A Randomized, Controlled, Open-label, 4 Parallel Arms Study to Demonstrate Reductions in Exposure to Selected Harmful and Potentially Harmful Constituents (HPHC) of Cigarette (CIG) Smoke in Healthy Smokers Switching to Different Versions of Tobacco Heating System (THS) Compared to Continuing CIG Smoking, for 5 Days in Confinement
Phase: NA
Conditions: Smoking, Tobacco Smoking, Tobacco Use
Sponsor: Philip Morris Products S.A.

 
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Clinical Study Protocol 
 
Study Number: 
P1-REXC-10 
Study Title: 
A randomized, controlled, open-label, 4 parallel 
arms study to demonstrate reductions in exposure to 
selected harmful and potentially harmful constituents 
(HPHC) of cigarette (CIG) smoke in healthy smokers 
switching to different versions of Tobacco Heating 
System (THS) compared to continuing CIG 
smoking, for 5 days in confinement 
Short title: 
Reduced exposure to HPHC in smokers switching 
from cigarettes to different versions of THS 
Product Name: 
THS Blade device 
THS Induction Mono device 
THS Induction Mid device 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 3 
2000 Neuchâtel, Switzerland 
Version: 
2.0, 
Approved 
Date: 
15 Jul 2022 
Authors: 
, PhD, Clinical Scientist 
, PhD, Biostatistician  
 MD, MSc, Medical Safety Officer 
 
 
 

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Clinical Study Protocol 
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VERSION HISTORY 
 
Version 
Date 
Protocol Update / 
Amendment 
Original Document 
1.0 
31 Mar 2022 
Not applicable 
2.0 
15 Jul 2022 
Update 
 
 
 

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Synopsis 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 3 
2000 Neuchâtel 
Switzerland 
Name of Investigational Products: 
THS Blade device 
THS Induction Mono device 
THS Induction Mid device 
Subjects’ own cigarette brands 
Study Title: 
A randomized, controlled, open-label, 4 parallel arms study to demonstrate reductions in 
exposure to selected harmful and potentially harmful constituents (HPHC) of cigarette 
(CIG) smoke in healthy smokers switching to different versions of Tobacco Heating 
System (THS) compared to continuing CIG smoking, for 5 days in confinement 
Study Number: 
P1-REXC-10 
Short Title: 
Reduced exposure to HPHC in smokers switching from cigarettes to different versions 
of THS 
Primary Objective and Endpoints: 
The primary objective is the joint evaluation of the following hypotheses:  
1. To demonstrate the reduction of biomarkers of exposure (BoExp) to selected 
harmful and potentially harmful constituents (HPHC) detailed in Table 1 in smokers 
switching from CIG to THS Blade device compared to continuing CIG smoking for 
5 days. 
2. And to demonstrate the reduction of BoExp to selected HPHC detailed in Table 1 in 
smokers switching from CIG to THS Induction Mono device compared to 
continuing CIG smoking for 5 days. 

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3. And to demonstrate the reduction of BoExp to selected HPHC detailed in Table 1 in 
smokers switching from CIG to THS Induction Mid device compared to continuing 
CIG smoking for 5 days. 
Table 1 
List of BoExp Used in the Primary Objective 
BoExp 
HPHC 
Matrix 
3-hydroxypropyl mercapturic acid (3-HPMA) 
Acrolein 
Urine1  
2-cyanoethyl mercapturic acid N-acetyl-S-(2-
cyanoethyl)-L-cysteine (2-CyEMA) 
Acrylonitrile 
Urine1 
Monohydroxybutenyl mercapturic acid 
(MHBMA) 
1,3-butadiene 
Urine1 
Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanol (total NNAL) 
4-(methylnitrosamino)-
1-(3-pyridyl)-1-
Urine1 
Carboxyhemoglobin (COHb) 
Carbon monoxide (CO) 
Blood2 
1BoExp in urine will be expressed as concentration adjusted for creatinine in 24-hour urine; 
2BoExp in blood expressed as % of saturation of hemoglobin. 
Secondary Objectives and Endpoints: 
Key secondary objectives 
1. To demonstrate the reduction of BoExp to selected HPHC detailed in Table 2 in 
smokers switching from CIG to THS Blade device compared to continuing CIG 
smoking for 5 days.  
2. To demonstrate the reduction of BoExp to selected HPHC detailed in Table 2 in 
smokers switching from CIG to THS Induction Mono device compared to 
continuing CIG smoking for 5 days.  
3. To demonstrate the reduction of BoExp to selected HPHC detailed in Table 2 in 
smokers switching from CIG to Induction Mid device compared to continuing CIG 
smoking for 5 days. 
Table 2 
List of BoExp Used in the Key Secondary Objective 
BoExp 
HPHC 
Matrix  
S-phenylmercapturic acid (S-PMA) 
Benzene 
Urine1  
2-hydroxyethylmercapturic acid (2-HEMA) 
Ethylene oxide 
Urine1 

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3-hydroxy-1-methylpropylmercapturic acid (3-
HMPMA) 
Crotonaldehyde 
Urine1 
Total N-nitrosonornicotine (total NNN) 
N-nitrosonornicotine 
Urine1 
Total 3-hydroxybenzo(a)pyrene (3-OH-B[a]P) 
Benzo(a)pyrene 
Urine1 
4-aminobiphenyl (4-ABP) 
4-aminobiphenyl 
Urine1 
2-aminonaphtalene (2-NA) 
2-aminonaphtalene 
Urine1 
1BoExp in urine expressed as concentration adjusted for creatinine in 24-hour urine 
Other Secondary objective  
1. To monitor the safety profile during the study. 
Endpoints  
• 
Incidents of adverse events (AEs) and serious adverse events (SAEs) 
• 
Incidence of Device malfunction and product complaints (e.g., events related to 
charger, holder, or sticks) 
• 
Vital sign changes from baseline (systolic and diastolic blood pressure, heart 
rate and respiratory rate)  
• 
Laboratory safety panel changes from baseline 
• 
Concomitant medication (ConMed)  
• 
Electrocardiogram (ECG) changes from baseline (heart rate, PR, QRS, QT and 
QTcF intervals) 
• 
Spirometry changes from baseline (forced expiratory volume in 1 second 
[FEV1], FEV1 % predicted, forced vital capacity [FVC]), FVC % predicted, 
FEV1/FVC) 
Exploratory Objectives and Endpoints:  
1. To describe the levels of nicotine over the exposure period in smokers switching 
from CIG to THS Blade device, Induction Mono device, or Induction Mid device, 
and in smokers continuing to smoke CIG.  
Endpoints (Day -1 to Day 5) 
• 
Nicotine equivalents (NEQ = molar sum of free nicotine, nicotine-glucuronide, 
free cotinine, cotinine-glucuronide, free trans-3’-hydroxycotinine, trans-
3’hydroxy-cotinine-glucuronide) in 24-hour urine (concentration adjusted for 
creatinine). 
2. To describe daily tobacco product use over the exposure period in smokers 
switching from CIG to THS Blade device, Induction Mono device, or Induction Mid 
device, compared to continuing CIG smoking. 

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Endpoints (Day -1 to Day 5) 
• 
Number of CIG/day 
• 
Number of sticks/day 
3. To describe product experience in smokers switching from CIG to THS Blade 
device, Induction Mono device, or Induction Mid device compared to smokers 
continuing CIG smoking. 
Endpoints (Day -1 to Day 5) 
• 
Subscale scores of Product Experience (ABOUT–Product Experience) 
questionnaire 
The estimands requested as per ICH guidelines [1] for all objectives will be described in 
the corresponding statistical protocol sections. 
Study Hypothesis: 
The primary hypothesis tested in this study is that BoExp considered for the primary 
objective will be significantly reduced for each THS variant (Blade device, or Induction 
Mono device, or Induction Mid device, respectively) in subjects who adhere to switching 
for 5 days to using THS, compared to subjects continuing CIG smoking.  
A set of key secondary hypothesis based on a set of BoExp considered for secondary 
objectives will be tested using a hierarchical approach to show significant reduction in 
subjects who adhere switching for 5 days to one of the THS variants (Blade device, 
Induction Mono device, or Induction Mid device) compared to subjects continuing CIG. 
Study Design: 
This is a randomized, controlled, open-label, 4 parallel arms study with a stratified 
randomization by sex (a quota for each sex (females and males) of at least 40% overall). 
This is an ad libitum use/smoking study. During confinement, in general, THS use and 
CIG consumption (according to randomization) will be allowed between 06:30 AM and 
11:00 PM.  
During the confinement period, adherence to product arm allocation (exclusive use of 
THS Blade device, or Induction Mono device, or Induction Mid device, or CIG) will be 
ensured by strict distribution of the devices, and of each stick/CIG upon demand of the 
subject to the site staff. 

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Figure 1 
Study Design 
Screening period (from Day -30 to Day -3, prior to admission): 
The screening period covers up to four weeks prior to admission. A demonstration of 
the THS Blade device, Induction Mono device, and Induction Mid device will be 
done by the site staff during the Screening visit. Screening procedures do not 
necessarily have to be conducted on the same day. All subjects will receive 
information on the risks of smoking, smoking cessation advice, and briefing on THS. 
Eligible subjects will return to the investigational site for verification of eligibility at 
Admission. 
Admission (admission on Day -2 until 06:29 AM of Day -1): 
Subjects will be in a confinement setting for 7 days from Day -2 onwards.  
Subjects will be enrolled if all eligibility criteria are met. Only adult subjects willing 
and able to use the products will be enrolled in the study. 

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CIG smoking will be allowed ad libitum from the time of admission of the subject 
until approximately 11:00 PM of Day -2, except before/during assessments requiring 
smoking breaks. Use of any tobacco and/or nicotine containing product (TNP) other 
than CIG (and THS Blade device and Induction Mono device for the product test) 
will not be allowed on Day -2 after admission. 
On Admission Day -2, as the last procedure of the eligibility assessments, subjects 
will have a product test of the THS Blade device and Induction Mono device (use of 
up to three sticks per device), prior to enrolment. In female subjects, the THS product 
tests will only be performed once pregnancy is excluded by a negative pregnancy test. 
After the product test, subjects not willing to use THS during the study will be 
discontinued and will be replaced. Subjects willing to continue participation will start 
their confinement period. 
Baseline (Day -1, 06:30 AM until Day 1, 06:29 AM): 
Subjects may continue smoking their CIG ad libitum, except before/during 
assessments requiring smoking breaks. The 24-hour urine collection for Day -1 will 
start in the morning of Day -1 (details provided in Appendix A). Baseline assessments 
will be performed as indicated in Appendix A. 
Eighty subjects will be randomized to one of the 4 study arms in a 1:1:1:1 ratio using 
a stratified randomization by sex with a minimum of 40% of each sex (male and 
female) overall: 
• 
THS Blade device: ad libitum use of Blade Regular sticks. 
• 
THS Induction Mono device: ad libitum use of the Induction Regular sticks. 
• 
THS Induction Mid device: ad libitum use of the Induction Regular sticks. 
• 
CIG: ad libitum use of their preferred regular CIG brand. 
Subjects will be informed of their randomized study arm by the study site staff on 
Day 1 prior to 06:30 AM.  
Exposure in confinement (Day 1, 06:30 AM until Day 5, 11:00 PM): 
The Exposure period will consist of 5 days of ad libitum use of the assigned 
investigational products (one out of the 3 versions of THS or CIG) between 06:30 AM 
and 11:00 PM. Use of any TNP other than the assigned investigational product will 
not be allowed and may, at the discretion of the Investigator(s), result in 
discontinuation of the subject from the study. 
Daily 24-hour urine will be collected from Day -1 to Day 5. On Day 1, product use 
must not start before the end of 24-hour urine collection of Day -1. The 24-hour urine 
collection period for Day 5 will end in the morning of Day 6 prior to discharge.    

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During the confinement period, site staff will distribute assigned investigational 
products to the subjects and record all products distributed in the source 
documentation.  
Discharge period (Day 5, 11:01 PM until Day 6, time of Discharge): 
Discharge procedures according to the schedule given in Appendix A will be 
conducted to complete the Discharge of the subject from the clinic after 7 days in a 
confined setting. Use of CIG will be allowed on Day 6 once all study procedures are 
completed.  
Safety follow-up (Day 6, time of Discharge, to Day 9): 
After Discharge on Day 6, subjects will enter a 3-day Safety follow-up period during 
which AEs/SAEs will be collected and follow-up of any ongoing AEs/SAEs will be 
conducted by the investigational site. The End of the study (EOS) is defined as the 
completion of the 3-day Safety follow-up period either after the Discharge on Day 6, 
or after Early termination. 
During the study, subjects in the CIG arm and the THS arms who want to quit smoking 
will receive appropriate medical advice and will be referred to a smoking cessation 
counsellor. This will not affect subject’s financial compensation, and the subject will 
remain in the study. 
Biobanking: 
If the subject consents, additional samples will be taken from the 24-hour urine collection 
for long-term biobanking (two years at most) in view of further measurements of BoExp 
and stored at the bioanalytical laboratory(Appendix B). 
Study Population and Main Criteria for Inclusion/Exclusion: 
A sufficient number of healthy adult female and male smokers who meet all the following 
inclusion and exclusion criteria will be enrolled into the study to ensure that 80 subjects 
will be randomized: 

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Inclusion Criteria 
Screening Day -2 
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 
X 
4. Subject has continuously smoked on average ≥10 
commercially available regular CIGs/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 
 
6. Subject does not plan to quit smoking within the next three 
months. 
X 
X 
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) during the Exposure period 
Subjects who meet any of the following exclusion criteria must not be enrolled into the 
study: 
Exclusion Criteria 
Screening  Day -2 
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 
 
2. Subject is legally incompetent, or physically or mentally 
incapable of giving consent (e.g., in emergency 
situations, under guardianship, prisoners).  
X 
 

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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 HCVa.   
X 
 
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 
 
11. The subject has a positive urine drug test.   
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 
 

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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 onlyc: subject does 
not agree to use an acceptable method of effective 
contraceptiond.   
X 
 
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 and Evaluation: 
In this study, 80 healthy adult smokers will be randomized in a 1:1:1:1 randomization 
ratio to:  
• 
THS Blade device arm 
• 
THS Induction Mono device arm 
• 
THS Induction Mid device arm  
• 
CIG arm  
This setting will provide more than 90% power to the trial to demonstrate a reduction for 
all BoExp tested in the primary objective for all THS study arms compared to the CIG 
arm, using a one-sided two-sample t-test with 2.5% type I error probability. This will 
also account for 15% data point loss due to missing, non-analyzable sample or major 
protocol deviation impacting evaluability of the primary objectives. This assumes, based 
on a similar study conducted by PMP S.A. (see ClinicalTrials.gov Identifier: 
NCT01959932), that the geometric mean ratio (GM) and the related geometric 
coefficient of variation (GCV) of the ratio between all the THS study arms and the CIG 
arm are the following: 

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• 
GMR = 23.45% and GCV = 16.84% for COHb at Day 5, 
• 
GMR = 41.63% and GCV = 26.10% for 3-HPMA at Day 5, 
• 
GMR = 13.16% and GCV = 34.41% for 2-CyEMA at Day 5, 
• 
GMR = 43.54% and GCV = 27.13% for total NNAL at Day 5, 
• 
GMR = 12.58% and GCV = 76.92% for MHBMA at Day 5. 
Investigational Products; Dose; and Mode of Administration: 
Investigational Products: 
Tobacco Heating System (THS) devices, together with corresponding sticks, will be 
provided by the sponsor, whereas for the CIG arm, subjects will provide their own supply 
of commercially available preferred single brand regular (non-mentholated) CIG, for the 
study duration: 
Investigational product  
Stick 
THS Blade device 
Blade Regular sticks 
THS Induction Mono device 
Induction Regular sticks  
THS Induction Mid device 
Induction Regular sticks 
CIG (Cigarette, non-mentholated) 
Not applicable 
During product testing on Day -2, subjects will be able to familiarize themselves with 
THS Blade device and THS Induction Mono device (considering that product experience 
with THS Induction Mono device will be very comparable to THS Induction Mid 
device). Only one variant of sticks will be tested (Regular). 
Duration of Study: 
The entire study duration per subject will be 12 to 39 days. This will include a Screening 
period of up to 28 days prior to Admission (Day -30 to Day -3), followed by a 7-day 
confinement period (Admission Day -2, Baseline Day -1, Exposure Day 1 to Day 5), 
followed by Discharge on Day 6, and a 3-day Safety follow-up period until and including 
Day 9. 
The End of the study (EOS) for a subject is defined as the completion of the 3-day Safety 
follow-up period either after the Discharge at Day 6, or after the Early termination of the 
subject. The end of the whole study corresponds to the EOS of the last subject.   

