A Randomized, Controlled, Open-label, 3-arm Parallel Group, Multi-center Study to Demonstrate Reductions in Exposure to Selected Smoke Constituents in Apparently Healthy Smokers Switching to the Tobacco Heating System 2.2 Menthol (THS 2.2 Menthol) or Observing Smoking Abstinence, Compared to Continuing to Use Menthol Conventional Cigarettes, for 5 Days in Confinement and Prolonged by 86 Days in an Ambulatory Setting
Phase: NA
Conditions: Smoking
Sponsor: Philip Morris Products S.A.

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Clinical Study Protocol 
ZRHM-REXA-08-US 
 
Study title: 
A randomized, controlled, open-label, 3-arm parallel group, 
multi-center study to demonstrate reductions in exposure to 
selected smoke constituents in apparently healthy smokers 
switching to the Tobacco Heating System 2.2 Menthol (THS 2.2 
Menthol) or observing smoking abstinence, compared to 
continuing to use menthol conventional cigarettes, for 5 days in 
confinement and prolonged by 86 days in an ambulatory setting  
Short title: 
Reduced exposure study using THS 2.2 Menthol with 5 days in a 
confinement setting followed by 86 days in an ambulatory setting  
Registration number: 
Not assigned 
Study number 
ZRHM-REXA-08-US 
Product name: 
Tobacco Heating System 2.2 Menthol (THS 2.2 Menthol)  
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland  
Version number: 
Final 5.0 
Revision date: 
14 April 2014 
Authors: 
 PhD, Manager Clinical Science 
 MEng MSc, Biostatistician 
, MD, Medical Safety Officer  
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and 
confidential commercial information, and the legal protections provided to such trade secrets and 
confidential information are hereby claimed under the provisions of United States law. No part of this 
document may be publicly disclosed without the written consent of Philip Morris International. 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
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Final 5.0/14 April 2014 
Page 2 of 197 
 
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SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Product Name:  
Tobacco Heating System 2.2 Menthol (THS 2.2 Menthol) 
Study Title: 
A randomized, controlled, open-label, 3-arm parallel group, multi-center study to 
demonstrate reductions in exposure to selected smoke constituents in apparently healthy 
smokers switching to the Tobacco Heating System 2.2 Menthol (THS 2.2 Menthol) or 
observing smoking abstinence, compared to continuing to use menthol conventional 
cigarettes, for 5 days in confinement and prolonged by 86 days in an ambulatory setting  
Study Number: 
ZRHM-REXA-08-US 
Short Study Title: 
Reduced exposure study using THS 2.2 Menthol with 5 days in a confinement setting and 
86 days in an ambulatory setting 
Primary Objectives: 
The primary objectives of this study are:  
• To demonstrate the reduction of primary biomarkers of exposure (BoExp) (Table S1) 
to harmful and potentially harmful constituents (HPHCs) (except Total 4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanol) (Total NNAL)) in a confinement setting 
in smokers switching from menthol conventional cigarettes (mCC) to THS 2.2 
Menthol as compared to smokers continuing to smoke mCC, and 
• To demonstrate the reduction of Total NNAL in an ambulatory setting in smokers 
switching from mCC to THS 2.2 Menthol as compared to smokers continuing to 
smoke mCC (Table S1). 

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Secondary Objectives: 
The secondary objectives of this study are:  
• To evaluate self-reported nicotine/tobacco product use including dual-use in an 
ambulatory setting in smokers switching from mCC to THS 2.2 Menthol as compared 
to smokers continuing to smoke mCC and to smoking abstinence (SA). 
• To determine the reduction of secondary BoExp in a confinement setting and in an 
ambulatory setting in smokers switching from mCC to THS 2.2 Menthol as compared 
to smokers continuing to smoke mCC. 
• To describe the levels of primary and secondary BoExp over the entire exposure 
period (confinement and ambulatory periods) in smokers switching from mCC to 
THS 2.2 Menthol as compared to smokers continuing to smoke mCC and to SA.  
• To determine the levels of nicotine over the entire exposure period (confinement and 
ambulatory periods) in smokers switching from mCC to THS 2.2 Menthol as 
compared to smokers continuing to smoke mCC and to describe their levels over the 
entire exposure period. 
• To describe the pharmacokinetic (PK) profiles of the nicotine and cotinine in a 
confinement setting in smokers switching from mCC to THS 2.2 Menthol as 
compared to smokers continuing to smoke mCC. 
• To describe the change in Cytochrome P450 1A2 (CYP1A2) enzymatic activity in 
smokers switching from mCC to THS 2.2 Menthol as compared to smokers 
continuing to smoke mCC and to SA. 
• To determine the changes in lung functions in smokers switching from mCC to THS 
2.2 Menthol as compared to smokers continuing to smoke mCC 
• To monitor the safety profiles during the study. 
• To monitor selected risk markers in a confinement and ambulatory setting in smokers 
switching from mCC to THS 2.2 Menthol as compared to smokers continuing to 
smoke mCC and to SA. 
Exploratory Objectives: 
The exploratory objectives of this study are: 
• To describe the following parameters in a confinement and/or ambulatory setting in 
smokers switching from mCC to THS 2.2 Menthol as compared to smokers 
continuing to smoke mCC and to SA: 
• Excretion of mutagenic material in urine.  

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• Subjective effect of smoking. 
• Cytochrome P450 2A6 (CYP2A6) activity.  
• To describe the following parameters over the course of the study in smokers 
switching from mCC to THS 2.2 Menthol as compared to smokers continuing to 
smoke mCC: 
• Product evaluation. 
• Smoking puffing behavior. 
• To describe the following parameter over the course of the study in smokers 
switching from mCC to THS 2.2 Menthol: 
• Potential combustion occurrences in tobacco plugs. 
• To describe the changes in levels of oxysterols on Day 6 and Day 90 Visit in smokers 
switching from mCC to THS 2.2 Menthol, and in smokers switching from mCC to 
SA. 
• To describe the product use over the course of the study according to the product 
preference of the subject. 
• To describe the smokers’ mental state for the intention to quit at Screening, on 
Day -2, Day 30 Visit, Day 60 Visit, and Day 90 Visit. 
• To describe the changes and reductions in the levels of urinary BoExp and risk 
markers measured in 4-hour urine fraction on Day 90 Visit in smokers switching from 
mCC to THS 2.2 Menthol as compared to smokers continuing to smoke mCC and to 
SA. 
• To evaluate in smokers switching from mCC to THS 2.2 Menthol, and smokers 
continuing smoking mCC the relationship between1 : 
• Primary and secondary BoExp and nicotine equivalents (NEQ).  
• To determine the concordance between the results for BoExp and risk markers in 24-
hour urine and in 4-hour urine fraction 2. 
• To monitor the BoExp in subjects quitting smoking according to the time since they 
quitted 2.  
1 The reporting of the objective will be the subject of a separate report. 
2 The reporting of the objective will be the subject of an appendix to the main Clinical Study Report. 

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Study Hypothesis: 
The hypothesis to be tested is that the geometric mean level of the BoExp for THS 2.2 
Menthol is lower relative to mCC. 
For primary BoExp, the hypothesis will be tested on Day 5 for monohydroxylbutenyl-
mercapturic acid (MHBMA), 3-hydroxypropylmercapturic acid (3-HPMA), S-
phenylmercapturic acid (S-PMA), and carboxyhemoglobin (COHb), and on Day 90 Visit 
for Total NNAL according to the primary and secondary objectives. For the secondary 
BoExp, the hypothesis will be tested on Day 5, and if significant, on Day 90. 
 
Study Endpoints: 
The primary and secondary BoExp to harmful and potentially harmful constituents (HPHCs) 
measured in the study are presented in Table S1 below:  
Table S1: Biomarkers of Exposure 
 
Biomarkers of Exposure (BoExp) 
HPHCs 
Matrix 
Primary 
BoExp on 
Day 5 
monohydroxybutenylmercapturic acid (MHBMA) 
1,3-butadiene 
Urine 
3-hydroxypropylmercapturic acid (3-HPMA) 
acrolein 
Urine 
S-phenylmercapturic acid (S-PMA) 
benzene 
Urine 
carboxyhemoglobin (COHb)  
carbon monoxide (CO) 
Blood 
Primary 
BoExp on 
Day 90 
Visit 
total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
(Total NNAL) 
4 (methylnitrosamino)-
1-(3-pyridyl)-1butanone 
(NNK) 
Urine 
Secondary BoExp 
carbon monoxide  
CO 
Exhaled 
breath 
total 1-hydroxypyrene (1-OHP) 
pyrene 
Urine 
total N-nitrosonornicotine (NNN) 
N-nitrosonornicotine 
Urine 
4-aminobiphenyl (4-ABP) 
4-aminobiphenyl 
Urine 
1-aminonaphthalene (1-NA) 
1-aminonaphthalene 
Urine 
2-aminonaphthalene (2-NA) 
2-aminonaphthalene 
Urine 
o-toluidine (o-tol) 
o-toluidine 
Urine 
2-cyanoethylmercapturic acid (CEMA) 
acrylonitrile 
Urine 
2-hydroxyethylmercapturic acid (HEMA) 
ethylene oxide 
Urine 
3-hydroxybenzo(a)pyrene 
benzo(a)pyrene 
Urine 

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3-hydroxy-1-methylpropyl-mercapturic acid 
(HMPMA) 
crotonaldehyde 
Urine 
S-benzylmercapturic acid (S-BMA) 
toluene 
Urine 
BoExp to nicotine 
nicotine equivalents (NEQ) 
free nicotine, nicotine-glucuronide, free cotinine, 
cotinine-glucuronide, free trans-3’-hydroxycotinine, 
trans-3’-hydroxycotinine-glucuronide 
nicotine 
Urine 
nicotine 
nicotine 
Plasma 
cotinine 
nicotine 
Plasma 
 
Primary endpoints: 
• To demonstrate the reduction of primary BoExp to HPHCs (except Total NNAL) in a 
confinement setting in smokers switching from mCC to THS 2.2 Menthol as compared to 
smokers continuing to smoke mCC. 
• MHBMA, 3-HPMA, S-PMA (concentration adjusted for creatinine) in 24-hour urine, 
and COHb in blood (expressed as % of saturation of hemoglobin) as measured on 
Day 5. 
• To demonstrate the reduction of Total NNAL in an ambulatory setting in smokers 
switching from mCC to THS 2.2 Menthol as compared to smokers continuing to smoke 
mCC. 
• Total NNAL level (concentration adjusted for creatinine) in 24-hour urine fraction as 
measured on Day 90 Visit. 
Evaluation criterion:  
The study will be considered successful if the study demonstrates a 50% reduction or more 
in MHBMA, 3-HPMA, S-PMA, and COHb at Day 5 and in Total NNAL at Day 90 in 
smokers switching from mCC to THS 2.2 Menthol as compared to smokers continuing to 
smoke mCC, using a one-sided test with 2.5% type I error probability. 
Secondary endpoints 
• To evaluate self-reported nicotine/tobacco product use including dual-use in an 
ambulatory setting in smokers switching from mCC to THS 2.2 Menthol as compared to 
smokers continuing to smoke mCC and to SA.  
• Number of mCC or Menthol Tobacco Sticks smoked daily as reported on the usage 
log during the confinement period and self-reported number of any nicotine/tobacco 
product use on a daily basis as reported on the product use electronic diary. 

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• To determine the reduction of secondary BoExp in a confinement setting and in an 
ambulatory setting in smokers switching from mCC to THS 2.2 Menthol as compared to 
smokers continuing to smoke mCC. 
• BoExp listed as secondary (Table S1) (expressed as quantity excreted or 
concentration adjusted for creatinine) on Day 5 in 24-hour urine and on Day 90 Visit.  
• To describe the levels of primary and secondary BoExp over the entire exposure 
(confinement and ambulatory periods) in smokers switching from mCC to THS 2.2 
Menthol as compared to smokers continuing to smoke mCC and to SA. 
• BoExp listed as primary and secondary (Table S1) from Day 1 to Day 5 and Day 30 
Visit, Day 60 Visit and Day 90 Visit as follows: 
• Carbon monoxide (expressed as ppm) in exhaled breath.  
• COHb in blood (expressed as % saturation of hemoglobin). 
• Urinary BoExp (expressed as quantity excreted and concentration adjusted for 
creatinine) in 24-hour urine. 
• To determine the levels of nicotine over the entire exposure period (confinement and 
ambulatory periods) in smokers switching from mCC to THS 2.2 Menthol as compared 
to smokers continuing to smoke mCC and to describe their levels over the entire 
exposure period. 
• NEQ (expressed as quantity excreted and concentration adjusted for creatinine) 
(Table S1) in 24-hour urine from Day 1 to Day 5 and on Day 30 Visit, Day 60 Visit, 
and Day 90 Visit. 
• Nicotine and cotinine in plasma from Day 1 to Day 4, Day 5, and on Day 30 Visit, 
Day 60 Visit, and Day 90 Visit. 
• To describe the pharmacokinetic (PK) profiles of the nicotine and cotinine in a 
confinement setting in smokers switching from mCC to THS 2.2 Menthol as compared to 
smokers continuing to smoke mCC.  
• Peak (highest concentration along the day) on Day 5. 
• Time to peak (actual time when the peak was observed compared to the time of the 
first cigarette) on Day 5. 
• Weighted average concentration over 24 hours on Day 5 
• To describe the change in CYP1A2 enzymatic activity in smokers switching from mCC 
to THS 2.2 Menthol as compared to smokers continuing to smoke mCC and to SA. 
• Molar metabolic ratio of paraxanthine/caffeine in plasma on Day 5 and Day 90 Visit. 
• To determine the changes in lung functions in smokers switching from mCC to THS 2.2 

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Menthol as compared to those continuing to smoke mCC. 
• Full lung functions: Diffusion capacity for Lung CO (DLCO), rate constant of CO 
(KCO), forced expiratory volume in 1 second (FEV1), force vital capacity (FVC), 
vital capacity (VC), total lung capacity (TLC), forced residual volume (FRV), 
inspiratory capacity (IC), mid expiratory flow (25-75). 
• To monitor the safety profiles during the study. 
• Adverse events (AEs)/serious adverse events (SAEs) and device events including 
THS 2.2 Menthol malfunction/misuse. 
• Respiratory symptoms: cough assessment by visual analog scale (VAS) and Likert 
scales and one open question. 
• Vital signs. 
• Electrocardiogram (ECG). 
• Clinical chemistry, hematology, and urine analysis safety panel. 
• Physical examination. 
• Concomitant medications. 
• To monitor selected risk markers in a confinement and ambulatory setting in smokers 
switching from mCC to THS 2.2 Menthol as compared to smokers continuing to smoke 
mCC and to SA. 
• Systolic and diastolic blood pressure on Day 6, Day 30 Visit, Day 60 Visit, and Day 
90 Visit. 
• High sensitive C-reactive protein (hs-CRP), homocysteine, blood glucose, low 
density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (TG), and 
total cholesterol (TC) in serum on Day 30 Visit, Day 60 Visit, and Day 90 Visit.  
• Fibrinogen in plasma on Day 30 Visit, Day 60 Visit, and Day 90 Visit. 
• Hemoglobin A1c (HbA1c) in blood on Day 90 Visit. 
• Apolipoprotein A1 (Apo A1) and apolipoprotein B (Apo B) in serum on Day 90 
Visit. 
• Soluble inter-cellular adhesion molecule-1 (sICAM-1) in serum on Day 6, Day 30 
Visit, Day 60 Visit, and Day 90 Visit. 
• White blood cell (WBC) and platelet counts in blood on Day 6, Day 30 Visit, Day 60 
Visit, and Day 90 Visit. 
• 8-epi-prostaglandin 
F2α 
(8-epi-PGF2α) 
and 
11-dehydro-thromboxane 
B2 
(11-DTX-B2) in 24-hour urine on Day 5 and on Day 30 Visit, Day 60 Visit, and Day 

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90 Visit (expressed as concentration adjusted for creatinine). 
• Body weight and waist circumference on Day 90 Visit. 
Exploratory Endpoints 
• To describe the following parameters in a confinement and/or ambulatory setting in 
smokers switching from mCC to THS 2.2 Menthol as compared to smokers continuing to 
smoke mCC and to SA: 
• Excretion of mutagenic material in urine: Ames Mutagenicity test (YG1024+S9) on 
Day 5 and Day 90 Visit in 24 hour urine. 
• Subjective effect of smoking: Questionnaire of Smoking Urges (QSU-brief 
questionnaire); questionnaire Minnesota Nicotine Withdrawal Scale (MNWS)-
Revised on Day 5 and Day 90 Visit, and nicotine dependence as assessed by the 
Fagerström Test for Nicotine Dependence (FTND) questionnaire score on Day 90 
Visit. 
• CYP2A6 activity: in plasma on Day 6, and on Day 90 Visit using the molar 
metabolic ratio of trans-3’-hydroxycotinine/cotinine. 
• To describe the following parameters over the course of the study in smokers switching 
from mCC to the THS 2.2 Menthol as compared to smokers continuing to smoke mCC: 
• Product evaluation: Modified Cigarette Evaluation Questionnaire (MCEQ) 
• Smoking puffing behavior: Human smoking topography (HST) parameters and HST 
questionnaire. 
• To describe the following parameter over the course of the study in smokers switching 
from mCC to THS 2.2 Menthol: 
• Potential combustion occurrences in tobacco plugs: visual inspection of the tobacco 
plugs. 
• To describe the changes in levels of oxysterols on Day 6 and Day 90 Visit in smokers 
switching from mCC to THS 2.2 Menthol, and in smokers switching from mCC to SA: 
• Plasma concentration of 6α-hydroxy-5α-cholestanol, 7α-hydroxycholesterol, 5α,6α-
epoxycholestanol, 7-ketocholesterol, 7β-hydroxycholesterol, 5β,6β-epoxycholestanol, 
24(R)-hydroxycholesterol, 25-hydroxycholesterol, 22(R)-hydroxycholesterol, 4ß-
hydroxycholesterol, and 27-hydroxycholesterol in addition to total cholesterol. 
• To describe the product use over the course of the study according to the product 
preference of the subject. 
• Number of mCC or Menthol Tobacco Sticks smoked daily as reported on the usage 
log during the confinement period and self-reported number of any nicotine/tobacco 

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product use on a daily basis as reported on the product use electronic diary. 
• To describe the smokers’ mental state for the intention to quit at Screening on Day -2, 
Day 30 Visit, Day 60 Visit, and Day 90 Visit. 
• By the means of the Prochaska ‘Stage of Change’ questionnaire.  
• To describe the changes and reductions in the levels of urinary BoExp and risk markers 
measured in 4-hour urine fraction on Day 90 Visit in smokers switching from mCC to 
THS 2.2 Menthol as compared to smokers continuing to smoke mCC and to SA. 
• Urinary BoExp (expressed as quantity excreted and concentration adjusted for 
creatinine). 
• 8-epi-PGF2α and 11-DTX-B2 (expressed as quantity and concentration adjusted for 
creatinine). 
• To evaluate in smokers switching from mCC to THS 2.2 Menthol, smokers continuing 
smoking mCC the relationship between 1: 
• Primary and secondary BoExp and nicotine equivalents (NEQ) on Day 5 and on 
Day 90 Visit in 24-hour urine.  
• To determine the concordance between the results for BoExp and risk markers in 24-hour 
urine and in 4-hour urine fraction2: 
• MHBMA, 3-HPMA, S-PMA, total NNAL, total 1-OHP, total NNN, 4-ABP, 1-NA, 
2-NA, o-tol, CEMA, HEMA, 3-hydroxybenzo(a)pyrene, HMPMA, S-BMA, NEQ, 
(expressed as quantity excreted in 24-hour urine collection and concentration 
adjusted for creatinine in 4-hour urine fraction) at baseline and at Day 90 Visit. 
• 8-epi-PGF2α and 11-DTX-B2 (expressed as quantity excreted in 24-hour urine 
collection and concentration adjusted for creatinine in 4-hour urine fraction) at 
baseline and at Day 90 Visit. 
• To monitor the BoExp in subjects quitting smoking according to the time since they 
quitted2: 
• Carbon monoxide (expressed as ppm) in exhaled breath.  
• COHb in blood (expressed as % saturation of hemoglobin). 
• Urinary BoExp (expressed as quantity excreted and concentration adjusted for 
creatinine) in 24-hour urine. 
• NEQ (expressed as quantity excreted and concentration adjusted for creatinine). 
• Selected risk markers (hs-CRP, homocysteine, blood glucose, LDL, HDL, TG, 
TC, fibrinogen, HbA1c, sICAM-1, WBC, platelet count, Apo A1, Apo B, 8-epi-
PGF2, 11-DTX-B2) in respective body matrix when available. 

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1 The reporting of the objective will be the subject of a separate report. 
2 The reporting of the objective will be the subject of an appendix to the main Clinical Study Report. 
Study Design: 
A randomized, controlled, open-label, 3-arm, parallel group study design with a stratified 
randomization by sex and average daily cigarette consumption over the last 4 weeks as 
reported during the Screening Visit (smokers smoking 10 to 19 mCC and smokers smoking 
>19 mCC per day) (Figure S1). 
This is an ad libitum smoking study. In general, smoking/product use during the confinement 
period will be allowed from 06:30 AM onwards until around 11:00 PM. During the 
ambulatory period, there will be no smoking/product use restriction except during the three 
visits on site (Day 30 Visit, Day 60 Visit, and Day 90 Visit), when product use will be 
allowed from the time of check-in prior to 08:30 AM to around 11:00 PM on Day 30, Day 
60, and Day 90. On Day 31, Day 61, product use will be allowed from 06:30 AM onwards. 
On Day 91, product use will be allowed after the CYP2A6 activity and full lung function 
have been performed until time of discharge of Day 91. 
During the confinement period, compliance to product/regimen allocation (exclusive use of 
THS 2.2 Menthol and mCC in THS 2.2 Menthol and mCC arms respectively, and full 
abstinence from smoking in the SA arm) will be ensured by strict distribution of each 
Menthol Tobacco Stick/mCC when requested by the subject. During the ambulatory period, 
the subjects randomized to the THS 2.2 Menthol arm will be instructed to exclusively use 
THS 2.2 Menthol and subjects randomized to the SA arm will be instructed to abstain from 
smoking. 
Figure S1: Study Design 

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• The Screening period covers 4 weeks (Day -30 to Day -3) prior to Admission to the clinic 
(Day -2): 
A demonstration of the THS 2.2 Menthol will be done by the site staff during the 
Screening Visit. Subjects will be in a confined setting for 9 days from Day -2 onwards. 
• The run-in period (from Admission on Day -2 until 06:29 AM of Day-1): 
Smoking will be allowed ad libitum from the time of check-in of the subject until around 
11:00 PM. Prior to enrolment on Day -2, as the last procedure of the eligibility 
assessments, subjects will have a product test of the THS 2.2 Menthol (use of up to three 
THS Menthol Tobacco Sticks). In female subjects, the THS 2.2 Menthol product test 
will only be done after pregnancy is excluded by a negative urine pregnancy test. 
Enrolment takes place after all inclusion and exclusion criteria have been satisfactorily 
met. Only subjects willing and able to use the product will be enrolled in the study. 
• The baseline period (from Day -1, 06:30 AM until Day 1, 06:29 AM): 
All subjects will continue smoking their single preferred brand of mCC ad libitum. On 
Day -1 and Day 0, smoking will be allowed from 06:30 AM onwards until around 11:00 
PM. However, on Day 0, smoking will be allowed only after sample for CYP2A6, 
MNWS and cough questionnaires, and full lung functions have been conducted. Four-
hour urine fraction will be collected on Day-1. On Day 0, 24-hour urine will be collected 
starting in the morning and ending 24 hours later on Day 1. 
Day 6 to Day 90
Day -1, Day 0
Day -2
Admission
Baseline
Day 91 to Day 119
9 days in confinement
mCC 
ad 
libitum
Safety  follow-up
THS 2.2 Menthol 
and mCC ad libitum
Day 1 to Day 5
Screening*
85 days ambulatory
*Screening 
within 1-4 
weeks 
prior to 
admission
THS 2.2 Menthol
Smoking Abstinence
mCC
Abbreviations: mCC = Menthol conventional cigarette(s); THS = Tobacco Heating System; Figure not to scale.
THS 2.2 Menthol and mCC ad 
libitum
28 days follow-up
THS 2.2 Menthol
Smoking Abstinence
mCC
← Day 30/Day31
← Day 60/Day61
← Day 90/Day91
← Day 6
9 day confinement
86 day ambulatory
28 day follow-up
mCC: menthol conventional cigarettes; THS: Tobacco Heating System; figure not scale

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On Day 0, subjects will be randomized to 1 of the 3 study arms in a 2:1:1 ratio using a 
stratified randomization 
• THS 2.2 Menthol Arm: ~80 subjects, ad libitum use of the product. 
• mCC Arm: ~40 subjects, ad libitum use of their preferred mCC brand. 
• SA Arm: ~40 subjects who will abstain from smoking. 
Subjects will be informed of their randomized study arm by the study site staff on Day 1 
prior to 06:30 AM. 
• The exposure period (from Day 1, 06:30 AM until time of discharge on Day 90 Visit 
(Day 91)): 
The exposure period will include both the exposure period in confinement, and the 
exposure period in ambulatory setting: 
• The exposure period in the confinement setting (from Day 1, 06:30 AM until time of 
Discharge on Day 6): 
The exposure period in confinement consists of 5 days of ad libitum use of the 
assigned product from 06:30 AM onwards until around 11:00 PM in THS 2.2 
Menthol and mCC arms. Subjects allocated to the SA arm will be asked to abstain 
from smoking and will not be provided with medication to support SA. Subjects will 
be provided with psychological support during the period of SA. Use of any 
tobacco/nicotine-containing product other than the assigned product/regimen will not 
be allowed. 
Twenty four-hour urine will be collected from Day 1 to Day 5 on site. The end of the 
24-hour urine collection from Day 5 will end in the morning on Day 6 prior to 
Discharge.  
On Day 6, the safety procedures will be conducted before discharge of the subject 
from the clinic after 9 days in a confined setting. Use of products will be allowed on 
Day 6 in the THS 2.2 Menthol and mCC arms according to product arm allocation, 
but only after the sample for CYP2A6 activity, MNWS and cough questionnaires, and 
full lung function have been performed.  
• The exposure period in ambulatory setting (from time of Discharge on Day 6 until the 
time of Discharge on Day 90 Visit (Day 91)): 
At the end of the confinement period prior to Discharge on Day 6, subjects will be 
instructed to continue their assigned product/regimen in an ambulatory setting for 86 
days. All subjects in the SA arm will receive smoking cessation counseling and will 
be able to use nicotine replacement therapy (NRT) if considered necessary by the 
Investigator or requested by the subject.  

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Subjects will be required to make three visits (Day 30 Visit, Day 60 Visit, and Day 90 
Visit) to the investigational site. Each visit will cover 2 consecutive days on site. For 
Day 30 Visit and Day 60 Visit, the subject will check-in in the morning prior to 08:30 
AM on Day 30 and Day 60, and will check-out on Day 31 and Day 61 respectively. 
For Day 90 Visit, the subject will checked-in in the morning prior to 08:30 AM on 
Day 90, and will be discharged on Day 91 after having performed all the safety 
examination procedures.  
Twenty four-hour urine will be collected at each ambulatory visit on Day 30 Visit, 
Day 60 Visit, and Day 90 Visit at the site. The collection of 24-hour urine will start 
on Day 30, Day 60, and Day 90 respectively and will end 24-hours later. On Day 90 
visit only, the end of 24-hour urine collection will be followed by the collection of a 
4-hour urine fraction. 
On Day 30, Day 60, and Day 90, subjects in the THS 2.2 Menthol and mCC arms will 
be allowed to use their assigned product from the time of check-in in the morning 
prior to 08:30 AM to around 11:00 PM. On Day 31, Day 61, product use will be 
allowed from 06:30 AM. On Day 91, product use will be allowed only after the 
sample for CYP2A6 activity and full lung function have been performed until time of 
discharge of Day 91. The end of the exposure period will be fixed at the time of 
discharge of Day 91.  
During the visits, the use of THS 2.2 Menthol will be strictly forbidden for subjects in 
the mCC or SA arms. 
Subject will not be withdrawn from the study for the use of nicotine/tobacco-containing 
products other than the assigned product/regimen. Subjects will record in a product use 
electronic diary any use of CC (menthol or non-menthol), NRT, or other nicotine/tobacco-
containing products on a daily basis. 
During the confinement and ambulatory settings: 
• Subjects in the SA arm will be provided with support including psychological support 
as requested by the subject or considered necessary by the Investigator/site staff. 
• Any subject, who wants to quit smoking during the study taking into account the 
outcome from the Prochaska ‘Stages of Change’ questionnaire, will be encouraged to 
do so and will be referred to appropriate medical services. This will not affect 
subject’s financial compensation and subject will remain in the study. 
• The safety follow-up period (from time of Discharge on Day 90 Visit (Day 91) until 
Day 119): 
After the time of Discharge on the Day 90 Visit (Day 91), subject will enter a 28-day 
safety follow-up period during which there will be recording of spontaneously reported 
new AEs/SAEs and the active follow-up of ongoing AEs/SAEs by the study site. In 

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general, all AEs will be followed-up until resolved, stabilized (i.e., no worsening of the 
event), or a plausible explanation for the event has been found. The end of the study 
(EOS) is defined as the time of Discharge on Day 90 Visit (Day 91) plus 28-day follow-
up. 
Study Population and Main Criteria for Inclusion: 
Female or male smoking, apparently healthy adult subjects without any restriction to races 
and ethnicities, meeting the following main inclusion criteria: 
• Subject is aged with a minimum of 22 years(inclusive). 
• Smoking, apparently healthy subject as judged by the Investigator. 
• Subject smokes at least 10 commercially available mCC per day (no brand restrictions) 
for the last 4 weeks, based on self-reporting.  
• Subject has smoked for at least the last 3 consecutive years.  
• Subject does not plan to quit smoking within the next 6 months. 
• Subject is ready to comply with the study protocol (e.g., to accept interruption of 
smoking for up to 91 days and to use THS 2.2 Menthol). 
 
Investigational Products; Dose; and Mode of Use: 
Test Product: 
Tobacco Heating System 2.2 Menthol (THS 2.2 Menthol). 
Reference Product: 
The reference product to the THS 2.2 Menthol during the randomized exposure period is the 
subject’s own preferred commercially available single brand of mCC. 
Reference Point: SA. 
Sample size: 
Approximately one hundred and sixty smokers in the full analysis set (FAS) (~80 in THS 2.2 
Menthol arm, ~40 in mCC and ~40 in SA) are required to attain 80% power to show at least 
a 50% reduction for any of the selected primary BoExp in THS 2.2 Menthol compared to the 
mCC arm, using a one-sided test with 2.5% type I error probability. 

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Statistical Methods: 
Primary confirmatory endpoint: The hypothesis to be tested is that the geometric mean level 
of the BoExp for THS 2.2 Menthol is lower relative to mCC. 
For BoExp, the hypothesis will be tested on Day 5 for MHBMA, 3-HPMA, S-PMA, and 
COHb, and on Day 90 Visit for Total NNAL.  
The transformed BoExp data will be analyzed by means of a generalized linear model using 
product arm as covariate adjusting for the following baseline information: sex, average 
cigarette consumption over the previous 4 weeks, and baseline value of endpoint. The test 
will be declared significant if the contrast THS 2.2 Menthol versus mCC is significant. 
Estimates of differences between groups will be back-transformed to provide relative effects. 
Descriptive statistics for continuous variables (number of subjects [n], number and percent of 
subjects with data, mean, standard deviation [SD], median, first and third quartiles, minimum 
and maximum for continuous data, and the n and absolute and relative [%] frequency for 
categorical data) will be presented by product arm and overall at each time point, where 
applicable. 
For BoExp, the geometric mean and coefficient of variation will be presented in addition to 
the mean and SD. 
Analyses over time will be descriptive statistics of parameters at each assessment timepoint. 
Unless stated otherwise, all statistical tests will be two-sided and conducted at the 5% level, 
and all quoted confidence intervals (CI) will be two-sided 95% CI. 
The per-protocol (PP) population will be the primary analysis for BoExp, and risk markers. 
The full analysis set will be the primary analysis set for compliance to randomization arm, 
exposure and questionnaires. Exposure and questionnaires will be described by 
randomization arm and according to the exclusive THS 2.2 Menthol, dual-use of THS 2.2. 
Menthol and mCC, mCC exclusive, SA groups.  
A sensitivity analysis will be run on the compliant population for the BoExp and risk 
markers. 
The full analysis set will be also a supplemental analysis set for BoExp and risk markers.  
Safety will be analyzed using the safety population by randomization arm and according to 
the exclusive THS 2.2 Menthol, dual-use of THS 2.2 Menthol and mCC, mCC exclusive, SA 
groups. 

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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS .........................................................................................................17 
LIST OF IN-TEXT TABLES AND FIGURES .......................................................................19 
LIST OF APPENDICES ..........................................................................................................20 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................21 
1 
ETHICS AND REGULATIONS .....................................................................................28 
1.1 
Institutional Review Board Approval ....................................................................28 
1.2 
Ethical Conduct of the Study .................................................................................29 
1.3 
Subject Information and Consent...........................................................................29 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................31 
2 
INTRODUCTION ...........................................................................................................32 
2.1 
Background ............................................................................................................32 
2.2 
Purpose of the Study ..............................................................................................33 
2.3 
Anticipated Benefits and Risks ..............................................................................34 
3 
STUDY OBJECTIVES ....................................................................................................36 
3.1 
Primary Objectives.................................................................................................36 
3.2 
Secondary Objectives.............................................................................................36 
3.3 
Exploratory Objectives ..........................................................................................37 
3.4 
Study Endpoints .....................................................................................................38 
4 
INVESTIGATIONAL PLAN ..........................................................................................44 
4.1 
Overall Study Design and Plan ..............................................................................44 
4.2 
Rationale for Study Design and Control Groups ...................................................48 
4.3 
Appropriateness of Measurements .........................................................................51 
4.4 
Study Duration .......................................................................................................51 
5 
STUDY POPULATION ..................................................................................................52 
5.1 
Selection of Study Population ................................................................................52 
6 
INVESTIGATIONAL PRODUCTS ...............................................................................59 
6.1 
Description of Investigational Products .................................................................59 
6.2 
Use of Investigational Product(s)...........................................................................61 
6.3 
Method for Assigning Subjects to Study Arms .....................................................63 
6.4 
Blinding..................................................................................................................63 
6.5 
Investigational Product Accountability and Compliance ......................................64 
6.6 
Restrictions ............................................................................................................66 

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6.7 
Concomitant Medication ........................................................................................68 
7 
STUDY PROCEDURES .................................................................................................72 
7.1 
Informed Consent/Subject Information Sheet .......................................................72 
7.2 
Information on the Risk of Smoking and Smoking Cessation Advice and 
Debriefing ..............................................................................................................72 
7.3 
Support for the Smoking Abstinence Arm.............................................................73 
7.4 
Clinical Assessments .............................................................................................73 
7.5 
Biomarker Assessment...........................................................................................80 
7.6 
Laboratory Assessments ........................................................................................85 
7.7 
Sampling Handling and Storage ............................................................................87 
7.8 
Other Study Procedures .........................................................................................90 
8 
ADVERSE EVENTS .......................................................................................................99 
8.1 
Definitions..............................................................................................................99 
8.2 
Assessment of Adverse Events ..............................................................................99 
8.3 
Reporting and Follow-Up of Serious Adverse Events .........................................102 
8.4 
Reporting of Other Events Critical to Safety Evaluations ...................................103 
8.5 
Reporting and Follow-Up of Pregnancies............................................................104 
8.6 
Adverse Events Leading to Withdrawal ..............................................................105 
8.7 
Investigational Device Misuse .............................................................................105 
8.8 
Investigational Device Malfunction .....................................................................106 
9 
STUDY ACTIVITIES ...................................................................................................107 
9.1 
Screening Visit .....................................................................................................107 
9.2 
Confinement Period (Days -2 to 6) ......................................................................109 
9.3 
Ambulatory Period (from time of Discharge on Day 6 to Day 90 Visit) ............129 
9.4 
Safety Follow-up Period ......................................................................................138 
9.5 
Early Termination Procedures .............................................................................138 
10 CONTROL AND QUALITY ASSURANCE ...............................................................140 
10.1 
Monitoring ...........................................................................................................140 
10.2 
Training of Staff ...................................................................................................141 
10.3 
Audits and Inspections .........................................................................................141 
11 DATA MANAGEMENT ACTIVITIES........................................................................142 
11.1 
Data Capture ........................................................................................................142 
11.2 
Data Handling ......................................................................................................143 
12 PLANNED STATISTICAL METHODS ......................................................................145 
12.1 
General Considerations ........................................................................................145 

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12.2 
Determination of Sample Size and Power Consideration ....................................147 
12.3 
Product use ...........................................................................................................150 
12.4 
Analysis Population .............................................................................................153 
12.5 
Primary Analysis ..................................................................................................154 
12.6 
Secondary Analysis ..............................................................................................155 
12.7 
Exploratory Analysis ...........................................................................................156 
12.8 
Demographics and Baseline Characteristics ........................................................157 
12.9 
Interim Analysis ...................................................................................................157 
12.10 Preference Analysis .............................................................................................157 
13 ADMINISTRATIVE CONSIDERATIONS ..................................................................158 
13.1 
Investigators and Study Administrative Structure ...............................................158 
13.2 
Subject Confidentiality ........................................................................................160 
13.3 
Access to Source Documentation ........................................................................160 
13.4 
Record Retention .................................................................................................160 
13.5 
Clinical Study Report ...........................................................................................162 
13.6 
Financial Disclosure.............................................................................................162 
13.7 
Publication and Disclosure Policy .......................................................................163 
14 REFERENCE LIST .......................................................................................................164 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1:  
Biomarkers of Exposure ............................................................................38 
Table 2. 
Measured Aerosol Fractions for the Menthol Tobacco Sticks ...................60 
Table 3. 
Examples of Medications with Effects on CYP1A2 and CYP2A6 
Activity 
70 
Table 4. 
Clinical Laboratory Parameters for Safety Panel.......................................86 
Table 5. 
Human Smoking Topography – Per-Puff Parameters ...............................92 
Table 6. 
Human Smoking Topography – Per-Cigarette Parameters ........................92 
Table 7. 
Time Schedule – Screening Visit .............................................................107 
Table 8. 
Time Schedule – Day -2 ..........................................................................109 
Table 9. 
Time Schedule – Day -1 ..........................................................................112 
Table 10. 
Time Schedule – Day 0 ............................................................................113 
Table 11. 
Time Schedule – Day 1 ............................................................................117 
Table 12. 
Time Schedule – Day 2 ............................................................................120 

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Table 13. 
Time Schedule – Day 3 ............................................................................121 
Table 14. 
Time Schedule – Day 4 ............................................................................123 
Table 15. 
Time Schedule – Day 5 ............................................................................124 
Table 16. 
Time Schedule – Day 6 ............................................................................126 
Table 17. 
Time Schedule – Day 30 Visit and Day 60 Visit (from the time of 
check-in in the morning prior to 08:30 AM to check-out of the subject on on the 
day after) 129 
Table 18. 
Time Schedule – Day 90 Visit (from the time of check-in in the 
morning prior to 08:30 AM of Day 90 to time of discharge of Day 91) ...................133 
Table 19. 
Expected Mean Ratios and Coefficients of Variation for THS 2.2 
Menthol/mCC ............................................................................................................148 
Table 20. 
 Expected Mean Ratios and Coefficients of Variation for THS 2.2 
Menthol/mCC ............................................................................................................148 
Table 21. 
Expected Mean Ratios and coefficients of Variation for THS 2.2 
Menthol/mCC ............................................................................................................149 
Table 22. 
Sample Size to Assess the Reductions .....................................................149 
Table 23. 
Expected power (YVD-CS01-EU and ZRHX‐EX‐01 studies 
assumptions) ..............................................................................................................150 
 
