed by IP and sequence, and 
overall. 
Post-baseline summaries will include change from baseline apart from log-normal variables 
which will present % change from baseline. 
When applicable, the number and % of subjects with values below the lower limit of 
quantification (LLOQ) or above the upper limit of quantification (ULOQ) will also be 
presented. If 50% or more data are below LLOQ or above ULOQ, only the number and 
percent of values below LLOQ or above ULOQ will be reported in the summaries, together 
with minimum (= LLOQ/2) and maximum (= ULOQ) of the observed values. 
12.1.3 
Handling of Missing Values and of Values outside the Detection Limits 
In general, missing data will not be imputed in this study, due to the nature of the 
measurements and the short periods of exposure and use. However, for questionnaire data, 
total scores and domain or subscale scores may use a certain degree of imputation by 
averaging across individual item scores. Further details will be provided in the SAP. 
In general, bioanalytical values below the lower limit of quantification (LLOQ) will be 
imputed using 0.5 x lower limit of quantification. For values above the upper limit of 
quantification (ULOQ), the ULOQ will be used for calculation and reporting in summary 
tables.  
For nicotine concentrations below the LLOQ (BLOQ): 
• BLOQ values before T0 will be imputed by LLOQ/2 
• BLOQ values after the last quantifiable value are not included in the analysis (e.g., for 
the calculation of AUC) 
• Any BLOQ value (after T0 and before the last quantifiable value) would need to be 
queried and, if confirmed, it will be imputed by LLOQ/2. 
The number and percent of values below LLOQ or above ULOQ will be presented in each 
summary table. 

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12.1.4 
 Significance Level for Inferential Analysis 
No significance level will be used. All confidence intervals will be computed at 95%.   
12.2 Analysis Sets 
Populations will be described based on the screened population. 
Demographics, baseline characteristics, PK and PD endpoints, and amount of nicotine 
delivered, will be analysed using the randomized and PK population.  
Safety will be analysed using the safety population. 
12.2.1 
Screened Population 
The screened population consists of all subjects who underwent at least one screening 
procedure. 
12.2.2 
 Safety Set (SAF) 
The safety population is a subset of the screened population and consists of all subjects 
who give informed consent and have at least one safety assessment. 
12.2.3 
 Randomized Population 
The randomized population is a subset of the safety population and consists of all the 
subjects who were randomized at Baseline (Day -1). Subjects for which inclusion/exclusion 
criteria were violated or subject for which the documentation for eligibility was incomplete 
at time of enrolment will be excluded from this population.  
12.2.4 
 Pharmacokinetics Population 
The Pharmacokinetic (PK) Population is a subset of the randomized population and consists 
of all randomized subjects for whom at least one nicotine PK parameter can be derived. 
Only subjects without major protocol deviations, as defined in the SAP, which have an 
impact on evaluability of the main objective, as described in Section 3.1, will be included 
in the PK population. 
12.3 Demographics and Baseline Characteristics 
Demographic information and baseline characteristics will be summarized for the PK 
population. This summary will also be performed for the randomized population if there is 
at least a difference of 1 subject between the populations.  
Summaries will include sex, age, height, weight, BMI, TNP use history, FTND score, and 
other endpoints that are only captured prior to product use.  