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Statistical Methods:  
Analysis Sets:  
The Full Analysis Set (FAS) will consist of all randomized subjects who have at least 
one post-randomization product use experience (if randomized to CIG or one of the THS 
arms) and who have at least one valid non-safety assessment. The FAS will be analyzed 
by randomized study arm.  
The Per Protocol Set (PP) will be a subset of FAS and will include all randomized subjects 
who fulfil key compliance criteria of the protocol and have no major protocol deviation 
impacting the evaluability of the primary objective. The PP will be analyzed by randomized 
study arm. 
The safety population (SAF) will consist of all the subjects enrolled in the study with at 
least one exposure to investigational product (product test at Admission Day -2), and 
who have at least 1 valid value for a safety assessment. The SAF will be analyzed 
according to actual exposure arm. 
Additional analysis sets may be defined in the SAP. 
Statistical Analysis: 
The BoExp tested in the primary objective (Table 1) will be analyzed using a linear 
mixed model for repeated measurements separately on the log scale for each THS study 
arm. A 1-sided pairwise test will compare in the PP set for each THS version the 
reduction in BoExp in subjects switching from CIG to THS, compared to continuing CIG 
smoking. 
Descriptive statistics will be presented at each timepoint, where applicable. Descriptive 
statistics will be presented for each arm separately.  
The other BoExp, including the ones related to key secondary objectives, will be 
analyzed using a similar model to the primary analysis. Product use and questionnaires 
will be summarized using descriptive statistics.  
Safety endpoints will be reported by list and descriptive statistics will be produced. AE 
data will serve for the assessment of the safety. 
 
 
 

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TABLE OF CONTENTS 
Version History .................................................................................................................... 2 
Synopsis ............................................................................................................................... 3 
Abbreviations and Definitions of Terms ............................................................................ 21 
Explanation of Terms ......................................................................................................... 24 
1. 
Ethics and Regulations ............................................................................................... 26 
1.1 
Independent Ethics Committee (IEC) Approval .................................................. 26 
1.2 
Ethical Conduct of the Study ............................................................................... 27 
1.3 
Subject Information and Consent ........................................................................ 27 
1.3.1 
Informed Consent Form for Study Participation ......................................... 27 
1.3.2 
Amendment to the Informed Consent Form ................................................ 28 
1.4 
Good Clinical Practice and Regulatory Requirements ........................................ 28 
2 
INTRODUCTION ..................................................................................................... 29 
2.1 
Background .......................................................................................................... 29 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy .......................... 29 
2.1.2 
Description of the Product and Scientific Findings ..................................... 29 
2.2 
Anticipated Benefits and Risks ............................................................................ 30 
2.2.1 
Anticipated Benefits..................................................................................... 30 
2.2.2 
Anticipated Foreseeable Risks due to Study Procedures ............................. 30 
2.2.3 
Anticipated Foreseeable Risks due to Investigational Products .................. 30 
2.2.4 
Unforeseeable Risks..................................................................................... 31 
3 
Study Objectives ........................................................................................................ 32 
3.1 
Primary Objective ................................................................................................ 32 
3.2 
Key Secondary Objectives ................................................................................... 32 
3.3 
Other Secondary Objective .................................................................................. 33 
3.4 
Exploratory Objectives ........................................................................................ 34 
4 
Investigational Plan .................................................................................................... 35 
4.1 
Overall Study Design and Plan ............................................................................ 35 
4.2 
Rationale for Study Design .................................................................................. 37 
4.3 
Appropriateness of Measurements ...................................................................... 38 
4.4 
Study Duration ..................................................................................................... 39 
5 
Study Population ........................................................................................................ 40 
5.1 
Selection of Study Population ............................................................................. 40 

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5.1.1 
Inclusion Criteria ......................................................................................... 40 
5.1.2 
Exclusion Criteria ........................................................................................ 41 
5.2 
Discontinuation of Subjects from the Study ........................................................ 42 
5.3 
Lost to Follow-up ................................................................................................ 44 
5.4 
Violation of Selection Criteria ............................................................................. 44 
6 
Investigational Products ............................................................................................. 45 
6.1 
Description of Investigational Products ............................................................... 45 
6.1.1 
Investigational Product: Tobacco Heating Systems .................................... 45 
6.1.2 
Investigational Product / Baseline Product: Cigarettes ................................ 45 
6.1.3 
Packaging and Labelling .............................................................................. 45 
6.2 
Use of Investigational Product(s) ........................................................................ 46 
6.2.1 
Admission Day (Day -2 to Day -1) .............................................................. 46 
6.2.2 
Baseline Period (Day -2 to Day -1) .............................................................. 46 
6.2.3 
Exposure Period (Day 1 to Day 5) ............................................................... 46 
6.2.4 
Day of Discharge (Day 6) ............................................................................ 46 
6.2.5 
Safety Follow-up Period .............................................................................. 46 
6.2.6 
Stopping Rules for Investigational Product ................................................. 47 
6.3 
Method for Assigning Subjects to Study Arms ................................................... 47 
6.4 
Blinding ............................................................................................................... 47 
6.5 
Investigational Product Accountability and Adherence ...................................... 47 
6.5.1 
Dispensing Investigational Products ............................................................ 47 
6.5.2 
Storage and Accountability .......................................................................... 48 
6.5.3 
Investigational Product Retention ................................................................ 48 
6.5.4 
Adherence to Investigational Products ........................................................ 48 
6.6 
Restrictions .......................................................................................................... 48 
6.6.1 
Smoking Restrictions ................................................................................... 48 
6.6.2 
Dietary Restrictions ..................................................................................... 49 
6.7 
Concomitant Medication ..................................................................................... 49 
7 
Study Procedures ....................................................................................................... 50 
7.1 
Informed Consent ................................................................................................ 50 
7.2 
Information on Smoking Risks, Smoking Cessation Advice, and THS Briefing 50 
7.3 
Clinical and Other Assessments .......................................................................... 51 

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7.3.1 
Demographic Data ....................................................................................... 51 
7.3.2 
Medical History, Concomitant Disease, Previous and Concomitant 
Medications ................................................................................................................ 51 
7.3.3 
Physical Examination................................................................................... 51 
7.3.4 
Body Height and Weight ............................................................................. 52 
7.3.5 
Vital Signs .................................................................................................... 52 
7.3.6 
Spirometry.................................................................................................... 52 
7.3.7 
Electrocardiogram ........................................................................................ 53 
7.3.8 
Biomarker Assessments ............................................................................... 53 
7.3.9 
Laboratory Assessments .............................................................................. 53 
7.3.10 Sample Handling, Storage, and Shipment ................................................... 54 
7.4 
Other Study Procedures ....................................................................................... 56 
7.4.1 
Demonstration of THS and Product Test ..................................................... 56 
7.5 
Questionnaires ..................................................................................................... 56 
7.5.1 
Tobacco/Nicotine Product Use History ....................................................... 56 
7.5.2 
Fagerström Test for Nicotine Dependence (Revised Version) .................... 56 
7.5.3 
ABOUT–Product Experience Questionnaire ............................................... 57 
8 
Adverse Events .......................................................................................................... 58 
8.1 
Definitions ........................................................................................................... 58 
8.1.1 
Adverse Events ............................................................................................ 58 
8.1.2 
Serious Adverse Events ............................................................................... 58 
8.1.3 
Conditions Existent Before the Start of the Period of Collection (ICF 
signature).................................................................................................................... 58 
8.2 
Collection and Reporting of Adverse Events ...................................................... 59 
8.2.1 
Collection of Information ............................................................................ 59 
8.2.2 
Period of Collection ..................................................................................... 59 
8.2.3 
Intensity of Adverse Event........................................................................... 59 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures .................................................................................................................. 60 
8.2.5 
Expectedness ................................................................................................ 60 
8.2.6 
Follow-up of Non-serious and Serious Adverse Events .............................. 60 
8.3 
Reporting Serious Adverse Events ...................................................................... 61 
8.4 
Reporting of Other Abnormal Findings ............................................................... 61 

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8.5 
Reporting and Follow-Up of Pregnancies ........................................................... 61 
8.5.1 Period of Collection and Follow-up .................................................................. 61 
8.5.2 Reporting of Pregnancies .................................................................................. 62 
8.6 
Adverse Events Leading to Discontinuation ....................................................... 62 
8.7 
Device Malfunction, Product Complaints and Misuse ........................................ 62 
9 
Study Activities .......................................................................................................... 63 
9.1 
Screening Period .................................................................................................. 63 
9.1.1 
Screening Visit (between Day -30 to Day -3) .............................................. 63 
9.2 
Baseline Period (Enrolment and Randomization) ............................................... 64 
9.2.1 
Admission Day -2 ........................................................................................ 64 
9.2.2 
Baseline Visit Day -1 ................................................................................... 65 
9.3 
Randomized Exposure Period .............................................................................. 66 
9.3.1 
Exposure in Confinement Period ................................................................. 66 
9.4 
Discharge ............................................................................................................. 67 
9.5 
Safety Follow-up Period ...................................................................................... 68 
9.6 
Early Termination Procedures ............................................................................. 68 
10 Quality Control and Quality Assurance ..................................................................... 70 
10.1 Monitoring ........................................................................................................... 70 
10.2 Training of Staff .................................................................................................. 70 
10.3 Audits and Inspections ......................................................................................... 71 
10.4 Risk Management ................................................................................................ 71 
11 Data Management Activities...................................................................................... 72 
11.1 Data Capture ........................................................................................................ 72 
11.1.1 Case Report Forms and Study Records ....................................................... 72 
11.1.2 Protocol Deviations ...................................................................................... 72 
11.1.3 Data Handling .............................................................................................. 73 
11.2.1 Data Verification .......................................................................................... 73 
11.2.2 Coding .......................................................................................................... 74 
11.2.3 Database Lock .............................................................................................. 74 
12 Planned Statistical Methods ....................................................................................... 75 
12.1 General Considerations ........................................................................................ 75 
12.1.1 Stratification Criteria ................................................................................... 75 

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12.1.2 Definitions for Statistical Data Analysis...................................................... 75 
12.1.3 Descriptive Statistics .................................................................................... 75 
12.1.4 Handling of Missing Values and of Values outside the Detection Limits ... 76 
12.2 Product Use .......................................................................................................... 76 
12.3 Analysis Sets ........................................................................................................ 76 
12.3.1 Screened Population..................................................................................... 76 
12.3.2 Full Analysis Set (FAS) ............................................................................... 76 
12.3.3 Per Protocol Set (PP) ................................................................................... 77 
12.3.4 Safety Set (SAF) .......................................................................................... 77 
12.4 Demographics and Baseline Characteristics ........................................................ 77 
12.5 Primary Objective ................................................................................................ 77 
12.5.1 Primary Estimand Analysis.......................................................................... 77 
12.5.2 Secondary Estimand Analysis ...................................................................... 80 
12.6 Secondary Objectives .......................................................................................... 82 
12.6.1 Key Secondary Objectives ........................................................................... 82 
12.7 Other Secondary Objective .................................................................................. 83 
12.8 Interim Analysis ................................................................................................... 84 
12.9 Measures to Control Bias ..................................................................................... 84 
12.9.1 Method for Assigning Subjects to Study Arms ........................................... 84 
12.9.2 Blinding........................................................................................................ 84 
12.9.3 Study Significance Level ............................................................................. 85 
12.9.4 Determination of Sample Size and Power Consideration ............................ 86 
13 Administrative Considerations................................................................................... 90 
13.1 Study Administrative Structure ........................................................................... 90 
13.1.1 Sponsor ........................................................................................................ 90 
13.1.2 List of Principal Investigators and Sites ...................................................... 90 
13.2 Subject Confidentiality ........................................................................................ 90 
13.3 Access to Source Documents ............................................................................... 90 
13.4 Record Retention ................................................................................................. 91 
13.5 Clinical Study Report .......................................................................................... 92 
13.6 Financial Disclosure ............................................................................................ 92 
13.7 Publication and Disclosure Policy ....................................................................... 92 

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13.8 Insurance .............................................................................................................. 93 
14 Reference List ............................................................................................................ 94 
Appendices ......................................................................................................................... 96 
Appendix A 
Schedule of Events ............................................................. 97 
Appendix B 
Participating Laboratories ................................................ 100 
Appendix C 
Clinical Laboratory Safety Panel ..................................... 101 
 
LIST OF IN-TEXT TABLES 
Table 1 
List of BoExp Used in the Primary Objective ................................. 4 
Table 2 
List of BoExp Used in the Key Secondary Objective ...................... 4 
Table 3 
List of BoExp Used in the Primary Objective ............................... 32 
Table 4 
List of BoExp Used in the Key Secondary Objective .................... 33 
Table 5 
Intensity of Adverse Events ........................................................... 59 
Table 6 
Time Schedule – Screening Visit ................................................... 63 
Table 7 
Time Schedule – Admission Day -2 .............................................. 65 
Table 8 
Time Schedule – Baseline Visit Day -1 ......................................... 66 
Table 9 
Time Schedule – Day 1, 2, 3, 4, and 5 ........................................... 66 
Table 10 
Time Schedule – Discharge Day 6 ................................................. 68 
Table 11 
Time Schedule – Early Termination Visit ..................................... 69 
Table 12 
Blinding Scheme ............................................................................ 85 
Table 13  
Power Computation for Primary Objective ................................... 87 
Table 14  
Power Computation for Key Secondary Objectives ...................... 88 
 
List of In-Text Figures 
Figure 1 
Study Design .................................................................................... 7 
Figure 2 
Study Design .................................................................................. 35 
Figure 3  
Representation of the Procedure of Fixed Sequence Testing ........ 83 
 
List of Appendices 
Appendix A 
Schedule of Events ......................................................................... 97 
Appendix B 
Participating Laboratories ............................................................ 100 
Appendix C 
Clinical Laboratory Safety Panel ................................................. 101 
 

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Abbreviations and Definitions of Terms 
Abbreviations  
2-CyEMA 
2-Cyanoethyl mercapturic acid N-Acetyl-S-(2-cyanoethyl)-L-
cysteine 
2-HEMA 
2-hydroxyethylmercapturic acid 
2-NA 
2-aminonaphtalene 
3-HMPA 
3-hydroxypropylmercapturic acid 
3-HMPMA 
3-hydroxy-1-methylpropylmercapturic acid 
3-OH-B[a]P 
Total 3-hydroxybenzo(a)pyrene 
4-ABP 
4-aminobiphenyl 
ABOUT 
Assessment of behavioral outcomes related to tobacco and 
nicotine products 
AE 
Adverse event 
ATS 
American thoracic society 
BMI 
Body mass index 
BoExp 
Biomarker of exposure 
BP 
Blood pressure 
CAF 
Caffeine 
CDISC 
Clinical data interchange standards consortium 
CFR 
Code of federal regulations 
CI 
Confidence interval 
CIG 
Conventional cigarette(s) 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTMS 
Clinical trial management system 
CV (statistics) 
Coefficient of variation 
DM-CRO 
CRO responsible for data management activities 
DMP 
Data management plan 
DVP 
Data validation plan 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
ERS 
European respiratory society 
FAS 
Full analysis set 
FDA 
Food and Drug Administration  

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FEV1  
Forced expiratory volume in 1 second 
FTND 
Fagerström test for nicotine dependence (revised version) 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GCV (statistics) 
Geometric coefficient of variation 
GMR (statistics) 
Geometric mean ratio 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HPHC 
Harmful and potentially harmful constituents 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IP 
Investigational product 
ITT 
Intention to treat 
IxRS 
Interactive web/voice response system 
LLOQ 
Lower limit of quantification 
MAR 
Missing at random 
MedDRA 
Medical dictionary for regulatory activities 
MHBMA 
Monohydroxybutenyl mercapturic acid 
NCT 
ClinicalTrials.gov identifier 
NEQ 
Nicotine equivalents 
NNAL 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
NNK 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 
NNN 
N-nitrosonornicotine 
PMP 
Philip Morris Products S.A. 
PP 
Per protocol set 
PX 
 
Paraxanthine 
QC 
Quality control 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical analysis system 
SDTM 
Study data tabulation model 
SFTP 
Secure file transfer protocol 
SHM 
Sample handling manual 
SOC 
System organ class 
SOP 
Standard operating procedure 
S-PMA 
S-phenylmercapturic acid 

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THS 
Tobacco Heating System 
TNP 
Tobacco and/or nicotine containing product 
ULOQ 
Upper limit of quantification 
USA 
United states of America 
WBC 
White blood cell (count) 
WHO 
World Health Organization 
WOCBP 
Women of child-bearing potential 

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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 inclusion and 
exclusion criteria, and have been enrolled (completing 
Screening visit and Admission Day -2), but did not proceed 
to Baseline Day -1 and have not been randomized due to a 
sufficient number of subjects available for randomization at 
that time.  
An alternate subject may join the following group if her/his 
28-day Screening period has not exceeded. The alternate 
subject will have to repeat the Admission Day -2 visit to re-
confirm eligibility. 
Blade device 
Tobacco Heating System (THS) device with Blade 
technology for Blade stick use 
Blade stick 
Tobacco stick designed specifically to be used with the Blade 
device.  
Cigarette(s) (CIG) 
The term ‘CIG’ refers to commercially available regular 
cigarettes 
(manufactured) 
and 
excludes 
hand-rolled 
cigarettes, cigars, pipes, bidis, and other nicotine-containing 
products. 
Early termination 
Premature termination of exposure to the Investigational 
Product after the start of the Exposure period in the 
confinement setting. 
End of study (EOS) 
The EOS for an exposed subject is defined as the completion 
of the 3-day Safety follow-up period either after Discharge 
on Day 6, or after the date of an Early termination, or after 
discontinuation of the exposed subject. The EOS of the entire 
study is the end of the Safety Follow-up Period for the last 
subject. 
Induction Mono device 
Tobacco Heating System (THS) device with Induction 
technology (combined Charger-Holder device for Induction 
stick use). 
Induction Mid device 
Tobacco Heating System (THS) device with Induction 
technology (device with Induction stick Holder for Induction 
stick use and separate Charger).  
Induction stick 
Tobacco stick designed specifically to be used with the 
Induction Mono device or Induction Mid device.  