Figure 1. 
Study Design ..............................................................................................45 
Figure 2. Product Use Pattern Categorization..................................................................152 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events ...................................................................................172 
Appendix 2 
Participating Laboratories ........................................................................184 
Appendix 3 
Investigational Product and Instructions for Use .....................................185 
Appendix 4 
HST SODIM® Device Description ..........................................................186 
Appendix 5 
Prochaska ‘Stage of Change’ Questionnaire............................................187 
Appendix 6 
Abnormal Laboratory Values ..................................................................190 
Appendix 7 
Procedure for Nasal Epithelial Collection ...............................................194 
Appendix 8 
Procedure for Buccal Collection ..............................................................196 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
11-DTX-B2 
11-dehydro-thromboxane B2 
1-NA 
1-aminonaphthalene 
1-OHP 
1-hydroxypyrene 
2-NA 
2-aminonaphthalene 
3-HPMA 
3-hydroxypropylmercapturic acid 
4-ABP 
4-aminobiphenyl 
8-epi-PGF2α 
8-epi-prostaglandine F2 α 
ADL 
Activities of daily living 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
Apo A1 
Apolipoprotein A1 
Apo B 
Apolipoprotein B 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
B 
Blood sample required 
BMI 
Body mass index 
BoExp 
Biomarker(s) of exposure 
BP 
Blood Pressure 
BUN 
Blood urea nitrogen 
CAF 
Caffeine 
CC 
Conventional cigarette 
CD 
Compact Disc 
CDC 
Centers for Disease Control and Prevention 
CEMA 
2-cyanoethylmercapturic acid 
CFR 
CI 
Code of Federal Regulations 
Confidence interval 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE  
Common Terminology Criteria for Adverse Events and Common 

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Toxicity Criteria 
CTMS 
Clinical Trial Management System 
CV (statistics) 
Coefficient of variation  
CYP1A2 
Cytochrome P450 1A2 
CYP2A6 
DMP 
Cytochrome P450 2A6 
Data Management Plan 
DLCO 
Diffusion capacity of lung for carbon monoxyde 
ECG 
eCRF 
ePRO 
Electrocardiogram 
Electronic Case Report Form 
Electronic patient reported outcome 
EOS 
End of study  
FAS 
Full analysis set 
FDA 
Food and Drug Administration  
FEV1  
Forced expiratory volume in 1 second 
FTND 
Fagerström Test for Nicotine Dependence 
FVC 
Forced vital capacity 
FRV 
Forced residual volume 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GVP 
Gas vapor phase 
HbA1c 
Hemoglobin A1c 
HDL 
High density lipoprotein 
HEMA 
2-hydroxyethyl mercapturic acid 
HIV 
Human immunodeficiency virus 
HMPMA 
3-hydroxy-1-methylpropylmercapturic acid 
HPHCs 
Harmful and potentially harmful constituents 
hs-CRP 
High sensitive C-reactive protein 
HST 
Human smoking topography 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IC 
Inspiratory capacity 
IOM 
Institute of Medicine 
IP 
Investigational Product 
IRB 
Institutional Review Board 

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ISO 
International Organization for Standardization 
IU 
International unit 
IV 
Intravenous 
IWRS 
Interactive web and voice response system 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LLN 
Lower limit of the normal range 
LLOQ 
Lower limit of quantification 
mCC 
Menthol conventional cigarette 
MCEQ 
Modified Cigarette Evaluation Questionnaire  
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEF 
Mid expiratory flow 
MHBMA 
Monohydroxybutenyl mercapturic acid 
MNWS 
Minnesota Nicotine Withdrawal Scale (revised version) 
MR 
Mean ratios 
mRNA 
messenger-ribonucleic acid 
MRTP 
n 
Modified risk tobacco product 
Number of subjects 
NEQ 
Nicotine equivalents 
NNAL 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
NNK 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 
NNN 
N-nitrosonornicotine 
NRT 
Nicotine replacement therapy 
NSAID 
Nonsteroidal anti-inflammatory drugs 
o-tol 
o-toluidine 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PMI 
Philip Morris International 
PP 
Per-protocol 
PT 
Preferred term 
PX 
Paraxanthine 
QC 
Quality control 

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QSU 
Questionnaire of Smoking Urges (brief version) 
RBC 
Red blood cell (count) 
RNA 
Ribonucleic acid 
SA 
Smoking abstinence 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
S-BMA 
S-benzylmercapturic acid 
SD 
Standard deviation 
SDTM 
Standards Consortium’s Study Data Tabulation Model 
SES 
Socio-Economic Status (questionnaire)  
SHM 
Sample Handling Manual 
sICAM-1 
Soluble inter-cellular adhesion molecule 
SMAR 
Smoking article 
SMP 
Safety management plan 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
S-PMA 
S-phenylmercapturic acid 
SQ 
Smoking Questionnaire 
T0 
Start time of the first product use 
TC 
Total cholesterol 
TG 
Triglycerides 
THS 2.2 
Tobacco Heating System 2.2 
TLC 
Total lung capacity 
TPM 
Total particulate matter 
U 
Urine sample required 
 
 
ULN 
Upper limit of the normal range 
ULOQ 
Upper limit of quantification 
USB 
Universal Serial Bus 
UV 
Ultraviolet 
VAS 
Visual analog scale 
VC 
Vital capacity 
WBC 
White blood cell (count) 
WHO 
World Health Organization 
 
 

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Explanation of Terms 
The following special terms are used in this protocol: 
Baseline period 
06:30 AM at Day -1 until 06:29 AM of Day 1. 
Charger:  
The function of the Charger (Model 4) is to recharge the Holder 
after use. It contains a battery with sufficient capacity to recharge 
the Holder approximately 20 times. It is a convenient size to carry 
around, and can itself be recharged from a mains power source. 
Day 30 Visit, Day 60 
Visit, and Day 90 Visit 
Day 30 Visit, Day 60 Visit, and Day 90 Visit start on Day 30, Day 
60, and Day 90 respectively at the time of check-in of the subject 
on site prior to 08:30 AM until the check-out of the day after 
respectively on Day 31, Day 61, and Day 91. 
End of study 
End of Study is defined as the time of discharge on Day 91 of the 
subject plus 28 days of safety follow-up. 
Enrolment 
On Day -2 for eligible subjects after all applicable inclusion and 
exclusion criteria have been satisfactorily met and the subject is 
willing and ready to use the THS 2.2 Menthol (the trial of THS 2.2 
Menthol is the last assessment prior to enrolment).  
Exposure period in 
confinement 
06:30 AM of Day 1 until time of Discharge on Day 6. 
Exposure period in the 
ambulatory setting 
From the time of discharge on Day 6 until the time of Discharge on 
Day 90 Visit (Day 91). 
mCC 
The term ‘menthol conventional cigarette’ refers to manufactured 
and commercially available menthol cigarettes and excludes 
hand-rolled 
cigarettes, 
cigars, 
pipes, 
bidis, 
and 
other 
nicotine-containing products. 
mCC incompatible 
with HST SODIM® 
device 
All mCCs that are incompatible with the HST SODIM® device 
(e.g., slim mCC). 

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Randomization  
Assignment of the subject randomization number in the Interactive 
Web and Voice Response System. This can be done any time on 
Day 0, however, subjects are not to be informed of their 
randomization group prior to Day 1. 
Run-in period 
Admission to site on Day -2 until 06:29 AM of Day -1. 
Safety follow-up 
After the time of Discharge on Day 90 Visit (Day 91), a 28-day 
safety follow-up will be done for the recording of spontaneously 
reported new adverse events (AEs)/serious adverse events (SAEs) 
and the active follow-up of ongoing AEs/SAEs by the site. In 
general, any AE will be followed-up until resolved, stabilized (i.e., 
no worsening of the event) or a plausible explanation for the event 
has been found.  
Screening failure 
Subjects who do not meet the entry criteria from the time of 
informed consent form signature to the time of enrolment will be 
considered a screening failure. 
THS Menthol Tobacco 
Stick 
The Menthol Tobacco Stick (product code C3 Menthol) contains 
tobacco which, when heated, generates an aerosol. It is custom-
designed to be used with the Holder. 
THS Tobacco Stick 
Holder (Holder) 
The function of the Holder (Model 4.2) is to heat the Tobacco 
Stick, delivering an aerosol to the user. The electrical heating is 
powered from an internal battery which delivers power for about 6 
minutes (allowing complete use of a single Menthol Tobacco 
Stick) 
Time of Discharge 
Time of Discharge on Day 6: time when the subject is released 
from the site (confinement period) after all the procedures of the 
day of Discharge (Day 6) have been conducted prior to entering 
into the ambulatory period 
Time of Discharge on Day 90 Visit (Day 91): time when the 
subject is released from the site and enters the 28-day safety 
follow-up period 
Tobacco Heating 
Device  
The Device comprises everything in THS 2.2 Menthol, except the 
Menthol Tobacco Stick 

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Tobacco Heating 
System 2.2 Menthol 
(THS 2.2 Menthol) 
THS 2.2 Menthol comprises the following components: Menthol 
Tobacco Stick, Holder, Charger, a Cleaning Tool, a mains power 
supply, and a USB cable. 

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1 ETHICS AND REGULATIONS 
1.1 
Institutional Review Board Approval 
Prior to the start of the study, the clinical study protocol, together with its associated 
documents (informed consent form [ICF], subject information sheet, subject recruitment 
procedures [e.g., advertisements], written information to be provided to the subjects, 
Investigator’s Brochure [IB], available safety information, the Investigator’s curriculum 
vitae [CV] and/or other evidence of qualifications and any other documents requested by 
an Institutional Review Board [IRB]), will be submitted for review and approval to the 
relevant IRB according to the appropriate provisions found in 21 Code of Federal 
Regulations (CFR) part 50 (Informed Consent of Human Subjects) and 21 CFR part 56 
(Institutional Review Boards). The IRB shall be appropriately constituted and perform its 
functions in accordance with the International Conference on Harmonization (ICH) 
Tripartite Guidance for Good Clinical Practice (GCP) and local requirements, as 
applicable. 
In accordance with GCP and 21 CFR part 56 (IRB review and approval of clinical 
investigation), a written confirmation of the IRB approval should be provided to the 
Sponsor. This should identify the study (Investigator’s name, study number, and title) and 
the documents that have been approved by the IRB, with dates and version numbers, as 
well as the date of approval. The composition of the IRB, 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 IRB will be filed in the Investigator 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 IRB. 
Any substantial change or addition to this protocol will require a written protocol 
amendment that must be approved by the Sponsor and the Investigator. All amendments 
will be submitted to the IRB, and substantial amendments will only be implemented after 
approval by the IRB. 
These requirements for approval should in no way prevent any action from being taken by 
the Investigator or designee or by the Sponsor in order to eliminate immediate hazards to 
the subjects. If such a change to the protocol is felt to be necessary by the Investigator or 
designee, and is implemented for safety reasons, the Sponsor and the IRB should be 
informed immediately. 
Relevant safety information will be submitted to the IRB during the course of the study in 
accordance with national regulations and requirements. 

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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 (2008) and are consistent with ICH/GCP applicable regulatory 
principles. 
The Investigator or designee agrees to conduct the clinical study in compliance with the 
protocol agreed with the Sponsor and approved by the IRB. The Principal Investigator and 
the Sponsor must sign the protocol (and protocol amendments, if applicable) to confirm 
this agreement. A copy of the Declaration of Helsinki (2008) is located in the 
Investigator’s Study File. 
1.3 
Subject Information and Consent 
1.3.1 Study Consent/Subject Information Sheet for Study Participation 
Before or at the Screening Visit, the Investigator or designee will ensure 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 or the designee 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 discontinue his/her participation at any time. Once the subject has 
received all necessary information, and if he/she agrees to participate, this will be 
documented in the ICF which includes both the subject information sheet and informed 
consent by the date, time and signature of both the subject and the person who conducted 
the inform consent discussion during the Screening Visit. No study-specific procedures 
will be performed before the ICF has been signed (including date and time). 
The original, dated and signed ICF(s) must be kept by the Investigator and filed in the 
Investigator study file at the site or with the subject’s files and a copy must be given to the 
subject. 
The subject will be informed that additional data analysis not mentioned in the protocol or 
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 Informed Consent Form/Subject Information Sheet for Long-term Bio-
Banking 
In addition to the ICF for the participation in the study, each subject will be asked for 
consent to the additional bio-banking: 

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• One separate ICF to obtain consent for serum/plasma and urine collection and long-
term storage for BoExp and risk markers. 
• One separate ICF to obtain consent for collection and long-term storage of blood for 
further transcriptomics (pharmacogenomics) analysis, of samples from nasal epithelial, 
and buccal collections. 
Each subject will be given full and adequate oral and written information about the nature, 
purpose, possible risks and benefits of bio-banking, and the Investigator will answer all 
questions the subject might have to his/her full satisfaction. The subject will be notified 
that he/she is free to discontinue his/her participation at any time. Once the subject has 
received all necessary information, and if he/she agrees to participate, this will be 
documented by the date, time and signature of both the subject and the Investigator and 
personnel who conducted the informed consent discussion. The subject’s consent to 
collection and storage of any samples in a bio-bank or for transcriptomics/nasal epithelial 
collection/buccal collection is not a requirement for study participation and the subject’s 
participation in the study (1.3.1) does not depend on their providing consent for sample 
bio-banking. 
1.3.2.1 Bio-bank for Biomarkers of Exposure and Risk Markers 
Subjects will be provided with information and will be asked for their consents for 
samples (serum/plasma/urine) that will be collected and stored in a bio-bank for 
subsequent analysis of biomarkers of exposure (BoExp) and/or risk markers following 
completion of this study. No genetic or transcriptomics testing will be done on these 
samples. 
1.3.2.2 Bio-bank for Transcriptomics/Nasal Epithelial Collection/Buccal Collection 
Subjects will be provided with information and asked for their consent to collect and store 
different types of samples in the same ICF: 
• Samples of blood for transcriptomics (pharmacogenomics) 
• Samples from nasal epithelial collection (molecular profiling) 
• Samples from buccal collection (molecular profiling). 
Blood samples for transcriptomics will be collected for long-term bio-banking in order to 
further study the variation of the ribonucleic acid (mRNA and miRNA) in smokers using 
THS 2.2 Menthol as compared to smokers continuing to smoke mCC or smokers 
switching to smoking abstinence (SA). In-house data from an exploratory study to assess 
the reduction of exposure to HPHCs (ZRHX-EX-01 study) in smokers switching to THS 
2.1 as compared to smokers continuing smoking CC shows that using THS 2.1, the earlier 

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version of THS 2.2 results in significant variation of RNA characteristics as compared to 
smoking CC. 
Nasal epithelial and buccal samples will be collected for long-term bio-banking in order to 
provide biological material for molecular profiling. The changing molecular profiles will 
provide insight into the biological processes that take place in mCC, THS 2.2 Menthol and 
SA arms. Given the similarities in the cell types along the respiratory tract, the biological 
processes identified in the nasal and buccal tissues may reflect those that give rise to lung 
diseases that are etiologically linked to smoking (Boyle et al., 2010.; Error! Reference 
source not found.). 
1.3.3 Amendment to the Informed Consent Form 
If a protocol amendment is required, or if new information regarding the risk profile of the 
IP becomes available, an amendment may be required to the ICF. If revision of the ICF is 
necessary, the Investigator will, with the support of the Sponsor, ensure that the 
documents have been reviewed and approved by a relevant IRB before subjects are 
required to re-sign the ICF (including date and time). 
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 and designee abide by the principles of the ICH guidelines 
on GCP. These guidelines apply specifically to pharmaceutical development, but 
nevertheless provide a robust and ethical framework for conducting clinical studies of 
tobacco products. The study will also be conducted in accordance with the general ethical 
principles outlined in the Declaration of Helsinki (2008). 
In addition, the Investigator or designee will carry out the clinical study in accordance 
with applicable national and local laws of the pertinent regulatory authorities. 
 
 

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2 
INTRODUCTION 
2.1 
Background 
2.1.1 Smoking-Related Diseases and Harm Reduction Strategy 
Cigarette smoking causes pulmonary, cardiovascular diseases and other serious diseases in 
smokers (U.S. Department of Health and Human Services, 2010). There is no safe 
cigarette and the best way for smokers to reduce the adverse health consequences of 
smoking is to quit. Despite the risks which are attributable to smoking, some smokers 
cannot refrain from smoking or decide to continue smoking. To those smokers who are 
not able or not willing to quit, Philip Morris International (PMI) is developing alternative 
approaches by developing products with the potential to reduce the risks of tobacco-
related diseases. These products are now referred by the United States Food and Drug 
Administration (FDA) as modified risk tobacco products (MRTPs) (FDA, 2012a). 
2.1.2 Description of the Product and Scientific Findings 
Thousands of chemicals - “smoke constituents” - are formed when tobacco is burned or 
combusted. More than 5,300 smoke constituents have been identified (Rodgman and 
Perfetti, 2009), and more than 100 of them have been categorized as harmful and 
potentially harmful constituents (HPHCs) (FDA, 2011). 
PMI’s focus has been the development of products that do not combust tobacco but which 
replicate the “smoking experience” as much as possible. Our approach limits pyrolysis 
and combustion, by heating tobacco at significantly lower temperatures than conventional 
cigarette (CC). PMI believes that such products present the best opportunity for reducing 
harm because they produce vastly lower levels of HPHCs and are more likely to be 
accepted by smokers as substitutes for CCs. Important to this effort has been providing 
nicotine in a way that closely parallels CC. 
The product developed by PMI, and to be assessed in this study, is the Tobacco Heating 
System 2.2 Menthol (THS 2.2 Menthol). With this product, the heating of the tobacco is 
maintained below 400°C, a temperature much lower than what is observed for CC, which 
can reach 900°C. The THS 2.2 Menthol is composed of the ‘THS Tobacco Stick Holder’, 
dedicated special Menthol Tobacco Sticks made of conventional tobacco, a Charger, and 
different accessories. The energy of the THS Tobacco Stick Holder is sufficient to 
maintain approximately a 6 minute session. Unlike CC, the Menthol Tobacco Sticks do 
not burn down during their consumption and their lengths remain constant after use. 
The non-clinical assessment of earlier development of THS 2.2 Menthol described in the 
investigator’s brochure (PMI, 2013a) supports the initiation of the clinical studies. No new 

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or increased toxicological hazard in the product’s aerosol was detected compared with CC 
smoke. Further details on the clinical and non-clinical data are provided in the 
Investigators’ Brochure Edition 2 (PMI, 2013a) 
Several clinical studies have been conducted on THS 1.0 (Menthol and non-menthol), an 
earlier development version of THS 2.2, in Europe, Asia, Africa and the United States. All 
studies showed reductions in exposure to the majority of measured HPHCs from both 
aerosol fractions, total particulate matter (TPM)and gas vapor phase (GVP), in subjects 
who used the THS 1.0 as compared to subjects continuing smoking CC, both, in 
controlled and ambulatory conditions. No clinical studies were conducted with THS 2.2 
Menthol. 
THS 2.1 non-Menthol, the predecessor of THS 2.2, was tested in two exploratory clinical 
studies to measure the nicotine plasma kinetic profile (PK) (ZRHX-PK-02 study) and to 
assess the reduction of exposure to HPHCs when switching from CC to THS 2.1 (ZRHX-
EX-01 study). The observed nicotine plasma PK profile for THS 2.1 was similar to CC as 
well, there were significant reductions in the exposure to the majority of selected HPHCs 
(PMI, 2013a). 
Clinical studies conducted so far revealed no safety concern for either of the previous 
versions of THS 2.2 tested. 
2.2 
Purpose of the Study 
The overall goal of the study is to provide information on the reduction in the levels of 
selected BoExp to HPHCs (except for BoExp to nicotine) and to obtain safety information 
in apparently healthy subjects using the THS 2.2 Menthol as compared to smokers 
continuing smoking their preferred brand of mCC in confinement setting for 5 days 
followed by an ambulatory setting of 86 days. Smokers who will be asked to abstain from 
smoking will be used as a reference point. The smokers in the THS 2.2 Menthol and mCC 
arms will be allowed to use the product they are allocated to ad libitum.  
Additional purpose of the study aim is to understand the effect of using THS 2.2 Menthol 
on selected variables and their potential association to the reduced exposure to HPHCs 
(e.g. cytochrome P450 1A2 [CYP1A2] and cytochrome P450 2A6 ([CYP2A6] enzymatic 
activity, pharmacokinetic [PK] profile of nicotine and cotinine, product evaluation, 
product use and subjective effects related to smoking, human smoking topography, risk 
markers).  

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2.3 
Anticipated Benefits and Risks 
2.3.1 Anticipated Benefits 
Advice on health risks associated with smoking and smoking cessation advice will be 
provided on Screening, on Admission Day (Day -2), on Day 6 (Day of Discharge), Day 30 
Visit, Day 60 Visit, and at Day 90 Visit. The advice will follow the recommendations of 
the U.S. Public Health Service (U.S. Department of Health and Human Services, 2008). 
Subjects who are motivated to quit smoking during the study in the THS 2.2 and mCC 
arms will be referred to appropriate stop smoking services for continuing support and 
counseling at a higher level. Subjects who participate in this study will also benefit from 
repeated, detailed health check-ups, which may help to uncover undiagnosed medical 
conditions. 
2.3.2 Anticipated Foreseeable Risks due to Study Procedures 
• Risks related to blood sampling, e.g. excessive bleeding, fainting, hematoma, 
paresthesia, or infection. 
• Risks related to chest X-rays, e.g. a small increase of risk to develop cancer later in 
life. 
• Risks related to drug application as part of testing procedures (i.e., spirometry with 
short-acting bronchodilator at Screening and at Day 6 and Day 90 Visit) per study 
protocol and scientifically accepted standards. 
2.3.3 Anticipated Foreseeable Risks due to Investigational Product (THS 2.2 
Menthol/mCC) 
• Change in smoking habits due to study requirements and related concomitant 
symptoms, (e.g., craving, withdrawal symptoms). 
• All risks related to study procedures, IP, or support for SA will be explained in detail 
to the subjects. Mitigation will include: 
• Close monitoring and medical evaluation of potential safety signals throughout the 
study and follow-up. 
• Using accepted research and scientific standards, (e.g., blood samples not to 
exceed local blood donation standards). 
• Management and follow-up of adverse events (AEs)/serious adverse events 
(SAEs). 

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2.3.4 
Unforeseeable Risks 
Substantial body of evidence already exists on the predecessors of THS 2.2 Menthol and no 
safety concerns were reported. The possibility of unforeseeable events/risks will be explained 
at Screening and at Admission. Mitigation will include close monitoring and medical 
supervision to detect any unforeseeable risk or safety signals at the earliest possibility. 
 
 

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3 STUDY OBJECTIVES 
3.1 
Primary Objectives 
The primary objectives of this study are: 
• To demonstrate the reduction of primary biomarkers of exposure (BoExp) (Table 1) to 
HPHCs (except Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) (Total NNAL)) in a 
confinement setting in smokers switching from mCC to THS 2.2 Menthol as compared to 
smokers continuing to smoke mCC, and 
• To demonstrate the reduction of Total NNAL in an ambulatory setting in smokers 
switching from mCC to THS 2.2 Menthol as compared to smokers continuing to smoke 
mCC. 
3.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To evaluate self-reported nicotine/tobacco product use including dual-use in an 
ambulatory setting in smokers switching from mCC to THS 2.2 Menthol as compared to 
smokers continuing to smoke mCC and to smoking abstinence (SA). 
• To determine the reduction of secondary BoExp in a confinement setting and in an 
ambulatory setting in smokers switching from mCC to THS 2.2 Menthol as compared to 
smokers continuing to smoke mCC. 
• To describe the levels of primary and secondary BoExp over the entire exposure period 
(confinement and ambulatory periods) in smokers switching from mCC to THS 2.2 
Menthol as compared to smokers continuing to smoke mCC and to SA.  
• To determine the levels of nicotine over the entire exposure period (confinement and 
ambulatory periods) in smokers switching from mCC to THS 2.2 Menthol as compared to 
smokers continuing to smoke mCC and to describe their levels over the entire exposure 
period. 
• To describe the pharmacokinetic profiles of the nicotine and cotinine in a confinement 
setting in smokers switching from mCC to THS 2.2 Menthol as compared to smokers 
continuing to smoke mCC. 
• To describe the change in CYP1A2 enzymatic activity in smokers switching from mCC to 
THS 2.2 Menthol as compared to smokers continuing to smoke mCC and to SA. 
• To determine the changes in lung functions in smokers switching from mCC to THS 2.2 
Menthol as compared to smokers continuing to smoke mCC. 

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• To monitor the safety profiles during the study. 
• To monitor selected risk markers in a confinement and ambulatory setting in smokers 
switching from mCC to THS 2.2 Menthol as compared to smokers continuing to smoke 
mCC and to SA. 
3.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
• To describe the following parameters in a confinement and/or ambulatory setting in 
smokers switching from mCC to THS 2.2 Menthol as compared to smokers continuing to 
smoke mCC and to SA: 
• Excretion of mutagenic material in urine.  
• Subjective effect of smoking. 
• Cytochrome P450 2A6 (CYP2A6) activity.  
• To describe the following parameters over the course of the study in smokers switching 
from mCC to THS 2.2 Menthol as compared to smokers continuing to smoke mCC: 
• Product evaluation. 
• Smoking puffing behavior. 
• To describe the following parameter over the course of the study in smokers switching 
from mCC to THS 2.2 Menthol: 
• Potential combustion occurrences in tobacco plugs. 
• To describe the changes in levels of oxysterols on Day 6 and Day 90 Visit in smokers 
switching from mCC to THS 2.2 Menthol, and in smokers switching from mCC to SA. 
• To describe the product use over the course of the study according to the product 
preference of the subject. 
• To describe the smokers’ mental state for the intention to quit at Screening, on Day -2, 
Day 30 Visit, Day 60 Visit, and Day 90 Visit. 
• To describe the changes and reductions in the levels of urinary BoExp and risk markers 
measured in 4-hour urine fraction on Day 90 Visit in smokers switching from mCC to 
THS 2.2 Menthol as compared to smokers continuing to smoke mCC and to SA. 
• To evaluate in smokers switching from mCC to THS 2.2 Menthol, and smokers continuing 
smoking mCC the relationship between1 : 
• Primary and secondary BoExp and nicotine equivalents (NEQ).  

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• To determine the concordance between the results for BoExp and risk markers in 24-hour 
urine and in 4-hour urine fraction 2. 
• To monitor the BoExp in subjects quitting smoking according to the time since they 
quitted 2.  
 
1 The reporting of the objective will be the subject of a separate report. 
2 The reporting of the objective will be the subject of an appendix to the main Clinical Study Report. 
3.4 
Study Endpoints 
The primary and secondary BoExp to HPHCs measured in the study are presented in Table 1:  
Table 1:  
Biomarkers of Exposure 
 
Biomarkers of Exposure (BoExp) 
HPHCs 
Matrix 
Primary 
BoExp on 
Day 5 
monohydroxybutenylmercapturic acid (MHBMA) 
1,3-butadiene 
Urine 
3-hydroxypropylmercapturic acid (3-HPMA) 
acrolein 
Urine 
S-phenylmercapturic acid (S-PMA) 
benzene 
Urine 
carboxyhemoglobin (COHb)  
carbon monoxide (CO) 
Blood 
Primary 
BoExp 
on Day 
90 Visit 
total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
(Total NNAL) 
4 (methylnitrosamino)-1-
(3-pyridyl)-1butanone 
(NNK) 
Urine 
Secondary BoExp 
carbon monoxide  
CO 
Exhaled 
breath 
total 1-hydroxypyrene (total 1-OHP) 
pyrene 
Urine 
total N-nitrosonornicotine (NNN) 
N-nitrosonornicotine 
Urine 
4-aminobiphenyl (4-ABP) 
4-aminobiphenyl  
Urine 
1-aminonaphthalene (1-NA) 
1-aminonaphthalene 
Urine 
2-aminonaphthalene (2-NA) 
2-aminonaphthalene 
Urine 
o-toluidine (o-tol) 
o-toluidine 
Urine 
2-cyanoethylmercapturic acid (CEMA) 
acrylonitrile 
Urine 
2-hydroxyethylmercapturic acid (HEMA) 
ethylene oxide 
Urine 
3-hydroxybenzo(a)pyrene 
benzo(a)pyrene 
Urine 
3-hydroxy-1-methylpropyl-mercapturic acid (HMPMA) 
crotonaldehyde 
Urine 
S-benzylmercapturic acid (S-BMA) 
toluene 
Urine 

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Biomarkers of Exposure (BoExp) 
HPHCs 
Matrix 
BoExp to nicotine 
nicotine equivalents (NEQ) 
free nicotine, nicotine-glucuronide, free cotinine, 
cotinine-glucuronide, free trans-3’-hydroxycotinine, 
trans-3’-hydroxycotinine-glucuronide 
nicotine 
Urine 
nicotine 
nicotine 
Plasma 
cotinine 
nicotine 
Plasma 
3.4.1 
Primary Endpoints 
• To demonstrate the reduction of primary BoExp to HPHCs (except Total NNAL) in a 
confinement setting in smokers switching from mCC to THS 2.2 Menthol as compared to 
smokers continuing to smoke mCC. 
• MHBMA, 3-HPMA, S-PMA (concentration adjusted for creatinine) in 24-hour urine, 
and COHb in blood (expressed as % of saturation of hemoglobin) as measured on 
Day 5. 
• To demonstrate the reduction of Total NNAL in an ambulatory setting in smokers 
switching from mCC to THS 2.2 Menthol as compared to smokers continuing to smoke 
mCC. 
• Total NNAL level (concentration adjusted for creatinine) in 24-hour urine fraction as 
measured on Day 90 Visit. 
Evaluation criterion:  
The study will be considered successful if the study demonstrates a 50% reduction or more in 
MHBMA, 3-HPMA, S-PMA, and COHb at Day 5 and in Total NNAL at Day 90 Visit in 
smokers switching from mCC to THS 2.2 Menthol as compared to smokers continuing to 
smoke mCC, using a one-sided test with 2.5% type I error probability. 
3.4.2 
Secondary Endpoints 
• To evaluate self-reported nicotine/tobacco product use including dual-use in an 
ambulatory setting in smokers switching from mCC to THS 2.2 Menthol as compared to 
smokers continuing to smoke mCC and to SA.  
• Number of mCC or Menthol Tobacco Sticks smoked daily as reported on the usage 
log during the confinement period and self-reported number of any nicotine/tobacco 
product use on a daily basis as reported on the product use electronic diary. 

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• To determine the reduction of secondary BoExp in a confinement setting and in an 
ambulatory setting in smokers switching from mCC to THS 2.2 Menthol as compared to 
smokers continuing to smoke mCC. 
• BoExp listed as secondary (expressed as quantity excreted or concentration adjusted 
for creatinine) (Table 1) as measured in 24-hour urine on Day 5 and on Day 90 Visit.  
• To describe the levels of primary and secondary BoExp over the entire exposure 
(confinement and ambulatory periods) in smokers switching from mCC to THS 2.2 
Menthol as compared to smokers continuing to smoke mCC and to SA. 
• BoExp listed as primary and secondary (Table 1) from Day 1 to Day 5 and Day 30 
Visit, Day 60 Visit and Day 90 Visit as follows: 
• Carbon monoxide (CO) (expressed as ppm) in exhaled breath.  
• COHb in blood (expressed as % saturation of hemoglobin). 
• Urinary BoExp (expressed as quantity excreted and concentration adjusted for 
creatinine) in 24-hour urine. 
• To determine the levels of nicotine over the entire exposure period (confinement and 
ambulatory periods) in smokers switching from mCC to THS 2.2 Menthol as compared to 
smokers continuing to smoke mCC and to describe their levels over the entire exposure 
period. 
• NEQ (expressed as quantity excreted and concentration adjusted for creatinine) (Table 
1) in 24-hour urine from Day 1 to Day 5 and on Day 30 Visit, Day 60 Visit, and Day 
90 Visit. 
• Nicotine and cotinine in plasma from Day 1 to Day 4, Day 5, and on Day 30 Visit, 
Day 60 Visit, and Day 90 Visit. 
• To describe the PK profiles of the nicotine and cotinine in a confinement setting in 
smokers switching from mCC to THS 2.2 Menthol as compared to smokers continuing to 
smoke mCC.  
• Peak (highest concentration along the day) on Day 5. 
• Time to peak (actual time when the peak was observed compared to the time of the 
first cigarette) on Day 5. 
• Weighted average concentration over 24 hours on Day 5. 
• To describe the change in CYP1A2 enzymatic activity in smokers switching from mCC to 
THS 2.2 Menthol as compared to smokers continuing to smoke mCC and to SA. 
• Molar metabolic ratio of paraxanthine (PX)/caffeine (CAF) in plasma on Day 5 and 
Day 90 Visit. 

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• To determine the changes in lung function in smokers switching from mCC to THS 2.2 
Menthol as compared to those continuing to smoke mCC. 
• Full lung functions: Diffusion capacity for lung CO (DLCO), rate constant of CO 
(KCO), forced expiratory volume in 1 second (FEV1), force vital capacity (FVC), vital 
capacity (VC) expressed as L, total lung capacity (TLC), forced residual volume 
(FRV), inspiratory capacity (IC), mid expiratory flow (25-75). 
• To monitor the safety profiles during the study. 
• AEs/ SAEs, and device events including THS 2.2 Menthol malfunction/misuse. 
• Respiratory symptoms: cough assessment by visual analogue scale (VAS) and Likert 
scales and one open question. 
• Vital signs. 
• Electrocardiogram (ECG). 
• Clinical chemistry, hematology, and urine analysis safety panel. 
• Physical examination. 
• Concomitant medications. 
• To monitor selected risk markers in a confinement and ambulatory setting in smokers 
switching from mCC to THS 2.2 Menthol as compared to smokers continuing to smoke 
mCC and to SA. 
• Systolic and diastolic blood pressure on Day 6, Day 30 Visit, Day 60 Visit, and Day 
90 Visit. 
• High sensitive C-reactive protein (hs-CRP), homocysteine, blood glucose, low density 
lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (TG), total 
cholesterol (TC) in serum on Day 30 Visit, Day 60 Visit, and Day 90 Visit  
• Fibrinogen in plasma on Day 30 Visit, Day 60 Visit, and Day 90 Visit 
• Hemoglobin A1c in blood on Day 90 Visit. 
• Apolipoprotein A1 (Apo A1) and Apolipoprotein B (Apo B) in serum on Day 90 Visit. 
• Soluble inter-cellular adhesion molecule-1 (sICAM-1) in serum on Day 6, on Day 30 
Visit, Day 60 Visit and Day 90 Visit. 
• White blood cell (WBC) and platelet count in blood on Day 6, Day 30 Visit, Day 60 
Visit, and Day 90 Visit. 
• 8-epi-prostaglandin F2α (8-epi-PGF2α) and 11-dehydro-thromboxane B2 (11-DTX-
B2) in 24-hour urine on Day 5 and on Day 30 Visit, Day 60 Visit, and Day 90 Visit 
(expressed as concentration adjusted for creatinine). 

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• Body weight and waist circumference on Day 90 Visit. 
3.4.3 
Exploratory Endpoints 
• To describe the following parameters in a confinement and/or ambulatory setting in 
smokers switching from mCC to THS 2.2 Menthol as compared to smokers continuing to 
smoke mCC and to SA: 
• Excretion of mutagenic material in urine: Ames Mutagenicity test (YG1024+S9) on 
Day 5 and Day 90 Visit in 24 hour urine. 
• Subjective effect of smoking: Questionnaire of Smoking Urges (QSU-brief 
questionnaire); questionnaire Minnesota Nicotine Withdrawal Scale (MNWS)-Revised 
on Day 5 and Day 90 Visit, and nicotine dependence as assessed by the Fagerström 
Test for Nicotine Dependence (FTND) questionnaire score on Day 90 Visit. 
• CYP2A6 activity: in plasma on Day 6, and on Day 90 Visit using the molar metabolic 
ratio of trans-3’-hydroxycotinine/cotinine. 
• To describe the following parameters over the course of the study in smokers switching 
from mCC to the THS 2.2 Menthol as compared to smokers continuing to smoke mCC: 
• Product evaluation: MCEQ 
• Smoking puffing behavior: HST parameters and HST questionnaire. 
• To describe the following parameter over the course of the study in smokers switching 
from mCC to THS 2.2 Menthol: 
• Potential combustion occurrences in tobacco plugs: visual inspection of the tobacco 
plugs. 
• To describe the changes in levels of oxysterols on Day 6 and Day 90 Visit in smokers 
switching from mCC to THS 2.2 Menthol , and in smokers switching from mCC to SA: 
• Plasma concentration of 6α-hydroxy-5α-cholestanol, 7α-hydroxycholesterol, 5α,6α-
epoxycholestanol, 7-ketocholesterol, 7β-hydroxycholesterol, 5β,6β-epoxycholestanol, 
24(R)-hydroxycholesterol, 25-hydroxycholesterol, 22(R)-hydroxycholesterol, 4ß-
hydroxycholesterol, and 27-hydroxycholesterol in addition to total cholesterol. 
• To describe the product use over the course of the study according to the product 
preference of the subject. 
• Number of mCC or Menthol Tobacco Sticks smoked daily as reported on the log 
during the confinement period and self-reported number of any nicotine/tobacco 
product use on a daily basis as reported on the product use electronic diary. 
• To describe the smokers’ mental state for the intention to quit at Screening on Day -2, 
Day 30 Visit, Day 60 Visit, and Day 90 Visit:  

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• By the means of the Prochaska ‘Stage of Change’ questionnaire.  
• To describe the changes and reductions in the levels of urinary BoExp and risk markers 
measured in 4-hour urine fraction on Day 90 Visit in smokers switching from mCC to 
THS 2.2 Menthol as compared to smokers continuing to smoke mCC and to SA. 
• Urinary BoExp (expressed as quantity excreted and concentration adjusted for 
creatinine). 
• 8-epi-PGF2α and 11-DTX-B2 (expressed as quantity and concentration adjusted for 
creatinine). 
• To evaluate in smokers switching from mCC to THS 2.2 Menthol, smokers continuing 
smoking mCC the relationship between 1: 
• Primary and secondary BoExp and nicotine equivalents (NEQ) on Day 5 in 24-hour 
urine and on Day 90 Visit.  
• To determine the concordance between the results for BoExp and risk markers in 24-hour 
urine and in 4-hour urine fraction 2: 
• MHBMA, 3-HPMA, S-PMA, total NNAL, total 1-OHP, total NNN, 4-ABP, 1-NA, 2-
NA, o-tol, CEMA, HEMA, 3-hydroxybenzo(a)pyrene, HMPMA, S-BMA, NEQ, 
(expressed as quantity excreted in 24-hour urine collection and concentration adjusted 
for creatinine in 4-hour urine fraction) at baseline and at Day 90 Visit. 
• 8-epi-PGF2α and 11-DTX-B2 (expressed as quantity excreted in 24-hour urine 
collection and concentration adjusted for creatinine in 4-hour urine fraction) at 
baseline and at Day 90 Visit. 
• To monitor the BoExp in subjects quitting smoking according to the time since they 
quitted 2: 
• Carbon monoxide (expressed as ppm) in exhaled breath.  
• COHb in blood (expressed as % saturation of hemoglobin). 
• Urinary BoExp (expressed as quantity excreted and concentration adjusted for 
creatinine) in 24-hour urine. 
• NEQ (expressed as quantity excreted and concentration adjusted for creatinine). 
• Selected risk markers (hs-CRP, homocysteine, blood glucose, LDL, HDL, TG, TC, 
fibrinogen, hemoglobin A1c, sICAM-1, white blood cell, platelet count, Apo A1, 
Apo B, 8-epi-PGF2, 11-DTX-B2) in respective body matrix when available. 
 
1 The reporting of the objective will be the subject of a separate report. 
2 The reporting of the objective will be the subject of an appendix to the main Clinical Study Report. 
 