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These data will be summarized using the appropriate summary statistics. 
12.4 Main Objective 
12.4.1 
Main Estimand Analysis 
The main estimand related to the main objective is defined by the following components: 
Product Use Under Evaluation:  
- 
Single use of THS with either a regular or a menthol stick or of a single CIG  
Target Population:  
- 
Healthy adult smokers, who satisfy all eligibility criteria (see Section 5.1) 
Variable(s) of Interest:  
• Maximum nicotine plasma concentration [Cmax] 
• Time to the maximum nicotine plasma concentration [Tmax] 
• Area under the curve of nicotine plasma concentration-time computed from T0 to 
T=24 hours [AUC0-24h]  
• Area under the curve of nicotine plasma concentration-time computed from T0 to 
the subject-specific time of maximum nicotine concentration [AUC0-t’] 
Cmax, Tmax, AUC0-24h and AUC0-t’ computed on observed plasma nicotine concentration-
time curves. 
Intercurrent Events: 
- 
Subject’s non-adherence with single IP use: If the subject uses other tobacco or 
nicotine product than the planned IP, or if the subject does not adhere with the 
planned single IP use, the variables of interest from the related sequence’s period 
will be set to missing and handled as Missing at random (MAR). 
- 
Subject’s non-adherence with abstinence periods: If the subject has used any TNP 
during an abstinence period, the subject’s variable of interest data from the related 
sequence’s period will be set to missing and handled as MAR. 
- 
Subject’s discontinuation. The corresponding subject’s variable of interest missing 
data will be handled as MAR. 
Population-Level Summary Statistic:  
- 
Geometric means ratios for Cmax, AUC0-24h, AUC0-t’ 
12.4.1.1 
Baseline Comparability 
Not applicable. 

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12.4.1.2 
Descriptive Analysis 
Endpoints will be summarized using the randomized and the PK population. 
12.4.1.3 
Missing Data Strategy 
See Section 12.1.3 for missing data strategy. 
12.4.1.4 
Main Analysis 
A mixed model analysis of variance (ANOVA) will be conducted on AUC0-24h, Cmax, and 
AUC0-t’ endpoints in the natural logarithmic scale.  
The model will include terms for sequence, period, product exposure as fixed effects and 
subject as a categorical random effect modeling the within subject correlations. The 
ANOVA analysis could be performed using the following SAS code: 
PROC MIXED data=< > method=REML;  
class subject sequence period product;  
model log(parameter) = sequence period product/ddfm=KR;  
repeated product / subject=subject type=csh;  
lsmeans product / pdiff=control(“CIG”) cl alpha=0.05;  
RUN; 
The results of this analysis for each of are presented in terms of geometric least square 
ratios and 95% confidence intervals for the THS / CIG ratio.  
This approach is consistent with the guidelines in the European Medicines Agency’s 
guidelines for bioequivalence investigations [24] and FDA’s Center for Drug Evaluation 
and Research [25].  
The analysis of Tmax will be performed by conducting a Wilcoxon signed rank test and 
calculating the median Tmax for each product along with the Hodges-Lehmann [26] estimate 
of the median difference between products, and the related 95% CI. This analysis could be 
performed using the following SAS code: 
PROC NPAR1WAY hl(refclass=<>) alpha=.05 data=<> hl; 
   class TRT; 
   var AVAL; 
   ods output HodgesLehmann=HodgesLehmann; 
RUN; 
12.4.1.5 
Sensitivity Analyses 
In case of any uncorrected nicotine concentration at T0 [uC0] greater than 5% of their 
uncorrected maximum value, a sensitivity analysis of the PK endpoints will be performed 
similarly to the main analysis, whereby data of these subjects for this specific study day 
will be excluded from the analysis. 