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Randomization  
Allocation of the respective product at any time on Day -1 
utilizing an interactive web and voice response system 
(IxRS). On Day 1, the subjects will be individually informed 
about the product they are randomized to prior to the first 
product use.  
Screening failure 
All subjects that are not enrolled are considered as screen 
failures. Re-screening of subjects who did not meet any entry 
criteria will not be permitted. 
Stick 
Refers to either Induction or Blade stick if not specified. 
THS 
In this protocol, the term THS generally includes use of any 
of the devices to be tested (i.e., Induction Mid device or 
Induction Mono devices or Blade device) with their 
respective tobacco sticks. 

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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  
Investigator(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. 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) [2] 
and local requirements, as applicable. 
In accordance with GCP, a written confirmation of the IEC approval should be provided to 
the Sponsor. This should identify the study (name of the Investigator(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 Investigator site 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 Principal Investigator(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 Investigator(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 Investigator(s)(s), and is implemented 
for safety reasons, the Sponsor and the IEC should be informed immediately. The 
Investigator(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. 
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. 

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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 [3] and are consistent with ICH/GCP [2] applicable regulatory 
principles. 
The Investigator(s) agree(s) to conduct the clinical study in compliance with the protocol 
agreed with the Sponsor and approved by the IEC. The Investigator(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 Screening visit, the Investigator(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 Investigator(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 he/she 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 the informed consent. No study-specific procedures 
will be performed before the ICF has been signed (including date and time). 
In addition to consenting to study participation, the subjects will be asked for their consent 
to the storage of urine samples for long-term biobanking (two years at most), i.e., the 
storage of samples from the 24-hour urine collection at the bioanalytical laboratory 
(Appendix B), in view of further measurements of BoExp. These analyses are not described 
in the protocol or statistical analysis plan (SAP) and will not be included in the clinical 
study report (CSR), but in a separate report. 
The subject’s consent to urine sample biobanking is not a requirement for the study 
participation and the subject’s participation in the study does not depend on their consenting 
to biobanking. 
The original, dated and signed ICF(s) must be kept by the Investigator(s) and filed in the 
Investigator site file or with the subject’s files, and a copy must be given to the subject. 

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The subject will be informed that if he/she 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 he/she disagrees in writing.  
Subjects will be informed that additional data analysis not mentioned in the protocol or in 
the statistical analysis plan (SAP) might be performed with the collected data at a later time. 
Any additional analysis performed will be covered by data confidentiality, as for the main 
analysis described in this protocol. 
 
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 investigational product (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 
Investigator(s) will, with the support of the Sponsor, ensure that the documents have been 
reviewed and approved by the 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 participation or are discontinued from the study will be informed 
by letter, email, 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, and Investigator(s) abide by the principles of the ICH guidelines on GCP 
[2]. These guidelines apply specifically to pharmaceutical development, but nevertheless 
provide a robust and ethical framework for conducting clinical studies with products such 
as THS devices. The study will also be conducted in accordance with the general ethical 
principles outlined in the Declaration of Helsinki [3]. 

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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]. There is no safe CIG, and 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 (TNPs) 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 HPHC generated 
from CIG smoke (except nicotine), while 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 
Several versions of the THS devices and of sticks specifically designed for these products 
are now available on the market. They all consist of at least a charging unit(s) (either one 
single integrated charger-holder system, or a separate charger and a separate stick holder) 
used to heat a stick. Some charging units are required to be charged between every use, and 
some have a larger battery, allowing several consecutive uses. Further details are provided 
in the Investigator’s Brochure [6].   
PMP has developed THS products either with Blade heating technology or Induction 
heating technology (marketed under the name of IQOS™ or ILUMA™, respectively). The 
Blade device is heating Blade sticks with a heating blade technology, while the Induction 
Mono device and the Induction Mid device do heat Induction sticks by using the heat 
induction technology. Independently of the technology, the temperature of the stick heating 
is controlled during the use to avoid burning of the tobacco.   
Specific sticks have been developed for THS Blade devices and Induction devices, called 
Blade sticks and Induction sticks, respectively. The sticks to be used with the Blade 

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technology are not compatible with the Induction technology, and vice versa. Only one 
flavor variant of the sticks (Regular, i.e., tobacco flavor) will be tested in this study. 
PMP has conducted an exhaustive pre-clinical and clinical assessment of the THS Blade 
device. In 2020, the FDA authorized the Blade device (IQOS™) to be marketed as a 
Modified Risk Tobacco Product with exposure modification orders [7]. PMP is now 
planning to demonstrate that using the new versions of THS, including the Induction Mono 
devices and Induction Mid device, will lead to comparable levels of reduction of exposure 
to selected HPHC in smokers switching exclusively to either one of these products.  
2.2 
Anticipated Benefits and Risks 
2.2.1 
Anticipated Benefits 
Information on health risks associated with smoking, and smoking cessation advice, will 
be provided at the Screening visit, the Admission visit on Day -2, and at Discharge on 
Day 6, respectively. The advice will follow the recommendations of the World Health 
Organization (WHO) “Evidence based Recommendations on the Treatment of Tobacco 
Dependence” [8]. 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. 
2.2.2 
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 95 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. 
2.2.3 
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 
feelings, restlessness, and difficulty to concentrate) as 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 

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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). 
2.2.4 
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 
The estimands requested as per ICH guidelines [1] for all objectives are listed in 
section 12.5.1 for the primary objective, and section 12.5.2 for secondary objectives. 
3.1 
Primary Objective 
The primary objective of this study is the joint evaluation of the following hypotheses: 
1. To demonstrate the reduction of biomarkers of exposure (BoExp) to selected harmful 
and potentially harmful constituents (HPHC) detailed in Table 3 in smokers switching 
from CIG to THS Blade device compared to continuing CIG smoking for 5 days. 
2. And to demonstrate the reduction of BoExp o selected HPHC detailed in Table 3 in 
smokers switching from CIG to THS Induction Mono device compared to continuing 
CIG smoking for 5 days. 
3. And to demonstrate the reduction of BoExp to selected HPHC detailed in Table 3 in 
smokers switching from CIG to THS Induction Mid device compared to continuing 
CIG smoking for 5 days. 
Table 3 
List of BoExp Used in the Primary Objective 
BoExp 
HPHC 
Matrix 
3-hydroxypropyl mercapturic acid (3-
HPMA) 
Acrolein 
Urine1  
2-cyanoethyl mercapturic acid N-acetyl-S-
(2-cyanoethyl)-L-cysteine (2-CyEMA) 
Acrylonitrile 
Urine1 
Monohydroxybutenyl mercapturic acid 
(MHBMA) 
1,3-butadiene 
Urine1 
Total 4-(methylnitrosamino)-1-(3-pyridyl)-
1-butanol (total NNAL) 
4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK) 
Urine1 
Carboxyhemoglobin (COHb) 
Carbon monoxide (CO) 
Blood2 
1BoExp in urine will be expressed as concentration adjusted for creatinine in 24-hour urine; 
2BoExp in blood expressed as % of saturation of hemoglobin. 
3.2 
Key Secondary Objectives  
1. To demonstrate the reduction of BoExp to selected HPHC detailed in Table 4 in 
smokers switching from CIG to THS Blade device compared to continuing CIG 
smoking for 5 days.  

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2. To demonstrate the reduction of BoExp to selected HPHC detailed in Table 4 in 
smokers switching from CIG to THS Induction Mono device compared to continuing 
CIG smoking for 5 days.  
3. To demonstrate the reduction of BoExp to selected HPHC detailed in Table 4 in 
smokers switching from CIG to THS Induction Mid device compared to continuing 
CIG smoking for 5 days. 
Table 4 
List of BoExp Used in the Key Secondary Objective 
BoExp 
HPHC 
Matrix 
S-phenylmercapturic acid (S-PMA) 
Benzene 
Urine1  
2-hydroxyethylmercapturic acid (2-HEMA) 
Ethylene oxide 
Urine1 
3-hydroxy-1-methylpropylmercapturic acid (3-
HMPMA) 
Crotonaldehyde 
Urine1 
Total N-nitrosonornicotine (total NNN) 
N-nitrosonornicotine 
Urine1 
Total 3-hydroxybenzo(a)pyrene (3-OH-B[a]P) 
Benzo(a)pyrene 
Urine1 
4-aminobiphenyl (4-ABP) 
4-aminobiphenyl 
Urine1 
2-aminonaphtalene (2-NA) 
2-aminonaphtalene 
Urine1 
1BoExp in urine expressed as concentration adjusted for creatinine in 24-hour urine 
3.3 
Other Secondary Objective  
1. To monitor the safety profile during the study. 
Endpoints  
• 
Incidents of adverse events (AEs) and serious adverse events (SAEs) 
• 
Incidence of device malfunction and product complaints (e.g., events related to 
device or sticks) 
• 
Vital sign changes from baseline (systolic and diastolic blood pressure, heart rate 
and respiratory rate)  
• 
Laboratory safety panel changes from baseline 
• 
Concomitant medication (ConMed) changes from baseline 
• 
Electrocardiogram (ECG) changes from baseline (heart rate, PR, QRS, QT, and 
QTcF intervals) 
• 
Spirometry changes from baseline (forced expiratory volume in 1 second 
[FEV1], FEV1 % predicted, forced vital capacity [FVC], FVC % predicted, 
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3.4 
Exploratory Objectives  
1. To describe the levels of nicotine over the exposure period in smokers switching from 
CIG to THS Blade device, Induction Mono device, or Induction Mid device, and in 
smokers continuing to smoke CIG.  
Endpoints (Day -1 to Day 5) 
• 
Nicotine equivalents (NEQ = molar sum of free nicotine, nicotine-glucuronide, 
free cotinine, cotinine-glucuronide, free trans-3’-hydroxycotinine, trans-
3’hydroxy-cotinine-glucuronide) in 24-hour urine (concentration adjusted for 
creatinine). 
2. To describe daily tobacco product use over the exposure period in smokers switching 
from CIG to THS Blade device, Induction Mono device, or Induction Mid device, 
compared to continuing CIG smoking. 
Endpoints (Day -1 to Day 5) 
• 
Number of CIG/day 
• 
Number of sticks/day 
3. To describe product experience in smokers switching from CIG to THS Blade device, 
Induction Mono device, or Induction Mid device compared to smokers continuing CIG 
smoking. 
Endpoints (Day -1 to Day 5) 
• 
Subscale scores of Product Experience (ABOUT–Product Experience) 
questionnaire. 
 

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4 
Investigational Plan 
4.1 
Overall Study Design and Plan 
This is a randomized, controlled, open-label, 4 parallel arms study with a stratified 
randomization by sex (a quota for each sex (females and males) of at least 40% overall). 
This is an ad libitum use/smoking study. During confinement, in general, THS use and CIG 
consumption (according to randomization) will be allowed between 06:30 AM and 11:00 
PM.  
During the confinement period, adherence to investigational product arm allocation 
(exclusive use of THS devices with designated sticks, or CIG smoking, respectively) will 
be ensured by strict distribution of the devices, and of each stick/CIG upon demand of the 
subject to the site staff.  
 
Figure 2 
Study Design 

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Screening period (from Day -30 to Day -3, prior to admission): 
The screening period covers up to four weeks prior to admission. A demonstration of 
the THS investigational products will be done by the site staff during the Screening 
visit. Screening procedures do not necessarily have to be conducted on the same day. 
All subjects will receive information on the risks of smoking and smoking cessation 
advice and briefing on THS. Eligible subjects will return to the investigational site for 
verification of eligibility at Admission. 
Admission (admission on Day -2 until 06:29 AM of Day -1): 
Subjects will be in a confinement setting for 7 days from Day -2 onwards.  
Subjects will be enrolled if all eligibility criteria are met. Only subjects willing and able 
to use the products will be enrolled in the study. 
CIG smoking will be allowed ad libitum from the time of admission of the subject until 
approximately 11:00 PM of Day -2, except before/during assessments requiring 
smoking breaks. Use of any tobacco and/or nicotine containing product (TNP) other 
than CIG (and THS during the product test) will not be allowed on Day -2 after 
admission. 
On Admission Day -2, as the last procedure of the eligibility assessments, subjects will 
have a product test of the THS Blade device and Induction Mono device (use of up to 
three sticks per device), prior to enrolment. In female subjects, the THS product tests 
will only be performed once pregnancy is excluded by a negative pregnancy test. After 
the product test, subjects not willing to use THS during the study will be discontinued 
and will be replaced. Subjects willing to continue participation will start their 
confinement period. 
Provided that the 28-day Screening period is not exceeded, alternate subjects (that have 
not performed Baseline Day -1 nor have been randomized formerly) have to repeat the 
Admission visit of the following group to re-confirm their eligibility for randomization. 
Baseline (Day -1, 06:30 AM until Day 1, 06:29 AM): 
Subjects may continue smoking their CIG ad libitum, except before/during assessments 
requiring smoking breaks. The 24-hour urine collection for Day -1 will start in the 
morning of Day -1 (details provided in Appendix A). Baseline assessments will be 
performed as indicated in Appendix A. 
Subjects will be randomized to one of the 4 study arms (THS Blade device, THS 
Induction Mono device, THS Induction Mid device, or CIG) in a 1:1:1:1 ratio using a 
stratified randomization. 

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Subjects will be informed of their randomized study arm by the study site staff on Day 1 
prior to 06:30 AM.  
Exposure in confinement (Day 1, 06:30 AM until Day 5, 11:00 PM): 
The exposure period will consist of 5 days of ad libitum use of the assigned 
investigational product between 06:30 AM and 11:00 PM in the THS and CIG arms. 
Use of any TNP other than the assigned investigational product (or CIG smoking in the 
CIG arm) will not be allowed and may, at the discretion of the Investigator, result in 
discontinuation of the subject from the study. 
Daily 24-hour urine will be collected from Day 1 to Day 5. On Day 1, product use must 
not start before the end of 24-hour urine collection of Day -1. The 24-hour urine 
collection period for Day 5 will end in the morning of Day 6 prior to discharge.    
During the confinement period, site staff will distribute assigned products to the subjects 
and record all products distributed in the source documentation.  
Discharge period (Day 5, 11:01 PM until Day 6, time of Discharge): 
Discharge procedures, including laboratory parameters, will be conducted to discharge 
the subject from the clinic after 7 days in a confined setting. Use of CIG will be allowed 
on Day 6 once all study procedures are completed.  
Safety follow-up (Day 6, time of Discharge, to Day 9): 
After Discharge on Day 6, or after Early termination, subjects will enter a 3-day Safety 
follow-up period during which AEs/SAEs will be collected and follow-up of any 
ongoing AEs/SAEs will be conducted by investigational site. The end of the study is 
defined as the completion of the 3-day Safety follow-up period either after the 
Discharge on Day 6, or after Early termination. 
During the study, subjects in the CIG arm and the THS arms who want to quit smoking will 
receive appropriate medical advice. This will not affect subject’s financial compensation, 
and the subject will remain in the study. 
4.2 
Rationale for Study Design  
This clinical study aims to demonstrate the reduction of BoExp to selected HPHC in 
smokers switching from CIG to each of the THS variants with different heating technology 
(Blade device, or Induction Mono device, or Induction Mid device, respectively), compared 
smokers who continue to smoke CIG. A reduction of exposure to HPHC derived from CIG 
smoke is expected to reduce the health risk of CIG consumption if switching completely to 
THS. 