 

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4 INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
A randomized, controlled, open-label, 3-arm, parallel group study design with a stratified 
randomization by sex and average daily cigarette consumption over the last 4 weeks as 
reported during the Screening Visit (smokers smoking 10 to 19 mCC and smokers smoking 
>19 mCC per day) (Figure 1). 
This is an ad libitum smoking study. In general, smoking mCC or use of THS 2,2 Menthol 
during the confinement period will be allowed from 06:30 AM onwards until around 11:00 
PM. During the ambulatory period, there will be no smoking/product use restriction except 
during the three visits on site (Day 30 Visit, Day 60 Visit, and Day 90 Visit), when product 
use will be allowed from the time of check-in prior to 08:30 AM to around 11:00 PM on Day 
30, Day 60, and Day 90. On Day 31, Day 61, product use will be allowed from 06:30 AM 
onwards. On Day 91, product use will be allowed after the sample for CYP2A6 activity and 
the full lung function have been performed until time of discharge of Day 91. 

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During the confinement period, compliance to product/regimen allocation (exclusive use of 
THS 2.2 Menthol and mCC in THS 2.2 Menthol and mCC arms respectively, and full 
abstinence from smoking in the SA arm) will be ensured by strict distribution of each 
Menthol Tobacco Stick/mCC when requested by the subject. During the ambulatory period, 
the subjects randomized to the THS 2.2 Menthol arm will be instructed to exclusively use 
THS 2.2 Menthol and subjects randomized to the SA arm will be instructed to abstain from 
smoking. 
Figure 1. 
Study Design 
 
• The Screening period covers 4 weeks (Day -30 to Day -3) prior to Admission to the clinic 
(Day -2): 
A demonstration of the THS 2.2 Menthol will be done by the site staff during the 
Screening Visit. Subjects will be in a confined setting for 9 days from Day -2 onwards. 
• The run-in period (from Admission on Day -2 until 06:29 AM of Day-1): 
Smoking will be allowed ad libitum from the time of check-in of the subject until around 
11:00 PM. Prior to enrolment on Day -2, as the last procedure of the eligibility 
assessments, subjects will have a product test of the THS 2.2 Menthol (use of up to three 
THS Menthol Tobacco Sticks). In female subjects, the THS 2.2 Menthol product test will 
only be done after pregnancy is excluded by a negative urine pregnancy test. Enrolment 
takes place after all inclusion and exclusion criteria have been satisfactorily met. Only 
Day 6 to Day 90
Day -1, Day 0
Day -2
Admission
Baseline
Day 91 to Day 119
9 days in confinement
mCC 
ad 
libitum
Safety  follow-up
THS 2.2 Menthol 
and mCC ad libitum
Day 1 to Day 5
Screening*
85 days ambulatory
*Screening 
within 1-4 
weeks 
prior to 
admission
THS 2.2 Menthol
Smoking Abstinence
mCC
Abbreviations: mCC = Menthol conventional cigarette(s); THS = Tobacco Heating System; Figure not to scale.
THS 2.2 Menthol and mCC ad 
libitum
28 days follow-up
THS 2.2 Menthol
Smoking Abstinence
mCC
← Day 30/Day31
← Day 60/Day61
← Day 90/Day91
← Day 6
9 day confinement
86 day ambulatory
28 day follow-up
mCC: menthol conventional cigarettes; THS: Tobacco Heating System; figure not scale

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subjects willing and able to use the product will be enrolled in the study. Subjects who do 
not meet eligibility criteria on Day -2 will be considered as screening failure until the time 
of enrolment. 
• The baseline period (from Day -1, 06:30 AM until Day 1, 06:29 AM): 
All subjects will continue smoking their single preferred brand of mCC ad libitum. On 
Day -1 and Day 0, smoking will be allowed from 06:30 AM onwards until around 11:00 
PM. However, on Day 0, smoking will be allowed only after sample for CYP2A6, MNWS 
and cough questionnaires, and full lung functions have been conducted. 
Four-hour urine fraction will be collected on Day-1. On Day 0, 24-hour urine will be 
collected starting in the morning and ending 24 hours later on Day 1. 
On Day 0, subjects will be randomized to 1 of the 3 study arms in a 2:1:1 ratio using a 
stratified randomization. The full analysis set (FAS) population will be as follows: 
• THS 2.2 Menthol Arm: ~80 subjects, ad libitum use of the product. 
• mCC Arm: ~40 subjects, ad libitum use of their preferred mCC brand. 
• SA Arm: ~40 subjects who will abstain from smoking. 
Subjects will be informed of their randomized study arm by the study site staff on Day 1 
prior to 06:30 AM. 
• The exposure period (from Day 1, 06:30 AM until time of Discharge on Day 90 Visit 
(Day 91)): 
The exposure period will include both the exposure period in confinement, and the 
exposure period in ambulatory setting: 
• The exposure period in confinement setting (from Day 1, 06:30 AM until time of 
Discharge on Day 6): 
The exposure period in confinement consists of 5 days of ad libitum use of the assigned 
product from 06:30 AM onwards until around 11:00 PM in THS 2.2 Menthol and mCC 
arms. Subjects allocated to the SA arm will be asked to abstain from smoking and will not 
be provided with medication to support SA. Subjects will be provided with psychological 
support during the period of SA. Use of any tobacco/nicotine-containing product other 
than the assigned product/regimen will not be allowed. 
Twenty four-hour urine will be collected from Day 1 to Day 5 on site. The end of the 24-
hour urine collection from Day 5 will end in the morning on Day 6 prior to Discharge.  
On Day 6, the safety procedures will be conducted before discharge of the subject from 
the clinic after 9 days in a confined setting. Use of products will be allowed on Day 6 in 
the THS 2.2 Menthol and mCC arms according to product arm allocation, but only after 

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the sample for CYP2A6 activity, MNWS and cough questionnaires, and full lung 
functions have been performed.  
• The exposure period in ambulatory setting (from time of Discharge on Day 6 until the 
time of Discharge on Day 91): 
At the end of the confinement period prior to Discharge on Day 6, subjects will be 
instructed to continue their assigned product/regimen in an ambulatory setting for 86 days. 
All subjects in the SA arm will receive smoking cessation counseling and will be able to 
use nicotine replacement therapy (NRT) if considered necessary by the Investigator or 
requested by the subject (no other medication supportive for smoking cessation will be 
allowed).  
Subjects will be required to make three visits (Day 30 Visit, Day 60 Visit, and Day 90 
Visit) to the investigational site. Each visit will cover 2 consecutive days on site. For Day 
30 Visit and Day 60 Visit, the subject will check-in in the morning prior to 08:30 AM on 
Day 30 and Day 60, and will check-out on Day 31 and Day 61 respectively. For Day 90 
Visit, the subject will checked-in in the morning prior to 08:30 AM on Day 90, and will be 
discharged on Day 91 after having performed all the safety examination procedures.  
Twenty four-hour urine will be collected at each ambulatory visit on Day 30 Visit, Day 60 
Visit, and Day 90 Visit at the site. The collection of 24-hour urine will start on Day 30, 
Day 60, and Day 90 respectively and will end 24-hours later. On Day 90 visit only, the 
end of 24-hour urine collection will be followed by the collection of a 4-hour urine 
fraction. 
On Day 30, Day 60, and Day 90, subjects in the THS 2.2 Menthol and mCC arms will be 
allowed to use their assigned product from the time of check-in in the morning prior to 
08:30 AM to around 11:00 PM. On Day 31, Day 61, product use will be allowed from 
06:30 AM. On Day 91, product use will be allowed only after the sample for CYP2A6 
activity and full lung function have been performed until time of discharge of Day 91. The 
end of the exposure period will be fixed at the time of discharge of Day 91.  
During the visits, the use of THS 2.2 Menthol will be strictly forbidden for subjects in the 
mCC or SA arms. 
Subject will not be withdrawn from the study for the use of nicotine/tobacco-containing 
products other than the assigned product/regimen. Subjects will record in a product use 
electronic diary any use of CC (menthol or non-menthol), NRT, or other nicotine/tobacco-
containing products on a daily basis. 
During the confinement and ambulatory settings: 
• Subjects in the SA arm will be provided with support including psychological support 
as requested by the subject or considered necessary by the Investigator/site staff. 

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• Any subject, who wants to quit smoking during the study (which takes into account the 
outcome from the Prochaska ‘Stage of Change’ questionnaire), will be encouraged to 
do so and will be referred to medical services. This will not affect subject’s financial 
compensation and subject will remain in the study. No NRT will be provided during 
the confinement period. 
• The safety follow-up period (from time of Discharge on Day 90 Visit (Day 91) until 
Day 119): 
After the time of Discharge on the Day 90 Visit (Day 91), subject will enter a 28-day 
safety follow-up period during which there will be recording of spontaneously reported 
new AEs/SAEs and the active follow-up of ongoing AEs/SAEs by the study site. In 
general, all AEs will be followed-up until resolved, stabilized (i.e., no worsening of the 
event), or a plausible explanation for the event has been found. The end of the study 
(EOS) is defined as the time of Discharge on Day 90 Visit (Day 91) plus 28-day follow-
up. 
4.2 
Rationale for Study Design and Control Groups 
The minimum age of 22 years in the inclusion criteria was selected based on: 
• The legal age of smoking in the location of the chosen sites is 19 years.  
• To account for the 3 years of smoking history. 
This clinical study aims to demonstrate reductions in exposure to selected HPHCs in 
apparently healthy smokers switching to the THS 2.2 Menthol, a candidate MRTP, as 
compared to using mCCs (see IB Edition 2). The main reference in this study will be 
smokers who continue to smoke mCC. Smokers who stop smoking (the SA arm) will be used 
as a reference point for the maximum possible reduction in exposure to HPHCs. 
The confinement period will provide information on maximum possible exposure reductions 
in a well-controlled environment and will allow full control of daily cigarette consumption. 
The ambulatory period will provide a perspective of product usage in the real world setting, 
where smoking of a few CC (menthol and non-menthol) in addition to THS 2.2 Menthol and 
SA is expected. It will provide information on reduction in selected BoExp and related 
changes in selected risk markers when THS 2.2 Menthol is used in a real world setting. 
The choice of HPHCs to be assessed in this study is derived from the World Health 
Organization (WHO) (Ashley et al., 2008) and the draft guidance on Reporting Harmful and 
Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke (FDA, 2011). 
In the WHO list, 9 HPHCs (acrolein, CO, 1-3 butadiene, benzene, NNN, NNK, acetaldehyde, 
benzo[a]pyrene, and formaldehyde) with evidence of carcinogenicity, respiratory and cardiac 

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toxicity were recommended to be measured as priority in the smoke chemistry for mandated 
lowering (Ashley et al., 2008).  
Exposure to 4 HPHCs (acrolein, CO, 1,3-butadiene, and benzene) among these 9 priority 
HPHCs will be assessed by measuring their respective BoExp as primary endpoints after 5 
days of exclusive use of THS 2.2 Menthol, mCC or SA. The following characteristics apply 
to these primary BoExp: 
 They are several-fold higher in smokers than in smokers abstinent from smoking (Lindner 
et al., 2011). 
 They exhibit, on average, an elimination half-life of ≤24 hours. Therefore, the 5 days of 
exposure are sufficient to reach the maximum reduced levels with the THS 2.2 Menthol 
and SA arms (4 to 5 times the half-life will lead to less than 5% of the original exposure 
levels of assessed biomarkers on Day 5). 
Total NNAL was selected as primary endpoints at Day 90 Visit of THS 2.2 Menthol use as: 
 This biomarker is tobacco specific (Goniewicz et al., 2009), and exhibits, on average, an 
elimination half-life of 10 to 15 days. Therefore, the 91 days of exposure are sufficient to 
reach the steady state with the THS 2.2 Menthol and SA arms (4 to 5 times the half-life 
will lead to less than 5% of the original exposure levels on Day 90 Visit). 
Some risk markers have been selected in order to evaluate biological changes in THS 2.2 
Menthol arm as compared to mCC arm using SA arm as a reference point to verify if the 
trend of changes upon THS 2.2 Menthol use follow the same trajectory as SA. Among the 
ones selected, some are well-known to be affected by smoking and to be reversible upon SA 
as follows: 
 CYP1A2 activity, the enzyme which mainly metabolizes caffeine, is decreased as soon as 
5 days of SA and after 5 days of use of another candidate MRTP (Faber et al., 2004) and 
data on file from a previous study (YVD-CS01-EU study).  
 11-DTX-B2 (a major stable metabolite of thromboxane A2, which elicits mainly platelet 
aggregation) was decreased after 1 week of SA (Benowitz et al., 1993) and after 5 days of 
use of another candidate MRTP (YVD-CS01-EU study).  
 Blood pressure, hs-CRP, fibrinogen, homocysteine, fasting blood glucose, LDL, HDL, 
TG, TC, hemoglobin A1c (HbA1c), waist circumference, sICAM-1, WBC count, Apo A1, 
Apo B, and 8-epi-PGF2α will be evaluated as risk markers (Eliasson et al., 2001; Vasan et 
al., 2006) for cardiovascular monitoring purposes. According to the literature, some of 
these risk markers are known to be sensitive to smoking cessation: the levels of HDL 
increase when the levels of sICAM-1, WBC count, and 8-epi-PGF2α decrease following 1 
to 3 months of smoking cessation (Pilz et al., 2000; Eliasson et al., 2001). 

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 Body weight as a mean increase of 4.5 kg is observed after 12 months of smoking 
abstinence with the most weight gain occurring within the first 3 months of quitting 
(Aubin et al., 2012). 
 Oxysterol will be measured in the study to verify that the reduction observed in animal 
models of disease upon smoking cessation and switching to candidate MRTP (in house 
data) is also observed in humans. 
• CYP2A6 activity, the enzyme involved in nicotine metabolism will be assessed in this 
study to evaluate if the use of THS 2.2 Menthol impacts the activity of this enzyme.  
• Lung function including Diffusion capacity for lung CO (DLCO), Forced expiratory 
volume in 1 second (FEV1), force vital capacity (FVC), vital capacity (VC), total lung 
capacity (TLC), forced residual volume (FRV), inspiratory capacity (IC), maximum 
expiratory flow (25-75) will be assessed in this study as it has been shown that some of 
these parameters may be improved early on after smoking cessation and are markers 
correlating with early but still reversible changes occurring in distal airway upon smoking 
(Verbank et al, 2006; Sansores et al., 2001). 
 
Other parameters such as human smoking topography, product evaluation, and subjective 
effects related to smoking including smoking urges and withdrawal symptoms will be 
evaluated. 
 
Twenty four-urine will be collected in this study as it is a well-established method to measure 
the levels of excretion of BoExp. Four-hour urine fraction will also be collected to better 
understand its accordance with 24-hour urine in the perspective of using such fraction in 
future ambulatory studies thereby minimizing operational and subject constraints. 
 
As part of the characterization of the study population it is important to measure variables 
that have been shown to be related to nicotine dependence and product reinforcing value. 
Based on prior tobacco research these factors include age, gender, ethnicity, educational and 
socio-economic status, tobacco use history, expectations of the effects of the products tested, 
nicotine exposure, health and mental health status and use of psychoactive substances. In 
order to capture, these data, subjects will be asked questions about their socio-economic 
status at screening. Such data would allow comparing populations across studies. 
 
All subjects will be asked to provide their own mCC according to their anticipated needs for 
the whole confinement period in order to minimize any changes in their smoking behavior. 

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4.3 
Appropriateness of Measurements 
The laboratory measures to be utilized in this study were selected based on the following 
criteria: 1) the availability of a validated analytical method; 2) measure is known to be 
directly or indirectly affected by smoking; 3) measure is readily reversible after smoking 
cessation/abstinence; 4) timeframe of reversibility of measure in the perspective of the study 
duration; 5) practicality/acceptability by subjects; 6) robustness of the method (rapid, simple, 
accurate). 
All questionnaires utilized for this study, except the cough, the socio-economic 
questionnaire, the smoking questionnaire, and the HST questionnaires, are available as 
validated questionnaires. 
4.4 
Study Duration 
The entire study duration per subject will be 123 to 150 days, including a Screening period of 
up to 28 days prior to baseline (Day -30 to Day -3), a 9-day confinement setting (Day -2 to 
time of Discharge of Day 6) followed by a 86-day ambulatory setting (from the time of 
Discharge on Day 6 to the time of Discharge on Day 91), and a 28-day safety follow-up 
period (until Day 119). The EOS is defined as the time of Discharge of Day 90 Visit (Day 
91) of the last subject plus 28-day follow-up. 
 
 

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5 STUDY POPULATION 
5.1 
Selection of Study Population 
In total, 160 female or male smoking, apparently healthy adult subjects who smoke per day at 
least 10 mCC for the last 4 weeks will be randomized in this study. All races/ethnicities will 
be considered eligible for the study. 
The maximum number of mCC smoked per day is not limited. Subjects must have a smoking 
history of at least 3 years of consecutive smoking prior to the Screening Visit. There will be 
no brand restrictions as long as the cigarettes are mentholated. Subjects can smoke different 
brands until Admission to the clinic. From Admission to the clinic onwards, however, they 
must restrict themselves to one preferred mCC brand. The smoking status will be verified 
with a urinary cotinine test (cotinine ≥200 ng/mL). Each sex and each of the smoking strata 
(those smoking 10 to 19 mCC and those smoking >19 mCC per day as reported by the 
subject in the 4 weeks prior to the Screening Visit) should have a quota applied to ensure 
they represent at least 40% of the population. 
5.1.1 
Inclusion Criteria 
At the Screening Visit/Day of Admission, each subject must meet the following criteria: 
Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
1. Subject has signed the ICF and is able 
to understand the information provided 
in the Subject Information Sheet and 
ICF. 
Administrative 
X 
 
2. Subject is at a minimum 22 years of 
age(inclusive). 
Safety 
X 
 
3. Smoking, apparently healthy subject as 
judged by the Investigator based on all 
available assessments from the 
Screening period/Day of Admission 
(e.g., safety laboratory, spirometry, 
vital signs, physical examination, 
ECG, chest X-ray, and medical 
history). 
Safety 
X 
X 

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Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
4. Subject smokes at least 10 
commercially available mCCs per day 
(no brand restrictions), for the last 4 
weeks, based on self-reporting. 
Furthermore, the subject has been 
smoking for at least the last 3 
consecutive years. The smoking status 
will be verified based on a urinary 
cotinine test (cotinine ≥200 ng/mL). 
Effect 
X 
X 
5. The subject does not plan to quit 
smoking within the next 6 months as 
assessed by the Prochaska ‘Stage of 
Change’ questionnaire. 
Safety 
X 
X 
6. The subject is ready to comply with 
study protocol (e.g. readiness to accept 
interruptions of smoking for up to 91 
days and to use THS 2.2 Menthol *). 
Effect 
X 
X 
*readiness to use THS 2.2 Menthol will only be asked at Day of Admission based on the 
product trial. 
 
 

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5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the 
study: 
Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
1. As per Investigator judgment, the 
subject cannot participate in the study 
for any reason (e.g., medical, 
psychiatric and/or social reason). 
Safety  
X 
X 
2. A subject who is legally incompetent, 
physically or mentally incapable of 
giving consent (e.g., emergency 
situation, under guardianship, subject 
in a social or sanitary establishment, 
prisoners or subjects who are 
involuntarily incarcerated). 
Administrative 
X 
 
3. The subject has clinically relevant 
diseases which required medications 
(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 as per CTCAE), which in 
the opinion of the Investigator would 
jeopardize the safety of the subject. 
Safety 
X 
X 
4. Subject who has forced expiratory 
volume in 1 second/forced vital 
capacity (FEV1/FVC) <0.7 and FEV1 
<80% predicted value at post-
bronchodilator spirometry (GOLD, 
2013). 
Safety 
X 
 
5. Subject with asthma condition 
(FEV1/FVC < 0.75 and reversibility in 
FEV1 > 12% (or > 200 mL) from pre 
Safety 
X 
 

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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
to post-bronchodilator values). 
6. Subjects with renal insufficiency as 
defined by serum creatinine levels of 
>1.3 mg/dL for females and >1.5 
mg/dL for males. 
Safety 
X 
 
7. The subject has a body mass index 
(BMI) <18.5 or ≥35 kg/m2. 
Safety 
X 
X 
8. As per Investigator judgment, the 
subject has medical conditions which 
require or will require in the course of 
the study, a medical intervention (e.g., 
start of treatment, surgery, 
hospitalization) which may interfere 
with the study participation and/or 
study results. 
Effect 
X 
X 
9. Any subject with an history of adverse 
events linked to caffeine or caffeine 
containing drugs (e.g., Vivarin), such 
as but not limited to hypersensitivity or 
allergy. 
Safety 
X 
X 
10. The subject has used 
nicotine-containing products other than 
commercially available mCC (either 
tobacco-based products or NRT), as 
well as electronic cigarettes and 
similar devices, within 4 weeks prior 
to assessment. 
Effect 
X 
X 
11. The subject has received medication 
(prescription or over-the-counter) 
within 14 days or within five half-lives 
of the drug (whichever is longer) prior 
to the Admission Day (Day -2), which 
has an impact on CYP1A2 or CYP2A6 
activity. 
Effect 
 
X 

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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
12. If a subject has received any 
medication (prescribed or over-the-
counter) within 14 days prior to 
Screening or prior to the Admission 
Day (Day -2), it will be decided at the 
discretion of the Investigator if these 
can potentially interfere with the study 
objectives or subject’s safety. 
Effect  
X 
X 
13. Concomitant use of nonsteroidal 
anti-inflammatory drugs (NSAIDs) or 
acetylsalicylic acid. 
Effect 
X 
X 
14. The subject has a positive alcohol test 
and/or the subject has a history of 
alcohol abuse that could interfere with 
the subject’s participation in the study. 
Administrative 
X 
X 
15. The subject has a positive urine drug 
test. 
Administrative 
X 
X 
16. Positive serology test for human 
immunodeficiency virus (HIV)1/2, 
hepatitis B or hepatitis C. 
Safety 
X 
 
17. Donation or receipt of whole blood or 
blood products within 3 months prior 
to Admission. 
Safety 
X 
X 
18. The subject is a current or former 
employee of the tobacco industry or of 
their first-degree relatives (parent, 
sibling, child). 
Administrative 
X 
 
19. The subject is an employee of the 
investigational site or any other parties 
involved in the study or of their first-
degree relatives (parent, sibling, and 
child). 
Administrative 
X 
 
20. The subject has participated in a 
clinical study within 3 months prior to 
the Screening Visit. 
Safety 
X 
 

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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
21. For women only: 
Subject is pregnant (does not have 
negative pregnancy tests at Screening 
and at Admission) or is breast feeding. 
Safety 
X 
X 
22. For women only : 
Subject does not agree to use an 
acceptable method of effective 
contraception* 
Safety 
X 
X 
* e.g., Intrauterine device, intrauterine system, established use of oral/injectable/implantable/transdermal 
hormonal methods, barrier methods of contraception (condoms, occlusive caps) with spermicidal 
foam/gel/film/suppository, 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. Hysterectomy, tubal 
ligation, bilateral oophorectomy or post-menopausal status are reasons for not needing to use birth control. Post-
menopausal status is defined as women who have not experienced menses for greater than 12 months. If a 
woman claims she’s post-menopausal, but has had her menses within 12 months, a follicle stimulating hormone 
test must be performed and must be within acceptable limits. 
5.1.3 
Removal of Subjects from the Study 
Subjects will be informed that they are free to withdraw from the study at any time. Subjects 
should be questioned for the reason of premature withdrawal, although they are not obliged 
to disclose it. This needs to be fully documented in the Source Document and electronic Case 
Report Form (eCRF). 
When a subject withdraws or is removed from the study (both confinement and ambulatory 
periods), the whole safety examination procedure planned at the day of Discharge on Day 6 
(Section 9.5) must be performed as soon as possible after the time of withdrawal unless the 
subject has withdrawn their informed consent to do so.  
After the time of withdrawal, the subject will enter into the 28-day period of safety 
follow-up. Subjects withdrawn or removed from the study cannot re-enter the study. 
Subjects must be withdrawn from the study for any of the following reasons: 
 Withdrawal of informed consent. 
 Any AE or condition (including clinically relevant changes in a laboratory parameter) 
which at the discretion of the Investigator no longer justifies the subject’s participation in 
this study. 

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 Positive pregnancy testing (any invasive procedures, including the drawing of blood 
MUST NOT be performed after diagnosis of pregnancy, see Section 8.5). 
 The Sponsor or Investigator terminates the study. If the Sponsor or the Investigator 
decides to prematurely terminate the study, the subject will be promptly informed and will 
follow the safety procedures for early termination as described in Section 9.5. The head of 
the medical institution should report the fact and the reason in writing to the IRB. 
 Withdrawal is considered to be in the best interest of the subject or the other subjects. 
Subjects may be discontinued from the study for any of the following reasons: 
 Lost to follow-up. 
 Concomitant treatment with non-authorized medication as defined in the context of this 
study (in general, any concomitant medication should be discussed with the Contract 
Research Organization [CRO] Medical Monitor on an ongoing basis). 
 During the confinement period, if a subject uses any mCC or nicotine/tobacco-containing 
product other than the product/regimen he/she is assigned to, he will be withdrawn from 
the study.  
 Noncompliance to the study procedures based on the judgment of the Investigator. 
Smoking of CC (menthol and non-menthol) in the THS 2.2 Menthol or SA arms during the 
ambulatory period will not be considered a reason for withdrawal of the subject from the 
study. However, the smoking of CCs (menthol and non-menthol) or use of any 
nicotine/tobacco-containing products including NRT other than the product/regimen the 
subject is assigned to during the ambulatory period will be documented in the daily product 
use electronic diary. 
Subjects withdrawn prematurely after randomization will not be replaced and will not be 
allowed to re-enter the study. All subject withdrawals have to be documented properly in the 
source documentation and the eCRF. 
5.1.4 
Violation of Selection Criteria 
Subjects who are eligible at Screening, but who do not meet the entry criteria at Admission 
Day (Day -2), will be considered a screening failure until the time of Enrolment and will be 
replaced by other subjects. 
Subjects who violate the entry criteria prior to Enrolment, but who are considered eligible, 
will be immediately withdrawn from the study when the violation is detected. If subjects are 
not yet randomized, they can be replaced. If subjects are randomized, they will be withdrawn 
from the study and will not be replaced. 
 

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6 INVESTIGATIONAL PRODUCTS 
6.1 
Description of Investigational Products 
6.1.1 
Test Product 
THS 2.2 Menthol comprises the following components: Menthol Tobacco Stick, Holder, 
Charger, a Cleaning Tool, a mains power supply, and a USB cable (see the user guide in 
Appendix 3): 
Charger:  
The function of the Charger (Model 4) is to recharge the Holder 
after use. It contains a battery with sufficient capacity to recharge 
the Holder approximately 20 times. It is a convenient size to carry 
around, and can itself be recharged from a main power source. 
THS Tobacco Stick 
Holder (Holder): 
The function of the Holder (Model 4.2) is to heat the Tobacco 
Stick, delivering an aerosol to the user. The electrical heating is 
powered from an internal battery which delivers power for about 6 
minutes (allowing complete use of a single Menthol Tobacco 
Stick) 
THS Menthol Tobacco 
Stick (Menthol 
Tobacco Sticks): 
The Menthol Tobacco Stick (product code C3 Menthol) contains 
tobacco which, when heated, generates an aerosol. It is custom-
designed to be used with the Holder. 
The overall objective of the design is to provide an acceptable experience in which the 
HPHC level in the aerosol is substantially reduced in comparison with mCC. 
The THS 2.2 Menthol will be provided by the Sponsor. 
Per cigarette tar, nicotine, and carbon monoxide yields are measured by standardized 
machined test methods. The most widely used test method is ISO 4387. PMI has developed a 
modified version of this method, which improves the determination of tar in products with 
high water content, which is typical for heated tobacco products (PMI, 2012a; PMI, 2012b; 
PMI, 2013a; PMI, 2013b). Another method is the more intensive smoking method developed 
by Health Canada (Health Canada, 1999). 
Table 2 lists the commonly reported measures (PMI, 2013a):  
 

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Table 2. 
Measured Aerosol Fractions for the Menthol Tobacco Sticks 
Constituent (mg/Menthol Tobacco 
Stick) 
ISO 1 
Health Canada Intense 
regime 2 
Tar/NFDPM  
5.0 
12.6 
Nicotine  
0.5 
1.20 
Carbon monoxide 
1.0 
0.60 
1 International Organization for Standardization (ISO machine-smoking regimen). The analytical 
method has been modified to avoid inaccuracies as a result of condensation from high water-content 
aerosols. 
2 Health Canada Intense machine-smoking regimen (55 mL puff volume, 2-second puff duration, 30-
second inter-puff interval) (Health Canada, 1999). 
NFDPM: nicotine-free dry particulate matter 
6.1.2 
Reference Product / Baseline Period Products 
During the run-in period (Admission to clinic until 06:29 AM of Day -1) and the baseline 
period (from 06:30 AM of Day -1 until 06:29 AM of Day 1), all subjects will continue 
smoking their preferred commercially available single brand of mCC. Subjects will not be 
allowed to roll their own mCC.  
The reference product to the THS 2.2 Menthol during the randomized exposure period will 
be the subject’s own preferred commercially available single brand of mCC.  
All eligible subjects will be asked to purchase their own preferred single brand of mCC prior 
to Admission and provide his/her anticipated amount of mCC for a total of 9 days plus 4 
extra packs on Day -2 (Admission Day) to the site staff. The mCCs will not be provided by 
the Sponsor. In case more mCC are needed during the confinement period, re-supply of mCC 
can be envisaged. 
6.1.3 
Packaging and Labeling 
At Admission, all study subjects will provide the anticipated amount of mCC in sealed packs 
to the study staff. The mCC packs provided by the subjects should not be opened and the 
cellophane wrapper should be intact. 
Each pack of mCC provided by the subject will be labeled to identify which subject the 
cigarettes belong to (labels should be affixed to the cellophane wrapper of the lower part of 
the pack by site staff). Each pack of mCCs will be labeled to identify necessary information 
to match the subject with its suppliers. 
For the Menthol Tobacco Sticks, the packs and cartons will be labeled with the necessary 
information. 

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6.2 
Use of Investigational Product(s) 
Subjects will never be requested or forced to smoke or to use the THS 2.2. Menthol and will 
be free to stop using their allocated product (THS 2.2 Menthol or mCC) at any time during 
the study. The study is designed as an ad libitum use study. During the screening period, 
subjects will be allowed to smoke except during the procedures of the Screening Visit at the 
discretion of the site. 
6.2.1 
Run-in Period 
Smoking of mCC ad libitum will be allowed prior to admission and throughout the day 
except during the procedures at the discretion of the site. Smoking will be allowed from the 
time of check-in of the subject until around 11:00 PM. All subjects (except women with a 
positive pregnancy test at Screening or at Admission) will undergo a THS 2.2 Menthol 
product test.  
Following the confirmation that the subject is ready to use the THS 2.2 Menthol product, 
subjects will be enrolled. 
6.2.2 
Baseline Period 
During the baseline period, all subjects will be allowed to continue smoking ad libitum their 
single preferred usual brand of mCC. On Day -1, smoking will be allowed from 06:30 AM 
onwards until around 11:00 PM. However, on Day 0, smoking will be allowed only after 
sample for CYP2A6 activity, MNWS and cough questionnaires, and full lung functions have 
been conducted. 
6.2.3 
Entire Exposure Period 
During the exposure confinement period from Day 1 until the time of Discharge on Day 6, 
subjects will not be allowed to use any nicotine/tobacco-containing products other than their 
assigned product/regimen. Smoking will be allowed from 06:30 onwards until around 11:00 
PM. On Day 6, the use of the products (THS 2.2 Menthol or mCC) will be allowed only after 
the sample for CYP2A6 activity, cough and MNWS questionnaires, and full lung functions 
have been done. Smoking will not be allowed in the SA arm. 
During the exposure ambulatory period, subjects will be instructed to continue using 
exclusively their assigned product/regimen. The use of any CCs (menthol or non-menthol) or 
nicotine/tobacco-containing products other than the product/regimen the subject is assigned 
to must be documented in the daily product use electronic diary. Subjects in the SA arm will 
be instructed to abstain from smoking.  

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In the morning of the Day 91, subjects in THS 2.2 Menthol and mCC arms will not be 
allowed to use their assigned product until the sample for CYP2A6 activity and full lung 
functions have been conducted at the clinic. Smoking will not be allowed in the SA arm.  
During the study, any subject who wants to quit smoking will be encouraged to do so and 
referred for further treatment as per the standard of care in the country in which the study is 
conducted. 
6.2.3.1 
THS 2.2 Menthol Arm 
During the exposure period in confinement, subjects randomized to the THS 2.2 Menthol 
arm will use exclusively THS 2.2 Menthol from Day 1, 06:30 AM onwards until time of 
Discharge on Day 6. 
At the time of Discharge on Day 6 and on each ambulatory visit, subjects will be instructed 
to continue using exclusively THS 2.2 Menthol ad libitum until time of discharge of Day 90 
Visit (Day 91).  
6.2.3.2 
Menthol Conventional Cigarettes Arm 
During the exposure period in confinement, subjects randomized to the mCC arm will 
continue smoking their mCC from Day 1, 06:30 AM onwards until time of Discharge on 
Day 6.  
On the time of Discharge on Day 6, subjects will be informed that they can continue to 
smoke their mCC ad libitum until the time of Discharge on Day 90 Visit (Day 91).  
6.2.3.3 
Smoking Abstinence Arm 
During the exposure period in confinement, subjects randomized to the SA arm will be 
instructed to abstain from smoking from Day 1, 06:30 AM onwards until the time of 
Discharge on Day 6. They will not be provided with medication supportive for smoking 
abstinence or NRT. 
On Day 6 and on each ambulatory visit and at any appropriate occasion, subjects in the SA 
arm will be instructed to remain abstinent with or without NRT (no other medication 
supportive for SA will be allowed) until time of discharge of Day 90 Visit (Day 91).  
6.2.4 
Stopping Rules for Investigational Product 
For safety purposes, smoking should be temporarily stopped in the event of any signs 
suggesting nicotine overexposure, (e.g., gastrointestinal disturbance [nausea, vomiting, 
diarrhea, stomach or abdominal pain], cold sweats, headache, dizziness, and breathing 
problems) or any reasons at the discretion of the Investigator. 

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6.2.5 
Safety Follow-up Period 
During the safety follow-up period (after the time of Discharge on Day 90 Visit (Day 91) 
until Day 119), There will be no smoking restrictions. Subjects in the SA arm who wish to 
continue their SA will be referred for further treatment as per the standard of care in the 
country in which the study is conducted, if requested by the subject.  
6.3 
Method for Assigning Subjects to Study Arms 
When all the eligibility criteria have been met, randomization will be done through the 
Interactive Web and Voice Response System (IWRS) on Day 0 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. 
Subjects will be randomized to one of the 3 study arms THS 2.2 Menthol:mCC:SA in a 2:1:1 
ratio. Stratified randomization will be conducted by sex and by daily average cigarette 
consumption in the 4 weeks prior to the Screening Visit (those smoking 10 to 19 mCC and 
those smoking >19 mCC per day) reported by the subject. In each arm, each sex and each of 
the smoking strata should have a quota applied to ensure they represent at least 40% of the 
study population. 
6.4 
Blinding 
This is an open-label study; therefore, the subjects and Investigators will be unblinded to 
subject’s arm. However, there will be a limited degree of blinding in the data review and data 
analysis process. In particular, PMI and CRO personnel will be blinded to the randomized 
arm as summarized in the following table: 
Blinded Study Personnel 
End of Blinding Period 
PMI and CRO study 
statisticians 
After the SAP finalization or PMI blind database lock(*), 
whichever comes last. 
PMI data manager 
After the finalization of PMI blind database review.(*) 
PMI safety and clinical 
scientists 
After the finalization of PMI blind database review(*). Can 
be actively un-blinded before that time point in case of the 
occurrence of any safety question, when appropriate. 
(*) As part of the PMI quality control (QC) activity, data listings will be reviewed by PMI before database lock, 
with no access to the randomization arm information. 
Any PMI and CRO personnel who are not listed in the above table will be unblinded by 
default.  

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6.5 
Investigational Product Accountability and Compliance 
6.5.1 
Dispensing Investigational Product 
During the confinement period, each mCC will be dispensed from Day -2 onwards to the 
subjects. Subjects in the THS 2.2 Menthol arm will be provided by the site personnel with 
Menthol Tobacco Sticks from Day 1 to Day 6 stick by stick. One mCC/Menthol Tobacco 
Stick will be allowed at a time, as per the study design, and documented in an appropriate 
log.  
On each day of the confinement period, the time of dispense and return for each product has 
to be documented from Day -2 for mCC and from Day 1 for Menthol Tobacco Sticks 
onwards. The start of product use on each day will correspond to the time of dispense of the 
first mCC/Menthol Tobacco Stick. The subject must not take a puff of the Menthol Tobacco 
Stick during the pre-heating time. The product will not be promoted for commercial 
distribution or test market. 
During the ambulatory period, subjects in the THS 2.2 Menthol arm will be provided 
THS 2.2 Menthol including anticipated amount of Menthol Tobacco Sticks to cover the 
period until the next study visit. An additional number of Menthol Tobacco Sticks will be 
dispensed to the subjects at these visits to cover for any unexpected delay to the visit 
schedule made by the subject. Extra delivery of THS Menthol Tobacco Sticks in between 
two visits may be envisaged. Subjects in the mCC arm will buy their mCCs directly from 
shops and will not be reimbursed. 
6.5.2 
Storage and Accountability 
A person in the site staff designated by the Investigator will be responsible for the storage 
and accountability of the IPs, in accordance with the Sponsor’s requirements. 
The THS 2.2 Menthol and mCCs will be stored in a secured storage site with access limited 
to authorized personnel only. Full accountability of the distributed products will be ensured 
by the designated site staff. 
6.5.2.1 
Confinement Period 
On each day of the confinement period, study site staff will record on the Accountability Log 
every occasion from Day -2 to time of Discharge on Day 6 that mCCs are dispensed to a 
subject by the study site staff and every occasion from Day 1 to time of Discharge on Day 6 
that the THS 2.2 Menthol product components (i.e., THS Tobacco Stick Holder, THS 
Charger, THS accessories) and Menthol Tobacco Sticks are dispensed to a subject. 

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Subjects will return each butt of mCC immediately after use from Day -2 to Day 6 for 
accountability. This will be documented in the appropriate log. 
Immediately after use, all tobacco plugs of all used Menthol Tobacco Sticks will be separated 
from the filters and the tobacco plugs will be collected from Day 1 to Day 5, using dedicated 
vials for accountability and subsequent analysis of potential combustion occurrences (see 
also Section 7.8.2.2). This will be documented in appropriate log. 
6.5.2.2 
Ambulatory Period 
THS 2.2 Menthol Arm: 
Subjects must return any unused packs, empty packs and partially used packs of Menthol 
Tobacco Sticks and the THS 2.2 Menthol product components they have used to the site for 
accountability.  
All tobacco plugs from Menthol Tobacco Sticks used after check-in at the investigational site 
until around 11:00 PM on Day 30 Visit, Day 60 Visit, and Day 90 Visit will be collected in 
dedicated vials for subsequent analysis of potential combustion occurrences.  
mCC Arm: 
No IP accountability will be done for mCC arm. 
SA Arm: 
No IP accountability will be done for SA arm. 
6.5.3 
Investigational Product Retention 
The study site will destroy or return to the Sponsor any unused Menthol Tobacco Sticks and 
will return to the Sponsor the THS 2.2 Menthol product components upon study completion. 
Retention of THS 2.2 Menthol products will be documented. 
Irrespective of the study arm at the time of Discharge from the clinic, the site staff will return 
to the subjects any remaining mCCs given to them on the day of Admission. 
6.5.4 
Compliance to Investigational Product 
During the confinement period, compliance for all study arms will be ensured by strict 
dispensation of the products (stick by stick) and collection of used Menthol Tobacco 
Sticks/mCC butts will be documented in the appropriate log. 

