A Randomized, Controlled, Multi-center Study to Demonstrate Reductions in Exposure to Selected Smoke Constituents in Smokers Switching to THS 2.2 Menthol or Smoking Abstinence Compared to Smoking Menthol Conventional Cigarettes, for 90 Days
Phase: NA
Conditions: Smoking
Sponsor: Philip Morris Products S.A.

Clinical Study Protocol 
ZRHM-REXA-07-JP 
 
Study title: 
A randomized, controlled, open-label, 3-arm parallel group, multi-
center study to demonstrate reductions in exposure to selected 
smoke constituents in 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 
85 days in an ambulatory setting  
Short title: 
Reduced exposure study using THS 2.2 Menthol with 5 days in a 
confinement setting and 85 days in an ambulatory setting 
Registration number:  Not assigned 
Study number: 
ZRHM-REXA-07-JP 
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 3.0 
Revision date: 
07 April 2014 
Authors: 
, PhD, Manager Clinical Science 
, MEng MSc, Study 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 applicable 
law. No part of this document may be publicly disclosed without the written consent of Philip 
Morris Products S.A. 

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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Final 3.0/ 07 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 
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without the written consent of Philip Morris Products S.A. 
 
SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Name of Product: 
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 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 85 days in an ambulatory setting  
Study Number: 
ZRHM-REXA-07-JP 
Short Study Title: 
Reduced exposure study using THS 2.2 Menthol with 5 days in a confinement setting and 85 
days in an ambulatory setting. 
Primary Objectives: 
The primary objectives of this study are: 
• To demonstrate the reduction of primary biomarkers of exposure (BoExp) to harmful and 
potential 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. 

 
 
 
 
 
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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 
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without the written consent of Philip Morris Products S.A. 
 
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 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 (CYP2A6) activity.  
• Nicotine dependence as assessed by the Fagerström test for Nicotine Dependence 
(FTND) questionnaire.  
• To evaluate in smokers switching from mCC to THS 2.2 Menthol and smokers 
continuing smoking mCC the relationship between nicotine equivalents (NEQ) and: 
• Primary and secondary BoExp .  
• Risk markers. 
• 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 smoking mCC: 
• Product evaluation. 
• Smoking pattern. 
• 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. 
• Filter analysis. 
• To describe the product use over the course of the study according to the product 
preference of the subject. 
 
Study Hypotheses: 
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 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (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 below: 

 
 
 
 
 
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Table S1: Biomarkers of Exposure 
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 
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: 
The primary endpoints of this study are: 
• 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 to creatinine) in 24-hour urine, 
 
Biomarkers of Exposure (BoExp) 
HPHCs 
Matrix 

 
 
 
 
 
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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 to creatinine) in 24-hour urine 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: 
The secondary endpoints 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).  
• 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 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 to creatinine) on Day 5 and on Day 90 Visit in 24-hour urine  .  
• 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: 
• CO (expressed as ppm) in exhaled breath  

 
 
 
 
 
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• COHb in blood  (expressed as % saturation of hemoglobin) 
• Urinary BoExp (expressed as quantity excreted and concentration adjusted to 
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 to creatinne) (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, Day 90 Visit. 
• 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.  
• 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 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 analogue scale (VAS) and Likert 
scales and one open question. 
• Vital signs. 
• Spirometry. 
• Electrocardiogram. 
• Clinical chemistry, hematology, and urine analysis safety panel. 
• Physical examination. 

 
 
 
 
 
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• 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. 
• Soluble inter-cellular adhesion molecule-1 in serum on Day 6, on Day 30, Day 60 and 
Day 90 Visit. 
• White blood cell 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, Day 30 Visit, Day 60 Visit, Day 90 Visit (expressed 
as concentration adjusted to 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-Revised on Day 
5, and 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. 
• Nicotine dependence as assessed by the FTND questionnaire: score from FTND 
questionnaire on Day 90 Visit. 

 
 
 
 
 
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• To evaluate in smokers switching from mCC to THS 2.2 Menthol and smokers 
continuing smoking mCC the relationship between nicotine equivalents (NEQ) and: 
• Primary and secondary BoExp on Day 5 and on Day 90 Visit in 24-hour urine . 
• Selected risk markers (hs-CRP, homocysteine, blood glucose, LDL, HDL, TG, TC, 
fibrinogen, hemoglobin A1c, sICAM-1, white blood cell, platelet count, 8-epi-
PGF2α, 11-DTX-B2) in respective body matrix when available, on Day 5 and on Day 
90 Visit. 
• 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 smoking mCC: 
• Product evaluation: Modified Cigarette Evaluation Questionnaire. 
• Smoking pattern: 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.  
• Filter analysis: smoke nicotine in filter and UV absorbance at 310 nm (during 
confinement setting only). 
• 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. 
 
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 10-19 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 between 06:30 AM and 11:00 PM. During the ambulatory period, 
there will be no smoking/product use restriction except during the three visits on site (Day 30 

 
 
 
 
 
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Visit, Day 60 Visit, and Day 90 Visit), when product use will be allowed from 08:00 AM to 
23:00 PM on Day 30, Day 60, and Day 90. Smoking/product use before 08:00 AM on Day 
30, Day 60 and Day 90 are not restricted. On Day 31, Day 61, product use will be allowed 
from 06:30 AM onwards. 
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 
 
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
 
 
• The Screening period covers 4 weeks (Day -30 to Day -3) prior to Admission to the clinic 
(Day -2): 

 
 
 
 
 
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A demonstration of the THS 2.2 Menthol will be done by the study collaborator 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): 
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 and baseline values 
will be recorded. On Day 0, subjects will be randomized to one of the three 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 collaborator on Day 1 
prior to 06:30 AM. 
• The exposure period (from Day 1, 06:30 AM until 11:00 PM on Day 90) and Day of 
Discharge of Day 90 Visit (from 11:00 PM to time of discharge of 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 between 06:30 AM and 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 smoking abstinence. Use of any 
tobacco/nicotine containing product other than the assigned product/regimen will not 
be allowed and may, at the discretion of the Investigator or designee, result in the 
subject withdrawal from the study.   
Twenty-fourhour urine will be collected from Day -1 to Day 6 on site. The end of the 

 
 
 
 
 
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24-hour urine collection for 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 CYP2A6, cough and MNWS questionnaires and spirometry have been 
performed.  
• The exposure period in ambulatory setting (from time of Discharge on Day 6 until 
Day 90 11:00 PM) and Day of Discharge of Day 90 Visit (from 11:00 PM to time of 
discharge of Day 91): 
After the time of Discharge on Day 6, subjects will be instructed to continue their 
assigned product/regimen in an ambulatory setting for 85 days. Subjects will be 
allowed to use nicotine replacement therapy (NRT) if considered necessary by the 
Investigator or requested by the subject.  
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, the subject will check-in at approximately 08:00 AM on Day 30, and 
will check-out on Day 31. For Day 60 Visit, the subject will check-in at 
approximatively 08:00 AM on Day 60, and will check-out on Day 61. For Day 90 
Visit, the subject will checked-in at approximately 08:00 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 end of the 24-hour urine collection for 
Day 90 Visit will end in the morning on Day 91 at 09:00 AM. 
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 approximately 08:00 AM to 23:00 PM. 
Smoking/product use before 08:00 AM on Day 30, Day 60 and Day 90 are not 
restricted. On Day 31, Day 61, product use will be allowed from 06:30 AM. The end 
of the exposure period will be fixed at Day 90 11:00 PM.  
The use of THS 2.2 Menthol will be strictly forbidden for subjects in the mCC or SA 
arms. 
On the day of discharge from Day 90 Visit (from Day 90 11:01 PM until time of 
discharge of Day 91), subject will be discharged from the investigational site after all 
safety examination procedures have be conducted.  

 
 
 
 
 
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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. 
 