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The exposure period in confinement will provide information on exposure reductions 
achievable in a well-controlled environment with full control on daily THS stick 
consumption and compared to CIG smoking.  
HPHC of cigarette smoke considered to be of health concern have been reported by 
different regulatory bodies and health organizations [9, 10]. Lists of HPHC to be reported 
in cigarette smoke have consequently been developed, as described, for example in the 
FDA draft guidance on “Reporting Harmful and Potentially Harmful Constituents in 
Tobacco Products and Tobacco Smoke” [11]. 
It is not possible to measure each of those potentially toxic constituents in humans, due to 
constraints in availability of validated, reliable methods, or simply the absence of suitable 
BoExp. A selection of HPHC to be evaluated in this study was thus performed based on 
the following criteria: 
1. The HPHC selected are representative of a variety of chemical classes and organ 
toxicity classes as defined by the FDA (carcinogen, cardiovascular toxicant, 
respiratory toxicant, reproductive and development toxicant, and addiction 
potential) [10] 
2. The HPHC selected reflect on a specific toxic exposure or are a reliable surrogate 
of exposure to HPHC 
3. The HPHC assessed cover a broad range of formation temperatures 
4. The HPHC are specific to smoking with other sources being minor or non-existent 
5. The BoExp to a HPHC is reliably detectable using validated, reproducible, precise 
analytical methods 
6. The BoExp to a HPHC has a half-life that is suitable with the schedule of 
assessments. 
Other parameters such as product evaluation, and subjective effects related to smoking 
including smoking urges will be evaluated. 
Twenty-four hours urine collection conducted in this study is the standard method to 
measure the levels of excretion of BoExp. 
All subjects in the CIG arm will be asked to buy their own CIG according to their 
anticipated needs for the study to minimize any changes in their smoking behavior. 
4.3 
Appropriateness of Measurements 
All laboratory measures utilized for this study are validated and are appropriate for the 
study assessments.  

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The ABOUT-Product Experience, the self-report measure to be used in this study, has been 
developed following the best practices (including the FDA’s Guidance for Industry Patient-
Reported Outcome (PRO) Measures [12]), which provide the scientific basis for the 
development, modification, and validation of PRO measures in support of clinical and 
regulatory research. The FTND [13, 14] and the ABOUT-Product Experience 
questionnaires [15, 16] to be used in this study are validated and previously published or 
adapted versions of validated questionnaires. 
4.4 
Study Duration 
The entire study duration per subject will be at least 12  and at most 39 days. This will 
include a screening period of up to 28 days prior to admission (Day -30 to Day -3), followed 
by a 7-day confinement period (Day -2 to Day 5), Discharge on Day 6, and a 3-day Safety 
follow-up period until and including Day 9.  
The EOS for an exposed subject is defined as the completion of the 3-day Safety follow-
up period following either after Discharge on Day 6, or after the date of Early termination 
of the subject, or after the discontinuation of the exposed subject. The EOS of the entire 
study is the end of the Safety follow-up period for the last subject. 

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5 
Study Population 
Eighty smoking healthy female or male adult subjects who have smoked on average at least 
10 regular CIGs per day for the last 4 weeks prior to Admission will be randomized 
(stratified by sex) using a 1:1:1:1 ratio into this study. Quotas will be applied to ensure that 
the randomized population contains at least 40% of both sexes (males and females) overall. 
The maximum number of CIG smoked daily is not limited. Subjects must have been 
smoking for at least 3 years prior to the Screening visit. There will be no brand restrictions 
of CIG (non-mentholated only). 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 enrolled into the study: 
Inclusion Criteria 
Screening 
Day -2 
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 
X 
4. Subject has continuously smoked on average ≥10 
commercially available regular CIGs/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 
 
6. Subject does not plan to quit smoking within the next three 
months. 
X 
X 
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) during the Exposure period 

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law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the 
study: 
Exclusion Criteria 
Screening   Day -2 
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 
 
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 
 
11. The subject has a positive urine drug test.   
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 onlyc: subject does not 
agree to use an acceptable method of effective 
contraceptiond.   
X 
 
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.   
5.2 
Discontinuation of Subjects from the Study 
Discontinued subjects (i.e., enrolled subjects that do not complete the study) 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 Investigator. 

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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 9.6, 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 Investigator 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 Investigator 
• 
Subject unwilling to use the product during the entire study duration after having done 
the product test 
• 
An alternate subject that has completed the 28-day Screening period and has not been 
randomized 
• 
The Sponsor terminates the study, or the study terminates at a particular site. If the 
Sponsor decides to prematurely terminate the study, the subjects will be promptly 
informed. The Investigator or designee should report the fact and the reason in writing 
to the IEC 
• 
The Investigator terminates the study or suspends the trial (e.g., due to a loss of key 
staff members, change of circumstances). If the Investigator terminates or suspends a 
trial without prior agreement of the sponsor, the investigator must inform the 
institution as applicable, and must promptly inform in the sponsor and the IEC in 
writing, including a detailed explanation. 

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Subjects may be discontinued from the study for the following reason: 
• 
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 enrolment will be replaced. After 
enrolment but before randomization, subjects who will be discontinued from the study will 
enter the 3-day Safety follow-up period and will be replaced (except alternate subjects). In 
general, subjects that are discontinued after randomization will not be replaced. Should 
there be the need to discontinue all subjects from one cohort, e.g., all subjects suspected to 
have contracted a disease pathogen, subjects for a replacement cohort may be enrolled and 
randomized. 
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., safety laboratory, physical examination, on-going AEs). Two 
contacts will be made via contact information provided by the subject (e.g., telephone 
number, cell phone number, email address), allowing 1 day between attempts for response. 
If contact is not possible, a follow-up letter will be sent to the participant, allowing 
approximately 5 business days from the time of delivery for a response. A progress note 
will be added in the data collection system for documentation. After a letter is sent, there 
should be no additional phone calls unless the participant has attempted to contact the 
investigational site and a return call attempt is made.  
If post-study follow-up has not been resolved within approximately five business days 
following delivery confirmation or the letter is not deliverable, the participant is considered 
lost to follow-up. This is documented in the progress note and outstanding AEs are updated. 
The date of lost to follow-up corresponds to the date of the end of study of the subject. 
The Investigator 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 (39 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 Investigator. 

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law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
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 
Investigational Product: Tobacco Heating Systems 
The products tested in this study are the THS Blade device (with corresponding Blade 
Regular sticks) and the THS Induction Mono device and Induction Mid device (with 
corresponding Induction Regular sticks). Blade sticks are incompatible with the Induction 
devices, and vice versa.  
The THS devices and one variant of the sticks (Regular, i.e., tobacco flavor) will be 
supplied by the Sponsor. 
The THS devices provided by the Sponsor comprise the following components:  
• 
THS Blade device: Charger, Holder, power supply/charging cable 
• 
THS Induction Mono device: Combined Charger-Holder, power supply/charging 
cable 
• 
THS Induction Mid device: Charger, Holder, power supply/charging cable. 
6.1.2 
Investigational Product / Baseline Product: Cigarettes 
Subject’s preferred brand of commercially available regular CIG will not be provided by 
the Sponsor.  
All eligible subjects will be asked to purchase their usual brand of CIG prior to Admission 
(Day -2). Every subject will bring a sufficient number of unopened, single-brand packs of 
CIG for the entire confinement period which will be kept in secured storage room at site 
with access limited to authorized personnel. 
6.1.3 
Packaging and Labelling 
At Admission (Day -2), all study subjects will provide sealed packs of CIG (sufficient for 
the confinement period) to the investigational site staff. The CIG packs 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 products to the subjects 
at Discharge or Early termination. 

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For THS, packs of Blade Regular sticks and Induction Regular sticks will be printed 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. 
6.2 
Use of Investigational Product(s) 
Subjects will not be forced to smoke CIG or use THS Regular sticks or Induction Regular 
sticks, respectively, and will be free to stop smoking/using THS at any time of 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 
Admission Day (Day -2 to Day -1)  
Subjects will be informed on the use of THS and will perform a product test with THS 
Blade device and THS Induction Mono device with at most three sticks per THS device. 
CIG smoking will be allowed ad libitum from the time of admission of the subject until 
approximately 11:00 PM, except before and during assessments requiring smoking breaks. 
Use of any TNP other than CIG and THS will not be allowed after admission. 
6.2.2 
Baseline Period (Day -2 to Day -1)  
All subjects may continue smoking their CIG ad libitum, except before/during assessments 
requiring smoking breaks.  
6.2.3 
Exposure Period (Day 1 to Day 5)  
Except during study procedures, subjects can use THS or consume CIG as per assigned 
study arm. Site staff will distribute assigned investigational products to the subjects and 
record all products distributed in the source documentation. Use of any TNP other than the 
assigned investigational product will not be allowed. The exposure period to the assigned 
investigational product (IP) will end at Day 5, 11:00 PM, after which subjects will be asked 
to remain abstinent of any use of TNP until the end of their 24-hour urine collection and 
completion of study procedures on Day 6.  
6.2.4 
Day of Discharge (Day 6)  
Subjects may smoke CIG or use other TNP at their discretion after Discharge. 
6.2.5 
Safety Follow-up Period  
Following the discharge on Day 6 (or Early termination or discontinuation) and during the 
subsequent 3-day Safety follow-up period, subjects will be free to use any TNP according 
to their usual habits. 

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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 pains, or abdominal pain), cold sweats, headache, dizziness, 
or breathing problems, or any reasons at the discretion of the Investigator.  
For subjects who are discontinued, the reason for discontinuation should be documented in 
the source documents and in the CRF and subjects will undertake early termination 
procedures (section 9.6), unless they disagree, or certain procedures have already been 
performed.  
6.3 
Method for Assigning Subjects to Study Arms 
At the end of the Baseline period enrolled subjects will be randomized using an interactive 
web and voice response system (IxRS) on Day -1 at any time during the day. Subjects will 
be informed of their randomized study arm in the morning of Day 1, prior to 06:30 AM 
(the start of the Exposure period). Subjects will be randomized (stratified by sex) to one of 
the four study arms (THS Blade device, THS Induction Mono device, THS Induction Mid 
device, or CIG) in a 1:1:1:1 ratio. 
Quotas will be applied to ensure that the randomized population contains at least 40% of 
both sexes (males and females) overall. 
Any alternate subject that has not been randomized will enter the 3-day Safety follow-up 
period. 
6.4 
Blinding 
This is an open-label study; hence the subjects and Investigator(s) will be unblinded to the 
subject’s arm. 
6.5 
Investigational Product Accountability and Adherence 
6.5.1 
Dispensing Investigational Products 
CIG for consumption during the confinement period, i.e., on Day -1, and in the CIG arm 
until end of Exposure period on Day 5 11:00 PM, will be dispensed by the investigational 
site staff as per the study design.  
THS Blade device, Induction Mono device, or Induction Mid device, and corresponding 
sticks (Blade Regular, Induction Regular) will be dispensed by the investigational site staff 
for use at the product test on Admission Day -2, and from Day 1 onwards until the end of 
Exposure period on Day 5 11:00 PM in the corresponding THS arms. 

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On each day of the confinement period, the time of dispense and return for each product 
(CIG/sticks) use will be documented for Day -1, and from Day 1 until end of Exposure 
period on Day 5 11:00 PM. 
6.5.2 
Storage and Accountability  
The sticks (Blade Regular, Induction Regular) and CIG will be stored in a secured storage 
location at site with access limited to authorized personnel only. The study collaborator 
designated by the PI will be responsible for the storage and accountability of the IPs in 
accordance with Sponsor’s requirements. Sticks must be stored under controlled conditions 
(temperature ≥+5° Celsius, ≤+30° Celsius; relative humidity ≤60%), whereas CIG can be 
stored in normal conditions (at ambient temperature with no temperature and humidity 
control). 
During the confinement period, subjects will return each used stick or CIG butt 
immediately after smoking to the site collaborators for accountability. The time of return 
of the products will be documented in an appropriate log. 
6.5.3 
Investigational Product Retention 
Used and unused THS devices and sticks will be returned to the Sponsor or disposed as per 
Sponsor’s instructions upon study completion. Smoked CIG butts will be disposed upon 
study completion once accountability is completed adequately. 
6.5.4 
Adherence to Investigational Products 
During the confinement and particularly the Exposure period, adherence will be ensured 
by strict distribution and collection of any used and unused sticks (and corresponding THS) 
and CIG/CIG butts by designated investigational site staff. Distribution and return of these 
products will be documented in appropriate logs. 
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 9.1.1). Spirometry 
assessments at Screening visit and at Day -1 will be performed at least 1 hour after stopping 
smoking (section 9.1.1 and 9.2.2). 
From Admission (Day -2) to Discharge (Day 6) or Early termination, use of any TNP, 
except use of the allocated investigational products, will not be permitted.  

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To avoid cross smoke contamination between the four study arms during confinement 
period, subjects must use their assigned product (THS or CIG) in separate smoking rooms. 
Using THS or smoking CIG will not be allowed during study procedures.  
6.6.2 
Dietary Restrictions 
A standard diet will be designed by a dietician for the whole confinement period. For each 
meal, the caloric and fat content should be controlled to avoid a “high-fat” diet. A “high-
fat” diet is defined as a diet which contains “approximately 50 percent of total caloric 
content of the meal [from fat] and is high in calories (approx. 800 to 1000 calories)” [17]. 
To avoid any effect on assessment of BoExp, grilled or pan-fried meat, pre-cooked meats 
(e.g., tuna, ham, corned beef, and smoked meats), bacon and sausage will not be permitted. 
In addition, alcohol, broccoli, brussels sprouts, cauliflower, grapefruit and xanthine-
containing foods and beverages (coffee, tea, chocolate, cocoa, mate, guarana, etc.) will not 
be allowed. 
Subjects will not be allowed to bring their own food (including sweets or chewing gum, 
etc.) or beverages to the investigational site. Meals will be served according to the agreed 
schedules. Additional light snacks, fruits (except grapefruits), and raw vegetables can be 
distributed to the subjects without restrictions at any time during confinement if they 
comply with the dietician’s standard diet. Consumption of non-carbonated water is 
allowed. Consumption of quinine-containing drinks (e.g., tonic water) is not allowed during 
the study. The same menu and meal schedule will be administered uniformly for all subjects 
in all study arms. 
A fasting state will be observed for at least 6 hours prior to blood drawings for safety 
laboratory panel on Day -1 and Day 6.  
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 Safety follow-up period 
will be considered Concomitant medication.  
Medications will be allowed and carefully monitored during the study by the Investigator 
or designee. The Investigator(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 
Personnel performing study assessments must have the appropriate and fully documented 
training. An overview of all study assessments is shown in the schedule of events (see 
Appendix A). In this section, only the expected/planned timepoints for the various 
assessments are described. 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 
Prior to any study assessment being performed, the subject will be asked to provide his/her 
written consent to participate to the study (ICF for study participation) (section 9.1.1). All 
the assessments must start after the time of ICF signature by the subject for study 
participation. 
In addition to the consent for study participation, the subject will be asked to provide her/his 
optional consent for biobanking (see section 1.3.1). The subject’s participation in the study 
does not depend on the optional ICF.  
All consents will be captured in the eCRF. 
7.2 
Information on Smoking Risks, Smoking Cessation Advice, and 
THS Briefing  
Each subject will be given during the same session i) information on the risks of smoking, 
ii) smoking cessation advice, and iii) briefing on THS as per schedule of events (see 
Appendix A). 
The information on the risk of smoking and the advice on smoking cessation will take the 
form of a brief interview according to the WHO recommendations and of the Public Health 
Service [18, 19]. The briefing of subjects on THS will address any intended or unintended 
beliefs that participants may have about THS. The goal of the briefing is to help ensure that 
subjects enter and exit the study with an accurate understanding of the product risks, 
including an understanding that THS have not been demonstrated to be less harmful than 
CIG. 
Details of the sessions will be recorded in the source document file. These sessions will be 
given to the subjects on an individual basis during a face-to-face meeting between the 
subject and the Investigator(s) and may additionally be given in a group session. 