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During the ambulatory period, subjects in the 3 study arms will capture, Day 6 to the time of 
Discharge on Day 90 Visit (Day 91), the number of product used (e.g., menthol and non-
menthol CC, Menthol Tobacco Sticks, or any other tobacco /nicotine-containing products 
including NRT) on a daily basis in the product use electronic diary. The product use 
electronic diary will be supplied by Sponsor and distributed to the subjects by the study site 
personnel. The product use electronic diary will serve as a compliance tool in the 3 arms. On 
Day 6, the compliance to the product will be ensured using both the accountability log (from 
06:30 AM to time of discharge) and the product use electronic diary. In case of discrepancy 
between the log and the electronic diary entries, the electronic diary will be considered as the 
primary source data. 
In addition, in the SA arm, compliance will be chemically verified using an exhaled CO 
breath test during both the confinement and at the ambulatory visits. The cut-off point for the 
CO breath test value to distinguish mCC use versus SA use will be 10 ppm (Benowitz et al., 
2002). 
6.6 
Restrictions 
6.6.1 
Smoking Restrictions and Restrictions to the Smoking Abstinence Arm 
6.6.1.1 
Confinement Period 
To avoid smoke cross-contamination among the 3 study arms, subjects in the 
THS 2.2 Menthol and the mCC arm must smoke in separate rooms and the subjects allocated 
to the SA arm should not have access to the smoking rooms. Precautions should be taken to 
remove cues to smoking for subjects who are randomized to the SA arm.  
In the THS 2.2 Menthol and SA arms, subjects will not be allowed to smoke any mCC or use 
any nicotine/tobacco-containing products (including NRT) from Day 1 (06:30 AM) until the 
time of Discharge on Day 6. In the mCC arm, subjects will not be allowed to use the THS 2.2 
Menthol, any nicotine/tobacco containing products and other mCC than brought to the site by 
the subject. In the SA arm, intensive support including psychological support will be 
provided upon the request of the subject or of the Investigator/site staff. 
Smoking will generally only be allowed during the designated smoking times, from 
06:30 AM onwards to around 11:00 PM (for more details on time restrictions see Section 
6.2). In general, the performance of scheduled procedures has priority over the wish of a 
subject to use the product. However, this is different at Day 5 due to the assessment of the 
nicotine profile. If the subject wants to use the product at Day 5 around the time of the blood 
draw, he/she should use the product first and the blood will be drawn after product use. 

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6.6.1.2 
Ambulatory Period 
Subjects in the THS 2.2 Menthol arm will be instructed to exclusively use THS 2.2 Menthol 
and subjects in the SA arm will be instructed to remain abstinent from smoking with or 
without NRT.  
In the THS 2.2 Menthol and mCC arms, product use will be allowed during the Day 30 Visit, 
Day 60 Visit, and Day 90 Visit (for more details on time restrictions see Section 6.2). 
Subjects in the SA arm may use NRT (no other medication supportive to smoking abstinence 
will be allowed) if considered necessary by the Investigator or if requested by the subject. 
NRT products will be used as per the product label, and may be purchased by subjects at a 
pharmacy. Subjects will be reimbursed. Intensive support including psychological support 
will be provided upon the request of the subject or of the Investigator/site staff. 
6.6.2 
Dietary Restrictions 
6.6.2.1 
Confinement Period 
A standard diet will be designed by a dietician. For each meal, the caloric and fat content 
should be controlled in order to avoid a “high-fat” diet. The FDA guidance on food-effect 
studies for bioequivalency testing identifies a high-fat diet as a diet which maintains 
“approximately 50 percent of total caloric content of the meal and is high in calories 
(approximately 800 to 1000 calories) (FDA, 2002).”  
In order to avoid any effect on assessment of BoExp, grilled or pan-fried meat, smoked 
pre-cooked meats (e.g., tuna, ham, corned beef, and meats), smoked bacon and sausage will 
not be permitted (Tiffany et al., 1991). In addition, to avoid any effect on the measurement of 
CYP1A2 activity, alcohol, broccoli, Brussels sprouts, cauliflower, grapefruit, and 
xanthine-containing foods and beverages (coffee, tea, chocolate, cocoa, mate, guarana, etc.) 
will be forbidden (Faber et al., 2004) except when the subject is asked to take caffeine tablet 
for CYP1A2 measurement. Consumption of quinine-containing drinks (e.g., tonic water) will 
not be allowed. 
Subjects are not allowed to bring their own food or beverages to the investigational site. 
Meals will be served according to the schedules provided in Section 9. Additional light 
snack, fruits, and raw vegetables can be distributed to the subjects without restrictions at any 
time during confinement as long as they fulfill the above requirements. Consumption of 
water is allowed as desired. The same menu and meal schedule will be administered 
uniformly for all subjects in all study arms. In addition for the purpose of the Ames test 
planned on Day 0 and Day 5, the menus served on Day -1 and Day 4 will be identical. 
Fasting state has to be observed for at least 10 hours prior to blood draws for: 

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1. Safety laboratory on screening, Day 0, Day 6.  
2. Risk markers in serum/plasma/blood on Day 0 and Day 6.  
3. Serum/plasma bio-banking samples for further analysis of BoExp and risk markers on Day 
0, and Day 6. 
4. Blood bio-banking for transcriptomics on Day 0 and Day 6. 
5. Oxysterols in plasma on Day 0 and Day 6. 
 
On Day 0 and Day 6, subjects must not have eaten at least 30 minutes prior to collection of 
buccal and nasal epithelial samples. 
6.6.2.2 
Ambulatory Period 
The above dietary restrictions are not applicable for the ambulatory period. However, 1 day 
prior to the Day 90 Visit, and during the visit on site, subjects will be asked by the site staff 
to refrain from consuming grapefruit or grapefruit-containing products, or quinine-containing 
drinks (e.g., tonic water). Alcohol, broccoli, Brussels sprouts, cauliflower, chargrilled meat, 
xanthine-containing foods and beverages (e.g., coffee, tea, chocolate, cocoa, mate, guarana) 
will not be allowed on site during the Day 90 Visit. 
A fasting state has to be observed for at least 10 hours prior to blood draws for:  
1. Safety laboratory on Day 30 Visit (Day 31), Day 60 Visit (Day 61), and Day 90 Visit (Day 
91). 
2. Risk factor assessments in serum/plasma/blood on Day 30 Visit (Day 31), Day 60 Visit 
(Day 61), and Day 90 Visit (Day 91).  
3. Serum/plasma bio-banking samples for further analysis of BoExp and risk markers at the 
Screening Visit, on Day 90 Visit (Day 91). 
4. Blood bio-banking for transcriptomics on Day 90 Visit (Day 91). 
5. Oxysterols in plasma on Day 90 Visit (Day 91). 
 
On Day 90 Visit (Day 90), subjects must not have eaten at least 30 minutes prior to collection 
of nasal epithelial and buccal samples. 
6.7 
Concomitant Medication 
No medication should be taken during the study from the screening to the EOS (time of 
discharge from Day 90 Visit (Day 91) plus 28 days safety follow-up period) without prior 
informing the Investigator. However, the Investigator is responsible for the medical care of 
the subjects during their participation in this study. Any decisions regarding the prescribing 
of medication will be made in the best interests of the subject. 

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In the SA arm, subjects may be provided with NRT if considered necessary by the 
Investigator or requested by the subject. The use of medication supportive for smoking 
abstinence other than NRT will not be allowed.  
Concomitant use of NSAIDs and acetylsalicylic acid (including over-the counter products) is 
not allowed, as all of them could interfere with risk markers such as 11-DTX-B2. 
Acetaminophen will be allowed at a daily total dose of up to 3000 mg. Any medication 
(except medication containing estrogen) with an impact on the CYP1A2 and CYP2A6 
metabolism (as prescription and over-the-counter products) as shown in Table 3 must be 
avoided. 
If the use of a concomitant medication cannot be avoided for the subject’s safety, it must be 
fully documented in the Source Document and transcribed into the eCRF (for details, see 
Section 7.4.7).  
The drugs and substances shown in Table 3 are a selection of drugs considered to have an 
impact on CYP1A2 and/or CYP2A6 activity (Chang et al., 1999, Ingelman-Sundberg et al., 
1999, Lacy et al., 2007). Prior to database close, concomitant medication will be assessed 
according to their potential impact on CYP1A2 and CYP2A6 activity and potential impact on 
the study results. 
Concomitant medication will first be assessed at the Screening Visit. To be eligible for the 
study, any medication with impact on CYP1A2 and CYP2A6 metabolism must be 
discontinued at least 2 weeks prior to Admission to the clinic or for at least 5 half-lives 
(whichever is longer). They must not be used during the entire study until the Day 91 
(completion of the study). 
Medication containing estrogens (e.g. for contraception and for hormone replacement 
therapy), even though known to be CYP1A2 inhibitors, will be allowed in this study but must 
be documented on the eCRF. 

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Table 3. 
Examples of Medications with Effects on CYP1A2 and CYP2A6 Activity 
Drug name 
Substance Class 
Rifampicin and fluoroquinolones including 
ciprofloxacin and ofloxacin,  
Antibiotics 
Fluvoxamine, fluoxetine, paroxetine, bupropion, 
duloxetine, amitriptyline, imipramine, sertraline, 
mirtazapine, citalopram, thioridazine 
Antidepressant 
Haloperidol, perphenazine, chlorpromazine, 
propoxyphene fluphenazine, clozapine, olanzapine 
Neuroleptic 
Phenobarbital, primidone, carbamazepine 
Antiepileptic 
Cholorquine, quinidine 
Antirheumatic 
Clotrimazole, terbinafine, fluconazole, ketoconazole, 
miconazole 
Antimycotic 
Erythromycin, ciprofloxacin, clarithromycin, 
norfloxacin 
Antibiotic 
Cimetidine, chlorpheniramine, diphenhydramine, 
ranitidine 
H2-receptor antagonist 
Amiodarone, verapamil, mibefradil, mexiletin, 
propafenone, propranolol, lidocaine 
Antiarrhythmic  
Losartan, amlodipine, nifedipine,  
Antihypertensive 
Drospirenone, estrogens 
Hormonal contraception, hormonal 
replacement therapy (estrogens) 
Fluvastatin 
Cholesterol-lowering agent 
Theophylline 
Antispasmodic pulmonological 
agent/Bronchodilator agent 
Omeprazole, lansoprazole 
Proton pump inhibitor 
Interferon 
Antiviral/Immunomodulating agent 
Methoxsalen   
Anti-psoriatic 
Modafinil, diclofenac, rofecoxib  
Analgesic 
Insulin 
Anti-diabetic 

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Drug name 
Substance Class 
Sildenafil  
Erectile dysfunction 
Quinine  
Leg cramps 
St. John’s Wort  
Over-the-counter (herbal remedy) 
antidepressant 
Psoralen 
Anti-psoriatic (substance class 
Furocoumarins) 
Pilocapine 
Cholinergic agonists (e.g., used for 
Glaucoma Therapy) 
Data sources: Chang et al., 1999, Ingelman-Sundberg et al., 1999, Lacy et al., 2007. The list is not exhaustive. 
 
 

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7 STUDY PROCEDURES 
Personnel performing study measurements or recordings must have the appropriate training 
fully documented. Quality control (QC) measures have to be in place. An overview of all 
study procedures is shown in the Schedule of Events (Appendix 1). In this section, only the 
expected/planned time points for the various measurements are described. As not all subjects 
can undergo a procedure at the same time, adequate time windows are given for each study 
procedure and each time point (Section 9). Site personnel will adhere to the site’s Standard 
Operating Procedures (SOPs) for all activities. Appropriate medical advice will be provided 
to the subject in case of any medial findings requiring health care. 
7.1 
Informed Consent/Subject Information Sheet 
Prior any study assessments is performed, the subject will be asked to provide his consent to 
participate to the study (ICF/subject information sheet for study participation) (Section 1.3). 
In addition to the ICF/subject information sheet for study participation, the subject will be 
asked to provide his separate consent for two kinds of bio-banking (Section 1.3.2).  
• ICF/subject information sheet to the additional bio-banking of serum/plasma/urine 
samples for further measurements of BoExp and risk markers.  
• ICF/subject information sheet to the additional bio-banking of blood sample for further 
transcriptomics (pharmacogenomics) analysis/samples for nasal epithelial collection and 
samples from buccal collection.  
The subject’s participation in the study does not depend on their consent for all kind of bio-
banking and will be separate to that for study participation. The three consents will be 
captured in the eCRF. 
7.2 
Information on the Risk of Smoking and Smoking Cessation Advice 
and Debriefing 
Each subject will be given information on the risks of smoking and smoking cessation advice 
6 times during the study: at the Screening Visit, at Admission (Day -2), at Day 6, Day 30 
Visit (Day 31), Day 60 Visit (Day 61), and Day 90 Visit (Day 91). This will take the form of 
a brief interview according to the recommendations of the U.S. Public Health Service (U.S. 
Department of Health and Human Services, 2008). Details of the interview will be recorded 
in the Source Document File. Information on the risk of smoking and smoking cessation 
advice will be given to the subjects on an individual basis during a face-to-face meeting 
between the subject and the Investigator, and may additionally be given in a group session. 

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In addition, a debriefing of subjects will be done at each information on risk of smoking/ 
smoking cessation advice session to address any intended or unintended beliefs participants 
have about the candidate MRTP. The goal of the debriefing would be to help ensure that 
subjects exit the study with an accurate understanding of product risks, including an 
understanding that the candidate MRTP has not been demonstrated to be less harmful than 
mCC. 
7.3 
Support for the Smoking Abstinence Arm 
All subjects in the SA arm will be closely monitored from Day 1 to Day 6 and during the 
ambulatory visits until time of discharge of the Day 90 Visit (Day 91) by the site staff for 
possible signs and symptoms of nicotine withdrawal. This includes clinical monitoring, e.g., 
vital signs, physical examination, and body weight when available. It will also involve close 
monitoring of the subject’s behavior, mood, and any AEs. A psychologist may be contacted 
and will be available upon subject’s request, or if considered necessary, upon the request of 
the Investigator or designee.  
7.4 
Clinical Assessments 
Any clinically relevant medical condition detected during the Screening Visit has to be 
documented as a concomitant disease. This also applies to clinically relevant findings in 
laboratory values, vital signs, and ECGs detected during the Screening Visit. Any untoward 
medical occurrence in a subject detected during the study which was not present at the 
Screening Visit must be documented as an AE. Worsening of a pre-existing condition from 
the Screening Visit onwards will also be documented as an AE. If a clinically relevant 
finding is detected during the Screening period, the Investigator or designee needs to check if 
inclusion criterion No. 04 is still fulfilled. 
7.4.1 
Demographic Data 
Demographic data (sex, date of birth/age, ethnicity, and race) will be recorded at the 
Screening Visit. 
7.4.2 
Identification of the Current Cigarette Brand 
Identification of the current mCC brand(s) smoked by the subject will be done at the 
Screening Visit and at Day -2. At the Screening Visit, smokers will be asked to bring a pack 
of their current mCC brand(s) to the site. On Day -2, subjects will hand their mCC supply for 
the entire confinement period to the site staff. Site staff will document the brand name. A 
photograph of the front and the side of the cigarette pack supplied by the subject will be 
taken by the study site staff in addition to recording the brand name. These photographs will 

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be considered as Source Documentation. A copy of the photographs will be provided to the 
Sponsor electronically (as Digital Video Disc or Compact Disc). 
7.4.3 
Smoking History Assessment  
Subjects will be asked about their smoking history. At Screening and on the Day of 
Admission (Day -2), this will include questions to evaluate whether the subject has smoked 
for at least the last 3 consecutive years, to determine the number of mCC smoked during the 
previous 4 weeks, and to check if the CCs smoked during the previous 4 weeks were mCCs. 
This self-reported mCC daily consumption will be used for eligibity. In addition, the subject 
will be asked if he/she has used nicotine-containing products other than commercially 
available mCC (either tobacco-based products or NRT), electronic cigarettes, or similar 
devices, within 4 weeks prior to assessment. 
At Screening and on the day of Admission (Day -2), subjects will also be asked if they are 
ready to abstain from smoking for up to 91 days (as required in the study protocol inclusion 
criteria No. 06). Only subjects who are prepared and able to comply with this requirement 
will be considered for participation in the study. 
7.4.4 
Intention to Quit Smoking  
Intention to quit smoking will be assessed at Screening, Day -2, Day 30 visit (Day 30), Day 
60 Visit (Day 60), and Day 90 Visit (Day 90) by the means of Prochaska ‘Stage of Change’ 
questionnaire see Section 7.8.3.8.  
Only smokers who are in the precontemplation stage (who are not willing to quit within the 
next 6 months) will be enrolled in the study.  
7.4.5 
Demonstration and Trial of the THS 2.2 Menthol  
All subjects will be shown a demonstration of the THS 2.2 Menthol product at the Screening 
Visit. On Day -2, as the last procedure of the eligibility assessments on that day, subjects will 
be offered a product test of the THS 2.2 Menthol (using of up to three THS Menthol Tobacco 
Sticks). In female subjects, the THS 2.2 Menthol test must only be done after pregnancy is 
excluded by a negative urine pregnancy test. Enrolment takes place after all requested 
inclusion and exclusion criteria have been satisfactorily met at Day-2. Only subjects who are 
willing and able to use the product can participate in the study (as required in the study 
protocol inclusion criteria No. 06). The product test will be the last assessment prior to 
enrolment. 

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7.4.6 
Product Preference 
In order to perform a complementary analysis on subjects’ preference, the following question 
will be asked to the subject; 
“Which product would you prefer to be randomized to: 
• THS 2.2 Menthol. 
• mCC. 
• SA. 
• no preference.” 
This question will be asked on Day -2 after enrolment in all subjects. If the subject would 
have preferred to be randomized to SA arm, then, the Prochaska ‘Stage of Change’ 
questionnaire will be re-administered If the subject says that he is planning to quit within 6 
months, the subject will be discontinued from enrolment during the study. . 
7.4.7 
Medical History, Concomitant Disease, Previous and Ongoing Medications 
Relevant medical history will be documented at the Screening Visit. Any concomitant 
disease will be documented at the Screening Visit. Medical history is defined as any 
condition that started prior to and ended prior to Screening. A concomitant disease is defined 
as any condition that started prior to the Screening Visit and is still ongoing at the Screening 
Visit. 
Prior medication taken 4 weeks prior to Screening Visit and any concomitant medication 
needs to be documented. Any medication which was started prior to the Screening Visit and 
is still being taken by the subject will be considered a concomitant medication. Medication 
initiated after Screening is also referred to as concomitant medication. This applies to both 
prescription and over-the-counter products. 
Records of any medication taken must include the drug name (preferably both generic and 
trade name), route of administration (e.g., oral, intravenous), total daily dose/unit (e.g. 
expressed in mg, mL, or IU), indication, the start and (if applicable), the stop date (day, 
month and year). Any therapy changes (including changes of regimen) during the study are 
to be documented. Any concomitant medication that is still being taken by the subject at the 
EOS will be recorded on the eCRF. 

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7.4.8 
Physical Examination 
A physical examination will be conducted at the Screening Visit, at Admission (Day -2), at 
Discharge from the clinic on Day 6, on Day 30 Visit (Day 30), Day 60 Visit (Day 60), and on 
Day 90 Visit (Day 91).  
7.4.9 
Body Height, Weight and Waist Circumference 
Body weight will be recorded on the Screening Visit, on Admission (Day -2), on Discharge 
on Day 6, on Day 30 Visit (Day 30), Day 60 Visit (Day 60), and on Day 90 Visit (Day 91). 
Body height will be measured only at the Screening Visit. Waist circumference will be 
measured on Admission (Day -2) and on Day 90 Visit (Day 91). Appropriate medical advice 
will be provided to the subject in case of any medical findings requiring health care. 
Body mass index (BMI) will be calculated from the body weight and height using the 
following formula: 
BMI =  
weight in kilograms 
————————     ( kg/m² ) 
height in meters² 
Weight and waist circumference will also be analyzed as risk markers (Section 7.5.2). 
7.4.10 Vital signs 
Systolic and diastolic blood pressure, pulse rate and respiratory rate will be measured at the 
Screening Visit, at Admission (Day -2), in the morning of every day of the confinement 
period (i.e., Days -1 to 6), and at each ambulatory visit (Day 30 Visit on Day 30, Day 60 
Visit on Day 60 and Day 90 Visit on Day 91). All measurements will be made after the 
subject has rested for at least 5 minutes in a supine position and at least 15 minutes after 
smoking/product use. For every measurement, it will be documented if the subject has 
smoked within 15 minutes prior to the measurement. 
7.4.11 Other Clinical Assessments 
7.4.11.1 
Spirometry to Assess Full Lung Functions 
The spirometry test will be performed in accordance with the 2005 guideline of the American 
Thoracic Society/European Respiratory Society Joint Task Force on the standardization of 
spirometry (ATS/ERS, 2005a). Spirometry predicted values will be standardized to the Third 
National Health and Nutrition Examination Survey (NHANES III) predicted set. All 
personnel performing full lung function testing should have the appropriate training and QC 

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measures should be put into place and be properly documented and filed at the pulmonary 
function laboratory (including the records of the calibration, if applicable). A certified 
respiratory therapist should perform the assessment and the results are being assessed by a 
pulmonologist. The subject will be at rest for at least 15 minutes prior to lung function 
testing. All lung function manoeuvres will be recorded with the subject in a sitting position 
throughout the study. 
 
The full lung function tests will be performed prior to product use (mCC or THS 2.2 
Menthol) on Day 0 (baseline values), Day 6, and Day 90 Visit (Day 91). Full lung function 
tests will include the recording of FEV1, FVC, the ratio FEV1 to FVC, and MEF 25-75 (using 
spirometry with bronchodilator), lung volumes (VC, TLC, and IC) using the helium dilution 
technique and the DLCO and KCO (using the single breath technique for CO). The 
assessments must be performed in the following sequence: 
 
• Gas transfer (DLCO, KCO). 
• Lung volume (VC, TLC, and IC). 
• Spirometry with bronchodilator. 
 
For full lung functions, the following must be performed:  
1. The ambient temperature, barometric pressure and humidity must be measured and 
entered into the software of the instrument. 
2. The instrument will be calibrated prior to every test. 
3. The subject will wear nose clips. 
4. The subject will be asked to place the mouthpiece in their mouth and breathe 
normally. They are then instructed to breathe in to total lung capacity (TLC) and 
exhale as hard and as fast as they possibly can until they reach forced residual volume 
(FRV). At this point they will be instructed to inhale as hard and as fast as possible 
until they are back to TLC. 
 
Spirometry with and without bronchodilator 
The following recommendations should be followed: 
 
1. The instrument should be calibrated prior to the procedure. 
2. The subject will be instructed to take a full inspiration away from the cardboard 
mouthpiece, seal his/her lips around the mouthpiece, making sure that his/her tongue 
does not occlude the mouthpiece, and perform an expiratory manoeuvre.  
3. The subject will be instructed to do the following: breathe out as rapidly and 
forcefully into the mouthpiece as possible and continue until he/she feels his/her 
lungs are completely empty.  

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Spirometry without bronchodilator 
Spirometry will be conducted without bronchodilator at screening only. Values for FEV1, 
FVC, the ratio FEV1 to FVC, and MEF 25/75 will be recorded. 
The spirometry without bronchodilator must be done prior to the spirometry with 
bronchodilator and must be done at least 1 hour after smoking.  
Spirometry with bronchodilator 
At the Screening Visit, on Day 0, on Day 6, and on Day 90 Visit (Day 91), spirometry with 
bronchodilator will be performed and post-bronchodilator values for FEV1, FVC, the ratio 
FEV1 to FVC, and MEF 25/75 will be recorded.  
The spirometry will be performed in all subjects 15-30 minutes post administration of around 
400 g salbutamol (usually equivalent to 2 -4 puffs assuming 90 g/puff).  
The results from FEV1, and the ratio FEV1 to FVC at screening will be used for eligibity 
criteria.  
 
Lung volume measurements (VC, TLC, and IC) 
Lung volume measurements (VC, TLC, and IC) This procedure will be conducted as part of 
the full lung function tests on Day 0, Day 6, and Day 90 Visit (Day 91) and the following 
values will be recorded: VC, FRC, IC and TLC values. 
 
The helium dilution technique will be used in accordance with the recommendations of the 
American Thoracic Society/European Respiratory Society Joint Task Force on the 
standardization of the measurement of lung volumes (ATS/ERS, 2005c). This technique is a 
closed-circuit system where a spirometer is filled with a mixture of helium and oxygen. The 
closed-circuit rolling seal spirometer will be filled to a starting volume of six liters with a 
mixture of containing helium, oxygen and balance room air. Oxygen will be set to 30% so 
that all test subjects will be comfortable; exact contents will be analysed The subject will be 
asked to seal their lips around the mouthpiece and breathe normally on the closed-circuit 
while the helium mixes and equilibrates. During this time carbon dioxide will be removed by 
a chemical absorber and oxygen will be automatically replaced. Once equlibration has 
occurred, the subject will be asked to perform one or more a vital capacity efforts to end the 
test. 
 
Gas Transfer (DLCO and KCO) 
This procedure will be conducted as part of the full lung function tests on Day 0, Day 6, and 
Day 90 Visit (Day 91) using the single breath technique according to the recommendations of 
the American Thoracic Society/European Respiratory Society Joint Task Force on the 
standardization of the single-breath determination of carbon monoxide uptake in the lung 

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ATS/ERS, 2005b. DLCO and KCO (DLCO to alveolar volume (VA) ratio) values will be 
recorded.  
As recommended by the guideline of single breath technique, gas transfer values will be 
adjusted to COHb levels. To that purpose, blood sampling for COHb measurement will be 
taken prior to gas transfer assessment on Day 0, Day 6, and Day 90 Visit (Day 91).  
The subject will be asked to seal their lips around the mouthpiece, with a nose clip on the 
nose. They will then be asked to breathe room air for a few tidal breaths.  
 
The subject will then be instructed to: 
 
1. To inhale as far as possible. This is estimated as at least 90 % of the subject’s VC.  
2. To hold their breath for 10 seconds without straining. The subject should relax against 
the shutter and be encouraged not to breath out or breath in against it, as this will alter 
the intrathoracic pressure and the pulmonary haemodynamics, resulting in either an 
increase (breathing in) or decrease (breathing out) in DLCO. 
3. To blow as far as possible. On completion of the manoeuvre, the subject will be 
rested in a sitting position, before repeating the test a minimum of two times. The 
time between manoeuvres will be at least 4 minutes.  
7.4.11.2 
Electrocardiogram 
An electrocardiogram (ECG) will be recorded at Screening, on Day 6, at Day 30 Visit (Day 
30), Day 60 Visit (Day 60), and Day 90 Visit (Day 91). ECG testing will be performed as per 
the site’s local practice. A standard 12-lead ECG will be recorded after the subject has rested 
for at least 5 minutes in a supine position. 
The following parameters will be documented: heart rate, PR interval, QRS interval, QT 
interval, and QTc interval corrected by the ECG machine according to Bazett’s formula and 
Federici’s formula. Every ECG has to be assessed as normal, abnormal – clinically not 
relevant, or abnormal – clinically relevant. A diagnosis has to be provided on the eCRF for 
all ECGs assessed as abnormal – clinically relevant. All ECG print-outs will be interpreted 
by a qualified physician. Any print-outs of ECGs on thermo-sensitive paper must be 
photocopied and stapled together for inclusion in the Source Documents. 
7.4.11.3 
Chest X-ray 
A chest X-ray (anterior-posterior and left lateral views) will be assessed during the Screening 
period to exclude subjects with relevant pulmonary diseases. Subjects will be referred to a 
radiology facility for this procedure. No new examination is required if the subject can 
present a chest X-ray with anterior-posterior and left lateral views at the Screening Visit 
which is not older than 6 months. 

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7.5 
Biomarker Assessment 
All bioanalytical assays and laboratory assessments except the assay to measure oxysterols 
will be carried out using validated methods (Sections 7.6 and 7.7). The bioanalytical methods 
used will be documented in the Bioanalytical Plans/Reports. A list of laboratories is provided 
in Appendix 2. 
Precautions should be taken during blood sampling and processing to prevent the 
contamination of samples with environmental smoke. 
7.5.1 
Biomarker of Exposure  
7.5.1.1 
Exhaled CO and COHb 
Carboxyhemoglobin measured in blood and exhaled CO will be investigated as a measure of 
exposure to CO in all three study arms. A CO breath test should be conducted in timely 
conjunction with the blood sampling for COHb, where applicable. In the SA arm, the CO 
breath test will serve as a verification of compliance during the confinement period and 
ambulatory visits (Section 6.5.4). 
CO Breath Test: 
Carbon monoxide in exhaled breath will be measured using the Smokerlyzer® device, such as 
the Micro 4 Smokerlyzer® device or similar in all 3 study arms. 
During the confinement period on Days -1 to Day 5, the CO breath test will be conducted 
4 times per day. The first assessment should be conducted within 15 minutes prior to the first 
product use. The other 3 assessments should be conducted as described in Section 9. 
For subjects in the SA arm from Day 1 onwards, the first CO breath test will be done 
between 08:00 AM and 09:30 AM. The other 3 assessments should be conducted, as 
described in Section 9. 
On Day -2 and Day 6, and during the ambulatory period on Day 30 Visit (Day 30), Day 60 
Visit (Day 60), and Day 90 Visit (Day 90), the CO breath tests will be conducted once, 
irrespective of time of product use. 
Carboxyhemoglobin 
Carboxyhemoglobin will be assessed on a daily basis from Day-2 until Day 6.  
On Day -1, and from Day 1 to Day 4: one blood sample will be collected in the evening 
between 08:00 PM and 09:30 PM. 

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On Day 0, two blood samples will be collected: one blood sample will be collected prior to 
gas transfer assessment and prior to product use (the COHb levels measured will serve for 
adjustment of gas transfer values only), the second blood sample will be collected in the 
evening between 08:00 PM and 09:30 PM.  
On Day 5: one blood sample will be collected within 15 minutes prior first product use. The 
3 other blood samples will be collected as described in Section 9. 
On Day 6: one blood sample will be collected prior to the gas transfer assessment and prior 
to product use (the COHb levels measured will serve for adjustment of gas transfer values 
only). 
For subjects in the SA arm from Day 1 onwards, the first COHb will be done between 
08:00 AM and 09:30 AM. The 3 other blood samples will be collected, as described in 
Section 9. 
On Day 30 Visit (Day 30), and Day 60 Visit (Day 60): For all study arms, one blood sample 
will be collected during the visit, irrespective of the time of product use. 
On Day 90 Visit: one blood sample will be collected on Day 90, irrespective of the time of 
product use. One blood sampling will be collected on Day 91 prior to gas transfer 
assessment, and product use (the COHb levels measured will serve for adjustment of gas 
transfer values only). 
7.5.1.2 
Plasma Nicotine and Cotinine 
Nicotine and cotinine concentrations will be measured in plasma to evaluate the exposure to 
nicotine in all three study arms. No sampling for PK profile will be done for subjects in the 
SA arm (Day 5 to Day 6) and only one blood sampling will be done on each of Day 5 and 
Day 6. 
• On Day 0 to Day 4 (all study arms): 
One blood sample per day will be taken in the evening between 08:00 PM and 09:30 PM. 
• Nicotine/Cotinine Pharmacokinetic (PK) Profile on Day 5 and Day 6 (THS 2.2 Menthol 
and mCC arms only): 
In total, 9 blood samples will be drawn on Day 5. The first blood sample on Day 5 will be 
drawn within 15 minutes prior to the first product use. On Day 5, the start time of the first 
product use (T0) will serve as reference for the time to peak concentration. An additional 
8 blood samples will be drawn in 2 hour intervals after the start of product use. The last 
blood sample should be drawn no later than 11:00 PM, corresponding to the end of 
product use. At all time points, if the subject wants to use the product around the time of 

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the blood draw, he/she should use it first and the blood will be drawn after product use. 
Depending on the time of the first product use, it may be that fewer than 8 blood samples 
will be collected from a subject after T0. 
On Day 6, two blood samples will be drawn. The first one will be 20 hours after T0 and 
the second blood sample will be 24 hours after T0 (with T0 being the start time of first 
product use at Day 5).  
• On Day 5 and Day 6 (SA arm only): 
On Day 5, one blood sample will be drawn in the evening between 08:00 PM and 09:30 
PM. 
On Day 6, one blood sample will be drawn between 08:00 AM-09:30 AM. 
• On Day 30 Visit (Day 30), Day 60 Visit (Day 60), Day 90 Visit (Day 90) (all study 
arms): 
One blood sample will be drawn during these visits, irrespective of the time of product 
use. 
7.5.1.3 
Other Biomarkers of Exposure 
BoExp will be measured as per the Schedule of Events (Appendix 1): 
• In 24-hour urine collection samples during both confinement and ambulatory periods 
from Day 0 onwards to Day 5 and on Day 30 Visit, on Day 60 Visit , and on Day 90 
Visit.  
• In 4-hour urine fraction during both confinement and ambulatory periods collected on 
Day -1, and Day 90 Visit (Day 91).  
The following BoExp will be measured: 
• Selected primary BoExp: MHBMA, 3-HPMA, S-PMA, and Total NNAL. 
• Selected secondary BoExp: Total 1-OHP, Total NNN, 4-ABP, 1-NA, 2-NA, o-tol, NEQ, 
CEMA, 3-hydroxybenzo(a)pyrene, HEMA, S-BMA and HMPMA. 
For normalization of BoExp, creatinine will also be measured in the 24-hour urine and 4-
hour urine samples. 

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7.5.2 
Other assessments 
7.5.2.1 
Risk Markers 
The following risk markers will be assessed in this study: 
• Systolic and diastolic blood pressure, hs-CRP, fibrinogen, homocysteine, blood 
glucose, LDL, HDL, TG, TC, HbA1c, sICAM-1, WBC count, Apo A1, Apo B, 8-epi-
PGF2α, 11-DTX-B2, platelet count, weight, and waist circumference. 
The assessment of systolic and diastolic blood pressure, blood glucose, TG, TC, platelet 
count, weight, and waist circumference will not be repeated because they are part of the 
safety parameters or clinical evaluation. 
Selected risk markers will be evaluated at the following time points in at least 10-hour of 
fasting state conditions for the assessments which require blood, serum, or plasma: 
• Systolic and diastolic blood pressure: to be evaluated as risk markers on Day 0, Day 6, 
Day 30 Visit (Day 30), Day 60 Visit (Day 60), and Day 90 Visit (Day 91). The results 
from vital signs on Day 0, Day 6, Day 30 Visit, Day 60 Visit, and Day 90 Visit will be 
used. 
• hs-CRP, homocysteine, blood glucose, LDL, HDL, TG, TC in serum: to be evaluated as 
risk markers on Day 0, at Day 30 Visit (Day 31), Day 60 Visit (Day 61), and Day 90 
Visit (Day 91). Samplings will be planned to measure hs-CRP, homocysteine, LDL, HDL 
at the mentioned timepoints. The results on blood glucose, TG, and TC from the safety 
laboratory panel on Day 0, Day 30 Visit, Day 60 Visit, and Day 90 Visit will be used. 
• Fibrinogen in plasma: to be evaluated as risk markers on Day 0, Day 30 Visit (Day 31), 
Day 60 Visit (Day 61), and Day 90 Visit (Day 91). Samplings will be planned to measure 
fibrinogen at the mentioned timepoints. 
• HbA1c in serum: to be evaluated as risk markers at Day 0, and Day 90 Visit (Day 91). 
Samplings will be planned to measure HbA1c at the mentioned timepoints. 
• Apo A1 and Apo B in serum on Day 0, and Day 90 Visit. Samplings will be planned to 
measure Apo A1 and Apo B at the mentioned timepoints. 
• sICAM-1 in serum: to be evaluated as risk markers on Day 0, Day 6, Day 30 Visit (Day 
31), Day 60 Visit (Day 61) , and Day 90 Visit (Day 91). Samplings will be planned to 
measure sICAM-1 at the mentioned timepoints. 
• 8-epi-PGF2α and 11-DTX-B2 in urine: to be evaluated as risk markers in 24-hour urine 
on Day 0, Day 5, on Day 30 Visit, Day 60 Visit, and Day 90 Visit and in 4-hour urine 
fraction in Day 90 Visit. Samplings will be planned to measure 8-epi-PGF2α and 11-

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DTX-B2 at the mentioned time points. The results will be normalized to creatinine and 
express as concentration adjusted for creatinine. 
• WBC and platelet count in whole blood: to be assessed as risk markers on Day 0, Day 6, 
Day 30 Visit (Day 31), Day 60 Visit (Day 61), and Day 90 Visit (Day 91). The results 
from the safety laboratory panel will be used. 
• Waist circumference and weight: evaluated on Day -2 and on Day 90 Visit (Day 91) (as 
evaluated as part of the clinical examination, see Section 7.4.9). 
7.5.2.2 
CYP1A2 activity test 
CYP1A2 activity will be assessed in plasma by measuring PX and CAF concentrations and 
calculating the PX/CAF molar metabolic ratio (Faber et al., 2004) on Day 0, Day 5, and Day 
90 Visit (Day 90). Samples to measure PX and CAF will be drawn approximately 6 hours 
(±15 minutes) after the intake of one “vivarin” caffeine tablet (around 200 mg caffeine) with 
240 mL ±10 mL water (Faber et al., 2004).  
The exact time of intake of the caffeine tablet in the morning and of the time of blood 
sampling 6 hours [±15 minutes] later must be recorded.  
7.5.2.3 
CYP2A6 activity test 
CYP2A6 activity will be measured in plasma on Day 0, Day 6, and Day 90 Visit (Day 91), 
using the molar metabolic ratio of trans-3’-hydroxycotinine to cotinine (Jacob et al., 2011). 
Blood sampling for CYP2A6 has to be done prior to product use. CYP2A6 activity drives the 
metabolism of nicotine to cotinine and subsequent metabolites. 
7.5.2.4 
Ames Mutagenicity Test 
Urine mutagenicity, a biomarker for measuring mutagen load, will be measured on Day 0, 
Day 5 and Day 90 Visit in 24-hour urine. The urinary determination of each sample will be 
done in one bacterial strain (S. typhimurium strain YG1024), using S9 metabolic activation 
and 4 doses for each of the urine extracts. 
7.5.2.5 
Oxysterols 
Oxysterols 
including 
6α-hydroxy-5α-cholestane, 
7α-hydroxycholesterol, 
5α,6α-
epoxycholestanol, 7-ketocholesterol, 7β-hydroxycholesterol, 5β,6β-epoxycholestanol, 24(R)-
hydroxycholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol in addition to total 
cholesterol will be measured in plasma on Day 0, Day 6 and Day 90 Visit (Day 91) using a 
non-validated method. Based on the outcome of the study, it will be determined if the assay 

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will be further validated. The samples need to be taken in at least 10 hours of fasting 
condition. 
7.6 
Laboratory Assessments 
A list of laboratories is provided in Appendix 2. 
7.6.1 
Clinical Chemistry, Hematology, and Urine analysis for the Safety Panel  
Hematology, clinical chemistry and urine analysis for the safety panel will be measured at 
Screening, Day 0, Day 6, Day 30 Visit (Day 31), Day 60 Visit (Day 61), and at Day 90 Visit 
(Day 91). Blood samples will be taken after at least 10 hours of fasting (Section 6.6.2). The 
urine test will be performed semi-quantitatively as a urine test. Parameters to be measured 
are listed in Table 4. 

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Table 4. 
Clinical Laboratory Parameters for Safety Panel 
Hematology 
Clinical Chemistry 
Urine analysis 
 Hematocrit 
 Hemoglobin 
 Mean corpuscular hemoglobin (MCH) 
 Mean corpuscular hemoglobin 
concentration (MCHC) 
 Mean corpuscular volume (MCV) 
 Platelet count 
 Red blood cell (RBC) count  
 White blood cell (WBC) count 
 Differential WBC count:  
 
Neutrophils 
 
Basophils  
 
Eosinophils  
 
Lymphocytes 
 
Monocytes 
 
 Albumin 
 Total protein 
 Alkaline phosphatase 
(AP) 
 Alanine aminotransferase 
(ALT) 
 Aspartate 
aminotransferase (AST) 
 Blood urea nitrogen 
(BUN) 
 Creatinine 
 Gamma-glutamyl 
transferase (GGT) 
 Fasting Glucose 
 Lactate dehydrogenase 
(LDH) 
 Potassium  
 Sodium 
 Total bilirubin 
 Direct bilirubin 
 Total cholesterol 
 Triglycerides 
 pH 
 Bilirubin 
 Glucose 
 Nitrite 
 Red blood cell traces 
 Protein 
 Specific gravity 
 
7.6.2 
Serology 
A test for Hepatitis B surface antigen, Hepatitis C virus, and human immunodeficiency virus 
(anti-HIV1/2) will be done at Screening. 
7.6.3 
Urine Drug Screen 
A urine drug screen will be performed at the study site at the Screening Visit and on the day 
of Admission (Day -2). The urine will be screened for amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, and opiates. 
7.6.4 
Urine Cotinine Screening 
A urine cotinine test will be performed at Screening in order to confirm the subject’s 
smoking status.The test must detect cotinine with a cotinine threshold of ≥200 ng/mL. 