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 or study 
collaborator. 
• During the study, any subjects who want to quit smoking will be encouraged to do so, 
will be referred to medical services and will be withdrawn from the study. This is 
applicable for all subjects during screening to the baseline period and for subjects 
allocated to THS 2.2 Menthol or mCC arms during the exposure period. 
• The safety follow-up period (from time of Discharge from Day 91 until Day 119): 
After the time of Discharge on the 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 is defined as the time of 
Discharge on Day 91 plus 28 day follow-up. 
Study Population and Main Criteria for Inclusion: 
Healthy adult Japanese female or male subjects, meeting the following main inclusion 
criteria: 
• Subject is aged from 23 to 65 years (inclusive). 
• Smoking, healthy subject as judged by the Investigator. 
• Subject is Japanese. 
• 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 in the next 3 months. 
• Subject is ready to accept interruption to smoking for up to 90 days. 
• Subject is ready to accept using the THS 2.2 Menthol for up to 90 days. 

 
 
 
 
 
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Subjects who do not complete the study after randomization will not be replaced. However, 
subjects enrolled at a study site that is discontinued for non-compliance with ICH/GCP will 
not be included in the primary study populations, and therefore enrolment will be extended to 
meet the sample size requirement. 
Investigational Product; 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 
Duration of Study: 
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), an 9-day confinement setting (Day -2 to 
time of Discharge of Day 6) followed by a 85-day ambulatory setting (from the time of 
Discharge of Day 6 to the time of Discharge on Day 91), and a 28-day safety follow-up 
period (until Day 119). The end of study is defined as the time of Discharge (Day 91) of the 
last subject plus 28-day follow-up. 
Expected Duration of the Study: 
01 July 2013 to 31 August 2014 
Sample size: 
Approximately, 160 smokers in the full analysis set (FAS) population (~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 BoExps in THS 2.2 Menthol compared to 
the mCC arm, using a one-sided test with 2.5% type I error probability. 
Statistical Methods: 
Primary confirmatory endpoint: The hypothesis to be tested is that the geometric mean level 

 
 
 
 
 
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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 MHBMA, 3-HPMA, S-PMA, 
and COHb, and on Day 90 Visit for Total NNAL according to the primary and secondary 
objectives.  
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 product use (exclusive THS 2.2 Menthol, dual-use of 
THS 2.2. Menthol and mCC, mCC exclusive, SA).  
A sensitivity analysis will be run on the compliant population for the 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 .........................................................................................................16 
LIST OF IN-TEXT FIGURES.................................................................................................18 
LIST OF APPENDICES ..........................................................................................................19 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................20 
1 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL ...........................................27 
1.1 
Institutional Review Board (IRB) Approval ..........................................................27 
1.2 
Ethical Conduct of the Study .................................................................................28 
1.3 
Subject Information and Consent...........................................................................28 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................30 
2 
INTRODUCTION ...........................................................................................................31 
2.1 
Background ............................................................................................................31 
2.2 
Purpose of the Study ..............................................................................................33 
2.3 
Anticipated Benefits and Risks ..............................................................................34 
3 
STUDY OBJECTIVES ....................................................................................................36 
3.1 
Primary Objective ..................................................................................................36 
3.2 
Secondary Objectives.............................................................................................36 
3.3 
Exploratory Objectives ..........................................................................................37 
3.4 
Study Endpoints .....................................................................................................38 
4 
INVESTIGATIONAL PLAN ..........................................................................................43 
4.1 
Overall Study Design and Plan ..............................................................................43 
4.2 
Rationale for Study Design and Control Groups ...................................................47 
4.3 
Appropriateness of Measurements .........................................................................49 
4.4 
Study Duration .......................................................................................................50 
5 
STUDY POPULATION ..................................................................................................51 
5.1 
Selection of Study Population ................................................................................51 
6 
INVESTIGATIONAL PRODUCTS ...............................................................................58 
6.1 
Description of Investigational Products .................................................................58 
6.2 
Use of Investigational Product(s)...........................................................................60 
6.3 
Method for Assigning Subjects to Study Arms .....................................................62 
6.4 
Blinding..................................................................................................................63 

 
 
 
 
 
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6.5 
Investigational Product Accountability and Compliance ......................................63 
6.6 
Restrictions ............................................................................................................66 
6.7 
Concomitant Medication ........................................................................................68 
7 
STUDY PROCEDURES .................................................................................................72 
7.1 
Informed Consent/Subject Information Sheet .......................................................72 
7.2 
Advice on the Risk of Smoking/Smoking Cessation Advice and Debriefing .......72 
7.3 
Support for the Smoking Abstinence Arm.............................................................73 
7.4 
Clinical Assessments .............................................................................................73 
7.5 
Biomarker Assessment...........................................................................................77 
7.6 
Laboratory Assessments ........................................................................................82 
7.7 
Sampling Handling and Storage ............................................................................84 
7.8 
Other Study Procedures .........................................................................................87 
8 
ADVERSE EVENTS .......................................................................................................94 
8.1 
Definitions..............................................................................................................94 
8.2 
Assessment of Adverse Events ..............................................................................95 
8.3 
Reporting of Serious Adverse Events ....................................................................97 
8.4 
Reporting of Other Events Critical to Safety Evaluations .....................................99 
8.5 
Reporting and Follow-Up of Pregnancies............................................................100 
8.6 
Adverse Events Leading to Withdrawal ..............................................................101 
8.7 
Investigational Device Misuse .............................................................................101 
8.8 
Investigational Device Malfunction .....................................................................101 
9 
STUDY ACTIVITIES ...................................................................................................103 
9.1 
Screening Visit .....................................................................................................103 
9.2 
Confinement Period (Days -2 to 6) ......................................................................105 
9.3 
Ambulatory Period (from time of Discharge on Day 6 to time of Discharge of 
Day 90 Visit on Day 91) ......................................................................................122 
9.4 
Safety Follow-up Period ......................................................................................129 
9.5 
Early Termination Procedures .............................................................................130 
10 CONTROL AND QUALITY ASSURANCE ...............................................................131 
10.1 
Monitoring ...........................................................................................................131 
10.2 
Training of Study Collaborators ..........................................................................132 
10.3 
Audits and Inspections .........................................................................................132 
11 DATA MANAGEMENT ACTIVITIES........................................................................133 
11.1 
Data Capture ........................................................................................................133 

 
 
 
 
 
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11.2 
Data Handling ......................................................................................................134 
12 PLANNED STATISTICAL METHODS ......................................................................136 
12.1 
General Considerations ........................................................................................136 
12.2 
Determination of Sample Size and Power Consideration ....................................138 
12.3 
Product use ...........................................................................................................141 
12.4 
Analysis Population .............................................................................................143 
12.5 
Primary Analysis ..................................................................................................144 
12.6 
Secondary Analysis ..............................................................................................146 
12.7 
Exploratory Analysis ...........................................................................................147 
12.8 
Demographics and Baseline Characteristics ........................................................148 
12.9 
Interim Analysis ...................................................................................................148 
13 ADMINISTRATIVE CONSIDERATIONS ..................................................................149 
13.1 
Principal Investigators and Study Administrative Structure ................................149 
13.2 
Subject Confidentiality ........................................................................................151 
13.3 
Access to Source Documentation ........................................................................152 
13.4 
Record Retention .................................................................................................152 
13.5 
Clinical Study Report ...........................................................................................154 
13.6 
Financial Disclosure.............................................................................................154 
13.7 
Publication and Disclosure Policy .......................................................................155 
13.8 
Insurance ..............................................................................................................155 
14 REFERENCE LIST .......................................................................................................156 
 