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7.3 
Clinical and Other Assessments 
The results of the clinical assessments described in this section will be recorded in the CRF. 
Any clinically relevant medical condition detected during Screening visit assessments has 
to be documented as a concomitant disease. This also applies to clinically relevant findings 
in laboratory values, vital signs, spirometry, and ECGs detected during Screening visit 
assessments. Any untoward medical occurrence in a subject detected during the study, 
which was not present at Screening visit must be documented as an AE. Worsening of a 
pre-existing condition from Screening visit onwards will also be documented as an AE. 
7.3.1 
Demographic Data 
Sex, year of birth, and race will be recorded. 
7.3.2 
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 four 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, for example, mg, mL, or IU [international units]), indication, and the start 
and, if applicable, the 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. 
7.3.3 
Physical Examination 
A physical 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, cardiovascular, musculoskeletal and neurological systems. The physical 
examination is to be conducted by the Investigator or designated fully trained 
representative. 

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For those results outside of the normal range, the Investigator will determine appropriate 
follow-up including reporting of any AEs. 
7.3.4 
Body Height and Weight   
Body weight and height will be recorded at the Screening visit, body weight will also be 
recorded at Admission Visit Day -2. 
The BMI will be calculated from the body weight and height using the following formula: 
BMI = weight in kilograms
height in meters2
= 𝑘𝑔
𝑚2 
The BMI will be used to assess eligibility for enrolment. 
7.3.5 
Vital Signs 
Vital signs will include systolic and diastolic blood pressure (BP), respiratory rate (RR) 
and heart rate (HR). 
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 Vital signs assessment. 
For those results outside of the normal range, the Investigator will determine appropriate 
follow-up including reporting of any AEs.  
7.3.6 
Spirometry 
Spirometry will be performed in accordance with the 2019 guideline of the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) Joint Task Force on the 
standardization of spirometry [20, 21]. Spirometry predicted values will be standardized to 
the National Health and Nutrition Examination Survey III predicted set [22]. 
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 1 hour after 
smoking CIG (Screening visit). 
For those results outside of the normal range, the Investigator will determine appropriate 
follow-up including reporting of any AEs. 

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Any printouts of Spirometry on thermo-sensitive paper must be photocopied and stapled 
together for inclusion in the source documents. 
7.3.7 
 Electrocardiogram 
A standard 12-lead ECG will be recorded after the subject has rested for at least 10 minutes 
in supine position.  
All ECGs will be reviewed on an ongoing basis by the Investigator 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.  
 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 
7.3.8 
Biomarker Assessments  
All bioanalytical assays and laboratory assessments will be carried out using validated 
methods. The bioanalytical methods used will be documented in the respective 
bioanalytical plans/reports. A list of laboratories is provided in Appendix B. 
Blood samples and 24-hours urine samples will be collected according to the schedule of 
events (Appendix A) to measure BoExp to nicotine and some HPHC: 
• In blood: carboxyhemoglobin (% of saturation of hemoglobin) 
• In 24-hours urine: 3-HPMA, 2CyEMA, MHBMA, total NNAL, S-PMA, 2-HEMA, 
3-HMPMA, total NNN, 3-OH-B[a]P, 4-ABP, and 2-NA (creatinine normalization). 
7.3.9 
Laboratory Assessments  
Subjects should have fasted for at least 6 hours prior to hematology and clinical chemistry 
analyses, except at Screening visit and Early Termination where non-fasting samples can 
be used. Tests will be conducted at a local laboratory (see Appendix B). If during the 
screening period 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 also assessed.  
Parameters to be tested are listed in Appendix C. 

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Serology  
At the Screening visit, tests for hepatitis B virus, hepatitis C virus, and human 
immunodeficiency virus will be performed. 
Urine Drug Screening 
The urine will be screened for amphetamine type substances, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, and methadone. 
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.  
Urine Cotinine Screening  
A urine cotinine test will be performed to confirm the nicotine/tobacco use status. 
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. 
Alcohol Test  
An alcohol breath test will be performed at Screening visit. 
Urine Pregnancy Test  
A urine pregnancy test will be performed for all female subjects of childbearing potential. 
Subjects with a positive pregnancy test or unclear results (from two repetitions) before 
product testing and enrolment will be considered as screen failures. In case of any positive 
pregnancy test, the Investigator or designee will inform the subject about the risks 
associated with smoking during pregnancy and subjects will be referred to 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. 
7.3.10 
Sample Handling, Storage, and Shipment 
Urine drug test, urine pregnancy tests, and urine cotinine test, as well as all safety panel 
tests, will be done by the site personnel at the site. All other blood and urine samples will 

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be managed by the laboratory designated in Appendix B. Detailed procedures for handling 
of samples will be described in the Laboratory Manual/Sample Handling Manual 
(LM/SHM). Safety laboratory samples will be destroyed as per laboratory local regulations. 
All other samples (except biobanking samples) will be destroyed after the Clinical Study 
Report (CSR) has been finalized. The facilities at which the samples are stored will request 
confirmation in writing by the Sponsor when destruction of the samples shall be performed. 
Blood Samples  
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 95 mL of blood will be collected for this study including samples 
for determination of serology (5 mL), COHb (30 mL) and safety laboratory (approximately 
60 mL). This calculation is based on an individual volume of each sample of 20 mL per 
safety laboratory assessments, 5 mL for serology, and 5 mL for COHb assessment. The 
total volume of blood drawn (approximately 95 mL) will not exceed the levels for a 
standard blood donation.  
Details on the procedures for collection, labelling, processing, and shipment of samples 
will be described in the LM/SHM. 
Urine Samples  
Spot urine samples will be used for the urine drug screen, urine cotinine screen, urine 
pregnancy test, and safety urine analysis at Screening visit, Admission visit on Day -2, and 
after completion of 24-hour urine sample collection on Day 6. 
24-hour urine collection Subjects will discard their first void in the morning of Day -1. 
The collection period will start immediately after. After 24-hours ±1h of urine collection, 
subjects will empty their bladder again in the morning of the visit and this urine will be 
used as the final portion of the 24-hour urine sample.  
During the collection period, all urine passed must be collected in the sampling container. 
No urine should be passed into the toilet. The start and the end time of urine collection will 
be recorded by the subject and checked by the site staff. The volume of 24-hour urine will 
be measured by the site staff upon collection of urine containers from the subjects. For 
assessment of urine BoExp, creatinine aliquots from the 24-hour urine collection will be 
taken. In the schedule of events for the 24-hour urine collection, the dot corresponds to the 
day on which the 24-hour urine collection period starts. 

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Biobanking of urine If a subject gives optional consent for biobanking, additional samples 
of urine from the 24-hour collection will be aliquoted. The samples intended for biobanking 
will be kept frozen and will be shipped to a central storage facility according to the 
LM/SHM. After the final CSR is signed, samples of urine will be stored for a maximum 
duration of 2 years. 
7.4 
Other Study Procedures  
7.4.1 
Demonstration of THS and Product Test 
All subjects will have a demonstration of THS by the investigational site staff at the 
Screening visit without product use.  
At Admission (Day -2), after enrollment, investigational site staff will inform subjects on 
product use and subjects will have a product test with THS Blade device and Induction 
Mono device with up to three sticks per THS for a duration of approximately one hour.  
7.5 
Questionnaires  
The study questionnaires will be completed by the subjects in a paper format. All subject-
reported measures as well as instructions will be provided in the subject’s local language. 
7.5.1 
Tobacco/Nicotine Product Use History 
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 cigarettes 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. 
7.5.2 
Fagerström Test for Nicotine Dependence (Revised Version) 
Self-reported level of nicotine dependence will be assessed via a questionnaire on Baseline 
Day -1 using the Fagerström Test for Nicotine Dependence (FTND) in its revised version 
[23], as updated in 2012 [14]. The questionnaire consists of six questions which will be 
answered by the subjects. The scores obtained on the test permit the classification of 
nicotine dependence into three levels: Mild (0-3 points), moderate (4-6 points), and severe 
(7-10 points) [23]. This information will be used as characteristics of the study subjects. 

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7.5.3 
ABOUT–Product Experience Questionnaire 
Product experience will be assessed via the ABOUT–Product Experience, a subject self-
reported outcome measure part of the ABOUT toolbox [24].  
The questionnaire consists of 3 multi-item scales and 2 single-item scales, arising from an 
adaptation and rewording of the modified cigarette evaluation questionnaire (mCEQ) [15] 
to RRPs and the Product Evaluation Scale [25]. 
The questionnaire assesses the perceived effects experienced by CIG smokers switching to 
THS Blade device, Induction Mono device, or Induction Mid device compared to the 
experience of subjects continuing CIG smoking by measuring: 
• Product satisfaction (satisfying, tastes good, enjoy the product). 
• Psychological rewards (calms down, more awake, less irritable, helps concentrate, 
reduces hunger). 
• Aversion (dizziness, nausea). 
• Enjoyment of respiratory tract sensations (single-item assessment). 
• Craving reduction (single-item assessment). 
Subjects will be asked to assess the items of the questionnaire on a 7-point scale, ranging 
from “not at all” to “extremely”. A score for each subscale will be computed based on the 
scoring rule established by the questionnaire developer [15]. 
Symptoms or worsening of symptoms documented in the questionnaire do not need to be 
documented as additional AEs as the main source for AE collection is the face-to-face 
interview between the subject and study site staff, using open, non-directive questions, as 
described in section 8.2.1. 

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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 
investigational product. 
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 had been 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, 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 Safety follow-up 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 5 
Intensity of Adverse Events 
Mild: 
Easily tolerated, not interfering with normal everyday activities 

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Moderate: 
Interferes with normal everyday activities, but the subject is still able to 
function 
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 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 Safety Follow-Up Period. If the subject 
is not responding 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 Safety Follow-Up 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. 

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All SAEs will be followed up by the Investigator or designee after the end of the Safety 
Follow-Up 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 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 within 
24 hours. 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. 

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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. 
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 IRB 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 9.5), as soon as practical after discontinuation and will enter the 3-day 
Safety Follow-Up Period.  
Any AEs or SAEs that are ongoing at the end of the Safety Follow-Up Period will be 
managed as described in section 8.2.6. 
8.7 
Device Malfunction, Product Complaints and Misuse 
Any occurrence of investigational product THS device malfunction, product complaints, or 
misuse (use not in accordance with its instructions) by a subject will be documented by the 
Investigator. Information regarding the investigational 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 investigational 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 (use not in accordance with its label and instructions), will be 
documented by the Investigator or his/her designee using a device issue log.   
Investigational product misuse may result in use-related hazards (section 2.2.3). 
Furthermore, any malfunction or misuse of the investigational 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. 
9.1 
Screening Period 
9.1.1 
Screening Visit (between Day -30 to Day -3) 
The Screening visit will be performed ≤28 days prior to enrollment at Admission (Day -2). 
First, the 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 
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. 
Screening activities and examinations are listed in Table 6:  
Table 6 
Time Schedule – Screening Visit 
Time 
Procedures 
Additional Information 
Start of Procedure 
Screening Visit 
 
Prior to any other study 
procedure 
Informed consent process and 
signature of ICF 
 
During the Visit 
Information on smoking risks, 
advice on smoking cessation  
Including THS briefing 
 
Inclusion/exclusion criteria 
 
 
Smoking history 
TNP Use History 
questionnaire 
 
ECG 
 
 
Spirometry 
 
 
Demographics 
 
 
Medical History /  
Concomitant Diseases 
 
 
Prior (≤4 weeks) and 
concomitant medication  
 

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Time 
Procedures 
Additional Information 
Start of Procedure 
Screening Visit 
 
 
Physical examination 
 
 
Body height and weight / BMI 
 
 
Vital signs  
 
 
Serology 
HBV, HCV, and HIV 
 
Collection of blood sample 
- 
Safety panel 
(hematology, clinical 
chemistry) 
 
Collection of spot urine  
 
- 
Safety panel 
- 
Drug test  
- 
Cotinine test 
- 
Pregnancy test (all 
WOCBP) 
 
Alcohol breath test 
 
 
Review of eligibility criteria  
 
 
THS demonstration 
Without product use 
 
Identification of current CIG 
brand 
Explain CIG provision 
for confinement period 
by subject 
 
AE/SAE recording 
 
Abbreviations:  
AE = Adverse event; BMI = Body mass index; ECG = electrocardiogram; CIG = regular cigarette; HBV = hepatitis B 
virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICF = informed consent form; SAE = Serious 
adverse event; THS = tobacco heating system; TNP = tobacco and/or nicotine containing product; WOCBP = women of 
child-bearing potential. 
If the eligibility criteria are met, the site staff will contact the subject to arrange the visit for 
Admission Day -2 at the site. 
9.2 
Baseline Period (Enrolment and Randomization) 
9.2.1 
Admission Day -2 
Day -2 should be scheduled within 28 days after Screening visit1.  
Enrollment of a subject will take place at Day -2 only if all eligibility criteria are met, and 
after confirmation of a negative pregnancy test (women of child-bearing potential 
[WOCBP] only). The confinement period will start after the successful enrollment. All 
                                                 
1 Alternate subjects will have to repeat the Admission Day -2 visit to qualify for randomization. The data of 
that repeated visit will be captured in the database as “Admission Day -2 visit – Second occurrence”. 

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other procedures (Table 7) and data collection will be completed following the enrollment 
of the subject. 
Table 7 
Time Schedule – Admission Day -2 
Time 
Procedures 
Additional Information 
Start of Procedure 
Admission Visit Day -2 
 
Start of the visit 
Check-in at site 
CIG use allowed on site on 
Day -2 
Prior enrolment 
Collection of spot urine 
- 
Drug test  
- 
Cotinine test 
- 
Pregnancy test 
(WOCBP) 
 
Body weight 
BMI calculation 
 
Vital signs  
 
 
Smoking history 
TNP Use History 
questionnaire 
 
Inclusion/exclusion criteria 
 
 
Information on smoking risks; 
advice on smoking cessation 
Including THS briefing 
Prior to breakfast 
Enrollment 
After confirmation of the 
eligibility of the subject 
 
Start of run-in period 
 
During the visit 
Breakfast 
 
 
Lunch 
 
 
THS product test 
Subject can test THS with 
three sticks per THS 
 
Concomitant medication 
 
 
Concomitant disease status 
 
 
AE/SAE recording 
 
 
THS product events and 
complaints 
 
End of the visit 
Subjects remain confined 
11:00 PM stop of smoking 
Abbreviations:  
AE = Adverse event; BMI = Body mass index; CIG = Conventional cigarette(s); FTND = Fagerström test on nicotine 
dependence; SAE = Serious adverse event; THS = tobacco heating system; TNP = tobacco and/or nicotine containing 
product(s); WOCBP = women of child-bearing potential. 
9.2.2 
Baseline Visit Day -1 
Baseline exams will be performed (Table 8), and subjects will be randomized at Baseline 
visit. Randomization will take place only for subjects who are willing to comply with study 

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procedures and to use THS for at least 5 days. Table 8 shows the assessments that will be 
performed at Baseline Visit Day -1. 
Table 8 
Time Schedule – Baseline Visit Day -1 
Time 
Procedures 
Additional Information 
Start of Procedure 
Baseline Visit Day -1 
 
Prior to breakfast 
Spirometry 
 
 
ECG 
 
 
Vital signs 
 
 
Collection of blood sample 
After ≥6 hours of fasting 
- 
Safety panel 
 
Collection of spot urine 
- 
Safety panel 
 
Start 24-hour urine collection 
For Day -1 
 
COHb in blood 
 
Prior to randomization 
Breakfast 
 
During the visit 
Randomization 
Per IxRS 
 
FTND 
Questionnaire 
 
Concomitant medication 
 
 
Concomitant disease status 
 
 
AE/SAE recording 
 
 
ABOUT–Product Experience 
Questionnaire 
 
Collection of CIG butts 
Accountability 
End of visit (11:00 PM) 
CIG ad libitum consumption 
stop 
Subject remains confined 
Abbreviations: 
ABOUT = Assessment of Behavioral OUtcomes related to Tobacco and Nicotine Products; AE = Adverse event; COHb 
= Carboxyhemoglobin; CIG = Conventional cigarette(s); FTND = Fagerström Test for Nicotine Dependence; IxRS = 
Interactive voice/web response system; SAE = Serious adverse event. 
9.3 
Randomized Exposure Period 
9.3.1 
Exposure in Confinement Period 
On Day 1, subjects will be informed about their allocation to a study arm, i.e., either THS 
Blade device, Induction Mono device, Induction Mono device, or CIG. Table 9 shows the 
assessments that will be performed at Day 1, 2, 3, 4, and 5. 
Table 9 
Time Schedule – Day 1, 2, 3, 4, and 5 
Time  
Procedures 
Additional Information 
Start of Procedure 
Day 1, 2, 3, 4, and 5 
 

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Prior to breakfast 
Vital signs 
 
COHb in blood 
 
 
Completion of former day 
urine collection 
Each day of the 
confinement period 
 
Start of next 24-hour urine 
collection 
Day 5 collection will be 
completed in the morning of 
Day 6, ahead of Discharge 
 
Day 1 only: Inform subjects 
on allocated study arm 
 
During the visit 
Breakfast 
 
 
Distribution of the THS  
Subjects in THS arms 
 
Provision of single sticks 
Subjects in THS arms 
 
Provision of single CIG 
Subjects in CIG arm 
 
Collection of sticks 
Subjects in THS arms 
 
Collection of CIG butts 
Subjects in CIG arms 
 
Concomitant Medication 
 
 
Concomitant Diseases 
 
 
AE/SAE recording 
 
ABOUT–Product Experience 
Questionnaire 
 
THS 
product 
events 
and 
complaints 
THS arms only 
End of visit (11:00 PM) 
 
Subjects remain confined 
Abbreviations: 
ABOUT = Assessment of Behavioral OUtcomes related to Tobacco and Nicotine Products; AE = Adverse event; COHb 
= Carboxyhemoglobin; CIG = Conventional cigarette(s); SAE = Serious adverse event; THS = tobacco heating system. 
9.4 Discharge 
At Day 6, following completion of the procedures and examinations (Table 10), the 
subjects will be discharged for the Safety follow-up period.  