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7.6.5 
Alcohol Test 
Subjects will have a urine or breath alcohol test at the Screening Visit and at Admission to 
the clinic (Day -2). 
7.6.6 
Urine Pregnancy Testing 
All female subjects will undergo pregnancy testing at the Screening Visit, at Admission 
(Day -2), at Day 6, at Day 30 Visit (Day 30), Day 60 Visit (Day 60), and Day 90 Visit (Day 
91). Female subjects with a positive pregnancy test at the Screening Visit or at Day -2 cannot 
be enrolled and will be considered a screening failure. The product test at Admission must be 
done only in female subjects with a negative urine pregnancy test. In any case of a positive 
urine pregnancy test, the Investigator or designee will inform the subject about the risks 
associated with smoking during pregnancy.  
 
The post-menopause is formally defined as the time after which a woman has experienced 12 
consecutive months of amenorrhea (lack of menstruation) without a period. If a woman 
claims she is post-menopausal, but has had her menses within 12 months, a follicle 
stimulating hormone test must be performed and must be within acceptable limits. 
All pregnancies detected during the study must be reported and handled as described in 
Section 8.5. 
7.7 
Sampling Handling and Storage 
All blood samples are to be tested at a central laboratory with the exception of COHb blood 
samples, and the safety laboratory panel at screening only which will be tested at a local 
laboratory (Appendix 2). The samples for measurement of oxysterols will to be tested at PMI 
R&D Laboratory, Neuchâtel, Switzerland. The urine test for the safety laboratory, urine 
pregnancy tests, urine drug screen, and urine cotinine tests will be done by personnel at the 
study sites. 
Detailed procedures for sample collection and handling of samples are described in a 
separate Sample Handling Manual (SHM). Safety laboratory samples will be destroyed as 
per the laboratory’s standard procedures. All other samples (except bio-banking samples) 
will be destroyed after the clinical study report (CSR) has been finalized. The facility/-ies at 
which the samples are stored will be informed in writing by the Sponsor when destruction of 
the samples will be allowed. 
The bioanalytical lab(s) are listed in Appendix 2. 

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7.7.1 
Blood samples 
Venous blood samples will be collected by qualified and trained site personnel. Subjects 
should be in a seated position during blood collection. The maximal total volume of blood 
drawn for each subject will be around 310 mL, which includes 40 mL for safety and repeated 
analysis, 30 mL of blood for long term storage of the bio-banking samples for further 
analysis of BoExp and risk markers (only if additional consents are given) and 15 mL for 
long-term storage bio-banking samples for further analysis of transcriptomics (only if 
additional consents are given) (Section 7.7.3). 
7.7.2 
Urine samples 
Spot urine samples will be used for the urine drug screen, urine cotinine screen, urine 
pregnancy test, and safety urinalysis.  
24-hour urine collection during confinement period 
Subjects will empty their bladders shortly before 06:30 AM on the study day indicated in the 
Schedule of Events (Appendix 1) and discard the urine. The collection period will start at 
06:30 AM ± 30 minutes and will end on the following day at 06:29 AM ± 30 minutes. 
Shortly before 06:29 AM, after nearly 24-hours of urine collection, subjects will empty their 
bladder again and this urine will be used as the final portion of the 24-hour urine sample.  
At time of Discharge on Day 6, subjects will empty their bladder shortly before 06:29 AM. 
This will be the last urine portion for the 24-hour urine for the Day 5 dot mark in the 
Schedule of Events. 
24-hour urine collection during ambulatory period 
Twenty four-hour urine will be collected on Day 30 Visit, Day 60 visit, and Day 90 visit. 
Subject will be asked to come at site in the morning on Day 30, Day 60 and Day 90 and will 
remain overnight until respectively Day 31, Day 61, and Day 91. Subject will be asked to 
empty his bladder on Day 30, Day 60, Day 90 shortly before 09:00 AM (this urine will be 
discarded). Then collection period will start at 09:00 AM ± 30 minutes and will end on the 
following day. After nearly 24-hours of collection at 08:59 AM ± 30 minutes, subject will 
empty his bladder again and this urine will be used as the final portion of the 24-hour urine 
sample.  
24-hour urine collection during both confinement and ambulatory periods 
During the sampling period, all urine passed must be collected and put into the sampling 
bottle, with the exception of about 10 mL for the spot urine tests (described above). No urine 
must be passed into the toilet. The volume of 24-hour urine, the start and the end time of 
urine collection will be recorded by the study site staff. For assessment of urine BoExp, 

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creatinine for normalization of urine BoExp, 8-epi-PGF2α and 11-DTX-B2, sample 
bio-banking and urine mutagenicity, aliquots from the 24-hour urine collection will be taken. 
In the Schedule of Events for the 24-hour urine collection (Appendix 1), the dot corresponds 
to the day on which the 24-hour urine collection period starts. For example, for NEQ 
measured at Day 5 in the 24-hour urine collection that starts on Day 5 and ends later on 
Day 6. 
4-hour urine collection on Day -1 and Day 90 Visit (Day 91) 
Four-hour urine fraction will be collected for each subject on Day -1 and on Day 90 Visit 
(Day 91). On Day -1, each subject will empty his/her bladder shortly before 10:00 AM, and 
the volume of urine collected will be discarded. The collection will start at 10:00 AM ± 30 
minutes (empty bladder) and will end 4 hours later at 02:00 PM ± 30 minutes. On Day 90 
Visit (Day 91), the 4-hour fraction will start immediately after the end of 24-hour urine 
collection (the start of 4-hour fraction will correspond to the end of 24-hour collection).  
The volume of the 4-hour urine fraction, the start and end time of urine collection have to be 
recorded by the study staff. 
7.7.3 
Bio-banking Long Term Storage  
The facility at which the samples are stored will follow their procedures for destruction of 
banked samples if a subject withdraws their consent for coded sample bio-banking. 
7.7.3.1 
Bio-banking Long Term Storage of Blood or Urine 
If a subject gives consent for sample bio-banking for further analysis of BoExp/risk markers, 
additional samples of urine from the 24-hour collection and serum/plasma will be collected 
as follows: 
• Samples will be collected from the 24-hour urine collections that started on Day 0 
and Day 5 and Day 90 Visit (Day 90) (10 tubes of 10 mL each per time point). 
• Serum/plasma will be collected on Day 0, Day 6, Day 90 Visit (Day 91) (30 mL 
of blood in total with 2 tubes of 5 mL of blood draw per timepoint: from one tube 
two X 1 mL of serum and plasma will be collected and stored). 
If a subject gives consent for sample bio-banking of whole blood for further transcriptomics 
analysis, blood will be collected as follows: 
• Blood will be collected on Day 0, Day 6, and Day 90 Visit (Day 91) (15 mL in total with 
5 mL per timepoint. The 5 mL will be split into two tubes of 2.5 mL each). 

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The blood samples for transcriptomics and the data related to these samples will be 
anonymized and will be the subject of a separate report. Anonymized data and samples are 
initially single or double coded where the link between the subjects’ identifiers and the 
unique code(s) is subsequently deleted. This is applicable for the blood bio-banking for 
transcriptomics only. 
The samples intended for sample bio-banking will be kept frozen; separate from the other 
samples collected, and will be shipped to a central storage facility according to the SHM. 
After the final CSR is signed, samples of plasma/serum/blood will be stored for a maximum 
of 5 years and samples of urine will be stored for a maximum of 2 years. The blood bio-
banking for transcriptomics will be stored for a maximum of 5 years. 
7.7.3.2 
Bio-Banking Long-term Storage from Nasal Epithelial Collection/ Buccal 
Collection. 
If a subject gives consent for sample bio-banking to collect and store samples, samples from 
nasal epithelial and from buccal collection will be collected on Day 0, Day 6, and Day 90 
Visit (Day 90) according to respective procedures Appendix 7 and Appendix 8. Site 
personnel will be trained to follow the procedures. 
For nasal epithelial collection the staff needs to investigate if the subject has presented any 
allergy to lidocaine if the subject wants to have the nostril numbed prior to starting the 
procedure.  
The samples and the all the related data will be anonymized and will be the subject of a 
separate report. Anonymized data and samples are initially single or double coded where the 
link between the subjects’ identifiers and the unique code(s) is subsequently deleted. The 
nasal epithelial and buccal samples will be stored for a maximum of 5 years. 
7.8 
Other Study Procedures 
7.8.1 
Product Use Electronic Diary 
A product use electronic diary will be used for the documentation of used Menthol Tobacco 
Sticks, smoked CCs (menthol and non-menthol), used NRTs product, or the use of other 
nicotine/tobacco containing products. All subjects (including those subjects randomized to 
the SA arm) must complete this diary on a daily basis from the time of Discharge on Day 6 
until the time of Discharge on Day 90 Visit (Day 91). Subjects will be trained by site staff in 
the use of this electronic diary during the confinement period at the time the diary is 
delivered to the subject. 

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7.8.2 
Human Smoking Topography Assessment 
Human smoking topography involves the measurement of each smoker’s unique way of 
smoking mCCs or using Menthol Tobacco Sticks using the HST SODIM® portable device. 
The HST SODIM® device, model SPA/M (SODIM® Instrumentation, Fleury les Aubrais, 
France) is a device which is used to measure smoking topography (Appendix 4). It consists 
of a special sample holder (containing a constriction in the middle) which is placed between 
the smoker’s mouth and the filter of the mCC or Menthol Tobacco Stick being smoked/used. 
The holder is connected by two narrow tubes to a portable data logger/recording system 
(Appendix 4 for a description of the device). 
At Day 0, the HST SODIM® device has to be used for all mCC smoked for all subjects. On 
Day 1 and Day 4 of the confinement period, the HST SODIM® device has to be used for 
every smoking event for all subjects in the mCC and THS 2.2 Menthol arms. On Day 30 
Visit (Day 30), Day 60 Visit (Day 60), and Day 90 Visit (Day 90) of the ambulatory period, 
HST assessment will start between 08:30 and 09:30 AM with 4 hours recording. Smoking 
topography with the HST SODIM® device will not be done in subjects smoking mCC that 
are incompatible with the HST SODIM® device (e.g., slim mCC). For subjects in the SA 
arm, no HST assessments will be performed. 
For each subject, one HST SODIM® device will be assigned at Day -1, which will be used by 
that subject on all HST assessment days (in the case of malfunction, the device will be 
exchanged). HST SODIM® devices will be assigned to all subjects smoking mCCs which are 
compatible with the HST SODIM® device at each cohort according to the screening number.  
The Sponsor will provide training on the use of the HST SODIM® device to the study site 
staff. The study site staff will, in turn, provide training to the subjects. All HST SODIM® 
devices will be returned to the Sponsor after completion of the study. 
7.8.2.1 
Human Smoking Topography Parameters 
The HST SODIM® device measures and records the flow and other per-puff parameters 
listed in Table 5, the per cigarette parameters shown in  
Table 6 will be derived (representing average values or totals per cigarette). 
Prior to calculation of the per cigarette parameters, the Sponsor HST group will validate the 
data and discard any invalid data. Only valid data for per-cigarette parameters a will be part 
of the study database and will be analyzed. 

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Table 5. 
Human Smoking Topography – Per-Puff Parameters 
Description 
Variable 
Unit 
Puff number  
Ni 
 
Puff volume 
Vi 
mL 
Puff duration 
Di 
S 
Average flow [Vi/Di] 
Qmi 
mL/s 
Peak flow 
Qci 
mL/s 
Inter puff interval 
Ii 
s 
Sum of Ii and Di 
DFi 
s 
Work [INT Pmi*FinalFlow*dt] 
Wi 
mJ 
Average pressure drop 
Pmi 
mmWG 
Peak pressure drop 
Pci 
mmWG 
Average resistance [Pmi/Qmi] 
Rmi 
mmWG/mL/s 
Peak resistance [Pci/Qci] 
Rci 
mmWG/mL/s 
 
Table 6. 
Human Smoking Topography – Per-Cigarette Parameters 
Description 
Variable 
Formula 
Unit 
Total number of puffs 
NPC 
∑ Ni 
  
Total puff volume 
TVOL 
∑ Vi 
mL 
Average puff volume  
AvgVi 
∑ Vi / NPC, i=1 ... NPC 
mL 
Average puff duration 
AvgDi 
∑ Di / NPC, i=1 ... NPC 
s 
Total puff duration 
TDi 
∑ Di 
s 
Average flow 
AvgQmi 
∑ Qmi / NPC, i=1 … NPC 
mL/s 
Peak flow  
AvgQci 
∑ Qci / NPC, i=1 … NPC 
mL/s 
Total inter puff interval  
TIi 
∑ Ii 
s 
Average inter puff interval 
AvgIi 
∑ Qci / NPC, i=1 … NPC 
s 
Total smoking duration 
TDFi 
∑ DFi  
s 
Total Work 
TWi 
∑Wi 
mJ 
Average Work 
AvgWi 
∑Wi / NPC, i=1 … NPC 
mJ 
Average pressure drop 
AvgPmi 
∑Pmi / NPC, i=1 … NPC 
mmWg 
Average Peak pressure drop 
AvgPci 
∑Pci / NPC, i=1 … NPC 
mmWg 
Smoking Intensity 
SMINT 
TVOL/TDFi 
mL/s 

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Description 
Variable 
Formula 
Unit 
Puffing Time Index 
PTI 
(100*TDi)/TDFi 
% 
Puff Frequency 
PFeq 
NPC/(TDFi/60) 
Min-1 
7.8.2.2 
Visual Inspection of the Tobacco Plugs 
All THS tobacco plugs collected during the study will be sent to the Sponsor for subsequent 
visual inspection to determine whether combustion occurred during product use (Section 9). 
7.8.3 
Questionnaires 
The subject questionnaires and the VAS used in this study will be entered by the subject 
directly in an electronic patient reported outcomes (ePROs) device or on paper copy. All 
subject reported outcome data will be provided in English or Spanish and instructions will be 
provided in the subject’s local language. The questionnaires and the VAS will be reviewed 
for completeness by the study site staff and subjects will be requested to complete any 
missing information. 
Symptoms or worsening of symptoms documented on any of the questionnaires or the VAS 
do not need to be documented as additional AEs because the questionnaires and the VAS will 
be analyzed as part of the final report. However, it is at the discretion of the Investigator to 
decide whether to document such symptoms as additional AEs. The main source for AE 
collection will be the face-to-face interview between the subject and study site staff, using 
open, non-directive questions (Section 8.2). 
7.8.3.1 Fagerström Test for Nicotine Dependence (revised version) 
Potential nicotine dependence will be assessed via a questionnaire at Screening and on Day 
90 Visit (Day 90) using the Fagerström Test for Nicotine Dependence (FTND) in its revised 
version (Fagerström et al., 2012). 
The questionnaire consists of six questions which will be answered by the subject 
himself/herself. 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) (Fagerström et al., 2012). 
7.8.3.2 Assessment of Cough 
Subjects will be asked to assess the respiratory symptom ‘cough’ on a VAS, on three Likert 
scales, and with an open question on a daily basis during the confinement period (from Day 0 
to Day 6), and at every visit on Day 30 Visit (Day 31), Day 60 Visit (Day 61) and Day 90 
Visit (Day 91). From Day 0 to Day 6 only, assessment of cough must be done prior to start of 

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product use/smoking and no later than 10:00 AM. On Day 31 and Day 61, and Day 91, 
assessment of cough will be conducted irrespective of the time of product use but no later 
than 10:00 AM.  
. 
Subjects will be asked if they have experienced a regular need to cough, e.g., whether they 
have coughed several times in the previous 24 hours prior to assessment. If the answer is 
‘yes’, subjects will be asked to complete a VAS, 3 Likert scales, and to answer the open 
question. 
On the VAS, subjects will assess how bothersome their cough was during the previous 
24 hours. The VAS ranges from ‘not bothering me at all’ to ‘extremely bothersome.’ 
Furthermore, subjects will assess the intensity and frequency of cough and the amount of 
sputum production during the previous 24 hours on Likert scales. 
The intensity of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = very mild – 2 = mild – 3 = moderate – 4 = severe – 5 = very severe. 
The frequency of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = rarely – 2 = sometimes – 3 = fairly often – 4 = often – 5 = almost always. 
The amount of sputum production will be assessed on a 4-point Likert scale ranging from 
0 to 3, with 0 = no sputum – 1 = a moderate amount of sputum – 2 = a larger amount of 
sputum – 3 = a very large amount of sputum. 
Finally, subjects will be asked to share any other important observations with the staff about 
their coughing. 
7.8.3.3 Modified Cigarette Evaluation Questionnaire  
Product evaluation will be assessed using the Modified Cigarette Evaluation Questionnaire 
(MCEQ) (Cappelleri et al., 2007). The MCEQ assesses the degree to which subjects 
experience the reinforcing effects of smoking, by measuring: 
• Smoking satisfaction (satisfying, tastes good, enjoys smoking). 
• Psychological rewards (calms down, more awake, less irritable, helps concentrate, 
reduces hunger). 
• Aversion (dizziness, nauseous). 
• Enjoyment of respiratory tract sensations (single-item assessment). 
• Craving reduction (single-item assessment). 

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The MCEQ will be completed by subjects during the confinement period on a daily basis 
from Day -1 to Day 5 and on every ambulatory visits on Day 30 Visit (Day 30), Day 60 Visit 
(Day 60), and Day 90 Visit (Day 90). On Day -1 and Day 0, all subjects will complete the 
questionnaire. From Day 1 onwards, only subjects who are randomized to the THS 2.2 
Menthol and mCC arms will complete this questionnaire. The subjects will complete the 
questionnaire by themselves. 
7.8.3.4 Questionnaire of Smoking Urges (QSU-brief) 
To assess the urge-to-smoke, all subjects will be asked to fill-in a 10-item brief version of the 
QSU (Cox et al., 2001). The QSU-brief is a self-reported questionnaire with 10 items to be 
rated on a 7-point scale, ranging from 1 (strongly disagree) to 7 (strongly agree). Higher 
scores in this questionnaire indicate a higher urge to smoke. 
The QSU-brief will be completed by the subject himself/herself on a daily basis from Day -1 
to Day 5, and on every visit during the ambulatory period, i.e., Day 30 Visit (Day 30), Day 
60 Visit (Day 60), and Day 90 Visit (Day 90). 
7.8.3.5 Minnesota Nicotine Withdrawal Scale (revised version) 
The MNWS revised version is a valid and reliable scale that has been used previously to 
examine signs and symptoms of withdrawal from cigarette smoking (Hughes et al., 1986, 
Hughes et al., 2008). It consists of 2 scales: a ‘self-report scale’ and an ‘observer scale.’ 
For the purpose of this study, only the self-reporting scale will be used and filled-in by the 
subject. Furthermore, the subject’s weight will not be recorded for the purpose of the 
MNWS. At the end of the assessment of the questionnaire, the subject’s pulse rate will be 
recorded. 
Subjects will be asked to rate the items for the previous 24 hours on a scale ranging from 0 to 
4 (where 0 = none, 1 = slight, 2 = mild, 3 = moderate, 4 = severe). 
The MNWS (revised version) will be completed on a daily basis from Day 0 to Day 6, and at 
every visit during the ambulatory period, i.e., Day 30 Visit (Day 31), Day 60 Visit (Day 61) 
and Day 90 Visit (Day 91). From Day 0 to Day 6 only, MNWS questionnaire must be asked 
prior to start of product use/smoking and no later than 10:00 AM. On Day 30 Visit (Day 31), 
Day 60 Visit (Day 61), and Day 90 Visit (Day 91), assessment of MNWS will be conducted 
irrespective of the time of product use but no later than 10:00 AM.  
HST Questionnaire 
A specific questionnaire, used for exploratory purposes has been developed to evaluate the 
impact of the utilization of the HST SODIM® device on smoker’s smoking/inhalation 
experience in terms of ritual disruption. 

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This is a questionnaire with 5 items to be rated on a 5-point scale and open questions. 
Subjects will be asked by the Investigator to complete the HST questionnaire on: 
• Day 0 for all subjects smoking mCC compatible with the HST SODIM® device (i.e., non-
slim mCC) 
• Day 4, Day 30 Visit (Day 30), Day 60 Visit (Day 60), and Day 90 Visit (Day 90) for all 
subjects in the THS 2.2 Menthol and mCC arms (except mCC which are not compatible 
with the HST SODIM® device). 
7.8.3.6 Socio-Economic Status 
As part of the characterization of the study population it is important to measure variables 
that have been shown to be related to nicotine dependence and product reinforcing value. 
Based on prior tobacco research these factors include age, gender, ethnicity, tobacco use 
history, educational as well as socio-economic status. 
Socio-economic status (SES) information is recorded in similar manner in the clinical 
program, in behavioral research and will be eventually assessed in postmarked studies once 
the product is commercialized. In order to predict and evaluate the effect of alternative, 
potentially less harmful tobacco product use might have in adult smokers the socio-economic 
status constitutes an important demographic characteristic. SES data will be reported across 
the randomized clinical studies and will be collected in observational pre-market and post-
market studies. At screening the subjects will be informed in detail about the exams and 
evaluations planned during the study, and similarly notified about the SES assessment which 
will be done on Day 4 once they provided informed consent and were enrolled into the study. 
On Day 4, subjects will fill a questionnaire, which will allow the Sponsor to determine 
subject’s Socio-Economic Status (SES). Subjects will be asked a series of questions related 
to their education, occupational status, size and annual income of their household. These data 
will be used to create a measure for SES that categorizes subjects into low, moderate and 
high SES (King et al., 2011). The method used to create SES tertiles will be described in the 
SAP. If the subject does not want to answer the questionnaire, he will not be withdrawn from 
the study. 
7.8.3.7 Current and Past Smoking Behavior 
Subjects will be assessed for their current and past smoking behavior at baseline on Day -1 
and on Day 5 by the means of 2 questionnaires. The questionnaires will be asked with the 
following sequence: 
• A standard questionnaire (Behavioral Risk Factor Surveillance System Questionnaire 
2011) (CDC, 2011a) which is validated. 

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• A Smoking Questionnaire (SQ) to be validated. Immediately after the administration of 
the SQ, some supplemental questions will be collected on the completion of the SQ 
questionnaire. 
The Behavioral Risk Factor Surveillance and the SQ are self-administrated to be answered by 
subjects. The supplemental questions will be asked by the site.  
The standard questionnaire is the questionnaire used in Behavioral Risk Factor Surveillance 
System Questionnaire 2011 (CDC, 2011a), Section 7 on tobacco use. The standard 
questionnaire consists of 5 questions. All 5 questions are close-ended questions and the 
responses are exhaustive and mutually exclusive.  
• Question 1 collects information on the 100 cigarettes criterion. 
• Question 2 allows for a broad classification of current cigarette smoking behavior (daily, 
occasional, non). 
• Question 3 captures quitting experience during past 12 months. 
• Question 4 records past smoking duration. 
• Question 5 provides information regarding other tobacco use e.g. smokeless tobacco.  
The SQ focuses on self-reported current and past cigarette smoking behavior. The SQ 
consists of 8 questions. The first 3 questions are close-ended questions and the responses are 
exhaustive and mutually exclusive. The last 5 questions refer to the individual smoking 
history and are answered to the degree applicable. 
• Question 1 allows for a broad classification of current cigarette smoking behavior (daily, 
occasional, ex, non).  
• Questions 2 and 3 collect information on the 100 cigarettes criterion and on ever smoking 
(defined as smoking at least one cigarette per day).  
• Question 4 captures age of initiation and Questions 5 and 6 capture the current as well as 
total quitting duration, respectively.  
• The brand of cigarettes predominantly smoked in the last 12 months of smoking is 
captured in Question 7. 
• Question 8 captures the tobacco smoking history. Daily numbers of manufactured 
cigarettes, as well as hand-rolled cigarettes, cigars, and pipes consumed, separately for 
seven time periods.  
Finally, the supplemental questions consist of 8 questions. This supplemental question 1 is 
related to the time which the subject spends to complete the SQ. Question 2-7 are close-

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ended questions and to be answered yes or no. Question 8 is open-end allowing for addition 
comments provided by subjects. 
The daily mCC consumption reported in these questionnaires will not be used for eligibility. 
The data from these questionnaires will be described as part of the CSR and further analysis 
will be the subject of a separate report. 
7.8.3.8 Prochaska ‘Stage of Change’ Questionnaire: Intention to Quit Smoking 
The Prochaska ‘Stage of Change’ questionnaire will be used to assess the smokers’ mental 
state for the intention to quit (7.4.4 and Appendix 5 for staging algorithm; DiClemente et al., 
1991 and Velicer et al, 1995). There are 5 stages of change describing smokers and former 
smokers: 1. Precontemplation, 2 Contemplation. 3. Preparation, 4. Action and 5. 
Maintenance. In the precontemplation stage, the individual does not recognize smoking as a 
problem.  
In the contemplation stage, the individual is gathering information about smoking, such as 
contacting a health care provided, or tobacco quit line for information on the effects of 
smoking or cessation classes. During this stage, the stress and inconvenience of quitting 
smoking is greater than the immediate and possible long-term health effects from continued 
smoking. In the preparation stage, intention and behavior begin to come together and the 
subject is preparing to enter the action stage in the next 30 days. It is necessary for the 
subject to recognize the benefits of not smoking, before a subject can enter the action stage 
and as a result, change their smoking behavior. After six months of not smoking, the 
individual reaches the maintenance stage when different skills may be needed to prevent 
relapse from those employed in the initial behavior change. 
The Prochaska ‘Stage of Change’ questionnaire will be performed at Screening, Admission 
(Day -2), Day 30 Visit (Day 30), Day 60 Visit (Day 60) and at Day 90 Visit (Day 90). The 
Prochaska ‘Stage of Change’ questionnaire will be asked to the subject prior to product trial. 

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8 ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
The FDA MRTP guideline (FDA, 2012a) specifies this definition towards tobacco products, 
as follows: 
An AE is any health-related event associated with the use of a tobacco product in humans, 
which is adverse or unfavorable, whether or not it is considered tobacco-product related. 
8.1.2 
Serious Adverse Events 
A Serious Adverse Event (SAE) is defined as, but not limited to, any untoward medical 
occurrence that: 
• Results in death. 
• Is life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate 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. 
Any pre-planned hospitalizations that are known at the time of signing the ICF will not be 
recorded as SAE; however they will be recorded as AEs only. Any AE that occurs during this 
pre-planned hospitalization will be considered according to the above definitions. 
8.2 
Assessment of Adverse Events 
The Investigator or designee is responsible for obtaining, assessing, and documenting all AEs 
during the study.  

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8.2.1 
Collection of Information 
Adverse event information will be collected from the time of signature of the ICF/Subject 
Information Sheet onwards until EOS either by the Investigator or designee via spontaneous 
reporting or by the use of consistent, open, non-directive questions from study site staff (e.g., 
“Have you had any health problems since the previous visit/How are you feeling since you 
were last asked?”). At the discretion of the Investigator or designee, the collection of AE 
information may also be triggered from the review of the subject questionnaires and the 
VAS. However, during the confinement period and during the ambulatory visits, the main 
source for AE collection will be face-to-face interview(s) with the subject. 
Information recorded will include: verbatim description of the AE, start and stop dates and 
times, seriousness, severity (intensity), action taken (e.g., whether or not the AE led to the 
subject’s withdrawal from the study), and outcome (e.g., resolved, withdrawal due to AE). 
For each AE, the intensity will be graded on a 3-point intensity scale (mild, moderate, 
severe) using the definitions provided in Section 8.2.5. 
Any exacerbation/worsening or increased frequency of an AE or pre-existing condition shall 
be evaluated and recorded. 
Correct medical terminology/concepts are preferred when recording AE terms, and 
abbreviations must be avoided. Wherever possible, a diagnosis is to be used to describe an 
AE as a diagnosed medical condition rather than individual signs and symptoms (e.g., record 
‘pneumonia’ rather than ‘fever’, ‘cough’, ‘pulmonary infiltrate’ or ‘septicemia’ rather than 
‘fever’ and ‘hypotension’ following blood sample). 
Any AE that meets the serious criteria must be recorded both on the AE report form of the 
eCRF and on a separate SAE report form (Section 8.3). 
8.2.2 
Period of Collection 
From the time of signature of the ICF/Subject Information Sheet onwards until EOS, all AEs 
(includes SAEs) will be collected by the study site staff as described below.  
8.2.3 
Screening Period  
All existing health conditions identified during the Screening period will be recorded as 
concomitant disease and the subject’s eligibility for admission to the study will be reviewed. 
Any AEs which occur during the Screening period will be captured by the study site staff and 
assessed by the Investigator or designee in order to establish relationship or relatedness in 
respect to study procedures. Only the study procedures-related AEs will be reported in the 
CSR and in accordance with respective regulatory guidelines.  

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8.2.4 
Admission Day until End of the Study 
From Admission onwards until Day of Discharge, all AEs will be actively collected by the 
study site staff.  
Any new, clinically relevant, abnormal finding or worsening of a pre-existing 
condition/concomitant disease detected during the study including the safety follow-up 
period will be documented as an AE and/or SAE as described in the Safety Management 
Plan.  
During the safety follow-up period new AEs and/or SAEs will be recorded after spontaneous 
reporting by the subject. Serious AEs will be reported by the Investigator as described in this 
document and the Safety Management Plan. Any ongoing AEs/SAEs during the safety 
follow-up period will be actively followed up by the site until they have been resolved, 
stabilized (i.e., no worsening of condition), or an acceptable explanation has been found. 
At the end of the safety follow-up period all ongoing AEs/SAEs will be followed up by the 
Investigator or designee on behalf of the Sponsor (Section 8.3) until they have resolved, 
stabilized (i.e., no worsening of condition), or an acceptable explanation has been found. 
8.2.5 
Intensity of Adverse Event 
For each AE, the intensity will be graded by the Investigator on a 3-point intensity scale 
(mild, moderate, severe) using the following definitions: 
Mild:   
 
The AE is easily tolerated and does not interfere with daily activity. 
Moderate:  
The AE interferes with daily activity, but the subject is still able to function. 
Severe:  
 
The AE is incapacitating and requires medical intervention. 
According to CIOMS (Council for International Organizations of Medical Sciences) VI 
Working group, changes in severity (Intensity) and maximum intensity of adverse events 
must be documented.  
8.2.6 
Relationship to Investigational Product and Relationship to Study Procedures 
It is difficult to establish a firm method to distinguish an adverse reaction (that is AE that is 
causally related to the IP) from a clinical adverse event that is  temporally associated to the 
use of an IP.   
In general, all AEs and/or SAEs will be assessed by the Investigator or designee as either 
‘related’ or ‘not related’ to IP as described below. In addition to the assessment of the 
relationship of the clinical event to the IP, the Investigator or designee shall document a 
potential relationship of the clinical event to any particular study procedure. 

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Not related: The temporal relationship of the clinical event to IP administration 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 clinical event to study IP administration 
makes a causal relationship possible, and concomitant medication, therapeutic 
interventions, or underlying conditions do not provide a sufficient explanation 
for the observed event. 
8.2.7 
Expectedness 
An AE will be regarded as ‘unexpected’ if its nature or severity is not consistent with 
information already known about the IP, and is not listed in the current IB. The IB provides 
further detail on signs or symptoms that might be expected with the use of the IP, including 
information relating to device malfunction or misuse. 
8.3 
Reporting and Follow-Up of Serious Adverse Events 
Any SAEs reported or observed during the study after signature of the ICF/Subject 
Information Sheet until the end of the safety follow-up period (i.e., up to 28 days after study 
Discharge on Day 90 Visit) whether or not attributable to the IP, to any other medication or 
to any study procedures, or any SAE related to the product and spontaneously reported after 
the safety follow-up must be reported by the Investigator or other study site staff within 24 
hours after first awareness by any party involved in the study to 
 
 and to the Sponsor. 
An SAE report form must be faxed or e-mailed as an attachment to: 
 
Fax number: 
 
Toll-free fax: 
 
E-mail: 
 
 
Address: 
 
 
 
 
Sponsor Contact: 
, MD, 
Phone: 
Mobile: 
+41 
 
+41 
 

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Medical Safety Officer 
E-mail: 
 
 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
The Investigator is responsible for local reporting (e.g., to the IRB) of SAEs that occur 
during the study, according to local regulations. 
Any SAE will be reported to the Center for Tobacco Products Office of Science within 
15 business days after the report is received by the Sponsor. 
Any additional/follow-up information that becomes available after the initial SAE report 
form has been completed will be forwarded to 
 and the Sponsor within 24 hours 
after first awareness by any person at the site using a follow-up to the existing SAE report 
form. 
The follow-up SAE report form must include the minimum information required as described 
in the safety management plan 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. 
All SAEs will be followed up by the Investigator or designee and/or 
 until their 
resolution or until the Investigator considers the event to be stabilized (i.e., no worsening of 
condition), or an acceptable explanation has been found (e.g., a chronic condition). 
The SAE report form to be used in this study is provided as a separate document and 
included in the study master file. All SAEs will be recorded, in addition to the SAE report 
form. 
8.4 
Reporting of Other Events Critical to Safety Evaluations 
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator or designee and assessed for clinical relevance. If the abnormal 
laboratory results was detected after screening, this should be recorded as AE. 

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The grading scheme shown in (reference to the Common Terminology Criteria for Adverse 
Events and Common Toxicity Criteria [CTCAE] version 4.03) will be used by the 
Investigator or designee to assess abnormal laboratory AEs as follows: 
• All Grade 1 abnormal laboratory values will be evaluated by the Investigator with respect 
to baseline value and clinical relevance. If considered to be clinically relevant the 
Investigator or designee must report it as an AE. All Grade 2 and higher abnormal 
laboratory values must be reported as or linked to an AE/concomitant disease. 
• If a subject has Grade 2 and higher abnormal laboratory values at Screening it is at the 
discretion of the Investigator or designee to enroll the subject or not. This decision must 
be documented in the source documentation and captured in the eCRF. 
• If there is any worsening in grade from Grade 2 and above during the study the 
Investigator or designee must report this worsening as an AE. 
• Where there is no grading available, the abnormal laboratory value will be evaluated by 
the Investigator or designee and assessed for clinical relevance. If considered to be 
clinically relevant, the Investigator will report it as an AE. 
• Any other abnormal clinical laboratory result (including those that are not part of the core 
safety assessments) can, at the discretion of the Investigator or designee, be reviewed and 
assessed. Even if they do not meet the criteria of the CTCAE grading scheme (please see 
above), the Investigator or designee may consider them to be of clinical relevance and, if 
they are, must report them as AEs. 
• In general, laboratory values will be recorded as ‘increased <lab parameter>’ or 
‘decreased <lab parameter>’ to ensure consistency of recording/coding. 
All other information (e.g., relationship to IP, intensity, seriousness, outcome) will be 
assessed as for other AEs. 
8.5 
Reporting and Follow-Up of Pregnancies 
For pregnancies detected after signature of the ICF/subject information sheet and prior to 
first THS 2.2 Menthol use, the subject will be considered as a screening failure and removed 
from the study. No Pregnancy Form will be filled, however the diagnosed pregnancy must be 
captured in the Screen Failure eCRF.  
Any pregnancy diagnosed after first exposure to the IP and potentially associated to exposure 
to the IP, including pregnancies spontaneously reported to the Investigator or designee after 
the EOS must be reported by the Investigator or designee and followed-up until the 
pregnancy outcome is reached. Potentially associated with exposure to the IP is defined as 
the conception date being calculated as after first exposure and before the last exposure to the 
IP. 

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The Investigator or designee will complete a Pregnancy Form (provided as a separate 
document) for all pregnancies diagnosed (including positive urine pregnancy tests). 
The procedure to report a pregnancy and provide any additional/follow-up information to 
 and the Sponsor must be followed in the same manner and within the same 
timelines as described for an SAE (Section 8.3). In addition, each pregnancy has to be 
reported as a non-serious AE. No invasive study procedures, including drawing of blood 
must be done in such subjects after the discovery of pregnancy.  
 will follow up pregnancies only if they were detected 
after first product use (i.e., after THS 2.2 Menthol product test on Admission Day). If 
pregnancies are to be followed up, they will be followed up until an outcome is reached (e.g. 
normal delivery, spontaneous abortion, or voluntary termination). Any pregnancy 
complication, adverse pregnancy outcome or maternal complications will be recorded. 
The Investigator is responsible for informing the IRB of any pregnancy that occurs during 
the study and its outcome, according to local regulations. 
8.6 
Adverse Events Leading to Withdrawal 
Subjects who are withdrawn from the study because of an AE will undergo the safety 
procedures (see Section 9.5), as described for the day of Discharge, as soon as possible and 
will enter the period of safety follow-up. The Investigator or designee and/or 
 will 
follow up these AEs until they have resolved, stabilized (i.e., no worsening of condition), or 
an acceptable explanation has been found. 
8.7 
Investigational Device Misuse 
Any occurrences of THS Tobacco Stick Holder or THS Charger misuse (use not in 
accordance with its label and instruction) by a subject will be documented by the Investigator 
or his/her designated staff using a Device Issue Log.  
Investigational device misuse may result in use-related hazards. 
Use-related hazards are derived from the US Food and Drug Administration Medical Device 
Use-Safety Guidance (FDA, 2012c): 
• Hazards caused specifically by how a device is used 
• Unanticipated use scenarios (e.g., modification of charging unit, applying any chemicals, 
using CCs, mechanical damage of the unit, etc.) that result in hazards must be 
documented and reported by the Investigator. 

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8.8 
Investigational Device Malfunction  
Any occurrences of malfunction of the THS Tobacco Stick Holder or THS Charger will be 
documented by the Investigator or his/her designated staff using a Device Issue Log. 
Furthermore, any malfunctions of the THS Tobacco Stick Holder or THS Charger that lead 
to an AE/SAE will follow the same processes as described above. 
 