LIST OF IN-TEXT FIGURES 
Table 1. 
Biomarkers of Exposure ............................................................................38 
Table 2. 
Measured Aerosol Fractions for the THS Menthol Tobacco Sticks ..........59 
Table 3. 
Examples of Medications with effects on CYP1A2 and CYP2A6 
activity 
70 
Table 4. 
Clinical Laboratory Parameters for Safety Panel.......................................83 
Table 5. 
Human Smoking Topography – Per-Puff Parameters ...............................88 
Table 6. 
Human Smoking Topography – Per-Cigarette Parameters ........................88 
Table 7. 
Time Schedule – Screening Visit .............................................................103 
Table 8. 
Time Schedule – Day -2 ..........................................................................105 

 
 
 
 
 
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Table 9. 
Time Schedule – Day -1 ..........................................................................107 
Table 10. 
Time Schedule – Day 0 ............................................................................108 
Table 11. 
Time Schedule – Day 1 ............................................................................110 
Table 12. 
Time Schedule – Day 2 ............................................................................112 
Table 13. 
Time Schedule – Day 3 ............................................................................114 
Table 14. 
Time Schedule – Day 4 ............................................................................115 
Table 15. 
Time Schedule – Day 5 ............................................................................118 
Table 16. 
Time Schedule – Day 6 ............................................................................120 
Table 17. 
Time Schedule – Day 30 Visit (from 08:00 AM on Day 30 to check-
out of the subject on Day 31) and Day 60 Visit (from 08:00 AM to check out of 
the subject on Day 61) ...............................................................................................123 
Table 18. 
Time Schedule – Day 90 Visit (08:00 AM of Day 90 to time of 
discharge of Day 91) ..................................................................................................126 
Table 19. 
Expected Mean Ratios and Coefficients of Variation for THS 2.2 
Menthol/mCC ............................................................................................................138 
Table 20. 
Expected Mean Ratios and Coefficients of Variation for THS 2.2 
Menthol/mCC ............................................................................................................139 
Table 21. 
Expected Mean Ratios and Coefficients of Variation for THS 2.2 
Menthol/mCC ............................................................................................................139 
Table 22. 
Sample Size to Assess the Reductions .....................................................140 
Table 23. 
Expected power (YVD-CS01-EU and ZRHX‐EX‐01 studies 
assumptions) ..............................................................................................................140 
 Figure 1. 
Study design ...............................................................................................44 
Figure 2 - Product Use Pattern Categorization ................................................................142 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events ...................................................................................163 
Appendix 2 
Participating Laboratories ........................................................................172 
Appendix 3 
Investigational Product and Instructions for Use .....................................174 
Appendix 4 
THS Package Labels ................................................................................175 
Appendix 5 
SODIM® Device Description ...................................................................177 
Appendix 6 
Abnormal Laboratory Values ..................................................................178 
 

 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
11-DTX-B2 
11-dehydro-thromboxane B2 
1-OHP 
1-hydroxypyrene 
1-NA 
1-aminonaphthalene 
2-NA 
2-aminonaphthalene 
3-HPMA 
3-hydroxypropylmercapturic acid 
4-ABP 
4-aminobiphenyl 
8-epi-PGF2α 
8-epi-prostaglandine F2α 
ADL 
Activities of daily living 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
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(s) 
CD 
Compact disc 
CEMA 
2-cyanoethylmercapturic acid 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
COPD 
Chronic obstructive pulmonary disease 
CRA 
Clinical Research Associate 

 
 
 
 
 
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CRO 
Contract Research Organization 
CSR 
Clinical study report 
CTCAE  
Common Terminology Criteria for Adverse Event and Common 
Toxicity Criteria 
CTMS 
Clinical Trial Management System 
CV 
Coefficients of variation 
CYP1A2 
Cytochrome P450 1A2 
CYP2A6 
Cytochrome P450 2A6 
DMP 
Data management plan 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EHCSS 
Electrically heated cigarette smoking system 
EOS 
End of Study 
ePRO 
Electronic patient report outcome 
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 
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 

 
 
 
 
 
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IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
INR 
International normalized ratio 
IOM 
Institute of Medicine  
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IU 
International unit 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LDH 
Lactic dehydrogenase 
LDL 
Low density lipoprotein 
LLN 
Lower limit of the normal range 
LLOQ 
Lower Limit of Quantification 
LOCF 
Last observation carried forward 
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 
MHBMA 
Monohydroxybutenyl mercapturic acid 
MNWS 
Minnesota Nicotine Withdrawal Scale (revised version) 
MR 
Mean ratios 
MRTP 
Modified risk tobacco product 
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 

 
 
 
 
 
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NSAID 
Nonsteroidal Anti-inflammatory Drugs 
o-tol 
o-toluidine 
PK 
Pharmacokinetic(s) 
PMI 
Philip Morris International 
PP 
Per-protocol 
PT 
Prothrombin time 
PX 
Paraxanthine 
QC 
Quality control 
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 
SDTM 
Standards Consortium’s Study Data Tabulation Model 
SES 
Socio-economic status 
SHM 
Sample handling manual 
sICAM-1 
Soluble inter-cellular adhesion molecule 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
S-PMA 
S-phenylmercapturic acid 
TC 
Total cholesterol 
TG 
Triglycerides 
THS 
Tobacco Heating System 
TPM 
Total particulate matter 
U 
Urine sample required 
UV 
Ultra violet 
 
 
ULN 
Upper limit of the normal range 

 
 
 
 
 
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ULOQ 
Upper limit of quantification 
VAS 
Visual analogue scale 
WBC 
White blood cell (count) 
WHO 
World Health Organization 
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. 
Back up subject  
Subjects who tested the product and were discontinued from 
enrollment. 
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 approximately 08:00 AM (check-in 
of  the subject on site) until the check-out of the day after 
respectively on Day 31, Day 61, and the discharge on Day 91. This 
is to allow 24-hour urine collection. 
End of study 
End of Study is defined as the time of discharge on Day 91 (Day 
90 Visit) 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 11:00 PM. 

 
 
 
 
 
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Investigator 
Principal Investigator or sub-investigator 
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). 
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 and number prior Day 1. 
Run-in period 
Admission to site until 06:29 AM of Day -1. 
Safety follow-up 
After the time of Discharge on the Day 91, a 28-day safety follow-
up will be done for the recording of spontaneously reported new 
AEs/SAEs and the active follow-up of ongoing AEs/SAEs by the 
site. In g eneral, 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 informed consent 
form (ICF) signature to the time of enrolment will be considered a 
screening failure and will be replaced by other subjects. 
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) 

 
 
 
 
 
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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 91 (Day 90 Visit): time when the 
subject is released from the site on Day 91 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 
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 INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL 
1.1 Institutional Review Board (IRB) Approval 
Prior to the start of the study, the clinical study protocol, together with its associated 
documents (informed consent form [ICF] which includes bothsubject information sheet 
and informed consent, subject recruitment procedures [e.g. advertisements], written 
information to be provided to the subjects, Investigator’s Brochure [IB], available safety 
information, the Principal Investigator’s curriculum vitae and/or other evidence of 
qualifications, the list of sub-Investigators and any other documents requested by the 
Institutional Review Board [IRB]), will be submitted for review and approval to the 
relevant IRB. 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 Ministerial Ordinance on Good Clinical 
Practice for Drugs and local requirements, as applicable. 
In accordance with GCP, a written confirmation of the IRB approval should be provided 
to the Sponsor. This should identify the study (Principal 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, should 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 another 
original copy will be filed in the Study Master File at the Sponsor or designated 
organization. The study must not start at a study site befo re 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 Principal 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 Principal Investigator or sub-Investigator (Investigator) 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, and is implemented for safety reasons, the Sponsor and the 
IRB should be informed immediately. 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A. 
 