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Table 10 
Time Schedule – Discharge Day 6 
Time 
Procedures 
Additional Information 
Start of Procedure 
Day 6 
 
Prior to breakfast 
Collection of blood sample 
After ≥6 hours of fasting 
- 
Safety panel  
 
Completion of Day 5 urine 
collection 
 
 
Collection of spot urine  
- 
Safety panel 
- 
Pregnancy test (WOCBP 
only) 
 
Vital signs 
 
 
Spirometry 
 
 
ECG  
 
During the visit 
Breakfast 
 
 
Concomitant medication 
 
 
Concomitant diseases 
 
 
AE/SAE recording 
 
THS 
product 
events 
and 
complaints 
THS arms only 
 
Information on smoking risk; 
smoking cessation advice; and 
briefing on THS 
 
End of the visit 
Discharge from site 
 
Abbreviations:  
AE = Adverse event; ECG = Electrocardiogram; SAE = Serious adverse event; THS = tobacco heating system; WOCBP 
= women of child-bearing potential. 
9.5 
Safety Follow-up Period 
After Discharge at Day 6, the subjects will enter a 3-day Safety Follow-Up Period during 
which AE/SAEs reported by the subjects will be collected and the follow-up of AEs/SAEs 
will be conducted by the study investigational site as described in section 8.2.6.  
9.6 
Early Termination Procedures 
When a subject is discontinued from the study, all Early termination procedures listed in 
Table 11 are performed unless the subject refuses to perform the assessments or the 
procedures have already been performed during that study day. 

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Table 11 
Time Schedule – Early Termination Visit 
Procedures 
Additional Information 
 
 
Collection of blood sample  
After ≥6 hours of fasting, if 
possible 
- 
Safety panel 
Collection of spot urine  
- 
Safety panel 
- 
Pregnancy test (WOCBP only) 
Vital signs  
 
ECG  
 
Spirometry 
 
Information on smoking risks; advice on smoking 
cessation; and briefing on THS  
 
Concomitant medication 
 
Concomitant diseases 
 
AE/SAE recording 
 
THS product events and complaints 
THS arms only 
Discharge  
 
Abbreviations:  
AE = Adverse event; ECG = Electrocardiogram; SAE = Serious adverse event; THS = tobacco heating system; WOCBP 
= women of child-bearing potential 

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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 Investigator(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 Investigator(s) shall provide access to medical records for the Monitor in order that 
entries in the CRFs may be verified. As part of his/her(their) responsibilities, the 
Investigator(s) is(are) expected to ensure that the study adheres to GCP requirements [2]. 
An Investigator’s meeting will be held prior to 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. 
Subsequently to 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. 
The monitoring is performed using a risk-based approach as described in the monitoring 
plan (please refer to section 10.4 describing overall study risk management). 
Communication by telephone, mail, and e-mail may be used as needed to supplement site 
visits. The Principal Investigator 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 
Principal Investigator 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 agreed with the Sponsor. 
The Investigator(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 meeting) may be conducted prior to site initiation. During 
this meeting, the Sponsor or its authorized representative will discuss the requirements of 
the clinical study protocol and related documents and will also provide training to the 

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relevant systems and other study-specific procedures. The activities of this meeting will be 
described in the monitoring plan. 
Further to the Investigator meeting, the Investigator(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 Investigator(s) will maintain a record of all individuals involved in 
the study. 
10.3 Audits and Inspections 
Good Clinical Practice 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 [2], and 
any applicable regulatory requirements. The Investigator(s) will contact the Sponsor or the 
authorized representative immediately if contacted by a regulatory agency about an 
inspection at their site. 
The Investigator(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 Investigator(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 as well as the definition of Key Risk Indicators (KRI) and 
Quality Tolerance Levels (QTL).  
This risk management approach will be captured in a Risk Management Plan/Report with 
risks assessed in the Risk Management Tool which will be used 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 the quality management approach 
implemented in the study and summarize important deviations from the predefined quality 
tolerance limits and remedial actions taken in the CSR. 

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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, eCRF and EDC (electronic data capture) 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 CRF is reviewed and signed by the Investigator. The 
final signed CRFs are 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 on paper and 
transcribed by the site personnel to eEDC. 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 Investigator 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 Investigator 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 defined as any departure from the procedures defined in this 
document, including, but not limited to, any violation of inclusion/exclusion criteria, mis-
randomization, use of any nicotine or tobacco-containing product other than the assigned 
product during the exposure period, assessments not performed or performed outside the 
scheduled time windows, or use of medications that are known to affect study endpoints.  
Protocol deviations will be entered into the clinical trial management system (CTMS) or 
any other approved format. Protocol deviations will be reconciled and categorized prior to 
locking the clinical database as described in the DMP.  

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Information from the source documents will represent the primary source of protocol 
deviations. Information following investigational site monitoring and other manual reviews 
will be documented in the investigational site visit reports, follow-up letters, audit 
documentation, or other manual review and will be recorded and tracked in the CTMS or 
any other approved format. Telecommunications and other verbal communications 
regarding deviations will be considered and handled as important communication, and 
documented and tracked as protocol deviations, as necessary.  
Individual entries for protocol deviations that are recorded in the CTMS, or other approved 
format, following investigational site monitoring and other manual reviews, will be 
reviewed against the individual data points in the database. The overall procedure for 
managing protocol deviations is defined in the SOPs and study specific procedures of the 
DM-CRO. All deviations will be reviewed, as defined at study start, to identify trends to 
improve monitoring and/or potential impact on the statistical analysis. 
11.1.3 
Data Handling 
All study data will be managed by the DM-CRO. The overall procedures for quality 
assurance of clinical study data are described in the SOPs of the DM-CRO. The DM-CRO 
will prepare the DMP that will be reviewed and approved by the Sponsor, prior to the start 
of the study, i.e., First Subject Screened. This document will describe, in detail, the 
procedures and processes related to data management.  
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, year of birth, sex, race, AEs, date, and reason for screen failure. 
All data collected during the study is property of the Sponsor, irrespective of the location 
of the database and the DM-CRO. 
The sponsor should ensure that the Investigator has control of and continuous access to the 
eCRF data reported to the sponsor. The sponsor should not have exclusive control of those 
data. 
The Investigator should have control of all essential documents and records generated by 
the Investigator/investigational site before, during and after the study. 
Additional details are covered in the DMP.  
11.2.1 Data Verification 
The data will be verified as defined in the DMP and data validation plan (DVP). Data 
queries will be raised for discrepant or missing data. All changes to data in the eCRF will 
be captured in the database with a comprehensive audit trail.  

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All changes to data will be captured in the database with a comprehensive audit trail. 
11.2.2 Coding 
Adverse events, concomitant diseases, medical/surgical history, prior/concomitant 
medication will be classified according to the terminology of the latest version of the 
following dictionaries, at time of coding the first entry: 
Medical history:  
Medical Dictionary for Regulatory Activities 
(MedDRA®)  
Adverse events / Procedures:  
MedDRA®  
Medications:  
WHO Drug Global  
11.2.3 Database Lock  
When all outstanding data management issues have been resolved and all validation, quality 
review and cleaning activities are complete as defined in the DMP, the Sponsor organizes 
a data review and ensures that the resolution of all raised queries and quality control of the 
changed data are performed by the CRO before approving the database locked.  
Any changes to the database after that time can only be made by written agreement between 
the Sponsor and the data management and statistical teams at the CRO. Any changes must 
be documented in the database log file and if these changes may impact the study analysis 
the PMP process for a database unlock may be requested.  
The study database will be transformed into a Clinical Data Interchange Standards 
Consortium (CDISC) compliant format and transferred to the Sponsor as specified in the 
DMP and defined in the data transfer agreement. The clinical data will adhere to the CDISC 
Study Data Tabulation Model (SDTM) Data Structure Specifications. 

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12 Planned Statistical Methods 
12.1 General Considerations 
Full details of the statistical analyses will be described in the Statistical Analysis Plan 
(SAP). Any changes to the planned statistical methods will be documented in the SAP and 
clinical study report. The statistical evaluation will be performed using SAS®, version 9.2 
or higher. 
12.1.1 
Stratification Criteria 
The following stratification factor at baseline will be used in some of the analyses: 
• Sex (male and female). 
12.1.2 
Definitions for Statistical Data Analysis 
The following definition will be used for the statistical analysis of safety data: 
Term 
Definition 
Actual exposure arm 
Categorical variable representing the actual study arm of enrolled 
subjects. Non-randomized subjects will be assigned to the 
category ‘Enrolled but not randomized’. Randomized subjects 
will be assigned to the category corresponding to their 
randomization study arm.  
In case of mis-randomization (use of a different product from the 
allocated one), subjects will be assigned to the arm 
corresponding to their actual exposure.  
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by randomization study arm, subject, and 
study day 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. Post-baseline 
summaries will include change from baseline apart from log-normal variables which will 
present % change from baseline.  

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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.  
For categorical data, the number and % of subjects with missing data, frequency counts, 
and percentages will be presented. 
12.1.4 
Handling of Missing Values and of Values outside the Detection Limits 
Values outside detection limits will be substituted using the following rules (e.g., for BoExp 
parameters): 
• Values below LLOQ will be imputed using LLOQ/2. 
• Values above ULOQ will be imputed using ULOQ. 
Except otherwise stated, other missing values will not be imputed. 
Handling of missing answers to questionnaires will be described in the SAP. 
12.2 Product Use 
Considering the design of the study, it is expected that, during the exposure period, subjects 
will only use products corresponding to their randomization arm. 
Mis-randomized subjects will be classified according to their actual exposure arm for safety 
analyses (see section 12.1.2) and excluded from all analyses using the Per Protocol Set (see 
section 12.3.3). 
12.3 Analysis Sets 
The following analysis sets will be used for the data analyses. 
12.3.1 
Screened Population 
The Screened Population consists of all subjects who signed the ICF and who underwent 
at least one of the screening procedures. 
12.3.2 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) will consist of all the randomized subjects who have at least 
one post-randomization product use experience (if randomized to CIG or one of the THS 
arms) and who have at least one valid non-safety assessment after randomization. The FAS 
will be analysed by randomized study arm. 

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12.3.3 
Per Protocol Set (PP) 
The Per Protocol Set (PP) will be a subset of FAS and include all randomized subjects who 
fulfil key compliance criteria of the protocol, i.e., have no major protocol deviation 
impacting the evaluability of the primary objective (to be further described in the SAP). 
The PP will be analysed by randomized study arm. 
12.3.4 
Safety Set (SAF) 
The safety population will consist of all the subjects enrolled in the study with at least one 
exposure to THS (product test at Admission Day -2), and who have at least 1 valid value 
for a safety assessment. The SAF will be analyzed according to actual exposure arm (see 
definition in section 12.1.2). 
12.4 Demographics and Baseline Characteristics 
Demographics and baseline characteristics include sex, age, race, body weight, height, 
body mass index (BMI). 
Baseline characteristics include TNP use history, spirometry measurements (FEV1, FEV1 
% predicted, FVC, FVC % predicted, and FEV1/FVC), and FTND questionnaire score. 
Demographics and baseline characteristics will be summarized as follows: 
• By randomization study arm for the FAS, 
• By randomization study arm for the PP, 
• By actual exposure arm for the SAF (see definition in section 12.1.2). 
12.5 Primary Objective 
The primary objective of the study is to demonstrate the reduction of BoExp to selected 
HPHC in smokers switching from CIG to each of the THS arms (THS Blade device and 
THS Induction Mono device and THS Induction Mid device) compared to continuing CIG 
smoking for 5 days. 
12.5.1 
Primary Estimand Analysis 
The primary estimand of the primary objective is defined by the following components: 
• Product Use Under Evaluation: This corresponds to the study arms (CIG, THS 
Blade device, THS Induction Mono device or THS Induction Mid device) randomly 
allocated to subjects and for which they have fulfilled key compliance criteria of 
the protocol without major protocol deviation impacting the evaluability of the 
primary objective (as defined by the PP). 

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• Target Population: This is the population of adult smokers who satisfy all eligibility 
criteria (see section 5.1). 
• Variables of Interest: 3-HPMA, 2-CyEMA, total NNAL, MHBMA (all expressed 
as concentration adjusted for creatinine in 24-hour urine), and COHb (expressed as 
% of saturation of hemoglobin). 
• Intercurrent Events (ICEs): 
o Non-adherences to the randomization study arm: these ICEs are out of scope 
of this primary estimand, and related subjects will be excluded from this 
analysis. 
o Study discontinuation and death: data related to subjects who discontinued 
or died during the exposure period will be included only if they were 
adherent until the time of discontinuation/death. Missing data after 
discontinuation/death will be dealt with as described in section 12.5.1.3. 
o Subjects being tested SARS-CoV2 positive during the study: these subjects 
will be included only until the time of the diagnosis. Data collected after or 
at the date of the SARS-CoV2 positive test will be set to missing and dealt 
with as described in section 12.5.1.3. 
o Changes in comorbidities: subjects with comorbidities or worsening of an 
existing comorbidity will be included as this change may be linked to the 
reduction or modification of their CIG consumption. 
• Population-Level Summary Statistic: geometric mean ratios between every THS 
arms (THS Blade device, THS Induction Mono device or THS Induction Mid 
device) and CIG of the BoExp under consideration (Table 3, Table 4) at Day 5. 
12.5.1.1 
Baseline Comparability 
Demographics and baseline characteristics (as described in section 12.4) will be reported 
by randomization study arm for the PP.  
Given that the study is randomized, demographics and baseline characteristics are expected 
to be balanced between study arms. Nevertheless, sex and baseline value of the BoExp will 
be used as covariates in the statistical model (see section 12.5.1.4). 
12.5.1.2 
Descriptive Analysis 
Descriptive statistics as mentioned in section 12.1.3 for the variables of interest and 
associated changes from baseline will be reported by randomization study arm for the PP 
and by study day. Descriptive statistics stratified by the factor described in section 12.1.1 
will also be computed. 