 

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9 STUDY ACTIVITIES 
A detailed schedule of assessment can be found in Appendix 1. The time points shown are to 
be considered at the time of assessment for the first subject. As not all subjects can be treated 
at the same time, a short time window will be implemented for subsequent subjects. 
Measurements not conducted at the exact time point, but conducted within the given time 
window (if applicable) do not constitute a protocol deviation but an accepted variability for 
the given time point. 
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 Visit 
The Screening Visit will be performed within 4 weeks (Day -30 to Day -3) prior to 
Admission (Day -2). Subjects will attend the investigational site in at least 10-hour fasting 
state for clinical laboratory to be assessed. First, the ICF along with study information should 
be given to the subject. When/if the ICF is signed, the other screening procedures can be 
performed in the order deemed most practical. While it is recommended to complete as much 
screening procedures as possible in one day, it is permissible to complete those over more 
than one day. Smoking is allowed during screening. 
Table 7 shows the procedures that will be performed at the Screening Visit: 
Table 7. 
Time Schedule – Screening Visit 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Screening 
 
 
 
Informed consent for study participation and 
two additional consents for bio-banking 
 
 
 
Information on the risk of smoking/smoking 
cessation advice and debriefing 
 
 
 
Demographic data collected 
 
 
 
Identification of current mCC brand 
 
 
 
Medical history/concomitant disease 
 
 
 
Prior medication (within 4 weeks prior to the 
Screening Visit) and concomitant 
medication 
 
 
 
Smoking history 
 

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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Screening 
 
 
 
Intention to quit smoking within the next 
6 months (Prochaska ‘Stage of Change’ 
questionnaire)  
 
 
 
Readiness comply to study protocol (e.g., 
readiness to abstain from smoking for up to 
91 days) 
 
 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position and at least 15 
minutes after smoking prior 
to measurement 
 
√ 
Clinical laboratory parameters (hematology, 
clinical chemistry) 
To be done after at least 10 
hours of fasting 
 
 
Urine safety analysis 
 
 
 
Urine pregnancy test (all females only) 
 
 
√ 
HIV, hepatitis B and C 
 
 
 
Physical examination, and height, weight, 
calculation of BMI 
 
 
 
THS 2.2 Menthol product demonstration 
 
 
 
Chest X-ray (if not performed within 6 
months prior to Screening Visit) 
 
 
 
Urine drug screen 
 
 
 
Urine cotinine screening test 
 
 
 
Alcohol urine or breath test screen 
 
 
 
Fagerström Test for Nicotine Dependence 
(FTND) 
 
 
 
Spirometry first without and then with short-
acting bronchodilator (recording of FEV1, 
FVC, FEV1/FVC, and MEF 25-75 only) 
Has to be done at least 1 
hour after smoking 
At rest for at least 15 
minutes prior to lung 
function testing 
In sitting position 
 
 
ECG 
At least 5 minutes in supine 
position prior to recording 

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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Screening 
 
 
 
AE/SAE recording 
If the screening visit is 
performed on two separate 
days, the AE/SAE 
questions will be asked 
again 
 
 
Inclusion/exclusion criteria 
 
Abbreviations: AE = adverse event; BMI = body mass index; mCC = menthol conventional cigarette(s); 
ECG = electrocardiogram; HIV = human immunodeficiency virus; SAE = serious adverse event; THS = tobacco heating 
system. 
The sequence of assessments/events is given just for illustrative purposes. The sequence will 
be at the discretion of the site after signature of the ICF. 
9.2 
Confinement Period (Days -2 to 6) 
9.2.1 
Admission (Day -2) 
The procedures of Day -2 can be performed in order deemed most practical, except the 
product test which will be the last assessment prior to enrolment after all eligibility criteria 
have been met and will be done in female only if the pregnancy test is confirmed negative 
Table 8 shows the procedures that will be performed at Admission (Day -2): 
Table 8. 
Time Schedule – Day -2 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Admission 
 
 
 
AE/SAE recording; Concomitant 
medication, prior medication 
All day 
Time of admission-
06:30 PM 
 
Urine pregnancy test (females only) 
 
Time of admission-
06:30 PM 
 
Information on the risk of smoking/smoking 
cessation advice and debriefing 
 
Time of admission-
06:30 PM 
 
Smoking history  
 

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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Admission 
 
Time of admission-
06:30 PM 
 
Readiness to comply to study protocol (e.g 
readiness to abstain from smoking for up to 
91 days) 
 
Time of admission-
06:30 PM 
 
Urine drug screen  
 
Time of admission-
06:30 PM 
 
Urine cotinine screening test 
 
Time of admission-
06:30 PM 
 
Alcohol urine or breath test screen 
 
Time of admission-
06:30 PM 
 
CO breath test   
Irrespective of the time of 
product use 
Time of admission-
06:30 PM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position and at least 15 
minutes after smoking prior 
to measurement 
Time of admission-
06:30 PM 
 
Physical examination, and weight, waist 
circumference, and BMI 
Weight and waist 
circumference to be 
evaluated also as risk 
markers 
Time of admission-
06:30 PM 
 
Identification of current mCC brand 
 
Time of admission-
06:30 PM 
 
Intention to quit smoking in the next 
6 months or less (Prochaska ‘Stage of 
Change’ questionnaire) 
Has to be done prior to 
product trial 
Time of admission-
06:30 PM 
 
Product test of THS 2.2 Menthol and 
subsequently readiness to use THS 2.2. 
Menthol 
Must be done only after the 
pregnancy test is confirmed 
negative. 
The product test is the last 
assessment prior to 
enrolment. 
Time of admission-
06:30 PM 
 
Inclusion/exclusion criteria 
 
Time of admission-
06:30 PM 
 
Enrolment 
After all inclusion and 
exclusion criteria have 
been satisfactorily met 
 
 
Preference product question 
Has to be done after 
enrolment 
Before 09:00 PM 
 
Dinner 
 

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2000 Neuchâtel 
Switzerland 
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Final 5.0/14 April 2014 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Admission 
 
Around 11:00 PM 
 
End of smoking period 
 
Abbreviations: AE = adverse event; BMI = body mass index; mCC = menthol conventional cigarette(s); CO = carbon 
monoxide; SAE = serious adverse event; THS = tobacco heating system. 
9.2.2 
Baseline Period (Day-1 06:30 AM to Day 1 06:29 AM) 
Table 9 and Table 10 shows the assessments that will be performed at baseline (Day -1 and 
Day 0, respectively): 

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Table 9. 
Time Schedule – Day -1 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Baseline Day -1 
 
 
 
AE/SAE questioning; Concomitant 
medication 
All day 
 
 
CO breath test 
Within 15 minutes before first 
mCC.  
06:30 AM 
 
Beginning of smoking 
 
10:00 AM +/-30 min 
 
Start collection of 4-hour urine to Day -1 
sampling bottle 
Subject must empty his 
bladder shortly prior to 10:00 
AM. This urine will be 
discarded prior to starting 
collection. 
The 4-hour fraction will be 
collected over a period of 4 
hours ± 30 minutes 
Before 11:00 AM 
 
Breakfast 
 
Before 11:30 AM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position and at least 15 
minutes after smoking prior to 
measurement 
12:00 PM-01:30 PM 
 
CO breath test 
 
02:00 PM +/-30 min 
 
End of 4-hour urine collection and 
sampling to urine samples to be taken 
from the 4-hour urine after the final 
portion of 4-hour urine fraction has been 
added to Day -1 sampling bottle. 
BoExp (primary, secondary 
and NEQ), creatinine,  
Risk markers: 11-DTX-B2, 8 
epi-PGF2α. 
Before 02:30 PM 
 
Lunch 
 
04:00 PM-05:30 PM 
 
CO breath test 
 
Afternoon 
 
Snacks 
 
Evening until 09:00 
PM 
 
Dinner 
 
08:00 PM-09:30 PM 
 
CO breath test 
 
08:00 PM-09:30 PM 
√ 
COHb in blood 
 

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08:00 PM-11:00 PM 
 
MCEQ questionnaire 
QSU-brief questionnaire 
Assessment of past and current Smoking 
behavior : 
• Behavioral Risk Factor 
Questionnaire 
• Smoking Questionnaire and 
supplemental data 
 
 
 
See Section 7.8.3 for all 
questionnaires. Behavorial 
Risk factor questionnaire has 
to be asked prior to smoking 
questionnaire. Supplemental 
questions will be asked 
immediately after the smoking 
questionnaire 
Around 11:00 PM 
 
End of smoking 
 
06:30 AM-11:15 PM 
 
Collection of all smoked mCC butts 
For accountability 
Abbreviations: AE = adverse event; COHb = carboxyhemoglobin; mCC = menthol conventional cigarette(s); CO = carbon 
monoxide; MCEQ = Modified Cigarette Evaluation Questionnaire; QSU = Questionnaire of Smoking Urges; SAE = serious 
adverse event. 
 
Table 10. Time Schedule – Day 0 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Baseline Day 0 
 
 
 
AE/SAE questioning; Concomitant 
medication 
All Day 
 
 
Randomization  
At any time of the day after 
eligibility criteria have been 
met. Subjects are not to be 
informed of their assigned 
arm until Day 1 
06:30 AM+/-30min 
 
Start collection of 24-hour urine to Day 0 
sampling bottle 
 
Subject must empty his 
bladder shortly prior to 06:30 
AM. This urine will be 
discarded prior to starting 
collection. 
 
√ 
CYP2A6 activity in plasma 
Has to be done prior to 
smoking 
 
 
CO breath test 
Within 15 minutes before first 
mCC.  
 
√ 
COHb in blood  
Has to be done prior to 
smoking and prior to gas 
transfer assessment 

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Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Baseline Day 0 
 
 
 
Full lung function (single breath test for 
CO first, then helium dilution technique, 
and finally spirometry with 
bronchodilator, ) 
Has to be done prior to 
smokingSubject at rest for at 
least 15 minutes prior to lung 
function testing 
In sitting position  
 
 
MNWS questionnaire 
Has to be done prior to 
smoking 
but no later than 10:00 AM 
 
 
Assessment of cough 
Has to be done prior to 
smoking but no later than 
10:00 AM 
06:30 AM to 11:00 
PM 
 
HST 
HST SODIM® device has to 
be done for all product uses,  
if compatible mCCs are 
smoked 
06:30 AM 
 
Beginning of smoking 
 
 
√ 
Clinical laboratory 
parameters*(hematology, clinical 
chemistry) and risk markers (hs-CRP, 
fibrinogen, homocysteine, LDL, HDL, 
HbA1c, sICAM-1, Apo A1, Apo B) 
Has to be done after at least 
10 hours of fasting. 
* Blood glucose, TG, TC, 
WBC, platelet count from 
safety will be also evaluated 
as risk markers 
 
√ 
Blood sampling for bio-banking for 
transcriptomics 
If consent is obtained 
Has to be done after at least 
10 hours of fasting 
 
√ 
Bio-banking for BoExp/risk markers in 
serum/plasma (if consent is obtained) 
If consent is obtained 
Has to be done after at least 
10 hours of fasting 
 
√ 
Oxysterols 
Has to be done after at least 
10 hours of fasting 
 
 
Urine safety analysis 
 
Before 11:00 AM 
 
Breakfast 
 

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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Baseline Day 0 
 
Before 11:30 AM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position and at least 15 
minutes after smoking prior to 
measurement 
Systolic and diastolic blood 
pressure to be evaluated also 
as risk marker 
10:00 AM-11:30 AM 
 
A caffeine tablet containing 
approximately 200 mg of caffeine ± 240 
mL ±10 mL of water 
The time of the tablet intake 
must be recorded 
12:00 PM:01:30 PM 
 
CO breath test 
 
Before 02:30 PM 
 
Lunch 
 
04:00 PM-05:30 PM 
 
CYP1A2 activity in plasma 
6 hours ± 15 minutes after 
intake of caffeine tablet 
04:00 PM-05:30 PM 
 
CO breath test 
 
In the afternoon 
before 09:00 PM 
 
Nasal Epithelial Collection  
Only if consent is obtained 
Subject must not have eaten at 
least 30 minutes prior to 
collection  
Prior to starting the 
procedure, the subject will be 
asked to blow his nose 
In the afternoon 
before 09:00 PM 
 
Buccal Collection  
Only if consent is obtained 
Subject must not have eaten at 
least 30 minutes prior to 
collection  
Subject will be asked to rinse 
his mouth with a minimum of 
20 mL of water prior to 
sample collection 
Afternoon 
 
Snacks 
 
Before 09:00 PM 
 
Dinner 
 
08:00 PM-09:30 PM 
 
CO breath test 
 
08:00 PM-09:30 PM 
√ 
COHb in blood 
 
08:00 PM-09:30 PM 
√ 
Nicotine, cotinine in plasma 
 
08:00 PM-11:00 PM 
 
HST questionnaire 
 

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2000 Neuchâtel 
Switzerland 
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Final 5.0/14 April 2014 
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Philip Morris International. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Baseline Day 0 
 
08:00 PM-11:00 PM 
 
MCEQ questionnaire (all subjects) 
QSU-brief questionnaire (all subjects) 
 
Around 11:00 PM 
 
End of smoking 
 

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Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Baseline Day 0 
 
06:30 AM-11:15 PM 
 
 
Collection of all mCC butts 
 
For accountability 
 
Abbreviations: AE = adverse event; Apo: Apolipoprotein; BoExp = biomarkers of exposure; BP = blood pressure; mCC = 
menthol conventional cigarette(s); CO = carbon monoxide; COHb = carboxyhemoglobin; CYP = cytochrome P450 enzyme; 
HbA1c = hemoglobin A1c; hs-CRP = high-sensitive C-reactive protein; HDL = high density lipoprotein; HST = human 
smoking topography; LDL = low density lipoprotein; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = 
Minnesota Nicotine Withdrawal Scale; QSU = Questionnaire of Smoking Urges; SA = smoking abstinence; SAE = serious 
adverse event; sICAM-1 = soluble inter-cellular adhesion molecule; TC = total cholesterol; TG = triglycerides; WBC = 
white blood cell count. 
 
9.2.3 
Exposure Period in Confinement (Day 1 06:30 AM to time of Discharge on Day 
6) 
The tables in this Section show the procedures that will be performed during the confinement 
period (Day 1 to time of Discharge on Day 6). Table 11 shows the procedures that will be 
performed on Day 1: 
Table 11. Time Schedule – Day 1 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 1 
 
 
 
AE/SAE questioning; Concomitant 
medication 
All day 
 
 
Support for smoking abstinence (SA 
arm only), if needed 
All day 
Before 06:30 AM 
 
Subjects are informed of their 
assigned study arm 
 
06:29 AM+/-30min 
 
Urine sample to be taken from the 
24-hour urine after final portion of 
urine has been added to Day 0 
sampling bottle.  
 
BoExp (primary, secondary and 
NEQ), creatinine, and Ames 
mutagenicity in 24-hour urine. 
Risk markers: 11-DTX-B2, 8 epi-
PGF2α. 
Bio-banking 
for 
BoExp/risk 
markers (if additional consent is 
obtained)  
Must be prior to first product use 
of Day 1 

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2000 Neuchâtel 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 1 
 
06:30 AM+/-30min 
 
Start collection to Day 1 sampling 
bottle 24-hour urine  
 
 
 
Assessment of cough (VAS) 
To be done prior to product use, 
but no later than 10:00 AM 
 
 
MNWS questionnaire 
To be done prior to product use, 
but no later than 10:00 AM 
 
 
CO breath test 
Within 15 minutes before first 
product use (for THS 2.2 Menthol 
and mCC arms) or between 08:00 
AM and 09:30 AM (SA arm) 
06:30 AM-11:00 PM 
 
HST 
In the THS 2.2 Menthol and mCC 
arms, it should be done for all 
smoking events with the HST 
SODIM® device, if compatible 
mCCs are smoked 
06:30 AM 
 
Beginning of product use 
 
Before 11:00 AM 
 
Breakfast 
 
Before 11:30 AM 
 
Vital signs (blood pressure, pulse 
rate, respiratory rate) 
At least 5 minutes in supine 
position and at least 15 minutes 
after 
smoking 
prior 
to 
measurement  
12:00 PM-01:30 PM 
 
CO breath test  
 
Before 02:30 PM  
 
Lunch  
 
04:00 PM-05:30 PM 
 
CO breath test 
 
Afternoon 
 
Snacks 
 
In the evening before 
09:00 PM 
 
Dinner  
 
08:00 PM-09:30 PM 
 
CO breath test 
 
08:00 PM-09:30 PM 
√ 
COHb in blood  
 
08:00 PM-09:30 PM 
√ 
Nicotine, cotinine in plasma 
 
08:00 PM-11:00 PM 
 
MCEQ questionnaire (THS 2.2 
Menthol and mCC arms only), QSU-
brief questionnaire 
 
Around 11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
 
Collection of used mCC butts 
 
For accountability 
 
6:30 AM-11:15 PM 
 
Collection of all tobacco plugs from 
Menthol Tobacco Sticks  
For accountability and further 
analysis 

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Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
Page 119 of 197 
 
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Philip Morris International. 
 
Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse event; 
BoExp = biomarkers of exposure; mCC = menthol conventional cigarette(s); CO = carbon monoxide; COHb = 
carboxyhemoglobin; HST = human smoking topography; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = 
Minnesota Nicotine /Withdrawal Scale; QSU = Questionnaire of Smoking Urges; SA = smoking abstinence; SAE = serious 
adverse event; THS = tobacco heating system. 
 
 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
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Final 5.0/14 April 2014 
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Table 12 shows the assessments that will be performed on Day 2 of the confinement period: 
Table 12. Time Schedule – Day 2 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 2 
 
 
 
AE/SAE questioning; Concomitant 
medication 
All day 
 
 
Support during smoking abstinence 
(SA arm only), if needed 
All day 
6:29 AM+/-30min 
 
Urine samples to be taken from the 24-
hour urine after the final portion of 
urine has been added to Day 1 
sampling bottle. 
BoExp (primary, secondary, and 
NEQ) and creatinine 
 
6:30 AM+/-30min 
 
Start collection to Day 2 sampling 
bottle 24-hour urine 
 
 
 
Assessment of cough 
To be done prior to product use, 
but no later than 10:00 AM 
 
 
MNWS questionnaire 
To be done prior to product use, 
but no later than 10:00 AM 
 
 
CO breath test 
Within 15 minutes before first 
product use (for THS 2.2 Menthol 
and mCC arms) or between 08:00 
AM and 09:30 AM (SA arm) 
6:30 AM 
 
Beginning of product use 
 
Before 11:00 AM 
 
Breakfast 
 
Before 11:30 AM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position and at least 15 minutes 
after smoking prior to 
measurement  
12:00 PM-01:30 PM 
 
CO breath test  
 
Before 02:30 PM 
 
Lunch  
 
04:00 PM-05.30 PM 
 
CO breath test 
 
Afternoon 
 
Snacks 
 
06:30 PM-09:00 PM 
 
Dinner  
 
08:00 PM-09:30 PM 
 
CO breath test 
 
08:00 PM-09:30 PM 
√ 
COHb in blood  
 
08:00 PM-09:30 PM 
√ 
Nicotine, cotinine in plasma 
 

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Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 2 
 
08:00 PM-11:00 PM 
 
MCEQ questionnaire (THS 2.2 
Menthol and mCC arms only), 
QSU-brief questionnaire 
 
Around 11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
Collection of used mCC butts 
For accountability 
6:30 AM-11:15 PM 
 
Collection of all tobacco plugs from 
Menthol Tobacco Sticks  
For accountability and further 
analysis 
Abbreviations: AE = adverse event; BoExp = biomarkers of exposure; mCC = menthol conventional cigarette(s); 
CO = carbon monoxide; COHb = carboxyhemoglobin; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = 
Minnesota Nicotine /Withdrawal Scale; QSU = Questionnaire of Smoking Urges; SA = smoking abstinence; SAE = serious 
adverse event; THS = tobacco heating system. 
Table 13 shows the assessments that will be performed on Day 3 of the confinement period: 
Table 13. Time Schedule – Day 3 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 3 
 
 
 
AE/SAE questioning; Concomitant 
medication 
All day 
 
 
Support during smoking abstinence 
(SA arm only), if needed 
All day 
6:29 AM+/-30min 
 
Urine samples to be taken from the 
24-hour urine after the final portion 
of urine has been added to Day 2 
sampling bottle 
BoExp (primary, secondary, and 
NEQ) and creatinine  
 
6:30 AM+/-30min 
 
Start collection to Day 3 sampling 
bottle 24-hour urine 
 
 
 
MNWS questionnaire 
To be done prior to product use, but 
no later than 10:00 AM 
 
 
Assessment of cough 
To be done prior to product use, but 
no later than 10:00 AM 

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2000 Neuchâtel 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 3 
 
 
 
CO breath test 
Within 15 minutes before first 
product use (for THS 2.2 Menthol 
and mCC arms) or between 08:00 
AM and 09:30 AM (SA arm) 
6:30 AM 
 
Beginning of product use 
 
Before 11:00 AM 
 
Breakfast 
 
Before 11:30 AM 
 
Vital signs (blood pressure, pulse 
rate, respiratory rate) 
At least 5 minutes in supine position 
and at least 15 minutes after smoking 
prior to measurement  
12:00 PM-01:30 PM  
 
CO breath test  
 
Before 02:30 PM  
 
Lunch  
 
04:00 PM-05:30 PM 
 
CO breath test 
 
Afternoon 
 
Snacks 
 
In the evening before 
09:00 PM 
 
Dinner  
 
08:00 PM-09:30 PM 
 
CO breath test 
 
08:00 PM-09:30 PM 
√ 
COHb in blood 
 
08:00 PM-09:30 PM 
√ 
Nicotine, cotinine in plasma 
 
08:00 PM-11:00 PM 
 
MCEQ questionnaire (THS 2.2 
Menthol and mCC arms only),  
QSU-brief questionnaire 
 
Around 11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
Collection of used mCC butts 
For accountability 
6:30 AM-11:15 PM 
 
Collection of all tobacco plugs from 
Menthol Tobacco Sticks 
For accountability and further 
analysis 
Abbreviations: AE = adverse event; BoExp = biomarkers of exposure; mCC = menthol conventional cigarette(s); CO = 
carbon monoxide; COHb = carboxyhemoglobin; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = 
Minnesota Nicotine /Withdrawal Scale; QSU = Questionnaire of Smoking Urges; SA = smoking abstinence; SAE = serious 
adverse event; THS = tobacco heating system. 
 
 
 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
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Final 5.0/14 April 2014 
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Table 14 shows the assessments that will be performed on Day 4 of the confinement period: 
Table 14. Time Schedule – Day 4 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 4 
 
 
 
AE/SAE questioning; Concomitant 
medication 
All day 
 
 
Support during smoking abstinence 
(SA arm only), if needed 
All day 
 
 
Socio-economic status 
questionnaire 
At any time of the day 
6:29 AM+/-30min 
 
Urine sample to be taken from 24-
hour urine after final portion of 
urine has been added to Day 3 
sampling bottle. 
BoExp (primary, secondary, and 
NEQ) and creatinine  
 
6:30 AM+/-30min 
 
Start collection to Day 4 sampling 
bottle 24-hour urine 
 
 
 
Assessment of cough 
To be done prior to product use, but 
no later than 10:00 AM. 
 
 
MNWS questionnaire 
To be done prior to product use, but 
no later than 10:00 AM. 
 
 
CO breath test 
Within 15 minutes before first 
product use (for THS 2.2 Menthol 
and mCC arms) or at 08:00 AM ±-
09:30 AM (SA arm) 
06:30 AM-11:00 PM 
 
HST  
In the THS 2.2 Menthol and mCC 
arms, it should be done for all 
smoking events with the HST 
SODIM® device, if compatible 
mCCs are smoked 
6:30 AM 
 
Beginning of product use 
 
Before 11:00 AM 
 
Breakfast 
 
Before 11:30 AM 
 
Vital signs (blood pressure, pulse 
rate, respiratory rate) 
At least 5 minutes in supine position 
and at least 15 minutes after 
smoking prior to measurement  
12:00 PM-01:30 PM 
 
CO breath test  
 
Before 02:30 PM 
 
Lunch  
 
04:00 PM-05:30 PM 
 
CO breath test 
 
Afternoon 
 
Snacks 
 
In the evening before 
09:00 PM 
 
Dinner  
 

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Quai Jeanrenaud 5 
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Philip Morris International. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 4 
 
08:00 PM-09:30 PM 
 
CO breath test 
 
08:00 PM-09:30 PM 
√ 
COHb in blood  
 
08:00 PM-09:30 PM 
√ 
Nicotine, cotinine in plasma 
 
08:00 PM-09:30 PM 
 
HST questionnaire for all subjects 
in the THS 2.2 Menthol and mCC 
arms  
If compatible mCC are smoked 
08:00 PM-11:00 PM 
 
MCEQ questionnaire (THS 2.2 
Menthol and mCC arms only), 
QSU-brief questionnaire 
 
Around 11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
Collection of used mCC butts 
For accountability 
6:30 AM-11:15 PM 
 
Collection of tobacco plugs from all 
Menthol Tobacco Sticks butts 
For accountability and further 
analysis 
Abbreviations: AE = adverse event; BoExp = biomarkers of exposure; mCC = menthol conventional cigarette(s); CO = 
carbon monoxide; COHb = carboxyhemoglobin; HST = human smoking topography; MCEQ = Modified Cigarette 
Evaluation Questionnaire; MNWS = Minnesota Nicotine /Withdrawal Scale; QSU = Questionnaire of Smoking Urges; SA = 
smoking abstinence; SAE = serious adverse event; THS = tobacco heating system 
Table 15 shows the assessments that will be performed on Day 5 of the confinement period: 
Table 15. Time Schedule – Day 5 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 5 
 
 
 
AE/SAE questioning; 
Concomitant medication 
All day 
 
 
Support for smoking 
abstinence (SA arm only), if 
needed 
All day 
6:29 AM+/-30min 
 
Urine samples to be taken 
from 24-hour after final 
portion of urine has been 
added to Day 4 sampling 
bottle. 
BoExp (primary, secondary, and NEQ) 
and creatinine 
 
6:30 AM+/-30min 
 
Start collection to Day 5 
sampling bottle 24-hour 
urine 
 

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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 5 
 
 
 
Assessment of cough 
To be done prior to product use, but no 
later than 10:00 AM. 
 
 
MNWS questionnaire 
To be done prior to product use, but no 
later than 10:00 AM. 
 
 
CO breath test 
Within 15 minutes before first product use 
(for THS 2.2 Menthol and mCC arms) or 
between 08:00 AM and 09:30 AM (SA 
arm) 
 
√ 
COHb in blood 
Within 15 minutes before first product use 
for THS 2.2 Menthol and mCC arms) or 
between 08:00 AM and 09:30 AM (SA 
arm) 
 
√ 
Nicotine, cotinine in plasma 
For THS 2.2 Menthol and mCC arms: 
within 15 minutes before first product use 
(T0): then additional blood samples at 
2 hour intervals from T0 until 11:00 PM. 
Each sample has a time window of +5 
minutes  
For SA arm: only one blood sampling 
between 08:00 PM-09:30 PM 
6:30 AM 
 
Beginning of product use 
 
Before 11:00 AM 
 
Breakfast 
 
Before 11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine position and at 
least 15 minutes after smoking prior to 
measurement 
10:00 AM-11:30 AM 
 
A caffeine tablet containing 
around 200 mg of caffeine ± 
240 mL ±10 mL of water. 
The time of caffeine tablet intake should 
must be recorded 
12:00 PM-01:30 PM 
 
CO breath test 
 
12:00 PM-01:30 PM 
√ 
COHb in blood 
 
Before 02:30 PM 
 
Lunch 
 
04:00 PM-05:30 PM 
 
CO breath test 
 
04:00 PM-05:30 PM 
√ 
COHb in blood 
 
04:00 PM-05:30 PM 
√ 
CYP1A2 activity in plasma 
6 hours ±15 minutes after intake of the 
caffeine tablet 
04:30 PM-05:00 PM 
 
Snacks 
 

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Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
Page 126 of 197 
 
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Philip Morris International. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 5 
 
In the evening before 
09:00 PM 
 
Dinner 
 
08:00 PM-09:30 PM 
 
CO breath test 
 
08:00 PM-09:30 PM 
√ 
COHb in blood 
 
08:00 PM-11:00 PM 
 
MCEQ questionnaire (THS 
2.2 Menthol and mCC arms 
only),  
QSU-brief questionnaire 
Assessment of past and 
curent smoking behavior : 
- Behavioral Risk Factor 
Questionnaire  
- Smoking Questionnaire 
- Supplemental questions 
 
 
 
See Section 7.8.3 for all questionnaires 
Around 11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
Collection of used mCC 
butts 
For accountability 
6:30 AM-11:15 PM 
 
Collection of tobacco plugs 
from Menthol Tobacco 
Sticks  
For accountability and further analysis 
Abbreviations: AE = adverse event; BoExp = biomarkers of exposure; mCC = menthol conventional cigarette(s); CO = 
carbon monoxide; COHb = carboxyhemoglobin; CYP = cytochrome P450 enzyme; MCEQ = Modified Cigarette Evaluation 
Questionnaire; MNWS = Minnesota Nicotine /Withdrawal Scale; QSU = Questionnaire of Smoking Urges; SA = smoking 
abstinence SAE = serious adverse event; THS = tobacco heating system. 
Table 16 shows the assessments that will be performed on Day 6, prior to the time of 
Discharge from the confinement period: 
Table 16. Time Schedule – Day 6 
Time 
Blood 
sample 
Procedure 
Additional information 
Start of procedure 
 
Exposure period 
procedures 
 
 
 
AE/SAE recording; 
Concomitant medication 
All day until discharge 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
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Final 5.0/14 April 2014 
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Philip Morris International. 
 
 
 
Support for smoking 
abstinence (SA arm only), if 
needed 
All day until discharge 
 
 
Nicotine, cotinine in plasma 
In THS 2.2 Menthol and mCC arms, 20 
and 24 hours blood sampling after T0 of 
Day 5. Each sample has a time window of 
±5 minutes 
In SA arm, one blood sample will be 
drawn at between 08:00 AM and 09:30 
AM 
6:29 AM+/-30min 
 
Urine samples to be taken 
from the 24-hour urine after 
final portion of urine has 
been added to Day 5 
sampling bottle 
BoExp (primary, secondary, and NEQ) 
and creatinine, and Ames mutagenicity 
Risk markers: 11-DTX-B2, 8 epi-PGF2α 
Bio-banking for BoExp/risk markers if 
consent is obtained 
 
 
√ 
CYP2A6 activity in plasma 
Has to be done prior to product use 
 
 
Assessment of cough 
To be done prior to product use, but no 
later than 10:00 AM 
 
 
MNWS questionnaire 
To be done prior to product use, but no 
later than 10:00 AM 
 
√ 
COHb in blood 
Has to be done prior to gas transfer 
assessment for all study arms and prior to 
product use in the THS 2.2 Menthol and 
mCC arms 
 
 
Full lung function (single 
breath test for CO first, then 
helium dilution technique, 
and finally spirometry with 
bronchodilator) 
Has to be done prior to product use in the 
THS 2.2 Menthol and mCC arms 
Subject at rest for at least 15 minutes prior 
to lung function testing 
In sitting position 
6:30 AM 
 
Beginning of product use 
 
 
√ 
Clinical laboratory 
parameters (hematology, 
clinical chemistry) *, risk 
markers (sICAM-1) 
Has to be done after at least 10 hours of 
fasting.  
*Platelet count, and WBC to be evaluated 
also as risk markers 
 
√ 
Bio-banking for BoExp/ risk 
markers in serum/plasma (if 
consent is obtained) 
Has to be done after at least 10 hours of 
fasting 
 
√ 
Bio-banking for 
transcriptomics (if consent is 
obtained) 
Has to be done after at least 10 hours of 
fasting 

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Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
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Final 5.0/14 April 2014 
Page 128 of 197 
 
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√ 
Oxysterols 
Has to be done after at least 10 hours of 
fasting 
Prior to discharge of 
Day 6 
 
Breakfast 
 
Prior to discharge of 
Day 6 
 
Physical examination, and 
weight and calculated BMI 
 
Prior to discharge of 
Day 6 
 
CO breath test 
Irrespective of the time of product use 
Prior to discharge of 
Day 6 
 
Urine safety analysis 
 
Prior to discharge of 
Day 6 
 
Urine pregnancy test (all 
females only) 
 
Prior to discharge of 
Day 6 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine position and at 
least 15 minutes after product use prior to 
measurement. 
Systolic and diastolic blood pressure to be 
assessed as risk markers 
Prior to discharge of 
Day 6 
 
ECG 
At least 5 minutes in supine position prior 
to recording 
 
 
Nasal Epithelial Collection 
Only if consent is obtained 
Subject must not have eaten at least 30 
minutes prior to collection  
Prior to starting the procedure, the subject 
will be asked to blow his nose 
Prior to discharge of 
Day 6 
 
Buccal Collection 
Only if consent is obtained 
Subject must not have eaten at least 30 
minutes prior to collection  
Subject will be asked to rinse his mouth 
with a minimum of 20 mL of water prior 
to sample collection 
Prior to discharge of 
Day 6 
 
Information on risk of 
smoking/smoking cessation 
advice and debriefing 
 
Prior to discharge of 
Day 6 
 
Distribution of product use 
electronic diary 
To be completed by the subject every day 
from time of Discharge on Day 6 until next 
visit. All Menthol Tobacco Sticks/mCC 
and any tobacco/nicotine containing 
products have to be recorded. 
 
 
Collection of all used 
Menthol Tobacco Sticks and 
smoked mCC butts  
For accountability 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
Page 129 of 197 
 
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Philip Morris International. 
 
 
 
Time of Discharge from 
confinement-/beginning of 
the ambulatory exposure 
period 
 
Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse event; 
BMI = body mass index; BoExp = biomarkers of exposure; BP = blood pressure; mCC = menthol conventional cigarette(s); 
CO = carbon monoxide; CYP = cytochrome P450 enzyme; ECG = electrocardiogram; MNWS = Minnesota Nicotine 
/Withdrawal Scale; PK = pharmacokinetics; SA = smoking abstinence; SAE = serious adverse event; sICAM-1 = soluble 
inter-cellular adhesion molecule; WBC = white blood cell count. 
9.3 
Ambulatory Period (from time of Discharge on Day 6 to Day 90 
Visit) 
For Day 30 Visit (Day 30 and Day 31), Day 60 Visit (Day 60 and Day 61), and Day 90 Visit 
(Day 90 and Day 91), a time window of +/- 5 days will be allowed with respect to Day 6, 
Day 30 Visit and Day 60 Visit respectively. The time of opening and end of the visit are 
given as an estimate.  
Table 17 shows the assessments that will be performed on Day 30 Visit and Day 60 Visit of 
the ambulatory period: 
Table 17. Time Schedule – Day 30 Visit and Day 60 Visit (from the time of check-in 
in the morning prior to 08:30 AM to check-out of the subject on the day 
after)  
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 30 and Day 60  
 
In the morning prior to 
08:30 AM 
 
Opening of the Day 30 Visit 
and Day 60 Visit 
No product restriction prior to the opening 
of the visit  
Product use will be allowed on site in the 
THS 2.2 Menthol and mCC arms from the 
time of check-in in the morning to around 
11:00 PM. 
The use of THS 2.2 menthol in smokers 
allocated to mCC and SA arms will be 
forbidden 
 
 
Support for smoking 
abstinence (SA arm only) if 
needed 
At any time of the day 
 
 
AE/SAE questioning; 
Concomitant medication 
At any time during the day 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
Page 130 of 197 
 
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Philip Morris International. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 30 and Day 60  
 
08:30 AM-09:30 AM 
 
Start of HST recording for 4 
hours  
In the THS 2.2 Menthol and mCC arms, 
the HST SODIM® device has to be used 
for all smoking events, if compatible 
mCCs are smoked 
HST recording will be done only on the 
subject’s assigned product  
09:00 AM ± 30 min 
 
Start of collection of 24-
hour urine fraction on the 
defined Visit 
The subject must empty his bladder and 
discard the urine prior to starting urine 
collection BoExp (primary, secondary, and 
NEQ), creatinine  
Risk markers: 11-DTX-B2 and 8-epi-
PGF2α  
Before 11:00 AM 
 
Breakfast 
 
10:00 AM-11:30 AM 
 
CO breath test 
Irrespective of the time of product use 
10.00 AM-11:30 AM 
√ 
COHb in blood 
Irrespective of the time of product use 
10.00 AM-11:30 AM 
√ 
Nicotine, cotinine in plasma 
One blood sample will be drawn, 
irrespective of the time of product use 
12:30 PM-01:30 PM 
 
End of collection of 4 –hour 
HST recording 
The HST should be recorded over a period 
of 4 hours ± 15 minutes. 
 
Before 02.30 PM 
 
Lunch 
 
02:30 PM-07:00 PM 
 
ECG 
At least 5 minutes in supine position prior 
to recording 
02:30 PM-07:00 PM 
 
Urine Pregnancy test 
 
02:30 PM-07:00 PM 
 
Physical examination, 
including weight calculated 
BMI  
 
02:30 PM-07:00 PM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine position and at 
least 15 minutes after product use prior to 
measurement 
At any time during the day 
Systolic and diastolic blood pressure to be 
evaluated also as risk markers 
08:00 PM-09:30 PM 
 
HST questionnaire (THS 2.2 
Menthol and mCC arms 
only) 
If compatible mCC are smoked 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
Page 131 of 197 
 
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information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under 
the provisions of United States law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris International. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 30 and Day 60  
 
08:00 PM-11:00 PM 
 
MCEQ questionnaire (THS 
2.2 Menthol and mCC arms 
only),  
QSU-brief questionnaire 
Intention to quit smoking in 
the next 6 months or less 
(Prochaska ‘Stage of 
Change’ questionnaire) 
 
In the evening before 
09:00 PM 
 
Dinner 
 
Around 11:00 PM 
 
End of product use 
 
08:00 AM-11:15 PM 
 
Collection of 
empty/partially used 
Menthol Tobacco Stick  
At any time of the day  
For accountability 
Partially used packs will be returned to the 
subject  
08:00 AM-11:15 PM 
 
Collection of tobacco plugs 
from each used Menthol 
Tobacco Sticks  
For further analysis  
Abbreviations: 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse event; BoExp = biomarkers of exposure; 
mCC = menthol conventional cigarette(s); CO = carbon monoxide; COHb = carboxyhemoglobin; INR = international 
normalized ratio;HDL: high density lipoprotein; LDL: low density lipoprotein; hs CRP: high sensitivity C-reactive Protein; 
MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = Minnesota Nicotine /Withdrawal Scale; QSU = 
Questionnaire of Smoking Urges; SAE = serious adverse event; TG = triglycerides; s-ICAM-1 soluble inter-cellular adhesion 
molecule; TC: total cholesterol; THS = tobacco heating system; WBC = white blood cell count. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 31 and Day 61  
 
 
 
Support for smoking abstinence (SA arm 
only) if needed 
At any time of the day 
 
 
AE/SAE questioning; Concomitant 
medication 
At any time during the day 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
Page 132 of 197 
 
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Philip Morris International. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 31 and Day 61  
 
 
√ 
Clinical laboratory parameters* (hematology, 
clinical chemistry), and risk markers 
(s-ICAM-1, hs-CRP, fibrinogen, 
homocysteine, LDL, HDL) 
Sample to be collected after at 
least 10 hours of fasting.  
*Blood glucose, TG, TC, 
WBC, and platelet count from 
safety lab will be also 
evaluated as risk markers 
06:30 AM 
 
Beginning of product use 
 
08:59 AM ± 30 min 
 
End of urine collection and urine sample to 
be taken from the 24-hour urine after final 
portion of urine has been added to Day 30 or 
Day 60 sampling bottles 
BoExp (primary, secondary, 
and NEQ), creatinine  
Risk markers: 11-DTX-B2 
and 8-epi-PGF2α 
Before 10:00 AM 
 
Assessment of Cough, and 
MNWS questionnaire 
Irrespective of the time of 
product use but no later than 
10:00 AM 
Before 10:00 AM 
 
Breakfast 
 
Prior to check-out 
of the given visit 
 
Urine safety analysis  
 
Prior to check-out 
of the given visit 
 
Information on the risk of smoking/smoking 
cessation advice and debriefing 
 
Check-out  
 
End of the Visit 
 
Abbreviations: 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse event; BoExp = biomarkers of exposure; CO = 
carbon monoxide; COHb = carboxyhemoglobin;  HDL: high density lipoprotein; ; hs CRP: high sensity lipoprotein;  HST = 
human smoking topography; LDL: low density lipoprotein; mCC = menthol conventional cigarette(s);  MCEQ = Modified 
Cigarette Evaluation Questionnaire; MNWS = Minnesota Nicotine Withdrawal Scale; SAE = serious adverse event; s-ICAM-
1: soluble inter-cellular Molecule 1; TC: total cholesterol; TG = triglycerides; THS = tobacco heating system; QSU = 
Questionnaire of Smoking Urges; WBC = white blood cell count. 
 
 
 
 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
Page 133 of 197 
 
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Philip Morris International. 
 