Relevant safety information will be submitted to the IRB during the course of the study in 
accordance with national regulations and requirements. 
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, Ethical Guidelines 
for Clinical Studies (Ministry of Health, Labour and Welfare, 2003 (as last amended on 
July 31, 2008)), Ministerial Ordinance on Good Clinical Practice for Drugs (Ministry of 
Health and Welfare, 1997(as last amended by the Ordinance of Ministry of Health, 
Labour and Welfare No. 161 of December 28, 2012)), and applicable regulatory 
principles.The Principal Investigator agree to conduct the clinical study in compliance 
with the protocol agreed upon 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 
should be 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 by the date and signature of both the subject and the person who 
conducted the inform consent discussion. No study-specific procedures will be performed 
before the ICF has been signed. 
The original, dated and signed ICF(s) must be kept in the Investigator file at the site, 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. 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A. 
 
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 for measurements of BoExp and risk markers in 
serum/plasma and urine and for consent to the additional bio-banking of blood for further 
transcriptomics (pharmacogenomics) analysis. 
1.3.2.1 Bio-bank for Biomarkers of Exposure and Risk Markers 
There 
will 
be 
a 
separate 
subject 
information 
and 
consent 
for 
samples 
(serum/plasma/urine) that will be 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 
Subjects will be provided with information and asked for their consent to collect blood 
samples for bio-banking for transcriptomics (pharmacogenomics) in order to 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. Comparison will be based on previously described biological networks. In-
house data from an exploratory study to assess the reduction of exposure to HPHCs 
(clinical trial dot. gov identifier: NCT01780714) in smokers switching to THS 2.1 as 
compared to smokers continuing smoking CC shows that using THS 2.1, the earlier 
version of THS 2.2 results in significant variation of RNA characteristics as compared to 
smoking CC. 
1.3.2.3 Information on Optional Consent to Bio-banking 
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 and signature of both the subject and the Investigator and 
personnel who conducted the informed consent discussion. The subject’s consent to 
storage of any samples in a bio-bank or for transcriptomics is not a requirement for study 
participation and the subject’s participation in the study does not depend on their 
providing consent for sample bio-banking. 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A. 
 
1.3.3 Amendment to the Informed Consent Form/Subject Information Sheet. 
If a protocol amendment is required, or if new information regarding the risk profile of 
the Investigational Product (IP) becomes available, an amendment may be required to the 
ICF. If revision of the ICF is necessary, the Principal 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. 
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 the Investigator 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. In addition, the Investigator or designee will carry out the clinical study 
in accordance with ICH GCP Ethical Guidelines for Clinical Studies. 

 
 
 
 
 
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2 INTRODUCTION 
2.1 Background 
2.1.1 Smoking-Related Diseases and Harm Reduction Strategy 
Cigarette smoking causes pulmonary and cardiovascular diseases and other serious 
diseases in smokers (U.S. Department of Health and Human Services, 2010). The effects 
of smoking and smoking cessation on mortality from cardiovascular disease among the 
Japanese population were investigated in cohort studies in Japan. These studies 
confirmed the association between smoking and mortality from cardiovascular disease 
and highlighted the importance of smoking cessation at any age to prevent cardiovascular 
disease in the Japanese population (Honjo et al., 2010a, Iso et al., 2005). In 2000 in 
Japan, the proportion of adult deaths due to smoking ranges from 20.0% to 24.9% in 
males and from 10.0% to 14.6% in females. In 2007, Japan became part of the top five 
conventional cigarette (CC)-consuming countries with a consumption of 234 billion 
annualy in 2009 (tobacco atlas, fourth edition). 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 can’t 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 US Food and Drug Administration (FDA) as modified risk 
tobacco products (MRTPs) (FDA, 2012a). 
The challenge in developing and commercializing MRTPs is two-fold, i.e. developing 
tobacco products that are shown to reduce risk and that are acceptable to smokers as 
substitutes for CCs. PMI is developing MRTPs that provide a smoking experience 
without combustion. The novel approach to achieve this is by heating tobacco at 
significantly lower temperatures than required for CC. 
PMI’s approach to scientifically assessing the risk-reduction potential of its candidate 
MRTPs is described in the reference document (PMI White Paper Docket). Smoking 
cessation is the only intervention proven to reduce the risk of smoking-related diseases in 
smokers. Accordingly, PMI utilizes smoking cessation/smoking abstinence as the 
benchmark for assessing the risk reduction potential of its candidate MRTPs. The 
Institute of Medicine (IOM) observed that cessation is the “gold standard” for assessing 
risk reduction, and that “the closer risks and exposures from the MRTP are to cessation 

 
 
 
 
 
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products, the more confident a regulator can be of achieving a net public health benefit” 
(Institute of Medicine, 2012). PMI has already conducted studies and plans to conduct 
further clinical studies which observe measurable changes in blood chemistry, risk factors 
and health effects in smokers who switch to a candidate MRTP, comparing the changes 
with those observed in both smokers who continue smoking CC and smokers who stop 
using tobacco products. Longer-term data from adults who continue to use the candidate 
MRTP can further substantiate reductions in individual risk in smokers and population 
harm. 
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, and more than 100 
of them have been categorized as harmful and potentially harmful constituents (HPHCs). 
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 
mCC. PMI believe that such products present the best opportunity for reducing harm 
because they produce vastly lower levels of harmful smoke constituents and are more 
likely to be accepted by smokers as substitutes for cigarettes. Important to this effort has 
been providing nicotine in a way that closely parallels mCC. 
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 minutes 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 or increased toxicological hazard in the product’s aerosol was detected compared 
with CC smoke. The aerosol was chemically analyzed confirming that none of the 
determined HPHCs in the THS 2.2 Menthol were increased compared to the conventional 
cigarettes. The biological activity was tested in a number of in vitro assays to assess the 
cytotoxicity and the genotoxicity of the aerosol fractions total particulate matter (TPM) 
and gas vapor phase (GVP). In vitro and in vivo results corroborated the concept that 
absence of combustion when consuming tobacco substantially lowers toxic effects seen 

 
 
 
 
 
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in these biological models. Further details on the clinical data are provided in the 
Investigators’ Brochure (PMI, 2013a). 
Several clinical studies have been conducted on THS 1.0 and THS 1.0 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, TPM and 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 was tested in two exploratory clinical studies to measure the 
nicotine plasma kinetic profile (PK) (www.clinical trial.gov identifier: NCT01780688) 
and to assess the reduction of exposure to HPHCs when switching from CC to THS 2.1 
(www.clinical trial. gov identifier: NCT01780714). 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 
version of THS 2.2 Menthol 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 and to obtain safety information in 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 85 days. Smokers 
who will be asked to abstain from using any nicotine/tobacco-containing products will be 
used as a reference point. The smokers allocated to 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. additional BoExp, cytochrome P450 1A2 (CYP1A2) and cytochrome P450 2A6 
(CYP2A6) enzymatic activity, pharmacokinetic (PK) profile of nicotine and cotinine, 
product evaluation, product use and related subjective effects, human smoking 
topography, risk markers). 

 
 
 
 
 
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2.3 Anticipated Benefits and Risks 
2.3.1 Anticipated Benefits 
In Japan, research conducted by the Ministry of Health, Labour and Welfare has shown 
that 35.9% of male and 43.6% of female respondents over 20 years of age expressed the 
wish to quit smoking (International Tobacco Online, 2012). In a large follow-up study of 
middle aged Japanese smokers, the predictors of smoking cessation were age, job, 
smoking habit, physical activity, health checkup participation, and health status (Honjo et 
al., 2010b). Advice on health risks associated with smoking and smoking cessation 
advice will be provided at Screening, at Admission, on Day 6 and on Day 90 Visit. The 
advice will follow the recommendations of the World Health Organization (WHO) (Raw 
et al., 2002) -“Evidence based Recommendations on the Treatment of Tobacco 
Dependence”. Subjects who are motivated to quit smoking during the study will be given 
the opportunity to continue their smoking cessation attempt and 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) 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 smoking abstinence will be 
explained in detail to the subjects. Mitigation will include, but will not be limited to: 
• Close monitoring and medical evaluation of potential safety signals throughout the 
study and follow-up. 