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12.4.1.6 
Supplementary Analysis 
No supplementary analysis is foreseen. 
12.5 Secondary Objectives  
12.5.1 
Secondary Objective 1 
To evaluate pharmacodynamic (PD) effects (subjective effects) of a single use of a THS 
with either a regular or a menthol stick or of a single CIG. Endpoints will be analysed by 
investigational product (IP). 
Descriptive statistics (n, mean, SD, CV%, SEM, minimum, Q1, median, Q3, maximum, 
and 95% CI of mean) VAS Craving assessment, VAS Liking assessment, and VAS 
Intention to Use Again assessment will be provided by IP and assessment time point, when 
applicable. Change from baseline (pre-product use) for VAS Craving score will be 
summarized by study product and assessment time point. Individual responses will be 
listed. Summaries will be further stratified by sex.  
12.5.2 
Secondary Objective 2 
This analysis refers to the secondary objective 2 defined in Section 3.2, which is to evaluate 
the safety of test products during the study. 
In general, all safety data will be listed and tabulated. Safety variables collected during 
exposure periods will also be reported by randomization sequence. 
AE data will serve for the assessment of safety. Other safety variables monitored in this 
study will include the incidence of THS product events including malfunction/misuse; vital 
signs (systolic and diastolic blood pressure, pulse rate, respiratory rate); spirometry; ECG 
data; clinical chemistry, hematology, and urine analysis safety panel; physical examination; 
concomitant medication.  
The number and percentage of subjects with AEs, SAEs, and IP events will be tabulated by 
system organ class and preferred term. Summaries will also be presented for AEs leading 
to discontinuation, AEs leading to death, AEs by relatedness to product exposure, AEs by 
severity, and laboratory AEs. Tabulations will be performed for both the number of subjects 
experiencing an event and the number of events. 
Safety laboratory assessments are performed on Day -1 and Day 3 in the morning prior to 
product use (Appendix A). Any lab related AEs on Day 3 will be assigned to the product 
used on the previous day. 
Summary tables showing actual values and change from baseline of clinical findings will 
be provided for spirometry, ECGs, vital signs, and laboratory parameter. Descriptive 
statistics will be summarized by study day for ECG, vital signs and for laboratory 
parameters. 

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12.6 Interim Analysis 
No interim analysis is foreseen in this study. 
12.7 Measures to Control Bias 
12.7.1 
Blinding 
A certain level of blinding, for study statisticians and study scientists (CRO personnel 
which will be author of the body SAP), will be required before the body SAP, document 
describing all the analysis, will be finalized, and signed. 
Table 11 
Blinding Scheme 
Blinded Study Personnel 
End of Blinding Period 
PMP and CRO Study Statisticians After the SAP finalization. Can be actively un-
blinded when appropriate. 
PMP and CRO Clinical Scientist 
After the SAP finalization. Can be actively un-
blinded when appropriate. 
12.7.2 
Multiple Testing Procedures 
Not applicable. 
12.7.3 
Determination of Sample Size and Power Consideration 
In this study 30 subjects will be randomized to 6 product use sequences, i.e., all full 
crossover sequences for three investigational products (THS regular, THS menthol and 
CIG). This sample size is empirically based as there are no considerations for statistical 
hypothesis. 
In an analysis of confidence interval precision on the THS / CIG Cmax ratios, performed 
with SAS 9.4 using 10,000 simulations. 
The precision of Cmax ratios has been determined to be of 0.191 or less. 
12.7.3.1 Assumptions 
The precision has been determined using the following geometric mean (GeoM), 
geometric coefficient of variation (GCV) and within subject correlation assumptions for 
Cmax: 
•  The GeoM of Cmax is assumed to be 10, 12, 14 ng/mL for THS menthol, THS 
regular and CIG respectively with a common GSD of 0.8. These are derived from 
the following study results. 

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Study 
ZRHM-PK-06-US 
ZRHM-PK-05-JP 
ZRHR-PK-01-EU 
ZRHR-PK-02-JP 
Product 
THS 
CIG 
THS 
CIG 
THS 
CIG 
THS 
CIG 
GeoMean 
(Stat Desc) 
7.4 
13.8 
10.7 
12.09 
9.62 
12.42 
14.3 
13.82 
GeoCV % 
(Stat Desc) 
99.83 
97.35 
171.0 
87.71 
84.26 
56.13 
82.82 
84.00 
 
12.7.3.2 Method 
The analysis of confidence interval precision on the THS / CIG Cmax ratios has been 
implemented using SAS version 9.4, simulating 10000 sets of log-transformed data for 30 
subjects with the assumptions described in section 12.7.3.1, and the 6 sequences of this full 
cross-over design. 
The statistical analysis has been performed with a linear model with repeated measurement 
including as fixed effect the sequence, the period, and the product exposure. 
The THS / CIG Cmax ratios and related confidence intervals have been determined by using 
the exponential of the difference between THS variants and CIG on the log-transformed 
data. 
Then precision has been determined as the 90th percentile of the 95% confidence interval 
of the THS / CIG Cmax ratios. 