The procedures for the last visit which will be conducted on Day 90 Visit +/- 5 days of the 
study are shown in Table 18. 
The time of opening and end of the visit are given as an estimate.  
Table 18. Time Schedule – Day 90 Visit (from the time of check-in in the morning 
prior to 08:30 AM of Day 90 to time of discharge of Day 91) 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 90 
 
In the morning 
 
Opening of the Visit 
No product restriction prior to the opening 
of the visit. 
Product use will be allowed on site in the 
THS 2.2 Menthol and mCC arms from the 
time of check-in in the morning to around 
11:00 PM 
The use of THS 2.2 menthol in smokers 
allocated to mCC and SA arms will be 
forbidden 
 
 
AE/SAE questioning; 
Concomitant medication 
At any time during the day 
 
 
Support for smoking 
abstinence (SA arm only), if 
needed 
At any time of the day 
08:30 AM-09:30 AM 
 
Start of HST recording for 4-
hour  
In the THS 2.2 Menthol and mCC arms, 
the HST SODIM® device has to be used 
for all smoking events if compatible mCCs 
are smoked 
HST recording will be done only on the 
subject’s assigned product 
09:00 ± 30 min 
 
Start of collection of 24-hour 
urine fraction 
The subject must empty his bladder and 
discard the urine prior to starting urine 
collection  
Before 11:00AM 
 
Breakfast with a caffeine 
tablet containing 
approximately 200 mg of 
caffeine ± 240 mL ±10 mL 
of water 
The time of caffeine tablet intake must be 
recorded 
10:00 AM-12:30 PM 
 
CO breath test 
Irrespective of the time of product use 
10:00 AM-12:30 PM 
√ 
COHb in blood 
Irrespective of the time of product use 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
Page 134 of 197 
 
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information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under 
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Philip Morris International. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 90 
 
10:00 AM-12:30 PM 
√ 
Nicotine, cotinine in plasma 
One blood sample will be drawn, 
irrespective of the time of product use 
12:30 PM-01:30 PM 
 
End of collection of HST 
recording 
The HST should be recorded over a period 
of 4 hours ± 15 minutes. 
Before 02:30 PM 
 
Lunch  
 
In the afternoon 
√ 
CYP1A2 activity in plasma 
6 hours ±15 minutes after intake of the 
caffeine tablet 
In the afternoon before 
09:00 PM 
 
Nasal Epithelial Collection 
Only if consent is obtained 
Subject must not have eaten at least 30 
minutes prior to collection 
Prior to starting the procedure, the subject 
will be asked to blow his nose 
In the afternoon before 
09:00 PM 
 
Buccal Collection 
Only if consent is obtained 
Subject must not have eaten at least 30 
minutes prior to collection 
Subject will be asked to rinse his mouth 
with a minimum of 20 mL of water prior 
to sample collection 
08:00 PM-09.30 PM 
 
HST questionnaire (THS 2.2 
Menthol and mCC arms 
only) 
If compatible mCC are smoked 
08:00 PM-11:00 PM 
 
Fagerström Test for Nicotine 
Dependence (FTND) 
 
08:00 PM-11:00 PM 
 
MCEQ (THS 2.2 Menthol 
and mCC arms, only) 
 
08:00 PM-11:00 PM 
 
QSU-brief questionnaire, 
Intention to quit smoking in 
the next 6 months or less 
(Prochaska ‘Stage of 
Change’ questionnaire) 
 
In the evening before 
09:00 PM 
 
Dinner 
 
Around 11:00 PM 
 
End of product use 
 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
Page 135 of 197 
 
Data and information contained in this document are considered to constitute trade secrets and confidential commercial 
information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under 
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Philip Morris International. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 90 
 
08:00 AM-11:15 PM 
 
Collection of empty/partially 
used menthol THS tobacco 
stick and mCC packs 
At any time of the day 
For accountability  
Partially used mCC packs will be returned 
to the subject  
08:00 AM-11:15 PM 
 
Collection of tobacco plugs 
from each used Menthol 
Tobacco Sticks  
All day 
For further analysis 
Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse event;; 
BMI = body mass index; BoExp = biomarkers of exposure; mCC = conventional cigarette(s); CO = carbon monoxide; COHb 
= carboxyhemoglobin; CYP = cytochrome P450 enzyme; ECG = electrocardiogram; HbA1c = hemoglobin A1c; hs-CRP = 
high-sensitive C-reactive protein; HDL = high density lipoprotein; HST = human smoking topography; LDL = low density 
lipoprotein; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = Minnesota Nicotine /Withdrawal Scale; QSU = 
Questionnaire of Smoking Urges; SAE = serious adverse event; sICAM-1 = soluble inter-cellular adhesion molecule; TG = 
triglycerides; THS = tobacco heating system; WBC = white blood cell count. 
 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 91 
 
 
 
Support for smoking 
abstinence (SA arm only), if 
needed 
At any time of the day 
 
 
AE/SAE questioning; 
Concomitant medication 
At any time during the day 
 
√ 
CYP2A6 activity in plasma 
Has to be done prior to product use 
 
√ 
COHb 
Has to be done prior to gas transfer 
assessment 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
Page 136 of 197 
 
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information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under 
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Philip Morris International. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 91 
 
 
 
Full lung function (single 
breath test for CO first, then 
helium dilution technique, 
and finally spirometry with 
bronchodilator, ) 
Has to be done prior to product use in the 
THS 2.2 Menthol and mCC arms 
Subject at rest for at least 15 minutes prior 
to lung function testing 
In sitting position 
At rest for at least 15 minutes prior to lung 
function testing 
In sitting position 
 
 
 
Beginning of product use 
 
 
√ 
Clinical laboratory 
parameters* (hematology, 
clinical chemistry), and risk 
markers (s-ICAM-1, hs-
CRP, fibrinogen, 
homocysteine, LDL, HDL, 
TG, HbA1c, Apo A1, Apo 
B) 
Sample to be collected after at least 10 
hours of fasting.  
*Blood glucose, TG, TC, WBC, and 
platelet count from safety to be evaluated 
also as risk markers 
 
 
√ 
Oxysterols 
Sample to be collected after at least 
10 hours of fasting 
 
 
√ 
Bio-banking for 
transcriptomics  
Sample to be collected after at least 
10 hours of fasting 
If consent is obtained 
 
√ 
Bio-banking for BoExp/risk 
markers in serum/plasma  
Sample to be collected after at least 
10 hours of fasting 
If consent is obtained 
Before 10:00AM 
 
Assessment of Cough, and 
MNWS questionnaire 
Irrespective of the time of product use but 
no later than 10:00 AM 
Before 11:00 AM 
 
Breakfast  
 
08:59 ± 30 min 
 
End of 24-hour urine 
collection and urine sample 
to be taken from the 24-hour 
urine after final portion of 
urine has been added to Day 
90 sampling bottle 
BoExp (primary, secondary, and NEQ), 
creatinine, Ames mutagenicity 
Urine bio-banking if consent is obtained 
Risk Markers: 11-DTX-B2 and 8-epi-
PGF2 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 91 
 
 
 
Start collection of 4-hour 
urine to Day 91 sampling 
bottle 
4-hour urine collection will start 
immediately after the end of collection of 
24-hour urine 
The 4.hour fraction will be collected over a 
4-hour period ± 30 minutes 
 
Before 02:30 PM 
 
Lunch  
 
 
 
End of 4-hour urine 
collection and sampling of 
urine samples to be taken 
from the 4-hour urine after 
the final portion of 4-hour 
urine fraction has been 
added to Day 91 sampling 
bottle. 
BoExp (primary, secondary and NEQ), 
creatinine, 4-hour urine fraction. 
Risk markers: 11-DTX-B2, 8 epi-PGF2α. 
In the afternoon prior 
to discharge of Day 91  
 
Physical examination, 
including weight calculated 
BMI, and waist 
circumference 
Weight and waist circumference to be 
evaluated also as risk markers 
In the afternoon prior 
to discharge of Day 91 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine position and at 
least 15 minutes after smoking prior to 
measurement 
At any time during the day 
Systolic and diastolic blood pressure to be 
evaluated also as risk markers 
In the afternoon prior 
to discharge of Day 91 
 
ECG 
At least 5 minutes in supine position prior 
to recording 
In the afternoon prior 
to discharge of Day 91 
 
Urine safety analysis and 
pregnancy test 
 
From 06:30 to time of 
discharge of Day 91 
 
Collection of empty/partially 
used menthol THS tobacco 
stick  
At any time of the day 
Partially used packs will be returned to the 
subject after accountability is performed 
In the afternoon prior 
to discharge of Day 91 
 
Return of electronic diaries 
by the subject to the site 
staff 
 
In the afternoon prior 
to discharge of Day 91 
 
Information on the risk of 
smoking/smoking cessation 
advice and debriefing 
 

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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 91 
 
 
 
Time of Discharge On Day 
90 Visit 
 
Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse event;; 
Apo. Apolipoprotein; BMI = body mass index; BoExp = biomarkers of exposure; mCC = conventional cigarette(s); CO = 
carbon monoxide; COHb = carboxyhemoglobin; CYP = cytochrome P450 enzyme; ECG = electrocardiogram; HbA1c = 
hemoglobin A1c; hs-CRP = high-sensitive C-reactive protein; HDL = high density lipoprotein; HST = human smoking 
topography; LDL = low density lipoprotein; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = Minnesota 
Nicotine /Withdrawal Scale; QSU = Questionnaire of Smoking Urges; SAE = serious adverse event; sICAM-1 = soluble 
inter-cellular adhesion molecule; TG = triglycerides; THS = tobacco heating system; WBC = white blood cell count. 
* Platelet count, WBC, blood glucose, triglycerides, and total cholesterol from safety will also be assessed as risk markers 
9.4 
Safety Follow-up Period 
All subjects participating in the product trial on Day -2 and are not enrolled into the study 
will enter a 28-day safety follow-up period.  
After subjects have completed the Day 91 safety assessments (or if they are prematurely 
withdrawn from the study), they will enter a 28-day safety follow-up period. 
During the 28-day safety follow-up period, there will be spontaneous reporting by the subject 
of new AEs and new SAEs. Any ongoing AEs/SAEs will be actively followed-up by the site.  
Any AEs or SAEs that are ongoing at the end of the 28-day safety follow-up period will be 
handled as described in Section 8. 
9.5 
Early Termination Procedures 
The following safety assessments as described on Day 6 will be performed as early 
termination procedures (Section 9.2.3): 
• AE/SAE recording. 
• Clinical laboratory parameters (hematology, clinical chemistry, and urine 
safety analysis). 
• Physical examination. 
• Full lung function. 
• Urine pregnancy. 
• Vital signs. 

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• ECG, and 
• Information on the risk of smoking/smoking cessation advice, and 
debriefing. 

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10 CONTROL AND QUALITY ASSURANCE 
10.1  Monitoring 
The CRO Clinical Research Associate (“Monitor”) 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 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. 
The Investigator shall access medical records for the Monitor in order that entries in the 
eCRFs may be verified. The Investigator, as part of their responsibilities, is expected to 
ensure that the study adheres to GCP requirements. 
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 done and documented. 
Subsequent to the Investigator’s meeting, and before the first subject is screened into the 
study, site initiation visit will be conducted by the Monitor and, if necessary, with Sponsor or 
its authorized representative. The purpose of the site initiation visit is described in the 
monitoring plan. 
During the study, the Monitor will have regular contact with the study site, including interim 
monitoring visits. The purpose of these visits is described in the monitoring plan. 
Communication by telephone, mail, and e-mail may be used as needed to supplement site 
visits. The 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 
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, or a designated member of the Investigator’s staff, must be available during 
the monitoring visit to review the data and resolve any queries, and to allow direct access to 
the subject’s records for source data verification. 

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10.2 Training of Staff 
A formal meeting (Investigator’s meeting) will 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 in the 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 or designee 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 to the staff involved in a 
timely manner. The Investigator or designee 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 IRB 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, and any 
applicable regulatory requirements. The Investigator or designee will contact the Sponsor or 
the authorized representative immediately if contacted by a regulatory agency about an 
inspection at their site. 
The Investigator and study staff 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 or designee understands and agrees to provide access 
to the necessary documentation and files. 
 
 

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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. 
11.1 Data Capture 
11.1.1 Case Report Forms and Study Records 
With the exception of subject-reported outcome data, all results from the clinical assessments 
will be recorded in the Source Documents by the Investigator or their authorized designee 
and then captured in the eCRFs at the study site. The subject questionnaires and the VAS will 
be entered by the subject directly in an electronic Patient Reported Outcomes (ePRO) device 
or on paper copy. 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 
then transferring the data into the eCRF according to the eCRF 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 electronically 
signed by the Investigator to attest that the data contained in the eCRF are true and accurate. 
Any corrections made to source documents and/or eCRFs 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 study site by the Monitor. Instances of missing 
or unclear data will be discussed with the Investigator for resolution. For the ePRO diary, all 
subject reported outcome data will be provided in English and instructions will be provided 
in the subject’s local language. An eCRF will be generated for all subjects that sign informed 
consent. 
11.1.2 Protocol Deviations 
All protocol deviations will be entered into the Clinical Trial Management System (CTMS) 
or other approved format. 
Information from the source documents will represent the primary source of protocol 
deviations. Information following site monitoring and other manual reviews will be 
documented in the site visit reports, follow-up letters, audit documentation, or other manual 
review and will be recorded and tracked in the CTMS or other approved format. 
Telecommunications and other verbal communications regarding deviations will be 
considered and handled as important communication, documented and tracked as protocol 
deviations, as necessary. 

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Individual entries for protocol deviations that are recorded in the CTMS, or other approved 
format, following site monitoring and other manual reviews will be reviewed against the 
individual data points in the eCRF database but will not be formally reconciled with the 
eCRF database (e.g., their description or occurrence date). The overall procedure for 
managing protocol deviations is described in the SOPs and/or agreed upon procedure of the 
CRO Data Management Team. All deviations will be reviewed periodically, as determined at 
study start, to identify trends to improve monitoring and/or potential impact on the statistical 
analysis. 
11.2 Data Handling 
All study data will be managed by the Data Management Team at the CRO. The overall 
procedures for quality assurance of clinical study data are described in the SOPs of the CRO 
Data Management Team. The Data Management Team at the CRO will prepare a DMP, to be 
reviewed and approved by the Sponsor, prior to the start of data entry. This document will 
describe, in detail, the Data Management-related procedures and processes. 
All data of all subjects enrolled and screening failures who experience an AE during the 
study (from time of informed consent to end of the safety follow-up period) will be captured 
in the Source Documents and all AEs will entered in the study database. 
All data collected during the study is property of the Sponsor irrespective of the location of 
the database and the Data Management CRO. 
11.2.1 Data Validation 
The data will be validated as defined in the DMP and Data Validation Specifications. 
Discrepancies will be generated electronically as necessary. 
Data queries will be raised for discrepant or missing data. All changes to data will be 
captured in the database with a comprehensive audit trail. 
11.2.2 Coding 
Adverse events, medical/surgical history, and prior/concomitant medication will be classified 
according to the terminology of the latest version of the following dictionaries: 
Medical history: 
Medical Dictionary for Regulatory Activities (MedDRA®) 
Adverse events: 
MedDRA® 
Medications: 
WHO Drug Dictionary Enhanced and Anatomical Therapeutic 
and Chemical  classification system 

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THS device issues and malfunction will be classified according to C54451/Medical Device 
Problem Codes, FDA, CDRH (FDA, 2012b). 
11.2.3 Database Lock 
When all outstanding Data Management issues have been resolved and all validation, quality 
review and cleaning activities are complete, the database or selected data is/are declared soft 
locked. Access to change data in the soft-locked database or to change selected data at this 
time is limited.  
After data review by the Sponsor, resolution of all raised queries and QC of the changed data 
the database or selected data upon Sponsor approval as applicable is/are declared 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 Team at the CRO. Any of those 
changes must be formally documented. 
After study completion, the study database will be transferred to the Sponsor in the format 
specified in the DMP in Clinical Data Interchange Standards Consortium 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 analysis will be given in a Statistical Analysis Plan (SAP). Any 
changes to the planned statistical methods will be documented in the Clinical Study Report. 
The statistical evaluation will be performed using SAS®, version 9.2 or later. 
12.1.1 Stratification Criteria 
For the primary analysis of the BoExp, the following stratification criteria will be used:  
1. Sex (male; female). 
2. Average daily CC consumption over the last 4 weeks as reported during the 
Screening. 
12.1.2 Definitions for Statistical Data Analysis 
Baseline: 
In general, baseline will be the last available time-point prior to Day 1, 06:30 AM. 
THS 2.2 Menthol users:  
Subjects switching from mCC to THS 2.2 Menthol whose product use pattern categorization 
is primarily THS 2.2 Menthol or predominantly THS 2.2 Menthol over a defined period will 
be considered as THS 2.2 Menthol users during that period. See Section 12.3 for further 
details on the product use. 
Dual use:  
Subjects switching from mCC to THS 2.2 Menthol whose product use pattern categorization 
is dual mostly THS 2.2 Menthol, dual balanced or dual mostly CC over a defined period will 
be considered as dual users. See Section 12.3 for further details on the product use. 
CC users: 
Subjects switching from mCC to THS 2.2 Menthol or subjects continuing to use mCC whose 
product use pattern categorization is primarily CC or predominantly CC over a defined 
period will be considered as CC users during that period. See Section 12.3 for further details 
on the product use. 
Smoking abstinence:  

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Smoking abstinence during a defined period is defined as using no tobacco-containing 
product as reported by the subject on the electronic diary. 
Non-compliance to randomization arm:  
 Confinement: 
Use of any nicotine or tobacco–containing product other than the assigned product. 
Exhaled CO breath test >10 ppm for subjects from the SA arm  
 Ambulatory: 
Non-compliance in the THS 2.2 Menthol and SA arms will be defined in reference to the 
time period 
- 
]Day 6-Day 30 Visit] 
- 
]Day 30 Visit-Day 60 Visit] 
- 
]Day 60 Visit-Day 90 Visit] 
as the use of more than 2 CC during a single day within a time period or the use of on 
average more than 0.5 CC per day over the exposure study. 
12.1.3 Descriptive Statistics 
All data will be presented in listings, ordered by product arm and subject, unless otherwise 
specified. 
Descriptive statistics for continuous variables (number of subjects [n], number and percent of 
subjects with data, mean, standard deviation [SD], median, first and third quartiles, minimum 
and maximum for continuous data, and the n and absolute and relative [%] frequency for 
categorical data) will be presented by product arm and overall at each time point, where 
applicable. 
For BoExp, the geometric mean and coefficient of variation (CV) will be presented in 
addition to the mean and SD. 
Analyses over time will be descriptive statistics of parameters at each assessment timepoint. 
12.1.4 Handling of Missing Values and of Values Outside the Detection Limits 
Missing values for the BoExp will be imputed using the last observation carried forward 
(LOCF) approach. 
Values below the lower limit of quantification (LLOQ) will be imputed using 0.5 x LLOQ. 
For values above the upper limit of quantification (ULOQ), the ULOQ will be used for 
calculation and reporting in summary tables. The number of values below LLOQ or above 
ULOQ will be presented in each summary table. 

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For questionnaire data total scores and domain or subscale scores may use a certain degree of 
imputation by averaging across individual item scores. 
Further details will be provided in the SAP. 
12.1.5 Significance Level for Inferential Analysis 
Unless stated otherwise, all statistical tests will be two-sided and conducted at the 5% level, 
and all quoted confidence intervals will be two-sided 95% confidence intervals. 
The primary endpoints will be tested using a multiple testing procedure to preserve the 
overall alpha level by simultaneously testing the endpoints using a closed procedure with 
each test performed at an one-sided alpha level of 2.5%. This implies that statistical 
significance is required for all primary endpoints in order to be able to make confirmatory 
claims about any of the endpoints. 
Further details will be provided in the SAP.  
12.2 Determination of Sample Size and Power Consideration 
The following discussion addresses the ability to demonstrate on Day 5 a reduction of at least 
50% on four selected primary BoExp and on Day 90 on a fifth primary BoExp in smokers 
switching from mCC to THS 2.2 Menthol as compared to smokers continuing to smoke 
mCC. 
Table 19 describes the expected coefficients of variation (CV) and mean ratios (MR) 
between THS 2.2 Menthol and the two control arms in COHb, 3-HPMA, MHBMA, and S-
PMA on Day 5 based on data from a controlled, randomized, open-label, 3-arm parallel 
single-center confinement study to investigate exposure to selected smoke constituents in 
smokers switching from CCs to smoking article (SMAR) cigarettes for 5 days, the YVD-
CS01-EU study (ClinicalTrials.gov: ID: NCT00812279) sponsored by PMI. The mean ratios 
and coefficients of variations for SMAR/CC are expected to be the same as THS 2.2 
Menthol/mCC. 

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Table 19. Expected Mean Ratios and Coefficients of Variation for THS 2.2 
Menthol/mCC 
 
THS 2.2 Menthol /mCC 
Mean Ratio (CV) 
THS 2.2 Menthol/SA 
Mean Ratio (CV) 
COHb 
0.40 (0.32) 
2.10 (0.20) 
3-HPMA 
0.30 (0.50) 
1.70 (0.33) 
MHBMA 
0.15 (0.70) 
1.00 (0.35) 
S-PMA 
0.20 (0.70) 
1.15 (0.42) 
Abbreviations: 3-HPMA = 3-hydroxypropylmercapturic acid; mCC = menthol conventional cigarettes; COHb = 
carboxyhemoglobin; CV = coefficients of variation; MHBMA = monohydroxybutenyl mercapturic acid; MR = mean ratios; 
S-PMA = S-phenylmercapturic acid; SA = smoking abstinence; THS 2.2 = Tobacco Heating System 2.2. 
Table 20 describes the expected coefficients of variation (CV) and mean ratios (MR) 
between THS 2.2 Menthol and the mCC control arm in Total NNAL on Day 90 based on 
data from a Philip Morris USA-sponsored randomized, controlled, switching, open-label, 
parallel-group, single-center study in 90 male and female adult smokers evaluated six 
biomarkers of tobacco smoke exposure over a 12-week period (Frost-Pineda et al., 2008). 
The mean ratios and coefficients of variations for EHCJLI /CC are expected to be the same as 
THS 2.2 Menthol/mCC. 
Table 20.  Expected Mean Ratios and Coefficients of Variation for THS 2.2 
Menthol/mCC  
 
THS 2.2 Menthol /mCC 
MR (CV) 
Total NNAL 
0.30 (0.60) 
Abbreviations: 
Total 
NNAL 
= 
total 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; 
MR 
= 
mean 
ratio; 
THS 2.2 = Tobacco Heating System 2.2; mCC = menthol conventional cigarettes; CV = coefficient of variation. 
Table 21 describes the expected coefficients of variation (CV) and mean ratios (MR) 
between THS 2.2 Menthol and the mCC control arm in COHb, 3-HPMA, MHBMA and S-
PMA based on data from a single-center, open-label, randomized, controlled, 2-arm parallel 
group study to evaluate the exposure to selected smoke constituents in smoking, apparently 
healthy subjects switching from conventional cigarettes to THS 2.1 compared to subjects 
continuing to smoke CC for 5 days, the ZRHX-EX-01 study (ClinicalTrials.gov: ID: 
NCT01780714) sponsored by PMI. The mean ratios and coefficients of variations for THS 
2.1/CC are expected to be the same as THS 2.2 Menthol/mCC. 

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Table 21. Expected Mean Ratios and coefficients of Variation for THS 2.2 
Menthol/mCC  
 
THS 2.2 Menthol /mCC 
MR (CV) 
COHb 
0.44 (0.14) 
3-HPMA 
0.28 (0.20) 
MHBMA 
0.11 (0.47) 
S-PMA 
0.07 (0.50) 
Abbreviations: 
3-HPMA 
= 
3-hydroxypropylmercapturic 
acid; 
mCC 
= 
menthol 
conventional 
cigarettes; 
COHb = carboxyhemoglobin; CV = coefficient of variation; MHBMA = monohydroxybutenyl mercapturic acid; MR = 
mean ratio; S-PMA = S-phenylmercapturic acid; THS 2.2 = Tobacco Heating System 2.2. 
Based on these two sets of assumptions on the mean ratios and coefficients of variations for 
the four primary BoExp on Day 5, the power to demonstrate a reduction was computed. 
The comparison will be run on the per protocol population as defined in Section 12.4.2.  
Subjects are expected not to have any reason for exclusion from the per protocol population 
in the confinement period for THS 2.2 Menthol arm and in ambulatory and confinement 
condition for the mCC arm. 
50% of the subjects are expected to be excluded from the per protocol population in the THS 
2.2 Menthol arm in the ambulatory (mostly due to lack of compliance to the randomized 
product). Thus the expected populations on which the reductions will be assessed as 
described in Table 22. 
Table 22. Sample Size to Assess the Reductions 
 
Sample size to assess the reduction 
(THS 2.2 Menthol:/mCC) 
COHb 
80:40 
3-HPMA 
80:40 
MHBMA 
80:40 
S-PMA 
80:40 
Total NNAL 
40:40 
Abbreviations: 3-HPMA = 3-hydroxypropylmercapturic acid; Total NNAL = total 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanol mCC = menthol conventional cigarettes; COHb = carboxyhemoglobin; MHBMA = monohydroxybutenyl 
mercapturic acid; S-PMA = S-phenylmercapturic acid; THS 2.2 = Tobacco Heating System 2.2. 
 

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Table 23 describes the expected power to demonstrate a reduction on 5 primary BoExp in 
smokers switching from CC to THS 2.2 Menthol as compared to those continuing to smoke 
mCC, using one-sided test with 2.5% type I error probability using the assumptions from 
YVD-CS01-EU and ZRHX-EX-01 given a sample size of 160 smokers (~80 in THS 2.2, ~40 
in CC, and ~40 in the SA arm). Therefore subjects will be enrolled into the study until there 
are 160 smokers in the FAS population. 
Table 23. Expected power (YVD-CS01-EU and ZRHX‐EX‐01 studies assumptions) 
Reduction 
Assumptions 
50% 
51% 
52% 
53% 
54% 
55% 
YVD-CS01-EU  
94% 
88% 
81% 
70% 
56% 
38% 
ZRHX‐EX‐01  
98% 
97% 
92% 
76% 
41% 
6% 
 
Power considerations related to secondary endpoints of biological changes: 
The sample size is sufficient to obtain 95% CIs for the ratio between (geometrical) mean 
levels of primary BoExp in THS 2.2 Menthol and SA with upper and lower limits deviating 
not more than 18% from the point estimates, with an 80% overall probability of achieving 
the desired precision of estimating the true mean. 
This study has 80% power using a one-sided test with 2.5% type I error probability: 
• To detect a 0.631 [mL/min/kg] (29%) difference between THS 2.2 Menthol and mCC in 
CYP1A2 activity, as measured by the caffeine clearance, assuming a SD of 0.564. Effect 
size and variability are derived from data obtained in the YVD-CS01-EU study sponsored 
by PMI. 
• To detect a 24.71 [ng/g creatinine] (20%) difference between THS 2.2 Menthol and mCC 
in 11-DTX-B2, assuming a SD of 43.78, as reported by Saareks et al., 2001. The 
anticipated effect size of THS 2.2 Menthol is assumed to be about 90% of the effect of 
smoking cessation reported in the paper by Saareks et al., 2001. 
12.3 Product use 
The FDA Draft Guidance on Modified Risk Tobacco Product Applications Draft (Section 
VI-A-2) (FDA, 2012a), requires that an MRTP Application should contain scientific 
evidence about the effect the product may have on tobacco use behavior among current 
tobacco users including consideration of areas such as the expected rates of use of the 
tobacco product by current tobacco users and the use of the tobacco product in conjunction 
with other tobacco products. 

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Although subjects are being requested to use solely the product allocated to their respective 
study arm, it is considered that during the ambulatory period not all subjects randomized to 
the THS 2.2 Menthol arm might be exclusively using THS 2.2 Menthol at all times during 
the study. Subjects may concomitantly use THS 2.2 Menthol and CC (dual-use). To assess 
dual use of THS 2.2 Menthol and CC, PMI has defined dual-use with regards to using THS 
2.2 Menthol in the following way: 
Dual-use will be calculated as percentage based on their reported THS 2.2 Menthol Tobacco 
Sticks consumption and the number of conventional cigarettes smoked (menthol and non-
menthol) by study period:  
• On Day 30 Visit, using the reported number of CC (menthol and non-menthol) and/or 
Menthol Tobacco Sticks consumption since time of Discharge of Day 6,  
• On Day 60 Visit, using the reported number of CC (menthol and non-menthol)and/or 
Menthol Tobacco Sticks consumption after Day 30 Visit and  
• On Day 90 Visit, using the reported number of CC (menthol and non-menthol)and/or 
Menthol Tobacco Sticks consumption after Day 60 Visit. 
 
Figure 2 presents a detailed overview on the definition of the product use categories. 

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Figure 2. Product Use Pattern Categorization 
 
 
The more granular categorization scheme will be used for the definition of the per-protocol 
population and for the description of the product use patterns observed in the study whereas 
the less granular scheme will be used for the presentation of other study endpoints (e.g. 
safety endpoints) to better understand the impact of product. 
As the calculation of the sample size was based on the primary objective (reduction of 
Biomarkers levels in THS 2.2 Menthol relative to mCC), we assumed 50% of the subjects in 
the THS 2.2 Menthol arm would be using THS 2.2 Menthol exclusively and therefore will be 
included in the per-protocol population on Day 90.  
In order to further optimize the assessment of BoExp and increase the comparability of the 
levels of biomarkers between THS 2.2 Menthol and SA the confounding effects of the use of 
any other tobacco or nicotine containing product (other than the assigned product) need to be 
controlled for. Therefore a subject will be considered abstinent based on the following 
categorization: 
• “Abstinence”:  
100% abstinence from tobacco or nicotine containing 
product use other than the assigned product 

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• Predominantly abstinent:  
not more than 0.5 uses of any tobacco or nicotine 
containing product (other than the assigned product) per day on average and no more than 
two uses on a single day occur. 
• “Not abstinent”: 
more than 0.5 uses of any tobacco or nicotine containing 
product (other than the assigned product) per day on average or more than two uses on a 
single day occur. 
The purpose of the defined threshold was to reduce the confounding effects of the use of any 
other tobacco or nicotine containing product (other than the assigned product). The results of 
a study PMI conducted in 2011 (PIPA_CEMA_01 study) to evaluate the capacity of the 
urinary biomarker CEMA to detect smoking of small amounts of CC use (down to 2 CCs) 
per day was used to help us identify this threshold. The results of this study show that CEMA 
used as a urinary biomarker of exposure to acrylonitrile is able to discriminate between non-
smokers and smokers who have smoked only 2 CCs and 4 CCs with a maximum level of 
sensitivity and specificity at an optimal threshold of the 2.56 µg/L (CEMA Cmax in non-
smokers) for CEMA and 3.76 µg/g for CEMA concentration adjusted for creatinine. For non-
smokers CEMA and CEMA concentration adjusted for creatinine were greater than the 
LLOQ on only one occasion.  
12.4 Analysis Population 
The per-protocol (PP) population will be the primary analysis for BoExp, and risk markers. 
The FAS will be the primary analysis set for compliance to randomization arm, exposure and 
questionnaires. Exposure and questionnaires will be described by randomization arm and 
according to the product use (exclusive THS 2.2 Menthol, dual-use of THS 2.2 Menthol and 
mCC, mCC exclusive, SA) groups.  
A sensitivity analysis will be run on the compliant population for the for BoExp and risk 
markers. 
The primary population for the assessment of safety will be the safety population. Safety will 
be summarized presented by randomization arm and according to product use (exclusive 
THS 2.2 Menthol, dual-use of THS 2.2 Menthol, Menthol and mCC, mCC exclusive, SA). 
12.4.1 Full Analysis Set 
The FAS consists of all the randomized subjects who had at least one post-randomization 
product use experience, if randomized to THS 2.2 Menthol or mCC, have at least one valid 
non-safety assessment (THS 2.2 Menthol, mCC, SA arms).. 

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12.4.2 Per Protocol Population 
The PP population is a subset of FAS and includes all randomized subjects who  
• Have had compliance to their randomized arm (see Section 12.1.2 for the definition of 
non-compliance to randomized arm).  
• Have not been misrandomized, and 
• Have no major protocol deviation (to be further described in the SAP). 
12.4.3 Safety Population 
The safety population consists of all the subjects who had at least one exposure to THS 2.2 
Menthol (product test at Admission Day). Subjects in the safety population will be analyzed 
according to actual exposure. 
12.4.4 Compliant Population 
The compliant population will be a subset of the Per Protocol Population for subjects from 
the THS 2.2 Menthol arm who are exclusive THS 2.2 Menthol users or exclusive mCC users, 
as defined in Section 12.3or for subjects from the mCC arm. 
12.5 Primary Analysis 
12.5.1 Primary Endpoint Analysis Variables 
The primary endpoints are: 
• COHb on Day 5 
• MHBMA on Day 5 
• 3-HPMA on Day 5 
• S-PMA on Day 5 
• Total NNAL on Day 90. 
See Section 3.4.1. 
Evaluation criterion: 
The study will be considered successful, if the study demonstrates a 50% reduction or more 
for all five primary BoExp in the THS 2.2 Menthol arm compared to the mCC arm, using a 
one-sided test with 2.5% type I error probability. 

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12.5.2 Baseline Comparability 
Not applicable. 
12.5.3 Descriptive Analysis 
Primary endpoints will be summarized as described in Section 12.1.3 on the FAS. 
12.5.4 Confirmatory Analysis 
The hypothesis to be tested is that the geometric mean level of the BoExp for THS 2.2 
Menthol is lower relative to mCC. 
For primary BoExp, the hypothesis will be tested on Day 5 for monohydroxylbutenyl-
mercapturic 
acid 
(MHBMA), 
3-hydroxypropylmercapturic 
acid 
(3-HPMA), 
S-
phenylmercapturic acid (S-PMA), and carboxyhemoglobin (COHb), and on Day 90 Visit for 
Total NNAL.  
The transformed BoExp data on a natural log scale will be analyzed by means of a 
generalized linear model using product arm as covariate adjusting for the following baseline 
information: sex, average cigarette consumption over the previous 4 weeks, and baseline 
value of endpoint. The test will be declared significant if the contrast THS 2.2 Menthol vs 
mCC is significant. Estimates of differences between groups will be back-transformed to 
provide relative effects.  
Assumptions of the analysis of variance model will be tested. Markedly non-lognormally 
distributed BoExp data will be transformed or analyzed by appropriate non-parametric 
methods. 
12.6 Secondary Analysis 
12.6.1 Secondary Endpoint Analysis Variables 
See Section 3.4.2. 
More details on derivation rules will be given in the SAP. 
12.6.2 Baseline Comparability 
Not applicable. 

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12.6.3 Descriptive Analysis 
In general, secondary endpoints will be summarized as described in Section 12.1.3 on the 
FAS. 
12.6.4 Inferential Analysis 
For the secondary BoExp and selected risk markers, the hypothesis to be tested is the same as 
described in Section 12.5.4. This will be tested for secondary BoExp on Day 5, and if 
significant, on Day 90. 
12.6.5 Safety Analysis  
In general, all safety data will be listed and tabulated on the safety population by study arm, 
using the approach described in Section 12.1.3. Safety variables collected during exposure 
periods will also be reported by product exposure. 
Adverse event data will serve as the primary assessment of safety. Other safety variables 
monitored in this study include: respiratory symptoms (cough assessment VAS and Likert 
scales); vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate); 
electrocardiogram (ECG) data; clinical chemistry, hematology, concomitant medications, and 
urine analysis safety panel; physical examination. 
The number and percentage of subjects with AEs and SAEs will be tabulated by system 
organ class (SOC) and preferred term (PT). Summaries will also be presented for AEs 
leading to withdrawal, AEs leading to death, AEs by relatedness to product exposure, AEs by 
severity, and laboratory AEs. Tabulations will be performed for both the number of subjects 
experiencing an event and the number of events. 
The number and percentage of subjects with clinical findings by sequence for laboratory 
parameters will be summarized for the safety population. Shift tables showing change from 
baseline of clinical findings will be provided for: ECGs, physical examinations and 
laboratory parameters (both shifts in normal ranges and toxicity grades). Descriptive 
statistics will be summarized by visit and change from baseline for laboratory parameters, 
ECG, respiratory symptoms, and vital signs.  
12.7 Exploratory Analysis 
12.7.1 Exploratory Endpoint Analysis Variables 
See Section 3.4.3. 

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12.7.2 Descriptive Analysis 
In general, exploratory endpoints will be summarized as described in Section 12.1.3 on the 
FAS. 
12.8 Demographics and Baseline Characteristics 
Demographic and other baseline characteristics will be reported for FAS and safety 
population. Summary statistics will be provided by exposure group and stratified by sex and 
by cigarette consumption. Formal statistical analysis will not be performed on baseline 
demographic data. 
12.9 Interim Analysis 
There are no planned interim analyses. 
12.10 Preference Analysis 
At admission, subjects will be asked for their preferred product (THS 2.2 Menthol, mCC, 
SA, or no preference). A sensitivity analysis will be run for the exposure according to the 
subjects’ preferred product. 
 
 

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13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Investigators and Study Administrative Structure 
13.1.1 Investigator 
Principal Investigator Covance Dallas 
Site: 
 
Dr. William Lewis 
 
 
Phone:
 
Principal Investigator Covance Daytona 
Beach Site 
 
 
Dr. Frank Farmer 
  
Phone: 
 
13.1.2 Sponsor 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5. 
2000 Neuchâtel. 
Switzerland. 
Phone: + 41 (58) 242 2111 
Fax: + 41 (58) 242 2811 
, PhD 
Manager Clinical Science 
Phone: +41
 
Mobile: +41 
 
E-mail:
@pmi.com 
 MEng, 
MSc 
Staff Scientist (Expert Statistician) 
Phone: +41 
 
Mobile: +41
 
E-mail: 
@pmi.com  
 MD 
Medical Safety Officer 
 
Phone: +41 
 
Mobile: +41 
 

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E-mail: 
@pmi.com 
, PhD 
Clinical Study Manager 
Phone: +41 
 
Mobile: +41 
 
E-mail: 
@pmi.com 
13.1.3 Other Responsibilities 
All duties and responsibilities transferred to 
 by PMI will be defined in the 
agreement signed between the two parties. 
 
 
 
 
 
 
Any SAEs or pregnancies will be handled by: 
 
 
 
 
 
 
 
Details of the laboratories conducting the clinical safety laboratory services, 
biopharmaceutical analyses and the analyses of BoExp are shown in Appendix 2. 

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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 eCRFs and other 
documents by their subject (or randomization) number/code, sex, and date of birth, but not by 
name, initial, or any other details relating to identifiable person (e.g., address, social security 
number, medical chart number, etc.). The assignment of a subject number/code for subject 
identification will be based on the appropriate data protection rules.  
The blood samples for transcriptomics and the data related to these samples will be 
anonymized. Anonymized data and samples are initially single or double coded where the 
link between the subjects’ identifiers and the unique code(s) is subsequently deleted. This is 
applicable for the blood bio-banking for transcriptomics only. 
Any documents that allow full identification of the subject (e.g., the subject’s signed Study 
Information Sheet and ICF) must be maintained in confidence by the Investigator. 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 Documentation 
Subjects will be informed that, during the course of the clinical study, the Sponsor, any 
authorized representatives of the Sponsor, IRB, or regulatory authorities may inspect their 
medical records to verify the information collected, and ensure that all personal information 
made available for inspection is handled in the strictest confidence and in accordance with 
national and local data protection and privacy legislation. 
The Investigator and all study site staff involved with the study must permit direct access to 
source data/documents for study related monitoring, audits, IRB 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 

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scans, X-rays, 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 and any other applicable local 
or national regulations. For X-rays, at least the radiologist’s assessment is required as source 
documentation. If the actual image is available, it can be stored on CD as well. 
Essential study documents/records, which individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced, are described in Section 8 of the 
ICH Tripartite Guideline for Good Clinical Practice (ICH Guideline for Good Clinical 
Practice E6 (R1), July 1996). 
Essential documents must be retained by the Investigator for a minimum of: 
• At least 15 years after completion or discontinuation of the study, or 
• At least 2 years depending on, for example, the circumstances 
• After formal discontinuation of clinical development of the IP. 
These documents should be retained for a longer period, however, if required by the 
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 Information 
Sheet. 
• Subject identification code list, Screening Log, and Enrolment Log (if applicable). 
• Record of all communications between the Investigator and the IRB, composition of the 
IRB. 
• Record of all communications/contact between the Investigator, 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. 
• eCRFs, 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., chest X-rays, ECGs, consultation reports, physical 
examination, laboratory records) or any electronically captured study source data. 
• Clinical laboratory reports, laboratory normal ranges. 