 
 
 
 
 
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• 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). 
2.3.4 Unforeseeable Risks 
As with any new IP, there may be unforeseeable risks and hazards that could occur. The 
possibility of such 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 Objective 
The primary objectives of this study are: 
• To demonstrate the reduction of primary biomarkers of exposure (BoExp) to 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. 
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 (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 monitor the safety profiles during the study. 

 
 
 
 
 
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• 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 (CYP2A6) activity.  
• Nicotine dependence as assessed by the Fagerström test for Nicotine Dependence 
(FTND) questionnaire.  
• To evaluate in smokers switching from mCC to THS 2.2 Menthol and smokers 
continuing smoking mCC the relationship between nicotine equivalent (NEQ) and: 
• Primary and secondary BoExp.  
• Risk markers. 
• 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 
smoking mCC: 
• Product evaluation. 
• Smoking pattern. 
• To describe the following parameters 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. 
• Filter analysis: smoke nicotine in filter and UV absorbance at 310 nm (during 
confinement setting only). 
• To describe the product use over the course of the study according to the product 
preference of the subject. 

 
 
 
 
 
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3.4 Study Endpoints 
The primary and secondary BoExp to harmful and potentially harmful constituents (HPHCs) 
measured in the study are presented in Table 1:  
 
Table 1. Biomarkers of Exposure 
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 
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 
 
Biomarkers of Exposure (BoExp) 
HPHCs 
Matrix 

 
 
 
 
 
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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 to 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 to 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. 
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 smoking abstinence (SA).  
• 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 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 to 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. 

 
 
 
 
 
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• 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: 
• CO (expressed as ppm) in exhaled breath  
• COHb in blood  (expressed as % saturation of hemoglobin) 
• Urinary BoExp (expressed as quantity excreted and concentration adjusted to 
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 to creatinne) 
(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, Day 90 Visit. 
• 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.  
• 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 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 analogue scale (VAS) and 
Likert scales and one open question. 

 
 
 
 
 
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• Vital signs. 
• Spirometry. 
• Electrocardiogram. 
• 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. 
• Soluble inter-cellular adhesion molecule-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 Day 30 Visit, Day 60 Visit and Day 90 Visit 
(expressed as concentration adjusted to creatinine). 
• 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. 

 
 
 
 
 
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• Subjective effect of smoking: Questionnaire of Smoking Urges (QSU Brief 
questionnaire); questionnaire Minnesota Nicotine Withdrawal Scale-Revised on 
Day 5, and 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. 
• Nicotine dependence as assessed by the FTND questionnaire: score from FTND 
questionnaire on Day 90 Visit. 
• To evaluate in smokers switching from mCC to THS 2.2 Menthol and smokers 
continuing smoking mCC the relationship between nicotine equivalent (NEQ) and: 
• Primary and secondary BoExp on Day 5 and on Day 90 Visit in 24-hour urine .  
• Selected risk markers (hs-CRP, homocysteine, blood glucose, LDL, HDL, TG, 
TC, fibrinogen, hemoglobin A1c, sICAM-1, white blood cell, platelet count, 8-
epi-PGF2α, 11-DTX-B2) in respective body matrix when available on Day 5 and 
on Day 90 Visit. 
• 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 
smoking mCC: 
• Product evaluation: Modified Cigarette Evaluation Questionnaire. 
• Smoking pattern: 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.  
• Filter analysis: smoke nicotine in filter and UV absorbance at 310 nm (during 
confinement setting only). 
• 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. 

 
 
 
 
 
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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 daily average cigarette consumption over the last 4 weeks as 
reported during the Screening Visit (smokers smoking 10-19 mCC and smokers smoking 
>19 mCC per day) (Figure 1). 
This is an ad libitum smoking study. In general, smoking/product use during the confinement 
period will be allowed between 06:30 AM and 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 08:00 AM to 
23:00 PM on Day 30, Day 60, and Day 90. Smoking/product use before 08:00 AM on Day 
30, Day 60 and Day 90 are not restricted.On Day 31, Day 61, product use will be allowed 
from 06:30 AM onwards. 
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 
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. 

 
 
 
 
 
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Figure 1. 
Study design 
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
 
• 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 study collaborator 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): 
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): 

 
 
 
 
 
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All subjects will continue smoking their single preferred brand of mCC and baseline 
values will be recorded. On Day 0, subjects will be randomized to one of the three study 
arms in a 2:1:1 ratio using a stratified randomization. The 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 collaborators on Day 1 
prior to 06:30 AM. 
• The exposure period (from Day 1, 06:30 AM until 11:00 PM onDay 90) and Day of 
Discharge of Day 90 Visit (from 11:00 PM to time of discharge of 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 between 06:30 AM and 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 smoking abstinence.  Use of any 
tobacco/nicotine containing product other than the assigned product/regimen will not 
be allowed and may, at the discretion of the Investigator, result in the subject 
withdrawal from the study.  
Twentyfour-hour urine will be collected from Day -1 to Day 5 on site. The end of the 
24-hour urine collection for 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 CYP2A6, cough and MNWS questionnaires and spirometry have been 
performed.  
• Exposure period in ambulatory setting (from time of Discharge on Day 6 until Day 90 
11:00 PM) and Day of Discharge (from Day 90 11:01 PM until time of discharge of 
Day 91: 

 
 
 
 
 
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After the time of Discharge on Day 6, subjects will be instructed to continue their 
assigned product/regimen in an ambulatory setting for 85 days. Subjects will be 
allowed to use nicotine replacement therapy (NRT) if considered necessary by the 
Investigator or requested by the subject.  
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, the subject will check-in at approximatively 08:00 AM on Day 30, and 
will check-out on Day 31. For Day 60 Visit, the subject will check-in at 
approximatively 08:00 AM on Day 60, and will check-out on Day 61. For Day 90 
Visit, the subject will checked-in at approximatively 08:00 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 end of the 24-hour urine collection for 
Day 90 Visit will end in the morning on Day 91 at 09:00 AM. 
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 approximately 08:00 AM to 23:00 PM. 
Smoking/product use before 08:00 AM on Day 30, Day 60 and Day 90 are not 
restricted.On Day 31, Day 61, product use will be allowed from 06:30 AM. The end 
of the exposure period will be fixed at Day 90 11:00 PM.  
The use of THS 2.2 Menthol will be strictly forbidden for subjects in the mCC or SA 
arms. 
On the day of discharge from Day 90 Visit (from Day 90 11:01 PM until time of 
discharge of Day 91), subject will be discharged from the investigational site after all 
safety examination procedures have be conducted. 
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. 
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/study collaborator. 
During the study, any subjects who want to quit smoking will be encouraged to do so, will be 
referred to medical services and will be withdrawn from the study. This is applicable for all 

 
 
 
 
 
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subjects during screening to the baseline period and for subjects allocated to THS 2.2 
Menthol or mCC arms during the exposure period. 
• The safety follow-up period (from time of Discharge from Day 91 until Day 119): 
After the time of Discharge on the 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 is defined as the time of 
Discharge on Day 91 plus 28 day follow-up. 
4.2 Rationale for Study Design and Control Groups 
The minimum age of 23 years age in the inclusion criteria was selected based on: 
• The legal age of smoking in Japan is 20 years.  
• To account for the 3 years of smoking history. 
This clinical study aims to demonstrate reductions in exposure to selected HPHCs in smokers 
switching to the THS 2.2 Menthol, a candidate MRTP, as compared to using mCCs (see 
current version of the IB). 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. 
In this study, smokers of mCC will be assessed because the menthol brands play a significant 
role within the Japanese market, with 20% of the overall market share in 2008 (Connolly et 
al., 2011). 
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 
toxicity were recommended to be measured as priority in the smoke chemistry for mandated 

 
 
 
 
 
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lowering (Ashley et al., 2008). Exposure to 4 HPHCs (acrolein, CO, 1,3-butadiene, and 
benzene) among these nine 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 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 of 
assessed biomarkers on Day 5). 
• They were decreased in smokers who switched to another candidate MRTP tested in 
exploratory studies for 5 days, similar to that observed in smokers who stopped smoking 
(data on file from the previous study, YVD-CS01-EU study). 
Total NNAL was selected as primary endpoints after 90 days 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 90 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). 
• It was decreased in smokers who switched to another candidate MRTP after 5 days, (data 
on file from the previous study, YVD-CS01-EU study). 
In addition, 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 well-known to be affected by smoking and to be reversible upon SA, 
will be measured in this study as follows: 
1. CYP1A2 activity, the enzyme which mainly metabolizes nicotine, is decreased as soon as 
5 days of smoking abstinence 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]).  
2. Platelet function will be assessed by measuring 11-DTX-B2 (a major stable metabolite of 
thromboxane A2, which elicits mainly platelet aggregation). This marker 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).  