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13 Administrative Considerations 
13.1 Study Administrative Structure 
13.1.1 
Sponsor 
The list of Sponsor personnel will be provided as a separate document. 
13.1.2 
List of Principal Investigators and Sites 
The list of principal investigators and sites will be provided as a separate document. 
13.2 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects' state 
of health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subject in writing and signed by the subject, in compliance with all local 
and national data protection and privacy legislation. 
The anonymity of subjects participating in this study will be maintained. Subjects will be 
identifiable by the Sponsor (or Sponsor’s authorized representative) on CRFs and other 
documents by their subject (or randomization) number/code, sex, and date of birth, but not 
by name, initial, or any other details relating to identifiable person (e.g., address, social 
security number, medical chart number, etc.). The assignment of a subject number/code for 
subject identification will be based on the appropriate data protection rules. 
Any documents that allow full identification of the subject (e.g., the subject’s signed ICF) 
must be maintained in confidence by the Principal Investigator or designee. If any 
document relating to this study shows a subject’s name or any other details relating to an 
identifiable person (e.g., address, social security number, medical chart number, etc.), the 
name or other identifiable details must be obscured before a copy of that document is 
supplied to the Sponsor or the Sponsor’s authorized representative. 
13.3 Access to Source Documents 
Subjects will be informed that, during as well as after the course of the clinical study, the 
Sponsor, any authorized representatives of the Sponsor, IEC, or regulatory authorities may 
inspect their medical records to verify the information collected and ensure that all personal 
information made available for inspection is handled in the strictest confidence and in 
accordance with national and local data protection and privacy legislation. 

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The PI(s) and all study site staff involved with the study must permit direct access to source 
data/documents for study related monitoring, audits, IEC review, and regulatory 
inspection(s). 
13.4 Record Retention 
All records of data, source data and source documents (original records or certified copies), 
in any form (including, but not limited to, written, electronic, magnetic, optical records and 
scans, ECGs) that describe or record the methods, conduct, and/or results of the study, the 
factors affecting the study, and the actions taken will be maintained by the 
Investigator/study site for the study, as required by ICH GCP [22] and any other applicable 
local or national regulations. 
Essential study documents/records, which individually and collectively permit evaluation 
of the conduct of a study and the quality of the data produced, are described in Section 8 of 
the ICH Tripartite Guideline for Good Clinical Practice [22]. 
Essential documents must be retained by the Investigator for a minimum of: 
• At least 15 years after completion or discontinuation of the study, or 
• At least 2 years depending on, for example, the circumstances. 
• After formal discontinuation of clinical development of the IP. 
These documents should be retained for a longer period, however, if required by applicable 
regulatory requirements or by an agreement with the Sponsor. 
Examples of essential records/documents include, but are not limited to: 
• Signed informed consent documents for all subjects and master ICF. 
• Subject identification code list, screening log, and enrollment log (if applicable). 
• Record of all communications between the Investigator and the IEC, composition 
of the IEC. 
• Record of all communications/contact between the PI(s) or designee(s), Sponsor, 
and its authorized representatives. 
• List of sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles 
in the study, curricula vitae, and their signatures. 
• Investigator logs. 
• CRFs, study specific questionnaires (and associated data/scoring), subject diaries. 