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12.5.1.3 
Missing Data Strategy 
In this analysis, some missing data might occur because of ICEs or because of missing 
samples, laboratory measurements errors, etc. The main analysis model (see 
section 12.5.1.4) assumes that subjects with missing data would have outcome data like 
those in similar subjects in the same group. This type of assumption is referred to as Missing 
at Random (MAR). This assumption is aligned with the definition of the primary estimand. 
12.5.1.4 
Main Analysis 
The primary analysis will be conducted in the PP and based on a mixed model for repeated 
measurements (MMRM). An unstructured matrix will be used to model the variance-
covariance structure within subjects. If this model fails to converge, then the following 
variance-covariance matrix will be used (in order) until one converges: Heterogeneous 
Toeplitz, Heterogeneous First Order Autoregressive, Heterogeneous Compound 
Symmetry, Variance Components, Compound Symmetry, and finally no repeated 
statement. 
The model for the endpoint expressed on the log-scale will adjust for the endpoint value at 
baseline (log-scale), the Day, the randomization study arm and its interaction with Day, 
and sex.  
The model described above will be implemented in the SAS® language as: 
PROC MIXED data=dataset method=reml nobound; 
    class Arm Day Subject Sex; 
    model Log(Endpoint) = Log(Baseline) Day Arm Arm*Day  
          Sex / ddfm=kenwardroger2 solution; 
    repeated Day / subject=Subject(Arm) type=un rcorr; 
    lsmeans Arm*Day / pdiff cl; 
    lsmestimate ‘Contrast every THS arms (THS Blade Device 1, THS Induction Device 1 or THS 
Induction Device 2) vs. CIG’ exact syntax to be adjusted depending on the coding of class 
variables / cl upper alpha=0.025; 
RUN; 
LS-means per randomization study arm and day will be obtained (on the log-scale), as well 
as pairwise differences between arms per day, together with their 95%-confidence intervals 
and (unadjusted) p-values. Exponentiation of these quantities will lead to the geometric LS-
means per randomization study arm and (geometric) ratios between arms with their 
associated 95%-confidence intervals.  
The exponentiation of the ‘lsmestimate’ statement above entitled ‘Contrast every THS arms 
(THS Blade device, THS Induction Mono device, or THS Induction Mid device) vs. CIG’ 
will allow contrasting all THS arms jointly against the CIG arm and will be used to assess 
the primary study hypothesis (see section 12.5.1.4). 

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12.5.1.5 
Success Criteria 
The primary study hypothesis is about demonstrating the reduction of the five BoExp to 
selected HPHC listed in Table 3 in smokers switching from CIG to each of the THS variants 
(THS Blade device, or THS Induction Mono device, or THS Induction Mid device, 
respectively) for 5 days as compared to those who continue smoking CIG. For each 
individual BoExp, this will be evaluated using the 1-sided statistical test with a type I error 
level of 2.5% given by the ‘lsmestimate’ statement ‘Contrast every THS arms (THS Blade 
device, THS Induction Mono device or THS Induction Mid device) vs. CIG’ of the model 
described in section 12.5.1.4.  
The study will be declared successful if all ratios of the geometric means between every 
THS arms (THS Blade device, THS Induction Mono device or THS Induction Mid Device) 
over CIG is statistically lower than 1 at Day 5 for all five BoExp tested in the primary 
objective given in Table 3. 
12.5.1.6 
Supplementary Analysis 
The model described in section 12.5.1.4 allows contrasting all randomization study arms at 
Days 1, 2, 3, 4, and 5. While only the contrast between the three THS arms jointly and CIG 
at Day 5 will be used for the primary objective assessment, the following pairwise 
comparisons at Days 1, 2, 3, 4, and 5 will also be reported, together with their unadjusted 
p-values and 95%-confidence interval: 
• THS arms jointly (THS Blade device, THS Induction Mono device or THS 
Induction Mid device) vs. CIG 
• THS Blade device vs. CIG 
• THS Induction Mono device vs. CIG 
• THS Induction Mid device vs. CIG 
12.5.2 
Secondary Estimand Analysis 
This analysis refers to the secondary estimand of the primary objective defined in 
section 3.1. This estimand is implementing the “treatment policy strategy” and reflects the 
intention‑to‑treat (ITT) principle. It will evaluate the effect of switching to THS as 
compared to continuing to smoke CIG in the FAS rather than in the PP. It is defined by the 
following components: 
• Product Use Under Evaluation: This corresponds to the study arm (CIG, THS Blade 
device, THS Induction Mono device or THS Induction Mid device) randomly 
allocated to subjects and is independent of whether subjects were adherent or not 
(FAS). 
• Target Population: This is the population of adult smokers who satisfy all eligibility 
criteria (see section 5.1). 

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• Variables of Interest: 3-HPMA, 2CyEMA, MHBMA, total NNAL (all expressed as 
concentration adjusted for creatinine in 24-hour urine), and COHb (expressed as % 
of saturation of hemoglobin). 
• Intercurrent Events (ICEs): All ICEs will be treated as ‘treatment policy strategy’. 
This means that the values of the variable of interest is used regardless of whether 
the ICEs occur. 
• Population-Level Summary Statistic: Geometric mean ratios between each THS 
arm (THS Blade device, THS Induction Mono device or THS Induction Mid device) 
and CIG of the BoExp under consideration at Day 5. 
12.5.2.1 
Baseline Comparability 
Demographics and baseline characteristics (as described in section 12.4) will be reported 
by randomization study arm for the FAS.  
Given that the study is randomized, demographics and baseline characteristics are expected 
to be balanced between study arms. Nevertheless, sex and baseline value of the BoExp will 
be used as covariates in the statistical model (see section 12.5.2.4). 
12.5.2.2 
Descriptive Analysis 
Descriptive statistics as mentioned in section 12.1.3 for the variables of interest and 
associated changes from baseline will be reported by randomization study arm for the FAS 
and by study day. Descriptive statistics stratified by the factor described in section 12.1.1 
will also be computed. 
12.5.2.3 
Missing Data Strategy 
In this analysis, some missing data might occur because of missing samples, laboratory 
measurements errors, etc. The main analysis model (see section 12.5.2.4) assumes that 
subjects with missing data would have outcome data like those in similar subjects in the 
same group (MAR assumption). This assumption is aligned with the definition of the 
secondary estimand. 
12.5.2.4 
Main Analysis 
This analysis will be conducted using the same model as the one described in 
section 12.5.1.4, except that it will use the FAS instead of the PP and all available data will 
be included in the model. 
In section 12.5.1.5 the criterion to declare the study successful was provided. For the 
secondary estimand, the same difference will be computed and interpreted exploratorily 
using the same type I error level as for the primary confirmatory hypothesis.  

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12.5.2.5 
Supplementary Analysis 
The model described in section 12.5.1.4 allows contrasting all randomization study arms at 
Days 1, 2, 3, 4, and 5. The following pairwise comparisons at Days 1, 2, 3, 4, and 5 will be 
reported, together with their unadjusted p-values and 95%-confidence interval: 
• THS arms jointly (THS Blade device, THS Induction Mono device or THS 
Induction Mid device) vs. CIG 
• THS Blade device vs. CIG 
• THS Induction Mono device vs. CIG 
• THS Induction Mid device vs. CIG 
12.6 Secondary Objectives 
12.6.1 
Key Secondary Objectives 
The key secondary objectives are to demonstrate the reduction of additional BoExp to 
selected HPHC given in Table 4 in smokers who switch from CIGs to THS use compared 
to those who continue to smoke CIG. The statistical analysis for each of these additional 
BoExp for each THS arm (THS Blade device, THS Induction Mono device or THS 
Induction Mid device) will be done similarly to those belonging to the primary objective 
(except the Success Criteria described in section 12.5.1.5). More specifically, the analyses 
described as primary estimand (see section 12.5.1.4) can be repeated, replacing the 
endpoints listed in Table 3 by those of Table 4 and performing the analysis by THS arm 
sequentially. 
The evaluation of the key secondary objectives will be done using a procedure of fixed 
sequence testing (see Figure 3). This first key secondary objective related to the THS Blade 
device will only be tested if the primary objective is demonstrated for all THS arms. This 
fixed sequence of study hypotheses ensures that the overall study-wise risk of type I error 
is preserved at the 2.5% (see section 12.9.3).  
If both the primary and first key secondary objectives are declared successful, then the 2nd 
key secondary objective will be tested with type I error level of 2.5%, this time using the 
contrast THS Induction Mono device vs. CIG and the BoExp listed in Table 4. If this 2nd 
key secondary objective is also declared successful, then the 3rd key secondary objective 
can be tested similarly, this time with the BoExp listed in Table 4 for the THS Induction 
Mid device arm. If, along the procedure from the primary objective up to the 3rd key 
secondary objective, any of the objectives are not declared successful, the sequence testing 
will stop, and further testing will not be permitted. 

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Figure 3  
Representation of the Procedure of Fixed Sequence Testing 
Note that, at each level of testing, all BoExp need to lead to a statistically significant test. 
If the statistical test for one of the BoExp for the given arm (or combination of arm) does 
not reach statistical significance (at the 2.5% level), then the corresponding level of testing 
cannot be declared successful, and the fixed sequence testing will stop. 
The formal testing procedure of this study will use the primary estimand based on the PP 
(see section 12.3.3). The procedure will be repeated exploratorily using the FAS (see 
section 12.3.1). 
12.7 Other Secondary Objective 
All safety analyses will be conducted on the SAF (inferential analyses will not be 
performed on safety endpoints). 
All safety data will be provided in listings by actual exposure arm, subject, and safety 
period. The safety periods are defined as: 
• 
Screening: from Screening visit to baseline  
• 
Exposure: from Day 1 to Day 5 11:00 PM  
• 
Follow-up: from end of Exposure period to end of Safety follow-up 
Unless otherwise specified, summaries will be produced by actual exposure arm and safety 
periods. 
Adverse event data will serve as the primary assessment of safety. Other safety variables 
monitored in this study will include vital signs (systolic and diastolic blood pressure, pulse 
rate, respiratory rate), ECG data, spirometry data, clinical chemistry, hematology, urine 
analysis safety panel, concomitant medications, body weight, and BMI. 

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The number and percentage of subjects with AEs and SAEs will be tabulated by the 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and 
preferred term (PT) for the safety population overall and by safety period. Summaries will 
also be presented for AEs leading to product discontinuation, AEs leading to study 
discontinuation, AEs by relatedness to product exposure (including expectedness) and 
relatedness to study procedures, AEs by severity, and AE by action taken related to the 
product. Tabulations will be performed for both the number of subjects experiencing an 
event and the number of events for the SAF. 
With respect to device malfunctions, the number and % of subjects with device events will 
be tabulated. The number and % of subjects with device events overall, leading to an AE, 
a SAE, discontinuation, or to non-adherence will also be tabulated. 
Descriptive statistics as defined in section 12.1.3 for actual values and changes from 
baseline will be produced for the following parameters: vital signs, ECGs, spirometry, 
clinical chemistry, hematology, urinalysis safety panel, body weight, and BMI. 
For the other exploratory objectives listed in section 3.3 (exploratory objectives 1, 2 and 
4), namely exploratory objectives related to description of NEQ, product use and product 
experience, descriptive statistics (see section 12.1.3) will be computed for both PP and FAS 
(see section 12.3). 
12.8 Interim Analysis 
In this study, no interim analysis is planned. 
12.9 Measures to Control Bias 
12.9.1 
Method for Assigning Subjects to Study Arms 
Randomization will be used to assign subjects to study arms. Given that the study is 
randomized, demographics and baseline characteristics are expected to be balanced 
between study arms. Nevertheless, sex and baseline value of the BoExp will be used as 
covariates in the statistical models (see sections 12.5.1.4, 12.5.2.4 and 12.6.1). 
12.9.2 
Blinding 
This is an open-label study. Therefore, the subjects and Investigators or designees or staff 
will be unblinded to the subject’s study arm. However, there will be a limited degree of 
blinding in the data review and data analysis process. PMP and contract research 
organization (CRO) personnel will be blinded to the self-selected groups as summarized in 
Table 12. 

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Table 12 
Blinding Scheme 
Blinded Study Personnel 
Blinded Data1  
End of Blinding Period  
PMP and CRO study statisticians  
Blinded to all BoExp data 
After the SAP finalization. 
PMP clinical scientists  
Blinded to all BoExp data 
After the SAP finalization 
1Blinded data will be made accessible to the blinded personnel by means of a dummy group or masking. As part of the PMP quality 
control (QC) activity, data listings will be reviewed by the CRO and PMP before database lock, with no access to the arm information. 
Full details will be available in the data review plan. 
Any PMP and CRO personnel who are not listed in the above table will not be blinded to 
the study data. 
Unblinded information will not be shared with the blinded study team, until the end of the 
blinding period. PMP will receive blinded and unblinded data for the pre-analysis data 
review as planned in the data review plan. Blinded data will be accessible by the blinded 
study personnel in a masked format or presented independently of the subject identifier to 
ensure that data cannot be associated to a subject. Unblinded data will only be reviewed by 
the unblinded study team. 
12.9.3 
Study Significance Level 
In this study, the overall familywise type I error will be preserved at the α-level of 2.5% (1-
sided tests will be conducted for the primary and key secondary study hypotheses). This 
will be done by using a fixed sequence of testing:  
• 
primary objective, then if significant 
• 
1st key secondary objective, then if significant 
• 
2nd key secondary objective, then if significant 
• 
3rd key secondary objective 
All objectives will be tested at the 2.5% type I error level until one of the objectives is 
rejected and no further testing will be performed (in this case, only subsequent exploratory 
testing will be conducted). 
The primary study hypothesis (as assessed using the primary estimand defined in 
section 12.5.1) will be tested one-sided with a type I error α-level of 2.5%. The associated 
1-sided 97.5% confidence interval will be provided. This will be applied to all BoExp of 
Table 3 that are part of the primary study hypothesis (every BoExp for each THS arms need 
to pass for the objective to be considered demonstrated). 
If the primary study hypothesis is demonstrated, the same α-level of 2.5% will be used for 
the 1st key secondary hypothesis and the associated 1-sided 97.5% confidence interval will 
be provided. This will be applied to all BoExp of Table 4 that are part of the 1st key 
secondary study hypothesis (all need to pass for the THS Blade device arm versus CIG for 
the 1st key secondary objective to be successful). 

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If the primary study hypothesis is not demonstrated, the 1st key secondary hypothesis (and 
all subsequent key secondary objectives) will be considered exploratory and conducted 
2-sided at the α-level of 5% and the associated 2-sided 95% confidence interval will be 
provided.  
The analysis will proceed in a similar way for the following key secondary objectives.   
For all the exploratory objectives, the statistical tests will be considered exploratory, 
2-sided, and conducted at the α-level of 5%. Associated 2-sided 95% confidence intervals 
will be provided. 
12.9.4 
Determination of Sample Size and Power Consideration 
In this study, 80 healthy smokers will be randomized in a 1:1:1:1 randomization ratio 
stratified by sex with an overeall quota of 40% per sex to:  
• 
THS Blade device arm 
• 
THS Induction Mono device arm 
• 
THS Induction Mid device arm  
• 
CIG arm  
Based on four previous similar studies conducted by PMP on the tobacco heating system 
(ClinicalTrials.gov identifiers are NCT01970995, NCT01989156, NCT01959932, and 
NCT01970982, respectively), Table 13 contains estimates of geometric mean ratios (GMR) 
and associated coefficients of variations (GCV) for the (adjusted) contrast of a tobacco 
heating system against CIG. The effect of THS is expected to be similar on the selected 
BoExp. In addition, based on these studies, a conservative estimation of 15% of missing 
values may be expected for various reasons (e.g., withdrawals, mis-randomization, etc.). 
Using the statistics displayed in Table 13, the sample size planned for this study accounting 
for 15% of missing values (resulting in 20 subject for each THS arms and 20 subjects in 
CIG arms, respectively), and a one-sided two-sample t-test (on the log-scale) with 2.5% 
type I error probability, the estimated power for each BoExp is displayed in Table 13. By 
multiplying the power for each individual BoExp over the four to be tested in the primary 
hypothesis (per study), a global estimate of power for each THS arm is obtained. Assuming 
independence of the THS arms, the overall power of the study is equal or larger than 97% 
=99%3 (to account for the 3 THS arms) for the primary objective 
Note that 10’000 simulations of one-sided two-sample t-test were also conducted to 
determine the 90 percentiles of the (upper) half-width of the 97.5%-confidence interval 
(CI) of the ratio between THS arms and CIG, as well as the 90 percentiles of the upper 
bounds of these CIs. These are also displayed in Table 13. These provide indications on the 
expected precision on the estimates of the ratios. Table 13 shows that the power of this 
study for the primary objective is expected to be at least 99%. 