 
 
 
 
 
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3. Blood pressure, hs-CRP, fibrinogen, homocysteine, fasting blood glucose, LDL, HDL, 
triglycerides, total cholesterol, HbA1c, waist circumference, sICAM-1, WBC, and 
8-epi-PGF2α will be evaluated as additional risk markers (Eliasson et al., 2001; Vasan, 
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, and 8-epi-PGF2α decrease following 1 to 3 months 
of smoking cessation (Pilz et al, 2000; Eliasson et al., 2001). 
4. Body weight as a mean increase of 4.5 kg in body weight 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). 
In addition, 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. 
Other parameters such as human smoking topography, product evaluation, and subjective 
effects including smoking urges and withdrawal symptoms will be evaluated.  
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 aked questions about their socio-economic status 
on Day 4. Such data would allow to compare populations across studies. 
All subjects will be asked to provide their own mCC according to their anticipated needs for 
the whole confinement period. This is to minimize any changes in their smoking behavior 
due to the participation in the study. 
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, and 2) measure is known to be 
directly or indirectly affected by smoking; 3) measure is readily reversible after smoking 
cessation, 4) timeframe of reversibility of measure in the perspective of the study duration, 5) 
practicality/acceptability by subjects, and 6) robustness (rapid, simple, accurate). 
All questionnaires utilized for this study, except the cough, the socio-economic 
questionnaire, risk/perception and intent to use questionnaire and HST questionnaires, are 
available as validated questionnaires. 

 
 
 
 
 
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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 85-day ambulatory setting (from the time of 
Discharge of Day 6 to the time of Discharge on Day 91), and a 28-day safety follow-up 
period (until Day 119). The end of study is defined as the time of Discharge on Day 91) of 
the last subject plus 28-day follow-up. 

 
 
 
 
 
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5 STUDY POPULATION 
5.1 Selection of Study Population 
Healthy, adult Japanese subjects who smoke at least 10 mCC per day for the last 4 weeks 
with a maximum yield of 1 mg nicotine International Organization for Standardization (ISO) 
per cigarette will be included in this study. Enough subjects will be enrolled into the study 
until there are 160 smokers in the FAS population. 
The maximum number of mCC smoked per day is not limited. Subjects will 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 flavored with menthol. 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 aged from 23 to 65 
years (inclusive). 
Safety 
X 
 
3. Subject is Japanese. 
Effect 
X 
 
4. Smoking, 
healthy 
subject 
as 
judged by the Investigator based 
on all available assessments from 
the 
Screening 
period/day 
of 
Admission (e.g. safety laboratory, 
Safety 
X 
X 

 
 
 
 
 
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Inclusion Criteria 
Rationale 
Screening 
Day of Admission 
(Day -2) 
spirometry [FEV1/FVC >0.7 at 
post-bronchodilator 
spirometry, 
post-bronchodilator FEV1 >80% 
predicted 
value, 
and 
post-bronchodilator FVC >80% 
predicted 
value], 
vital 
signs, 
physical examination, ECG, chest 
X-ray and medical history). 
5. Subject 
smokes 
at 
least 
10 
commercially available menthol 
mCCs 
per 
day 
(no 
brand 
restrictions) with a maximum 
yield of 1 mg nicotine ISO/mCC, 
as 
labelled 
on 
the 
cigarette 
package, for the last 4 weeks, 
based 
on 
self-reporting. 
Furthermore, the subject has been 
smoking for at least the last three 
consecutive years. The smoking 
status will be verified based on a 
urinary cotinine test (cotinine 
≥200 ng/mL). 
Effect 
X 
X 
6. The subject does not plan to quit 
smoking in the next 3 months. 
Safety 
X 
 
7. The subject is ready to accept 
interruptions of smoking for up 
to 90 days. 
Safety 
X 
X 
8. The subject is ready to accept 
using the THS 2.2 Menthol. 
Effect 
 
X 
 
 
 

 
 
 
 
 
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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, prisoners or 
subjects who are involuntarily 
incarcerated). 
Administrative 
X 
 
3. The subject has medical condition 
requiring smoking cessation, or 
clinically 
relevant 
diseases 
(including but not limited to 
gastrointestinal, 
renal, hepatic, 
neurological, 
hematological, 
endocrine, 
oncological, 
urological, 
immunological, 
pulmonary 
and 
cardiovascular 
disease or any other medical 
condition 
[including 
but 
not 
limited 
to 
clinically 
relevant 
abnormal laboratory parameters]) 
in 
the 
judgment 
of 
the 
Investigator. 
Safety 
X 
X 
4. The subject has a body mass 
index (BMI) <18.5 or ≥32 kg/m2. 
Safety 
X 
 
5. As per Investigator judgment, the 
subject has medical conditions 
Effect 
X 
X 

 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of Admission 
(Day -2) 
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. 
6. 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 
7. 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 
8. 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 
9. Concomitant use of NSAIDs or 
acetylsalicylic acid. 
Effect 
X 
X 

 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of Admission 
(Day -2) 
10. 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 
11. The subject has a positive urine 
drug test. 
Administrative 
X 
X 
12. Positive serology test for HIV1/2, 
hepatitis B or hepatitis C. 
Safety 
X 
 
13. Donation or receipt of whole 
blood or blood products within 3 
months prior to Admission. 
Safety 
X 
X 
14. The subject is a current or former 
employee of the tobacco industry 
or of their first-degree relatives 
(parent, sibling, child). 
Administrative 
X 
 
15. 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, child). 
Administrative 
X 
 
16. The subject has participated in a 
clinical study within 3 months 
prior to the Screening Visit. 
Safety 
X 
 
17. The 
subject 
has 
previously 
participated in the same study at a 
different time (i.e. each subject 
can be included in the study 
population only once). 
Administrative 
X 
 
18. For women only: 
Subject is pregnant (does not have 
negative pregnancy tests at Screening 
Safety 
X 
X 

 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of Admission 
(Day -2) 
and at Admission) or is breast 
feeding. 
19. For women only: 
Subject does not agree to use an 
acceptable 
method 
of 
effective 
contraception* 
Safety 
X 
X 
* 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. 
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, the whole safety examination 
procedure planned on Day 6 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. 
• 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 Principal Investigator terminates the study. If the Sponsor or the Principal 
Investigator decide to prematurely terminate the study, the subject will be promptly 
informed and will follow the end of study procedures as described in Section 9.5. The 
head of the medical institution will report this fact and the reason in writing to the IRB. If 
a study site is discontinued for non-compliance with ICH/GCP, subjects enrolled at that 

 
 
 
 
 
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site will not be included in the primary study populations, and therefore enrolment will be 
extended to meet the sample size requirement. 
• Withdrawal is considered to be in the best interest of the subject or the other subjects. 
• The subject wish to quit smoking (this is applicable for all subjects during screening to 
the baseline period and for subjects allocated to THS 2.2 Menthol or mCC arms during 
the exposure period). 
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 CRO 
Medical Monitor on an ongoing basis). 
• If a subject uses any CC or nicotine/tobacco-containing product other than the 
product/regimen he/she is assigned to, it will be at the discretion of the Investigator to 
decide whether or not to withdraw the subject from the study. 
• Non-compliance to the study procedures. 
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. 