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• AE reports and details of follow-up investigations, details of concomitant 
medication. 
• All other source documents (e.g., ECGs, consultation reports, physical examination, 
laboratory records) or any electronically captured study source data. 
• Clinical laboratory reports, laboratory normal ranges. 
• Original medical/hospital records, if applicable (the medical files of study subjects 
must be retained in accordance with local legislation and in accordance with the 
maximum period of time permitted by the hospital or study site). 
• Record of any body fluids or tissue samples collected and retained. 
• Device issue log, IP accountability logs, dispensing records. 
• Information regarding subjects’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the PI(s)/study site(s) as to when these 
documents no longer need to be retained. 
The PI/study site must take measures to prevent accidental or premature destruction of these 
documents. 
If the PI wishes to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
The PI or designee(s) must obtain written approval from the Sponsor before destruction of 
any records. Normally, these records will be held in the archives of the PI. If the PI is unable 
to meet this obligation, he/she must ask the Sponsor for permission to make alternative 
arrangements. Details of these arrangements must be documented. 
The Sponsor or Sponsor’s authorized representative will maintain documentation relating 
to the study as long as the IP is on the market, and/or for 15 years after the CSR has been 
finalized. 
13.5 Clinical Study Report 
The Sponsor must ensure that a Clinical study report (CSR) for this study is prepared 
regardless of whether the study is completed or prematurely terminated. 
The CSR will be written based on standards of the ICH Guideline for the structure and 
content of clinical study reports. In certain circumstances, an abbreviated CSR may be 
acceptable. Submission of the CSR to the IEC will be complied with as requested by local 
requirements. 
The results of the additional variables for analysis will be presented in reports separate from 
the study CSR. 

Philip Morris Products S.A. 
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Document ID: VV-TMF-11280 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets 
and confidential commercial information, and the legal protections provided to such trade 
secrets and confidential information are hereby claimed under the provisions of applicable 
law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
13.6 Financial Disclosure 
The PI is required to provide financial disclosure information to the Sponsor. In addition, 
the PI must provide to the Sponsor a commitment to promptly update this information if 
any relevant changes occur during the investigation and for 1 year following the completion 
of the study. 
13.7 Publication and Disclosure Policy 
This document contains information that is confidential and proprietary to the Sponsor. 
This information is being provided solely for the purpose of evaluation and/or conducting 
this clinical study for the Sponsor. Disclosure of the content of this document is allowed 
only to study personnel, IEC, or duly authorized representatives of regulatory agencies for 
this purpose under the condition that confidentiality is maintained. The contents of this 
document may not be used in any other clinical study, disclosed to any other person or 
entity without the prior written permission of the Sponsor. The foregoing shall not apply to 
disclosure required by any regulations; however, prompt notice will be given to the Sponsor 
prior to any such disclosure. 
The Sponsor plans to disclose details of the study protocol on a web-based, publicly 
available, clinical trial register database (e.g., ClinicalTrials.gov). 
13.8 Insurance 
The Sponsor is responsible for AEs and health damage to patients associated with the 
products that are used during the study, except for AEs and health damage to patients 
caused by a negligent or an intentional misconduct and/or significant deviation to the 
protocol of the Investigator or the clinical study site or the patients. The Sponsor has taken 
out insurance to cover any bodily injury and property damage caused by the operations 
carried out by the insured. 