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• Original medical/hospital records, if applicable (the medical files of study subjects must 
be retained in accordance with local legislation and in accordance with the maximum 
period of time permitted by the hospital or study site). 
• Record of any body fluids or tissue samples collected and retained. 
• Device Issue Log, IP Accountability Logs, dispensing records. 
• Information regarding subjects’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the Investigator/study site as to when these 
documents no longer need to be retained. 
The Investigator/study site must take measures to prevent accidental or premature destruction 
of these documents. 
If an Investigator wishes to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
The Investigator must obtain written approval from the Sponsor before destruction of any 
records. Normally, these records will be held in the Investigator’s archives. If an Investigator 
is unable to meet this obligation, they must ask the Sponsor for permission to make 
alternative arrangements. Details of these arrangements must be documented. 
The Sponsor or Sponsor’s authorized representative will maintain documentation relating to 
the study as long as the IP is on the market, and/or for 15 years after the CSR has been 
finalized. 
13.5 Clinical Study Report 
The Sponsor must ensure that a 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 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 
Investigators are required to provide financial disclosure information to the Sponsor. In 
addition, the Investigators must provide to the Sponsor a commitment to promptly update 

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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 only to 
study personnel, IRB, 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). 
 
 

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14 REFERENCE LIST 
Ashley et al., 2008 
Ashley DL, Burns D, Djordjevic M, Dybing E, Gray N, Hammond SK, et al. WHO Study 
Group on Tobacco Product Regulation. The scientific basis of tobacco product regulation. 
World Health Organ Tech Rep Ser. 2008; (951): 1-277, 1 p following 277.  
Aubin et al., 2012 
Aubin HJ, Farley A, Lycett D, Lahmek P, Aveyard P. Weight gain in smokers after quitting 
cigarettes: meta-analysis. BMJ. 2012;345:e4439. doi: 10.1136/bmj.e4439. Available at: 
http://www.ncbi.nlm.nih.gov/pubmed/22782848. 
ATS/ERS, 2005a 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, 
van der Grinten CPM, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, 
Navajas D, Pedersen OF, Pellegrino R, Viegi G, and Wanger J. Standardisation of 
spirometry. Eur Respir J. 2005; 26: 319–338. 
ATS/ERS, 2005b 
MacIntyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CPM, Brusasco V, Burgos 
F, Casaburi R, Coates A, Enrigh P, Gustafsson P, Hankinson J, Jensen R, McKay R, Miller 
MR, Navajas D, Pedersen OF, Pellegrino R, and Wanger J. Standardisation of the single-
breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005; 26: 720–
735. 
ATS/ERS, 2005c 
Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, Casaburi R, Crapo R, 
Enright P,  van der Grinten CPM, Gustafsson P, Hankinson J, Jensen R, Johnson D, 
MacIntyre D, McKay R, Miller MR, Navajas D, Pellegrino R and Viegi G. Standardisation 
of Standardisation of the measurement of 
lung volumes. Eur Respir J. 2005; 26: 511–522. 

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Benowitz et al., 1993 
Benowitz NL, Fitzgerald GA, Wilson M, Zhang Q. Nicotine effects on eicosanoid formation 
and hemostatic function: comparison of transdermal nicotine and cigarette smoking. J Am 
Coll. Cardiol. 1993; 22 (4): 1159-67. 
Benowitz et al., 2002 
SNRT subcommittee on biochemical verification. Biochemical verification of tobacco use 
and cessation. Nicotine Tob Res. 2002; 4 (2): 149-159. 
Boyle et al., 2010. 
Boyle JO, Gümüs ZH, Kacker A, Choksi VL, Bocker JM, Zhou XK, Yantiss RK, Hughes 
DB, Du B, Judson BL, Subbaramaiah K, Dannenberg AJ. Effects of cigarette smoke on the 
human oral mucosal transcriptome. Cancer Prev Res (Phila). 2010;3(3):266-78. 
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Switzerland 
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Appendix 1 
Schedule of Events 
Table A1   
Study Assessments (separate table [Table A2] shown for 24 hour urine collections) 
 
Screenin
g 
Confinement Period 
Ambulatory Period 
Safety Follow-up z 
 
 
 
 
 
 
 
 
 
 
 
Day 30 
Visit ± 5 
days 
Day 60 
Visit ± 5 
days 
Day 90 
Visit ± 5 
days 
 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 y 
30  
31 
60  
61 
90  
91 
91 to 119 
Informed consent for study 
participation and two 
informed consents for bio-
banking 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission/Discharge 
 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
Information on the risk of 
smoking/smoking cessation 
advice and debriefing 
● 
● 
 
 
 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
Monitoring/Intensive 
support for SA arm 
 
 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Inclusion/exclusion criteria 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical 
history  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Screenin
g 
Confinement Period 
Ambulatory Period 
Safety Follow-up z 
 
 
 
 
 
 
 
 
 
 
 
Day 30 
Visit ± 5 
days 
Day 60 
Visit ± 5 
days 
Day 90 
Visit ± 5 
days 
 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 y 
30  
31 
60  
61 
90  
91 
91 to 119 
Concomitant diseases 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-economic 
questionnaire 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
 
 
 
Vital signs a 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
● 
 
 
● 
 
Physical examination  
● 
● 
 
 
 
 
 
 
 
● 
● 
 
● 
 
 
● 
 
Body height and weight b 
● 
● 
 
 
 
 
 
 
 
● 
● 
 
● 
 
 
● 
 
Waist circumference c 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
Spirometry d 
● 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
Prior/concomitant 
medication 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
B/U: Hematology, clinical 
chemistry, urine analysis e 
● 
 
 
● 
 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
Electrocardiogram 
● 
 
 
 
 
 
 
 
 
● 
● 
 
● 
 
 
● 
 
Chest X-ray f 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B: HIV, hepatitis B and C 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine cotinine Screening 
test 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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publicly disclosed without the written consent of Philip Morris International. 
 
 
 
Screenin
g 
Confinement Period 
Ambulatory Period 
Safety Follow-up z 
 
 
 
 
 
 
 
 
 
 
 
Day 30 
Visit ± 5 
days 
Day 60 
Visit ± 5 
days 
Day 90 
Visit ± 5 
days 
 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 y 
30  
31 
60  
61 
90  
91 
91 to 119 
U: Urine drug screen 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U: Pregnancy test 
● 
● 
 
 
 
 
 
 
 
● 
● 
 
● 
 
 
● 
 
Alcohol urine or breath test 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FTND 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
Smoking history 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intention to quit smoking in 
the next 6 months 
(prochaska ‘Stage of 
Change’ questionnaire) 
● 
● 
 
 
 
 
 
 
 
 
● 
 
● 
 
● 
 
 
Readiness to comply with 
study protocol: to abstain 
from smoking for up to 91 
days 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Identification of mCC 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THS 2.2 Menthol 
demonstration 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THS 2.2 Menthol product 
test and readiness to use the 
product g 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Screenin
g 
Confinement Period 
Ambulatory Period 
Safety Follow-up z 
 
 
 
 
 
 
 
 
 
 
 
Day 30 
Visit ± 5 
days 
Day 60 
Visit ± 5 
days 
Day 90 
Visit ± 5 
days 
 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 y 
30  
31 
60  
61 
90  
91 
91 to 119 
Question on product 
Preference 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of mCC butts for 
accountability 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
 
 
 
 
 
Collection tobacco plugs of 
used Menthol Tobacco 
Sticks for further analysis  
 
 
 
 
● 
● 
● 
● 
● 
 
● 
 
● 
 
● 
 
 
Collection of 
empty/partially used 
Menthol Tobacco Stick 
packs for accountability 
 
 
 
 
 
 
 
 
 
 
● 
 
● 
 
● 
 
 
CO breath test h 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
● 
 
● 
 
 
B: BoExp in blood: COHb i 
 
 
● 
● 
● 
● 
● 
● 
●  
● 
● 
 
● 
 
● 
● 
 
B: BoExp to nicotine in 
plasma: nicotine, cotinine j 
 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
 
● 
 
● 
 
 
U: Ames Mutagenicity (see 
Table A2) 
 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
● 
 
 
U:all urinary BoExp  in 24-
hour urine (primary and 
secondary, and BoExp to 
 
 
 
● 
● 
● 
● 
● 
● 
 
● 
 
● 
 
● 
 
 

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Screenin
g 
Confinement Period 
Ambulatory Period 
Safety Follow-up z 
 
 
 
 
 
 
 
 
 
 
 
Day 30 
Visit ± 5 
days 
Day 60 
Visit ± 5 
days 
Day 90 
Visit ± 5 
days 
 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 y 
30  
31 
60  
61 
90  
91 
91 to 119 
nicotine) (see Table A2) 
U:all urinary BoExp  in 4-
hour fraction (primary and 
secondary, and BoExp to 
nicotine) (see Table A3) 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
B:Risk markers: hs-CRP, 
fibrinogen, homocysteine, 
LDL, HDL k 
 
 
 
● 
 
 
 
 
 
 
 
● 
 
● 
 
● 
 
B: Risk Marker: sICAM-1 l 
 
 
 
● 
 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
B: Risk Marker: HbA1c, 
Apo A1, and Apo B m 
 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
 
U: Risk markers in 24-hour 
urine: 8-epi-PGF2α and 11-
DTX-B2 (see Table A2) n 
 
 
 
● 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
 
U: Risk markers in 4-hour 
fraction: 8-epi-PGF2α and 
11-DTX-B2 (see Table A3)  
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
One caffeine tablet (200 mg 
caffeine) 
 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
● 
 
 
B: CYP1A2 activity 
 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
● 
 
 

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publicly disclosed without the written consent of Philip Morris International. 
 
 
 
Screenin
g 
Confinement Period 
Ambulatory Period 
Safety Follow-up z 
 
 
 
 
 
 
 
 
 
 
 
Day 30 
Visit ± 5 
days 
Day 60 
Visit ± 5 
days 
Day 90 
Visit ± 5 
days 
 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 y 
30  
31 
60  
61 
90  
91 
91 to 119 
B: CYP2A6 activity 
 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
B: Oxysterols 
 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
Product use diary o 
 
 
 
 
 
 
 
 
 
● 
● 
● 
● 
● 
● 
● 
 
QSU-brief questionnaire p 
 
 
● 
● 
● 
● 
● 
● 
● 
 
● 
 
● 
 
● 
 
 
MNWS (revised version) q 
 
 
 
● 
● 
● 
● 
● 
● 
● 
 
● 
 
● 
 
● 
 
MCEQ (modified version; 
THS 2.2 Menthol and mCC 
arms) r 
 
 
● 
● 
● 
● 
● 
● 
● 
 
● 
 
● 
 
● 
 
 
HST (THS 2.2 Menthol and 
mCC arms) s 
 
 
 
● 
● 
 
 
● 
 
 
● 
 
● 
 
● 
 
 
HST questionnaire  
 
 
 
● 
 
 
 
● 
 
 
● 
 
● 
 
● 
 
 
Assessment of cough t 
 
 
 
● 
● 
● 
● 
● 
● 
● 
 
● 
 
● 
 
● 
 
Risk Factor Surveillance 
System Questionnaire 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
 
 
 
Smoking Questionnaire 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
 
 
 
Supplemental questions u 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
 
 
 
AE/SAE recording 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
●  

Philip Morris Products S.A. 
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2000 Neuchâtel 
Switzerland 
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Confidential 
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provided to such trade secrets and confidential information are hereby claimed under the provisions of United States law. No part of this document may be 
publicly disclosed without the written consent of Philip Morris International. 
 
 
 
Screenin
g 
Confinement Period 
Ambulatory Period 
Safety Follow-up z 
 
 
 
 
 
 
 
 
 
 
 
Day 30 
Visit ± 5 
days 
Day 60 
Visit ± 5 
days 
Day 90 
Visit ± 5 
days 
 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 y 
30  
31 
60  
61 
90  
91 
91 to 119 
B: Bio-banking for BoExp 
and risk markers vw 
 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
U: Bio.banking for BoExp 
and risk markers v 
 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
● 
 
 
B: Bio-banking for 
transcriptomics vw 
 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
Nasal Epithelial collection x 
 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
● 
 
 
Buccal Collection x 
 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
● 
 
 

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Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse event; Apo: Apolipoprotein;  B = blood sample required; BMI 
= body mass index; BoExp = biomarkers of exposure; mCC = menthol conventional cigarette(s); CO = carbon monoxide; COHb = carboxyhemoglobin; CYP = cytochrome P450 
enzyme; FTND = Fagerström Test for Nicotine Dependence; HbA1c = hemoglobin A1c; HDL = high density lipoprotein; HST = human smoking topography; HIV = human 
immunodeficiency virus; hs-CRP = high-sensitive C-reactive protein; HST = human smoking topography; LDL = low density lipoprotein; MCEQ = Modified Cigarette Evaluation 
Questionnaire; MNWS = Minnesota Nicotine Withdrawal Scale; QSU = Questionnaire of Smoking Urges; SA = smoking abstinence; SAE = serious adverse event; sICAM-1 = 
soluble inter-cellular adhesion molecule; THS = tobacco heating system; U = urine sample required; WBC = white blood cell count; TC: total cholesterol, TG: triglycerides.  
a: Systolic and diastolic blood pressure, pulse rate, and respiratory rate (systolic and diastolic blood pressure will also be analyzed as risk markers on Day 0, Day 6, Day 30 Visit 
(Day 30), Day 60 Visit (Day 60), and Day 90 Visit (Day 91)). 
b: Including height (only at Screening). Weight will be evaluated also as risk marker on Day -2 Visit on D 90 Visit (Day 91). 
c: Waist circumference will be evaluated also as risk markers on Day -2 and Day 90 Visit (Day 91). 
d: Spirometry without bronchodilator will be performed at screening only and must be done prior to spirometry with bronchodilator. 
Spirometry with bronchodilator will be done at Screening, Day 0, Day 6, and Day 90 Visit (Day 91). At screening, spirometry with bronchodilator will be done at least 1 hour after 
smoking. On Day 0, Day 6, and Day 90 Visit, spirometry with bronchodilator will be performed prior to product use (mCC or THS 2.2 Menthol). 
Spiromety using helium technique and spirometry using the single breath technique for CO will be performed Day 0, Day 6, and Day 90 Visit (Day 91) prior to product use.  
e: WBC count, platelet count, from the safety laboratory panel to be evaluated also as risk markers on Day 0, Day 6, Day 30 Visit (Day 31), Day 60 Visit (Day 61) and Day 90 
Visit (Day 91). Blood glucose, TG, and TC from the safety laboratory panel to be evaluated as risk markers on Day 0, Day 30 Visit (Day 31), Day 60 Visit (Day 61), and Day 90 
Visit (Day 91). 
f: Pre-study chest X-ray (with anterior-posterior and left lateral views) may be used, if performed within 6 months prior to Screening. 
g: THS 2.2 Menthol product test to be conducted as the last procedure of eligibility check at Day -2 (and after urine pregnancy test has been confirmed negative in female subjects 
to exclude pregnancy). 
h: CO breath test; Days -1 to Day 5: the test will be conducted four times per day. On Day -1, the first test should be conducted within 15 minutes prior to the first product use. on 
Day 5, the first test should be conducted within 15 minutes prior to the first product use (for subjects in the THS Menthol 2.2 and mCC arms) and at between 08:00 AM and 09:30 
AM for subjects in the SA arm. The other three tests should be conducted as described in Section 9. Day -2, Day 6, Day 30 Visit (Day 30), Day 60 Visit (Day 60) and Day 90 Visit 
(Day 90): once during the visit, irrespective of the time of product use. 
i: COHb; Assessments should be done in conjunction with CO breath tests, where applicable. 
Day -1 and from Day 1 to Day 4: one blood sample in the evening around 08:00 PM. 
On Day 0, two blood samples will be collected: one blood sample will be collected prior to gas transfer assessment and prior to product use (the COHb levels measured will serve 
for adjustment of gas transfer values only), the second blood sample will be collected in the evening between 08:00 PM and 09:30 PM.  

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Day 5: one blood sample within 15 minutes prior to first product use (for subjects in THS 2.2 Menthol and mCC arms) and between 08:00 AM and 09:30 AM for subjects in the 
SA arm. The three other blood samplings will be conducted as described in Section 9.  
On Day 6: one blood sample will be collected prior to the gas transfer assessment and prior to product use (the COHb levels measured will serve for adjustment of gas transfer 
values only). 
Day 30 Visit (Day 30), Day 60 Visit (Day 60): one blood sample to be collected during the visit, irrespective of the time of product use.  
On Day 90 Visit: one blood sample will be collected on Day 90, irrespective of the time of product use. One blood sampling will be collected on Day 91 prior to gas transfer 
assessment, and product use (the COHb levels measured will serve for adjustment of gas transfer values only). 
j: Nicotine/cotinine; Day 0 to Day 4 (all study arms): one blood sample between 08:00 PM and 09:30 PM. 
Day 5 and Day 6 (THS 2.2 Menthol and mCC arms): one sample within 15 minutes prior to the first product use; eight blood samples after the start of product use (T0), each at 2 
hour intervals. On Day 6, two blood samples will be drawn. The first sample will be 20 hours after T0 and the second blood sample will be 24 hours after T0 (with T0 being the 
time of the first product use on Day 5). 
Day 5 and Day 6 (SA arm): one blood sample in the evening between 08:00 PM and 09:30 PM on Day 5 and one blood sampling between 08:00 AM and 09:30 AM on Day 6. 
Day 30 Visit (Day 30), Day 60 Visit (Day 60), Day 90 Visit (Day 90) (all study arms): one blood sample to be drawn during the visit, irrespective of the time of product use. 
k:To be evaluated also as risk markers on Day 0, Day 30 Visit (Day 31), Day 60 Visit (Day 61), and Day 90 Visit ( Day 91). 
l: . To be evaluated also as risk markers on Day 0, Day 6, Day 30 Visit (Day 31), Day 60 Visit (Day 61), and Day 90 Visit (Day 91). 
m: To be evaluated also as risk markers on Day 0, and Day 90 Visit (Day 91). 
n: To be evaluated also as risk markers on Day 0, Day 5, Day 30 Visit, Day 60 Visit, and Day 90 Visit. 
o: Daily during ambulatory period only (from time of Discharge on Day 6 to time of discharge of Day 91). Use of any tobacco/nicotine containing products will be captured in the 
e-diary. 
o: QSU-brief: Daily, from Day -1 to Day 5 and at every visit during the ambulatory period, i.e. Day 30 Visit (Day 30), Day 60 Visit (Day 60) and Day 90 Visit (Day 90) . 
q: MNWS daily from Day 0 to Day 6 prior product use, but no later than 10:00 AM and at every visit during the ambulatory period, i.e. Day 30 Visit (Day 31), Day 60 Visit (Day 
61) and Day 90 Visit (Day 91) no later than 10:00 AM irrespective of the time of product use. 

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. 
r: MCEQ: Day -1 to Day 5 on a daily basis, and on Day 30 Visit (Day 30), Day 60 Visit (Day 60) and Day 90 Visit (Day 90) in Day -1 and Day 0 on all subjects, from Day 1 in 
THS 2.2 Menthol and mCC arms. 
s: On Day 0, HST assessment will be done in all subjects smoking mCC compatible with the HST SODIM® device. On Day 1, Day 4, Day 30 Visit (Day 30) , and Day 60 Visit 
(Day 60) and Day 90 Visit (Day 90), HST will be done in all subjects in the THS 2.2 Menthol and mCC arms. On Day 1 and Day 4, full day HST recording will be done. On Day 
30 Visit (Day 30), Day 60 Visit (Day 60), and Day 90 Visit (Day 90), 4 hours of recording will be done. Smoking topography with the HST SODIM® device will not be done in 
subjects smoking mCC that are incompatible with the HST SODIM® device (e.g. slim mCC). No HST assessments will be done in subjects in the SA arm. 
t: Cough questionnaire to be done daily from Day 0 to Day 6 prior product use but no later than 10: 00 AM and on Day 30 Visit (Day 31) Day 60 Visit (Day 61) and Day 90 visit 
(Day 91) no later than 10:00 AM, irrespective of product use. 
u: Subjects will be assessed for their current and past smoking behavior at baseline on Day -1 and on Day 5 by the means of 2 questionnaires. The questionnaires will be asked 
with the following sequence: 
        1-a standard questionnaire (Behavioral Risk Factor Surveillance System Questionnaire 2011) (CDC, 2011a) which is validated 
        2 a Smoking Questionnaire (SQ) to be validated. Immediately after the administration of the SQ, some supplemental questions will be collected on the completion of the SQ 
questionnaire. This supplemental question 1 is related to the time which the subject spends to complete the SQ and should be completed by site. 
The Behavioral risk factor surveillance and the SQ are self-administrated to be answered by subjects. The supplemental questions will be asked by the site. 
v: Samples will only be taken if additional consent for bio-banking is given by the subject. 
w: Has to be done in at least 10 hours of fasting condition. 
x:Subject must not have eaten 30 minutes prior to the start of procedures. 
y: All examinations listed at the Day of Discharge (Day 6) will be conducted in subjects whose participation in the study is prematurely terminated and for all subjects who have 
tried the product on admission 
z: Spontaneous reporting of new AEs/SAEs by the subject and active follow-up of ongoing AEs/SAEs by the site. 

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publicly disclosed without the written consent of Philip Morris International. 
 
 
Table A2   
Schedule for 24-hour Urine Collection Assessments 
 
Baseline 
Period 24-
hour 
urine 
Confinement Exposure Period 
24-hour urine 
Ambulatory Exposure Period 
24-hour-urine 
 
Day 0 to  
Day 1 
Day 1 to  
Day 2 
Day 2 to  
Day 3 
Day 3 to  
Day 4 
Day 4 to  
Day 5 
Day 5 to  
Day 6 
Day 30 
to Day 31 
Day 60 
to Day 61 
Day 90 to 
Day 91 
BoExp in urine a 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Creatinine 
● 
● 
● 
● 
● 
● 
● 
● 
● 
11-DTX-B2, 8-epi-
PGF2 
● 
 
 
 
 
● 
● 
● 
● 
Ames test 
● 
 
 
 
 
● 
 
 
● 
Bio-banking b 
● 
 
 
 
 
● 
 
 
● 
a: MHBMA, 3-HPMA, S-PMA, Total NNAL, 1-OHP, total NNN, 4-ABP, 1-NA, 2-NA, o-tol, CEMA, HEMA, 3-hydroxybenzo(a)pyrene, HMPMA, S-BMA, NEQ. 
b: Samples will only be taken if additional consent for the relevant sample bio-banking is given by the subject 
Abbreviations: 1-NA = 1-aminonaphthalene; 2-NA = 2-aminonaphthalene; 1-OHP = 1-hydroxypyrene; 3-HPMA = 3-hydroxypropylmercapturic acid; 4-ABP = 4-aminobiphenyl; 
8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; BoExp = biomarker(s) of exposure; CEMA = 2-cyanoethylmercapturic acid; HEMA = 2-
hydroxyethyl mercapturic acid; HMPMA = 3-hydroxy-1-methylpropyl-mercapturic acid; NEQ = nicotine equivalents; Total NNAL = 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanol; total NNN = N-nitrosonornicotine; MHBMA = monohydroxybutenyl mercapturic acid; S-BMA = S-benzylmercapturic acid; S-PMA = S-phenylmercapturic acid. 
 
 

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Table A3   
Schedule for 4-hour Urine Collection Assessments 
 
Baseline Period 
4-hour urine fraction 
Ambulatory Period 
4-hour urine fraction 
 
Day -1  
Day 90 Visit (Day 91)  
BoExp in urine a 
● 
● 
Creatinine 
● 
● 
11-DTX-B2 and 
8-epi-PGF2  
● 
● 
a: MHBMA, 3-HPMA, S-PMA, Total NNAL, 1-OHP, total NNN, 4-ABP, 1-NA, 2-NA, o-tol, CEMA, HEMA, 3-hydroxybenzo(a)pyrene, HMPMA, S-BMA, NEQ. 
Abbreviations: 1-NA = 1-aminonaphthalene; 2-NA = 2-aminonaphthalene; 1-OHP = 1-hydroxypyrene; 3-HPMA = 3-hydroxypropylmercapturic acid; 4-ABP = 4-aminobiphenyl; 
8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; BoExp = biomarker(s) of exposure; CEMA = 2-cyanoethylmercapturic acid; HEMA = 2-
hydroxyethyl mercapturic acid; HMPMA = 3-hydroxy-1-methylpropyl-mercapturic acid; NEQ = nicotine equivalents; Total NNAL = 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanol; total NNN = N-nitrosonornicotine; MHBMA = monohydroxybutenyl mercapturic acid; S-BMA = S-benzylmercapturic acid; S-PMA = S-phenylmercapturic acid.

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Switzerland 
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information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under 
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Philip Morris International. 
 
 
Appendix 2 
Participating Laboratories 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
More details will be found in the study laboratory manuals.  
For bio-banking of samples: 
 
 
 
 
 
R&D PMI Laboratory 
Quai Jeanrenaud, 5 
2000, Neuchâtel 
Switzerland 

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Philip Morris International. 
 
 
Appendix 3 
Investigational Product and Instructions for Use 
The product user guide will be provided as a separate document. 

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Appendix 5 
Prochaska ‘Stage of Change’ Questionnaire 
The Prochaska questionnaire is structured as follows: 
CURRENTLY SMOKING
Yes
No
quit in last 6 months
(Action)
quit more than 6 months
(Maintenance)
Seriously considering quitting 
next 6 months
Yes
No
(Precontemplation)
Planning to quit next 30 days
Yes
No
(Contemplation)
24 hour quit attempt past year
Yes
(Preparation)
No
(Contemplation)
 
 
 

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The questionnaire to be asked, is as follows, with the scoring sheet not to be read aloud: 
Smoking algorithm for the Classification of the stages of change for smoking cessation 
Assessment 
1. Are you currently a smoker? 
A) Yes, I currently smoke 
B) No, I quit within the last 6 months 
C) No, I quit more than 6 months ago 
D) No, I have never smoked 
Smokers only 
2. In the last year, how many times have you quit smoking for at least 24 hours? ___ 
 
3. Are you seriously thinking of quitting smoking? 
A) Yes, within the next 30 days 
B) Yes, within the next 6 months 
C) No, not thinking of quitting 
 
 
 

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Scoring Sheet (do not read to subject): 
1. Are you currently a smoker? 
A) Yes, I currently smoke 
B) No, I quit within the last 6 months (ACTION STAGE) 
C) No, I quit more than 6 months ago (MAINTENANCE STAGE) 
D) No, I have never smoked (NONSMOKER) 
 
Smokers only 
2. In the last year, how many times have you quit smoking for at least 24 hours? --- 
3. Are you seriously thinking of quitting smoking? 
A) Yes, within the next 30 days (PREPARATION STAGE if they have one 24-hour quit 
attempt in the past year, if there was no quit attempt in the past year, then 
CONTEMPLATION STAGE) 
B) Yes, within the next 6 months (CONTEMPLATION) 
C) No, not thinking of quitting (PRECONTEMPLATION) 

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Appendix 6 
Abnormal Laboratory Values 
ABNORMAL 
LABORATORY 
VALUES 
RATING: 
SERUM 
CHEMISTRY 
PARAMETERS 
Serum Chemistry* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Sodium – Hyponatremia (mmol/L) ** (1) 
<LLN - 130 
- 
<130 - 120 
Sodium – Hypernatremia (mmol/L) ** (1) 
>ULN - 150 
>150 - 155 
>155 - 160; 
hospitalization 
indicated 
Potassium – Hyperkalemia (mmol/L)**(1) 
>ULN - 5.5 
>5.5 - 6.0 
>6.0 -7.0; 
hospitalization 
indicated 
Potassium – Hypokalemia (mmol/L) ** (1) 
<LLN - 3.0 
<LLN - 3.0; 
symptomatic; 
intervention 
indicated 
<3.0 - 2.5; 
hospitalization 
indicated 
Glucose – Hypoglycemia ** (1)    (mg/dL) 
                                                   (mmol/L)  
<LLN – 55; 
<LLN – 3.0 
<55 – 40; 
<3.0 – 2.2 
<40 – 30; 
<2.2 – 1.7 
Glucose – Hyperglycemia: ** (1) 
 
 
 
 
 
     Fasting (mg/dL) 
(mmol/L) 
 
 
 
 
    Non-fasting (mg/dL) 
(mmol/L) 
 
 
>ULN-160; 
>ULN-8.9 
- 
- 
 
 
>160-250; 
>8.9-13.9 
- 
- 
 
 
- 
- 
>250-500; 
>13.9-27.8; 
hospitalization 
indicated 
Blood Urea Nitrogen (BUN) (mg/dL) (2) 
23 – 26 
27 – 31 
> 31 
Creatinine increased** (1) 
>1 – 1.5 x baseline; 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x 
baseline; 
>1.5 – 3.0 x ULN 
>3.0 x baseline; 
>3.0 – 6.0 x ULN 
Albumin – Hypoalbuminemia** (1) (g/dL) 
                                                          (g/L) 
<LLN – 3; 
<LLN - 30 
<3 – 2; 
<30 - 20 
<2; 
<20 
Total Protein – Hypoproteinemia (2) 
(g/dL) 
 
5.5 – 6.0 
 
5.0 – 5.4 
 
< 5.0 
Alkaline phosphatase increased** (1) 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
ALT / AST increased** (1) 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
Gamma-glutamyl transferase (GGT) 
increased (1) 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
Blood bilirubin increased ** (1) 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 ULN 
Cholesterol high** (1)                   
 
 
 
 
 
 
 
 
 
 
 
 
(mg/dL) 
 
>ULN - 300; 
>ULN - 7.75 
 
>300-400; 
>7.75-10.34 
 
>400-500; 
>10.34-12.92 

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(mmol/L) 
Triglycerides - Hypertriglyceridemia (1) 
(mg/dL) 
(mmol/L) 
 
150 – 300; 
1.71 – 3.42 
 
>300 – 500; 
>3.42 – 5.70 
 
>500 – 1000; 
>5.70 – 11.40 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; GGT = 
gamma-glutamyl transferase; LLN = lower limit of the normal range; ULN = upper limit of the normal range. 
Data Sources: 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, 
FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
(2) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
U.S. Department of Health and Human Services, FDA, Center for Biologics Evaluation and Research - Guidance for 
Industry. 
 
* Those parameters that are not listed do not have grading categories in either the CTCAE or the FDA guidance documents 
and will therefore be reviewed by the Investigator and only reported as an AE if considered to be clinically relevant. 
** Where parameters in this table are listed in both the CTCAE and the FDA guidance documents, and each document has 
different values within each grading category, the grading in CTCAE guidance document predominates. 

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ABNORMAL LABORATORY VALUES RATING: HEMATOLOGY PARAMETERS 
Hematology* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Hemoglobin (Female) – (g/dL) (1) 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
change from baseline value – (g/dL) (1) 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
Hemoglobin (Male) – (g/dL) (1) 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
change from baseline value – (g/dL) (1) 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
Hemoglobin increase – (g/dL) (2) 
Increase in >0 – 2 
above ULN or above 
baseline if baseline is 
above ULN 
Increase in >2 – 4 
above ULN or above 
baseline if baseline is 
above ULN 
Increase in >4 above 
ULN or above baseline 
if baseline is above 
ULN 
WBC Increase  – (cell/mm3) (1) 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25,000 
WBC Decrease - (cell/mm3) (2)** 
<LLN – 3000; 
<LLN – 3.0 x 10-9/l 
<3000 - 2000; 
<3.0 – 2.0 x 10-9/l 
<2000 - 1000; 
<2.0 – 1.0 x 10-9/l 
Lymphocytes Increase - (cell/mm3) (2) 
- 
>4,000 – 20,000 
>20,000 
Lymphocytes Decrease  - (cell/mm3) (2)** 
<LLN – 800; 
<LLN – 0.8 x 10-9/l 
<800 - 500; 
<0.8 – 0.5 x 10-9/l 
<500 - 200; 
<0.5 – 0.2 x 10-9/l 
Neutrophils Decrease  - (cell/mm3) (2)** 
<LLN – 1500; 
<LLN – 1.5 x 10-9/l 
<1500 - 1000; 
<1.5 – 1.0 x 10-9/l 
<1000 - 500; 
<1.0 – 0.5 x 10-9/l 
Eosinophils - (cell/mm3) (1) 
650 – 1500 
1501 - 5000 
>5000 
Platelets Decrease - (cell/mm3) (2)** 
<LLN – 75,000; 
<LLN – 75.0 x 10-9/l 
<75,000 – 50,000; 
<75.0 – 50.0 x 10-9/l 
<50,000 – 25,000; 
<50.0 – 25.0 x 10-9/l 
Abbreviations: LLN = lower limit of the normal range; ULN = upper limit of the normal range; WBC = white blood cell. 
Data Source: 
(1) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
U.S. Department of Health and Human Services, FDA, Center for Biologics Evaluation and Research - Guidance for 
Industry. 
(2) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
* Those parameters that are not listed do not have grading categories in either the CTCAE or the FDA guidance documents 
and will therefore be reviewed by the Investigator and only reported as an AE if considered to be clinically relevant. 
** Where parameters in this table are listed in both the CTCAE and the FDA guidance documents, and each document has 
different values within each grading category, the grading in CTCAE guidance document predominates. 

Philip Morris Products S.A. 
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2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
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Philip Morris International. 
 
 
ABNORMAL LABORATORY VALUES RATING: URINALYSIS PARAMETERS 
Urine* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Protein** (1) 
1+ proteinuria; urinary 
protein <1.0 g/24 hours 
2+ proteinuria; urinary 
protein 1.0-3.4 g/24 
hours 
Urinary protein ≥3.5 g/24 
hours 
Glucose (2) 
Trace 
1+ 
2+ 
Blood – Hematuria ** (1) 
Asymptomatic; clinical or 
diagnostic observations 
only; intervention not 
indicated 
Symptomatic; urinary 
catheter or bladder 
irrigation indicated; 
limiting instrumental 
ADL 
Gross hematuria; 
transfusion, IV 
medications or 
hospitalization indicated; 
elective endoscopic, 
radiologic or operative 
intervention indicated; 
limiting self-care ADL 
Abbreviations: ADL = activities of daily living; IV = intravenous. 
Data Source: 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
(2) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
U.S. Department of Health and Human Services, FDA, Center for Biologics Evaluation and Research - Guidance for 
Industry. 
* Those parameters that are not listed do not have grading categories in either the CTCAE or the FDA guidance documents 
and will therefore be reviewed by the Investigator and only reported as an AE if considered to be clinically relevant. 
** Where parameters in this table are listed in both the CTCAE and the FDA guidance documents, and each document has 
different values within each grading category, the grading in CTCAE guidance document predominates. 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
Page 194 of 197 
 
 
Data and information contained in this document are considered to constitute trade secrets and confidential commercial 
information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under 
the provisions of United States law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris International. 
 
 
Appendix 7 
Procedure for Nasal Epithelial Collection 
Materials to prepare ahead before sample collection: 
• 2 Cyto-Pak soft brushes (Item #CP-5B, Medical Packaging Corporation) 
• 2 of 2-mL round bottom microfuge tube with cap, sterile (Fisher Scientific Catalog # 02-
681-375), containing: 1mL RNAprotect Cell Reagent (Qiagen Catalog #76526). These 
tubes are labeled “a” and “b” for first and second sampling, respectively  
• Nasal speculum (Bionix # 9877, Bionix Medical Technologies, Toledo, OH) 
• 1% Lidocaine Solution may be administered at participant request using a syringe with 
removable needle, which would be removed prior to use. 
• RNaseZap (Ambion Catalog # AM9780; or AM9782) to decontaminate equipment and 
working area before handling the biological material. 
• Tube rack 
• Tube labels 
• Wire cutter 
• 70% isopropyl alcohol wipes (Fisher Scientific Catalog # 19-015-744) 
• Liquid nitrogen or a quick access to -80oC storage 
 
Protocol for the preparation of the nasal collection: 
1. Ask subject to blow his/her nose 
2. Place the two of 2-mL round bottom microfuge tubes filled with 1 mL RNAprotect 
Cell Reagent in the tube. 
3. Treat the wire cutter with few sprays of RNaseZap, wipe the cutter with paper towels, 
then wipe the cutter with 2 isopropyl alcohol wipes  
4. If the subject wishes to have the nostril numbed for the procedure, use a 1% 
Lidocaine Solution. 
   A. Draw 1 mL of Lidocaine into a syringe with a removable needle. Remove the 
needle once completed. 
   B. Have the participant hold a paper towel under his/her nose. 
   C. Have the participant verbally and rapidly repeat the letter "K" over and over 
again. Explain that this helps prevent the Lidocaine from getting into the throat, 
which can feel/taste unpleasant. 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
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Data and information contained in this document are considered to constitute trade secrets and confidential commercial 
information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under 
the provisions of United States law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris International. 
 
 
   D. While the participant is saying the letter "K", quickly administer the Lidocaine 
into the nostril against the outside of the nose, which is opposite the septum. 
 
Protocol of the nasal collection: 
1. Use the nasal speculum to widen the left nostril then locate the inferior turbinate (a 
pen light may help to visualize the area 
1.1. While the speculum still widening the nostril, insert the Cyto-Pak soft brush into 
the nostril just past the inferior turbinate and press against the outside of the 
nostril (opposite from the septum) while being rotated. This step should take 
approximately 3 seconds 
1.2. Remove the Cyto-Pak soft brush from the nostril and immediately place the 
brush head in the 2-mL round bottom microfuge tube filled with 1 mL 
RNAprotect Cell Reagent (tube “a” for the first collection) 
1.3. Cut off the shaft of the brush with the cleaned wire cutter 
1.4. Repeat steps 1.1.-1.3. with the second Cyto-Pak soft brush (in the same nostril) 
for the second collection that will be collected in tube “b” 
2. Vortex sample to ensure that all collected cells come into contact with the 
RNAprotect Cell Reagent 
3. Store samples at -80oC 
 
Note: All samples should not undergo any freeze-thaw cycle prior to shipping. 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
Page 196 of 197 
 
 
Data and information contained in this document are considered to constitute trade secrets and confidential commercial 
information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under 
the provisions of United States law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris International. 
 
 
Appendix 8 
Procedure for Buccal Collection 
Material required: 
• Cytobrush Plush®GT Sterile (Cooper Surgical # C0112 )  
• 2 of 2-mL round bottom microfuge tube with cap, sterile (Fisher Scientific Catalog # 02-
681-375), containing 1 mL RNALater (Qiagen Catalog # 76104). These tubes are labeled 
“a” and “b” for left and right cheek, respectively  
• Tube rack  
• Tube labels 
• RNaseZap (Ambion Catalog # AM9780; or AM9782) to decontaminate equipment and 
working area before handling the biological material. 
• 2 pair of scissors (autoclaved to sterilize then subsequently wiped with RNaseZap, see 
detailed protocol below as water vapor in most autoclaves contains RNases) 
• 70% isopropyl alcohol wipes 
• Liquid nitrogen or a quick access to -80oC storage 
 
Protocol for the preparation of the buccal collection: 
1. Ask subject to rinse their mouths with a minimum of 20 mL of water before the 
sample collection 
2. Treat the scissors with few sprays of RNaseZap®, wipe the cutter with paper towels, 
then wipe the cutter with 2 isopropyl alcohol wipes  
3. Place the two of 2-mL round bottom microfuge tubes (“a” and “b” filled with 
RNALater® reagent) in the tube rack. 
 
Protocol of the buccal collection (two samples will be collected from each subject, one from 
each side of the inner cheek): 
1. Collect buccal sample using sterile Cytobrush Plush®GT Sterile by insert the brush 
into the mouth 
2. Applied sufficient lateral pressure to make contact with the buccal mucosa and bend 
the plastic shaft of the brush slightly (left cheek first, then right cheek) 
3. Spin the brush in place, for 10 seconds in a single direction, while applying consistent 
pressure to the mucosa 
4. Withdraw the brush from the cheek 

Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-08-US 
Final 5.0/14 April 2014 
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Data and information contained in this document are considered to constitute trade secrets and confidential commercial 
information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under 
the provisions of United States law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris International. 
 
 
5. Immediately place the brush head in the 2-mL round bottom microfuge tube filled 
with 1 mL RNALater reagent (tube “a” first, then tube “b”) 
6. Cut off the shaft of the brush with the sterile scissor 
7. Repeat steps 1-6 with the second Cytobrush Plush®GT Sterile (for the other side of 
the cheek) 
8. Vortex sample to ensure that all collected cells come into contact with the RNALater 
reagent 
Store samples at -80°C until shipment.  
Note: All samples should not undergo any freeze-thaw cycle prior to shipping.