 
 
 
 
 
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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 mains 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 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/Tobacco Stick 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, 2013b). Another method is the more intensive smoking method developed 
by Health Canada (Health Canada, 1999). 
Table 2 below lists the commonly reported measures (PMI, 2013a):  

 
 
 
 
 
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Table 2. 
Measured Aerosol Fractions for the THS Menthol Tobacco Sticks 
 
Constituent (mg/THS Menthol 
Tobacco Stick) 
ISO 1 
Health 
Canada  Intense 
regime 2 
Tar (NFDPM)  
5 
12.6 
Nicotine  
0.5 
1.2 
Carbon monoxide 
1 
0.6 
NFDPM: Nicotine-free dry particulate matter 
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). 
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 are not 
allowed to roll their own mCC.  
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.  
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 study collaborator. The mCCs will not be 
provided by the Sponsor. 
During the ambulatory period, for the Day 30 Visit, Day 60 Visit, and Day 90 Visit, the 
subjects will be asked to bring his/her own mCC and provide his/her anticipated amount of 
mCC , plus 2 extra packs. 
6.1.3 Packaging and Labeling 
At Admission (all study subjects), subjects will provide the anticipated amount of mCC in 
sealed packs to the study site collaborator. The mCC packs provided by the subjects should 
not be opened and the cellophane wrapper should be intact. 

 
 
 
 
 
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Each pack of mCC provided by the subject will be labeled to identify which subject the 
cigarettes belong to (labels should be affixed by the study site collaborator to the cellophane 
wrapper of the lower part of the pack). 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 pre-labeled with the necessary 
information including, but not limited toproduct code. The labels will be translated into 
Japanese. See Appendix 4. 
6.2 Use of Investigational Product(s) 
Subjects will never be requested or forced to smoke and will be free to stop smoking 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 according to their smoking habits except during the 
procedures of the screening Visit at the discretion of the site. 
During the confinement period product (mCC or THS 2.2 Menthol) use will generally be 
allowed between 06:30 AM to 11:00 PM.  
During the ambulatory period, there will be no smoking/product restriction except on Day 30 
Visit, Day 60 Visit, and Day 90 Visit: on Day 30, Day 60, and Day 90: product use will be 
allowed from 08:00 AM to 23:00 PM and during the Visit. Smoking/product use before 
08:00 AM on Day 30, Day 60 and Day 90 are not restricted. On Day 31, Day 61, product use 
will be allowed from 06:30 AM. In the morning of Day 91 after the end of exposure 
ambulatory period (11:00 PM on Day 90), subjects will not be allowed to smoke CC until 
CYP2A6, cough and MNWS questionnaires and spirometry have been done on site. The use 
of THS 2.2 Menthol will be strictly forbidden for subjects in the mCC or SA arms. 
6.2.1 Run-in Period 
Smoking ad libitum will be allowed prior to admission and throughout the day except during 
the procedures. All subject s will be allowed to continue smoking ad libitum their single 
preferred brand of usual mCC. All subjects (except women with a positive pregnancy test at 
Screening or at Admission) will undergo a THS 2.2 Menthol product test prior to enrolment.  
Following the confirmation that the subject is able and willing to use the THS 2.2 product, 
subjects will be enrolled. 

 
 
 
 
 
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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. 
6.2.3 Exposure Period 
During the exposure confinement period 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. On Day 6, when the safety procedures of discharge will be conducted, the 
use of product (THS 2.2 Menthol or mCC) will be allowed but after CYP2A6, cough and 
MNWS questionnaires and spirometry 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.  
In the morning of the Day 91, smoking will not be allowed to smoke until CYP2A6, cough 
and MNWS questionnaires and spirometry have been conducted at the clinic. After, subjects 
will be allowed to smoke. On Day 91, safety procedures of Discharge will be conducted prior 
the time of Discharge of the subject from the site (completion of the study). 
During the study, any subjects who is willing to stop smoking will be 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. 
On 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 Day 90 11:00 PM. 
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.  

 
 
 
 
 
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On the time of discharge on Day 6, subjects will be informed that they can continue to smoke 
their mCC ad libitum if they wish until the time of Discharge on Day 90 11: 00 PM.  
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 until the time of Discharge on 
Day 6. They will not be provided with medication supportive for smoking abstinence. 
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 until time of discharge of 
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. 
6.2.5 Safety Follow-up Period 
During the safety follow-up period (after the Time of Discharge at Day 91 until Day 119), 
subjects in the THS 2.2 Menthol and mCC arms are free to smoke their own mCC ad libitum. 
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. If subjects in the SA arm cannot refrain from smoking, they may start smoking their 
own brand of mCC after the time of Discharge at Day 91. 
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 three 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 CC and 
those smoking >19 CC per day) reported by the subject. In each arm, each sex and each of 

 
 
 
 
 
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the smoking strata should have a quota applied to ensure they represent at least 40% of the 
population. 
6.4 Blinding 
This is an open-label study; therefore, the subjects and Investigator will be unblinded to the 
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 statistical analysis plan (SAP) finalization or PMI 
blind database review(*), 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. 
6.5 Investigational Product Accountability and Compliance 
6.5.1 Dispensing Investigational Product 
From Day-2 onwards during the confinement period, each mCC will be dispensed to the 
subjects one by one. Subjects in the THS 2.2 Menthol arm will be provided by the site study 
collaborators with Menthol Tobacco Sticks from Day 1 to Day 5 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-1 for CC and from Day 1 for Menthol Tobacco Sticks onwards. 
The start of product use 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 

 
 
 
 
 
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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 with an 
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 and will buy their mCCs directly from shops. 
6.5.2 Storage and Accountability 
The study collaborator (the IP product storage manager) designated by the head of the 
investigational site will be responsible for the storage and accountability of the IPs in 
accordance to sponsor’s requirements. 
The THS 2.2 Menthol and mCC 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 
designated IP storage manager.  
6.5.2.1 Confinement Period 
On each day of the confinement period, study collaborators will record on the Accountability 
Log every occasion from Day -1 to time of Discharge on Day 6 that mCCs are dispensed to a 
subject by the study collaborator 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 
charging unit, THS accessories) and Menthol Tobacco Sticks are dispensed to a subject. 
Subjects will return each butt of mCC immediately after use from Day -1 to Day 6 for 
accountability. This will be documented in appropriate log. 
Immediately after use, all tobacco plugs of all used Menthol Tobacco Sticks will be separated 
from the filters and the tobacco plugs and the filters will be collected from Day 1 to Day 5, 
using dedicated vials for accountability and subsequent analysis of potential combustion 
occurrences and nicotine retained in the filters (see also Section 7.8.2). This will be 
documented in an appropriate log. 