Philip Morris Products S.A. 
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Confidential 
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Document ID: VV-TMF-11280 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets 
and confidential commercial information, and the legal protections provided to such trade 
secrets and confidential information are hereby claimed under the provisions of applicable 
law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
14 Reference List 
1. 
ICH E6(R2), Guideline for good clinical practice. 2016. Available from: 
https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-r2-
guideline-good-clinical-practice-step-5_en.pdf (Accessed on 17 January 2010). 
2. 
World Medical Association (WMA), Declaration of Helsinki - Ethical principles 
for medical research involving human subjects. 2013. Available from: 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-
principles-for-medical-research-involving-human-subjects/ (Accessed on 12 
July 2018). 
3. 
FDA (Food and Drug Administration), Guidance for industry - Modified risk 
tobacco product applications - Draft Guidance. 2012. 
4. 
U.S. Department of Health and Human Services, The health consequences of 
smoking - 50 years of progress: a report of the Surgeon General - Executive 
summary. 2014. 
5. 
WHO Study Group, et al., WHO study group on tobacco product regulation - 
Report on the scientific basis of tobacco product regulations: fifth report of a WHO 
study group. 2015. 
6. 
Philip Morris Products S.A., Unpublished on file data: Investigator's Brochure for 
the Tobacco Heating Systems. Edition 1. 2022. 
7. 
Raw, M., et al., WHO Europe evidence based recommendations on the treatment of 
tobacco dependence. Tob Control, 2002. 11(1): p. 44-6. 
8. 
Helen, G.S., et al., Nicotine delivery, retention and pharmacokinetics from various 
electronic cigarettes. Addiction, 2015: p. 535-544. 
9. 
Helen, G.S., et al., Impact of e-liquid flavors on nicotine intake and pharmacology 
of e-cigarettes. Drug and alcohol dependence, 2017. 178: p. 391-398. 
10. 
Ebajemito, J.K., et al., A randomised controlled single-centre open-label 
pharmacokinetic study to examine various approaches of nicotine delivery using 
electronic cigarettes. Scientific reports, 2020. 10(1): p. 1-10. 
11. 
Voos, N., et al., Effect of e-cigarette flavors on nicotine delivery and puffing 
topography: results from a randomized clinical trial of daily smokers. 
Psychopharmacology, 2020. 237(2): p. 491-502. 
12. 
Fagerström, K.O., Measuring degree of physical dependence to tobacco smoking 
with reference to individualization of treatment. Addict Behav, 1978. 3(3-4): p. 
235-41. 
13. 
Heatherton, T.F., et al., The Fagerström test for Nicotine Dependence: a revision 
of the Fagerström Tolerance Questionnaire. Br J Addict, 1991. 86(9): p. 1119-27. 
14. 
Moyses, C., A. Hearn, and A. Redfern, Evaluation of a novel nicotine inhaler 
device: part 2-effect on craving and smoking urges. Nicotine Tob Res, 2015. 17(1): 
p. 26-33. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P1-PK-12 
2.0, Approved 
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Document ID: VV-TMF-11280 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets 
and confidential commercial information, and the legal protections provided to such trade 
secrets and confidential information are hereby claimed under the provisions of applicable 
law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
15. 
FDA (Food and Drug Administration), Guidance for industry - Assessment of abuse 
potential of drugs. 2017. 
16. 
Vansickel, A., et al., Human abuse liability assessment of tobacco and nicotine 
products: approaches for meeting current regulatory recommendations. Nicotine 
& Tobacco Research, 2021. 24(3): p. 295-305. 
17. 
FDA (Food and Drug Administration), Food-effect bioavailability and fed 
bioequivalence studies. 2002. 
18. 
Miller, M.R., et al., Standardisation of spirometry. Eur Respir J, 2005. 26(2): p. 
319-38. 
19. 
Graham, B.L., et al., Standardization of spirometry 2019 update. An official 
American Thoracic Society and European Respiratory Society technical statement. 
Am J Respir Crit Care Med, 2019. 200(8): p. e70-e88. 
20. 
Hu, G. and P.A. Cassano, Antioxidant nutrients and pulmonary function: the Third 
National Health and Nutrition Examination Survey (NHANES III). Am J Epidemiol, 
2000. 151(10): p. 975-81. 
21. 
Fagerstrom, K., et al., The Fagerstrom Test for Nicotine Dependence as a predictor 
of smoking abstinence: a pooled analysis of varenicline clinical trial data. Nicotine 
and Tobacco Research, 2012. 14(12): p. 1467-73. 
22. 
ICH E6 (R1), Guideline for Good Clinical Practice. 1996. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Eff
icacy/E6/E6_R1_Guideline.pdf (Accessed on 14 August 2014). 
23. 
Benowitz, N.L., J. Hukkanen, and P. Jacob, 3rd, Nicotine chemistry, metabolism, 
kinetics and biomarkers. Handbook of Experimental Pharmacology, 2009(192): p. 
29-60. 
24. 
Committee for Medicinal Products for Human Use (CHMP) and European 
Medicines Agency (EMA), Guideline on the investigation of bioequivalence 
(CPMP/EWP/QWP/1401/98 Rev.1/Corr). 2010. 
25. 
FDA (Food and Drug Administration), Guidance for industry - Statistical 
approaches 
to 
establishing 
bioequivalence. 
2001. 
Available 
from: 
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070244.pdf (Accessed 
on 24 April 2014). 
26. 
Hodges, J.L. and E.L. Lehmann, Estimation of location based on ranks tests. Annals 
of Mathematical Statistics, 1963. 34(2): p. 598-611. 
  