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Table 13  
Power Computation for Primary Objective 
NCT 
(Region) 
Endpoint 
GMR (%) 
GCV (%) 
Individual 
Power 
Study-
wise 
Power 
90%ile of 
the upper 
half width 
of the 
95%-CI 
90%ile of 
the upper 
bound of 
the 95%-CI 
1970995 
(JP) 
3-HPMA 
50.67 
32.72 
>99% 
>99% 
16.0 
69.6 
2-CyEMA 
18.23 
32.43 
>99% 
6.2 
27.8 
COHb 
44.94 
17.24 
>99% 
7.2 
55.6 
MHBMA 
13.49 
58.68 
>99% 
10.1 
28.6 
Total NNAL 
43.69 
26.09 
>99% 
11.9 
60.6 
1989156 
(US) 
3-HPMA 
45.77 
36.45 
>99% 
>99% 
17.4 
68.0 
2-CyEMA 
17.21 
45.68 
>99% 
9.9 
35.0 
COHb 
38.14 
26.5 
>99% 
10.3 
51.4 
MHBMA 
12.58 
76.92 
>99% 
15.9 
35.4 
Total NNAL 
43.81 
40.7 
>99% 
18.7 
69.7 
1959932 
(EU) 
3-HPMA 
41.63 
26.1 
>99% 
>99% 
11.1 
53.4 
2-CyEMA 
13.16 
34.41 
>99% 
4.0 
18.6 
COHb 
23.45 
16.84 
>99% 
3.8 
28.5 
MHBMA 
8.38 
54.57 
>99% 
5.6 
18.2 
Total NNAL 
43.54 
27.13 
>99% 
11.8 
61.8 
1970982 
(JP) 
3-HPMA 
52.86 
39.57 
>99% 
>99% 
21.4 
79.5 
2-CyEMA 
21.21 
43.16 
>99% 
9.5 
33.1 
COHb 
47.1 
16.08 
>99% 
6.9 
56.1 
MHBMA 
23.09 
64.59 
>99% 
14.6 
43.0 
Total NNAL 
49.03 
42.51 
>99% 
22.8 
77.1 
Of note, the GMR and GCV are assumptions extracted from the corresponding trial. The 
columns: individual power and study-wise power are computed through standard formulas.  
The columns: 90%ile of the upper half width of the 95%-CI and 90%ile of the upper bound 
of the 95%-CI are simulated values with 20 subjects per arms. The 90%ile of the upper half 
width of the 95%-CI is a simulated estimate of the precision for the corresponding BoExp. 
The 90%ile of the upper bound of the 95%-CI is a simulated estimate of the upper bound 
of the 95%-CI for the corresponding BoExp. Due to the independence of the distributions 
of the estimates, one cannot deduce the 90%ile of the upper bound of the 95%-CI with the 
GMR and the 90%ile of the upper half width of the 95%-CI. 

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A similar reasoning and assumptions for the key secondary objectives can be made. Table 
14 displays the power estimates for the key secondary hypothesis. As one can see, each 
THS arm thus each key secondary objective has a power of at least 99%. By multiplying 
the power for each objective (≈ 99%) across all 6 objectives (1 primary (union of 3 
objectives) + 3 key secondary), the power for all objectives altogether is then estimated to 
be at least 94% (= 0.94 ≈ 0.996, assuming independence of the 6 objectives with a 99% 
power).  
Table 14  
Power Computation for Key Secondary Objectives 
Study 
Endpoint 
GMR 
(%) 
GCV 
(%) 
Power 
Overall 
Power 
90%ile of the 
upper half width 
of the 95%-CI 
90%ile of the 
upper bound 
of the 95%-CI 
1970995 (JP) 
2-NA 
13.66 
33.99 
>99% 
>99%
5.6 
21.5 
3-HMPMA 
43.06 
35.59 
>99% 
18.5 
72.2 
3-OH-B[a]P 
27.19 
43.93 
>99% 
12.9 
46.4 
4-ABP 
20.10 
44.68 
>99% 
8.2 
31.1 
HEMA 
50.14 
34.79 
>99% 
14.8 
63.2 
S-PMA 
10.97 
46.63 
>99% 
7.2 
22.0 
Total NNN 
27.02 
61.84 
>99% 
23.6 
59.9 
1989156 (US) 
2-NA 
12.78 
51.37 
>99% 
>99%
7.6 
23.7 
3-HMPMA 
38.26 
53.56 
>99% 
21.7 
67.8 
3-OH-B[a]P 
28.94 
54.77 
>99% 
24.2 
67.7 
4-ABP 
19.47 
63.66 
>99% 
14.4 
38.1 
HEMA 
38.67 
55.45 
>99% 
24.2 
74.5 
S-PMA 
12.58 
69.68 
>99% 
9.6 
23.5 
Total NNN 
14.06 
78.93 
>99% 
12.2 
27.6 
1959932 (EU) 
2-NA 
11.54 
36.52 
>99% 
>99%
4.0 
16.9 
3-HMPMA 
22.54 
30.76 
>99% 
6.5 
31.4 
3-OH-B[a]P 
27.50 
46.17 
>99% 
14.0 
44.1 
4-ABP 
14.94 
40.4 
>99% 
6.4 
23.5 
HEMA 
32.00 
45.75 
>99% 
18.0 
60.6 
S-PMA 
5.99 
37.3 
>99% 
2.0 
8.3 
Total NNN 
24.12 
95.15 
>99% 
27.2 
55.6 
1970982 (JP) 
2-NA 
17.62 
49.52 
>99% 
>99%
9.0 
30.1 
3-HMPMA 
37.71 
49.07 
>99% 
21.3 
63.3 
3-OH-B[a]P 
29.99 
52.2 
>99% 
19.4 
51.9 
4-ABP 
18.21 
48.07 
>99% 
9.5 
31.3 
HEMA 
46.50 
44.34 
>99% 
24.7 
81.0 
S-PMA 
15.68 
49.76 
>99% 
8.2 
25.5 
Total NNN 
30.06 
67.69 
>99% 
23.6 
65.2 

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Of note, the GMR and GCV are assumptions extracted from the corresponding trial. The 
columns: individual power and study-wise power are computed through standard formulas.  
The columns: 90%ile of the upper half width of the 95%-CI and 90%ile of the upper bound 
of the 95%-CI are simulated values with 20 subjects per arms.  
The 90%ile of the upper half width of the 95%-CI is a simulated estimate of the precision 
for the corresponding BoExp. The 90%ile of the upper bound of the 95%-CI is a simulated 
estimate of the upper bound of the 95%-CI for the corresponding BoExp. Due to the 
independence of the distributions of the estimates, one cannot deduce the 90%ile of the 
upper bound of the 95%-CI with the GMR and the 90%ile of the upper half width of the 
95%-CI. 

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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 investigator(s) and site(s) 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 year 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 in the study 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 Investigator(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, and 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 [2] and any other applicable 
local or national regulations.  
Essential documents must be retained by the Investigator for a minimum of: 
• At least 25 years after completion or discontinuation of the study. 
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. 
• 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). 
• Device issue log, IP accountability logs, dispensing records. 
• Information regarding subjects’ discontinuation and any follow-up. 

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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(s)/study site(s) must take measures to prevent accidental or premature destruction 
of these documents. 
If the PI(s) wish(es) to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
The PI(s) 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(s). If a 
Principal Investigator 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 for 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 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/IRB 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. 
13.6 Financial Disclosure 
Investigator(s) are required to provide financial disclosure information to the Sponsor. In 
addition, the Investigators must provide to the Sponsor a commitment to promptly update 
this information if any relevant changes occur during the course of 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 

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law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
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 participants 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. 

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14 Reference List 
1. 
ICH E9 (R1), Addendum on estimands and sensitivity analysis in clinical trials to 
the guideline on statistical principles for clinical trials - Step 5. 2020. 
2. 
ICH E6 (R2), Integrated addendum to ICH E6 (R1): guideline for good clinical 
practice - Current Step 4 version dated 9 November 2016. 2016. Available from: 
https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf 
(Accessed 
on 17 January 2020). 
3. 
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). 
4. 
U.S. Department of Health and Human Services, The health consequences of 
smoking - 50 years of progress: a report of the Surgeon General. 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. 
Food and Drug Administration (FDA), FDA News Release, July 7 2020: FDA 
Authorizes Marketing of IQOS Tobacco Heating System with ‘Reduced Exposure’ 
Information. 2020. 
8. 
Raw, M., et al., WHO Europe evidence based recommendations on the treatment of 
tobacco dependence. Tob Control, 2002. 11(1): p. 44-6. 
9. 
WHO Study Group, et al., The scientific basis of tobacco product regulation: 
second report of a WHO study group. World Health Organ Tech Rep Ser, 
2008(951): p. 1-277. 
10. 
U.S. Department of Health and Human Services and FDA (Food and Drug 
Administration), [Docket No. FDA-2012-N-0143]: harmful and potentially harmful 
constituents in tobacco products and tobacco smoke; established list. Federal 
Register, 2012. 77(64): p. 20034-37. 
11. 
FDA (Food and Drug Administration), Guidance for industry - Reporting harmful 
and potentially harmful constituents in tobacco products and tobacco smoke under 
Section 904(a)(3) of the Federal Food, Drug, and Cosmetic Act - Draft guidance. 
2012. 
12. 
FDA (Food and Drug Administration), Guidance for industry - Patient-reported 
outcome measures: use in medical product development to support labeling claims. 
2009. 

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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. 
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. 
14. 
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. 
15. 
Cappelleri, J.C., et al., Confirmatory factor analyses and reliability of the modified 
cigarette evaluation questionnaire. Addictive Behaviors, 2007. 32: p. 912–923. 
16. 
Salzberger, T., et al., Psychometric evaluation of the mCEQ applied to cigarettes 
and heat-notburn products in the US and Japan. 2018. Poster presented at the 
Society for Research on Nicotine and Tobacco Annual Meeting, Baltimore, 
MD, 
USA. 
Available 
from: 
https://www.pmiscience.com/library/publication/psychometric-evaluation-of-
the-mceq-applied-to-cigarettes-and-heat-notburn-products-in-the-us-and-
japan (Accessed on 16 April 2018). 
17. 
FDA (Food and Drug Administration), Food-effect bioavailability and fed 
bioequivalence studies. 2002. 
18. 
U.S. Department of Health and Human Services, Treating tobacco use and 
dependence: 2008 update. Clinical practice guideline. 2008. Available from: 
http://bphc.hrsa.gov/buckets/treatingtobacco.pdf (Accessed on 18 July 2014). 
19. 
U.S. Department of Health and Human Services, Helping smokers quit. A guide for 
clinicians. 2008. 
20. 
Miller, M.R., et al., Standardisation of spirometry. Eur Respir J, 2005. 26(2): p. 
319-38. 
21. 
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. 
22. 
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. 
23. 
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. 
24. 
Chrea, C., et al., Developing fit-for-purpose self-report instruments for assessing 
consumer responses to tobacco and nicotine products: the ABOUT Toolbox 
initiative. F1000Res, 2018. 7: p. 1878. 
25. 
Hatsukami, D.K., et al., Subjective responses to oral tobacco products: scale 
validation. Nicotine Tob Res, 2013. 15(7): p. 1259-64. 
 

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Appendices 
 

 
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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 
 
Screening 
Confinement Period 
Early 
termination h 
Safety 
follow-up 
Visit (Time Window) 
 
Admission g 
Baseline 
Exposure period 
Discharge 
 
+ 3 days post 
Discharge 
Study Day 
-30 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6 
 
7 to 9 
Informed consent for study participation   
● 
 
 
 
 
 
 
 
 
 
 
Information smoking risks; smoking 
cessation advice, and THS briefing  
● 
● 
 
 
 
 
 
 
● 
● 
 
Identification of current cigarette brand  
● 
Inclusion/exclusion criteria a 
● 
● 
THS demonstration  
● 
Demographics   
● 
Medical history, concomitant diseases  
● 
Concomitant disease status 
 
● 
● 
● 
● 
● 
● 
● 
● 
Prior/concomitant medication  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
●i 
B: HIV, HBV and HCV  
● 
U: Cotinine test  
● 
● 
U: Drug screen b 
● 
● 
U: Pregnancy test  
● 
● 
 
 
 
 
 
 
● 
● 
 
U: Safety Panel urine analysis 
● 
 
● 
 
 
 
 
 
● 
● 
 
B: Safety panel hematology clinical 
chemistry 
● 
 
● 
 
 
 
 
 
● 
● 
 

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Screening 
Confinement Period 
Early 
termination h 
Safety 
follow-up 
Visit (Time Window) 
 
Admission g 
Baseline 
Exposure period 
Discharge 
 
+ 3 days post 
Discharge 
Study Day 
-30 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6 
 
7 to 9 
Alcohol breath test  
● 
 
 
 
 
 
 
 
 
 
 
Vital signs c 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Physical examination  
● 
 
 
 
 
 
 
 
 
 
 
Body height and weight d 
● 
● 
 
 
 
 
 
 
 
 
 
Spirometry 
● 
 
● 
 
 
 
 
 
● 
● 
 
Electrocardiogram 
● 
 
● 
 
 
 
 
 
● 
● 
 
THS product test 
 
● 
 
 
 
 
 
 
 
 
 
Enrolment  
 
● 
 
 
 
 
 
 
 
 
 
Tobacco/nicotine product use history e  
● 
● 
 
 
 
 
 
 
 
 
 
FTND 
 
 
● 
 
 
 
 
 
 
 
 
Randomization 
 
 
● 
 
 
 
 
 
 
 
 
Informing subjects about allocated 
 
 
 
● 
 
 
 
 
 
 
 
Collection of cigarette butts 
 
 
● 
● 
● 
● 
● 
● 
 
 
 
Collection of used THS sticks 
 
 
 
● 
● 
● 
● 
● 
 
 
 
B: BoExp in blood: COHb 
 
 
● 
● 
● 
● 
● 
● 
 
 
 
U: 24-h urine for BoExp (see below)  
 
 
● 
● 
● 
● 
● 
● 
 
 
 
ABOUT–Product Experience 
 
 
● 
● 
● 
● 
● 
● 
 
 
 
AE/SAE recording f 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
THS product events and complaints 
 
● 
 
● 
● 
● 
● 
● 
● 
● 
 
Abbreviations: ABOUT = Assessment of Behavioral OUtcomes related to Tobacco and Nicotine Products; AE = Adverse event; B = Blood sample required; BMI = Body mass 
index; BoExp = Biomarker(s) of exposure; COHb = Carboxyhemoglobin; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = Human immunodeficiency virus; SAE = 
Serious adverse event; FTND = Fagerström Test for nicotine dependence; U = Urine sample required.  

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a) 
On Day -2 (admission), after eligibility criteria are re-checked, eligible subjects will be enrolled and perform a product test using 2 THS devices. After the product test, subjects 
not willing to use THS will be discontinued.  
b) 
Urine will be screened for the following drugs: amphetamine type substances, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, and methadone.  
c) 
Systolic and diastolic blood pressure, pulse rate, and respiratory rate.  
d) 
Height will be recorded at Screening visit only and will serve as Baseline value.  
e) 
Tobacco/nicotine product use history: average of daily cigarette consumption recorded at Screening visit and Admission Day -2 will serve as Baseline values. 
f) 
Spontaneous reporting of new AEs/SAEs by the subject and active follow-up of ongoing AEs/SAEs by the site. During the Safety follow-up period, only medication taken for 
the treatment of AEs will be recorded.  
g) 
Provided the 28-day Screening period has not exceeded, alternate subjects have to repeat the Admission visit Day -2of the following group to re-confirm their eligibility for 
randomization. 
h) 
If a subject is discontinued from the study, listed Early termination procedures are performed unless the subject refuses to perform the assessments or is Lost to follow-up.  
i) 
Only medication used for AE treatment 
 
Schedule and Sampling Start of 24-hour Urine Collections 
 
Baseline   
Confinement Exposure Period   
Study Day  
Day -1  
Day 1  
Day 2  
Day 3  
Day 4  
Day 5  
BoExp and creatinine in 24-h urine  
●  
●  
●  
●  
●  
●  
Bio-banking samples a   
● 
● 
● 
● 
● 
● 
Abbreviations: BoExp = Biomarker(s) of exposure 
a) 
Collected only if subject has signed optional ICF (section Error! Reference source not found.). 
 

 
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 B 
Participating Laboratories  
 
Safety Laboratory 
 
 
 
 
 
Bioanalytical Laboratory 
 
 
 
 

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Appendix C 
Clinical Laboratory 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 (WBC) 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  
- 
Fasting glucose*  
- 
Lactate dehydrogenase  
- 
Potassium  
- 
Sodium  
- 
Total bilirubin  
- 
Direct bilirubin  
- 
Total cholesterol  
- 
Triglycerides  
 
- 
pH  
- 
Bilirubin  
- 
Glucose  
- 
Nitrite  
- 
Red blood cell traces  
- 
Protein  
- 
Specific gravity 
 
* Except at Screening visit or Early termination visit when non-fasting glucose can be assessed   
 
 

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