Philip Morris Products S.A. 
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Document ID: VV-TMF-11280 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets 
and confidential commercial information, and the legal protections provided to such trade 
secrets and confidential information are hereby claimed under the provisions of applicable 
law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
Appendices 
 

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Document ID: VV-TMF-11280 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, 
and the legal protections provided to such trade secrets and confidential information are hereby claimed under the provisions of 
applicable law. No part of this document may be publicly disclosed without the written consent of Philip Morris Products S.A 
Appendix A Schedule of Events 
Study Assessments  
 
Screening 
Baseline 
Exposure  
Safety Follow-up 
Visit 
1 
2 
Early 
Termination 
Phone contact 
Study Day (D) 
Day -28 to Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
 
+ 3 Days 
Informed consent 
● 
 
 
 
 
 
 
FTND 
● 
 
 
 
 
 
 
Information on risks of smoking, smoking 
cessation advice, and briefing on THS 
● 
● 
 
 
● 
● 
 
TNP use history questionnaire  
● 
● 
 
 
 
 
 
Inclusion/exclusion criteria 
● 
● 
 
 
 
 
 
ECG 
● 
● 
 
 
● 
● 
 
Spirometry 
● 
● 
 
 
● 
● 
 
Demographics 
● 
 
 
 
 
 
 
Medical history 
● 
 
 
 
 
 
 
Concomitant diseases and medication 
● 
● 
● 
● 
● 
● 
 
Physical examination 
● 
 
 
 
 
 
 
Body height, body weight, BMI 
● 
 
 
 
 
 
 
Vital signs 
● 
● 
● 
● 
● 
● 
 
B: HIV, HBV, and HCV 
● 
 
 
 
 
 
 
Identification of CIG brand 
● 
 
 
 
 
 
 

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Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, 
and the legal protections provided to such trade secrets and confidential information are hereby claimed under the provisions of 
applicable law. No part of this document may be publicly disclosed without the written consent of Philip Morris Products S.A 
 
Screening 
Baseline 
Exposure  
Safety Follow-up 
Visit 
1 
2 
Early 
Termination 
Phone contact 
Study Day (D) 
Day -28 to Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
 
+ 3 Days 
U: Drug screen 
● 
● 
 
 
 
 
 
U: Cotinine test 
● 
● 
 
 
 
 
 
U: Pregnancy test 
● 
● 
 
 
● 
● 
 
Alcohol breath test 
● 
● 
 
 
 
 
 
B & U: Safety laboratory panel (non-fasting Day 3 + ET) 
● 
● 
 
 
● 
● 
 
THS demonstration (without use) 
● 
 
 
 
 
 
 
Randomization 
 
● 
 
 
 
 
 
IP use (THS or CIG) 
 
 
● 
● 
● 
 
 
B: plasma nicotine samples   
 
 
● 
● 
● 
 
 
VAS Craving assessment  
 
 
● 
● 
● 
 
 
VAS Liking assessment 
 
 
● 
● 
● 
 
 
VAS Intention to Use Again assessment  
 
 
● 
● 
● 
 
 
AE/SAE recording 
● 
● 
● 
● 
● 
● 
●  
Product events, malfunctions, misuse 
 
 
● 
● 
● 
● 
 
Phone call at end of SFU period 
 
 
 
 
 
 
● 
Abbreviations:  
AE = Adverse event; B: Blood sample required; BMI = Body mass index; CIG = Combustible cigarette(s); ECG = Electrocardiogram; ET = Early termination; FTND = 
Fagerstroem test for nicotine dependence; HBV = Hepatitis B virus; HCV = Hepatitis C virus; HIV = Human immunodeficiency virus; SAE = Serious adverse event; THS = 
Tobacco Heating System; U = Urine sample required; VAS = Visual analog scale 

Philip Morris Products S.A. 
Clinical Study Protocol 
 
Confidential 
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2.0, Approved 
Page 87 of 89 
Related to QMS-0017588 
 
Document ID: VV-TMF-11280 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
Appendix B Participating Laboratories  
 
Safety Laboratory 
 
 
 
 
 
Bioanalytical Laboratory 
 
 
 
 
 
 
 

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Confidentiality Statement 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
Appendix C FTND Scoring Manual 
Scoring procedure (FTND_TS2.0 (AU2.0))  
Test for Nicotine Dependence (UK-English)  
 
FTND Question  
Answer  
Score  
1  How soon after you wake up do you 
smoke your first cigarette?  
Within 5 minutes  
6 to 30 minutes  
31 to 60 minutes  
After 60 minutes  
3  
2  
1  
0  
2  Do you find it difficult to refrain from 
smoking in places where it is 
forbidden?  
Yes  
No  
1  
0  
3  Which cigarette would you hate most 
to give up?  
The first one in the morning  
Any other  
1  
0  
4  How many cigarettes per day do you 
smoke?  
10 or less  
11 to 20 
21 to 30  
31 or more  
0  
1  
2  
3  
5  Do you smoke more frequently during 
the first hours after awakening than 
during the rest of the day?  
Yes  
No  
1  
0  
6  Do you smoke if you are so ill that you 
are in bed most of the day?  
Yes  
No  
1  
0  
The FTND total score is derived by summing the individual item scores if all items are non-
missing, otherwise the total score is set to missing. For the FTND total score, descriptive 
statistics and frequency tables according to the following classification are provided 
(Fagerström et al. 2012): Mild [0 – 3 points]; Moderate [4 – 6 points]; Severe [7 – 10 points]. 

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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
Appendix D Questionnaire scoring rules 
VAS Craving Assessment 
Cigarette craving will be evaluated using a one-item self-reported VAS Craving assessment 
[14], asking subjects to rate craving for cigarettes (How strong is your craving for cigarettes?), 
on a 100 mm unipolar scale, ranging from 0 (no craving) to 100 (strong craving). 
Prior to T0 
• TV0: within 15 minutes prior to T0  
After T0 
• TV1 after 4 minutes (± 2 minutes) 
• TV2 after 10 minutes (± 2 minutes) 
• TV3 after 15 minutes (± 2 minutes) 
• TV4 after 30 minutes (± 2 minutes) 
• TV5 after 10 hours (± 5 minutes) 
VAS Liking Assessment 
Liking will be evaluated using a one-item self-reported VAS Liking assessment, asking 
subjects to rate liking for the product (Overall, my liking for this product is:) on a 100 mm 
bipolar scale, ranging from 0 (strong disliking) to 100 (strong liking), with a neutral middle 
point, as recommended in the FDA guidance for industry on abuse liability assessment [15]. 
• Tv3 after 15 minutes (± 1 minute) 
VAS Intention to Use Again Assessment 
Intention to use the product again will be evaluated using a one-item self-reported VAS [16], 
asking subjects to rate intention to use product again (How likely are you to use this product 
again) on a 100 mm bipolar scale, ranging from 0 (very unlikely) to 100 (very likely), with a 
neutral middle point. 
• Tv3 after 15 minutes (± 1 minute) 

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