 
 
 
 
 
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6.5.2.2 Ambulatory Period 
THS 2.2 Arm: 
Subjects must return any empty packs and partially used packs of Menthol Tobacco Sticks 
they have used during the preceding weeks to the site for accountability. After accountability 
they will be destroyed at study completion in accordance with sponsor’s requirements. 
All tobacco plugs from Menthol Tobacco Sticks used after check-in to the investigational site 
until 11:00 PM on Day 30, Day 60, and Day 90 will be collected in dedicated vials for 
subsequent analysis of potential combustion occurrences. No filter analysis of the Menthol 
Tobacco Sticks will be conducted during the visits of the ambulatory period. 
mConventional Cigarettes Arm: 
No IP accountability will be done for mCC. 
Smoking Abstinence 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 on the time of Discharge from the clinic, the study collaborators 
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 (product by product) and collection of used Menthol Tobacco 
Sticks/CC butts will be documented in appropriate log.. 
During the ambulatory period, subjects in the 3 study arms will capture, from the time of 
Discharge on Day 6 to Day 90 11:00 PM 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 
collaborator. The product use electronic diary will serve as a compliance tool in the three 
arms. On Day 6, the compliance to the product will be ensured by the merge of the 

 
 
 
 
 
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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 
entries will be considered as source of data.  
In addition, in the SA arm, compliance will be chemically verified using an exhaled CO 
breath test during both the confinement and ambulatory periods. The cut-off point for the CO 
breath test value to distinguish mCC use versus no mCC 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 between the three study arms, subjects in the THS 2.2 
Menthol and the mCC arm must smoke in separate rooms and subjects allocated to the SA 
arm should not have access to the smoking rooms. All precautions should be taken to remove 
any temptation to smoke 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 other than mCC brought to the site by the 
subject to the site. In the SA arm, intensive support including psychological support will be 
provided upon the request of the subject or of the Investigator or study site collaborator. 
Smoking will generally only be allowed during the designated smoking times, from 06:30 
AM to 11:00 PM. Smokers will not have free access to their mCC or THS 2.2 Menthol; these 
will be dispensed by the study collaborator individually as described in Section 6.5.1. 
From admission on site, smoking will not be allowed during assessments on the Admission 
Day at the discretion of the site. Smoking will be allowed on Day 6 after CYP2A6 activity 
measurements, assessment of cough and MNWS questionnaire completion and 
spirometry,have been conducted. 
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. Subjects in the SA arm may use NRT 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 or study collaborator. 
Product use will be allowed during the ambulatory visits from 08:00 AM to 11:00 PM on 
Day 30 and Day 60, and on Day 90. On Day 31, and Day 61, product use will be allowed 
from 06:30 AM. However, in the morning of Day 91, smoking will not be allowed until 
assessment of cough and MNWS questionnaires completion and CYP2A6 and spirometry, 
have been performed on site.  
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 “high-fat” diet. The FDA guidance on food-effect 
studies for bioequivalency testing identifies a “ high-fat” diet as a diet which maintains 
approximatively 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 for the intake of the caffeine tablet for CYP1A2 
measurement). Consumption of quinine-containing drinks (e.g., tonic water) is not 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 described in this 
section. 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. 

 
 
 
 
 
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Fasting state has to be observed for at least 10 hours prior to blood draws for: 
1. safety laboratory on screening, Day 0, Day 6  
2. risk marker in serum/plasma/blood on Day 0 and Day 6.  
3. serum/plasma bio-banking samples for further analysis of BoExp and risk markers at the 
Screening Visit, on Day 0, Day 6. 
4. blood bio-banking for transcriptomics on Day 0, Day 6. 
6.6.2.2 Ambulatory Period 
The above dietary restrictions are not applicable for the ambulatory period. However, 3 days 
prior to the Day 30 Visit, the Day 60 Visit, and the Day 90 Visit, and during visits on site, 
subjects will be asked by the study collaborators 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 ambulatory visits.  
A fasting state has to be observed for at least 10 hours prior to blood draws for: 
1. safety laboratory on Day 31, Day 61, and Day 91  
2. risk factor assessments in serum/plasma/blood on Day 31, Day 61 and Day 91.  
3. serum/plasma bio-banking samples for further analysis of BoExp and risk markers on 
Day 91. 
4. blood bio-banking for transcriptomics on Day 91. 
6.7 Concomitant Medication 
No medication should be taken during the study from the screening to the time of discharge 
on Day 91 without prior informing the Investigator. However, the Principal 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. 
During the ambulatory period, subjects in the SA arm may use NRT on the judgment of the 
Investigator or on request of the subject. No medication supportive for smoking cessation 
other than NRT will be allowed in the study. 
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. 
Paracetamol will be allowed at a daily total dose of up to 1500 mg. Any medication with an 

 
 
 
 
 
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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 7.4.5).. 
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 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 time of discharge on 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 
Fluoroquinolones, including ciprofloxacin and ofloxacin, 
nafcillin, rifampicin 
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, 
propanolol, 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 
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) 

 
 
 
 
 
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Data source: 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 and control 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 (see Section 9). Study collaborators 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 for study participation) (Section 1.3). 
In addition to the ICF for study participation, the subject will be asked to provide his separate 
consent for two kinds of biobanking (Sections 1.3.2).  
• ICF to the additional bio-banking of serum/plasma/urine samples for further 
measurements of BoExp and risk markers.  
• ICF to the additional bio-banking of blood sample for further transcriptomics 
(pharmacogenomics) analysis.  
The subject’s participation in the study does not depend on their consent for both bio-banking 
for BoExp of exposure/risk markers and for pharmacogenomics analysis) will be separate to 
that for study participation. The three consents will be captured in the eCRF. 
7.2 Advice on the Risk of Smoking/Smoking Cessation Advice and 
Debriefing 
Each subject will be given advice on the risks of smoking six times during the study: at the 
Screening Visit, at Admission (Day -2), at Day 6, and at 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 WHO recommendations (Raw et al., 2002). Details of the interview will be recorded in the 
Source Document File. Information on the risk of smoking will be given to the subjects on an 
individual basis during a face-to-face meeting between the subject and the Investigator, or 
dedignee and may additionally be given in a group session. 

 
 
 
 
 
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In addition to the smoking cessation advice, a debriefing of subjects will be done at each 
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. 
7.3 Support for the Smoking Abstinence Arm 
All subjects in the SA arm will be closely monitored from Day 1 onwards until Day 91 by the 
study collaborators for possible signs and symptoms of nicotine withdrawal. This includes 
clinical monitoring e.g. vital signs, physical examination, and body weight. It also involves 
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 study site collaborator.  
7.4 Clinical Assessments 
Any clinically relevant finding detected during the Screening Visit has to be documented as a 
concomitant disease. This also applies to clinically relevant findings in e.g. 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 needs to check if inclusion criterion no. 04 is still 
fulfilled. 
7.4.1 Demographic Data 
Demographic data (sex, date of birth/age) 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 study collaborators. The study collaborator will 
document the brand name and yields. A photograph of the front and the side of the cigarette 
pack supplied by the subject (bearing the tar, nicotine) will be taken by the study 
collaborators in addition to recording the brand name and yield. These photographs will be 
considered as Source Documentation. A copy of the photographs will be provided to the 
Sponsor electronically (as Digital Video Disk or Compact Disk). 

 
 
 
 
 
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7.4.3 Smoking History and Willingness to Quit Smoking 
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 three 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. At the Screening Visit only, the subject will also be asked if he/she plans to quit 
smoking within the next 3 months. 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 90 days (as required in the study protocol inclusion 
criteria number 7). Only subjects who are prepared and able to comply with this requirement 
will be considered for participation in the study. 
7.4.4 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 3 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. The product test will be the last 
assessement prior to enrolment. 
7.4.5 Product Preference 
In order to perform a complementary analysis on subjects’ preference, the following question 
will be asked on Day -2 after enrolment to all subjects. 
Which product would you prefer to be randomized to: 
• THS 2.2 menthol. 
• mCC. 
• SA. 
• no preference. 

 
 
 
 
 
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7.4.6 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 end of 
the study will be recorded on the eCRF. 
7.4.7 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).  
7.4.8 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 ) 

 
 
 
 
 
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height in meters² 
 
Weight and waist circumference will also be analyzed as risk markers (Section 7.5.2.1). 
7.4.9 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. For every measurement, it will 
be documented if the subject has smoked within 15 minutes prior to the measurement. 
Systolic and diastolic blood pressure will also be analyzed as risk markers (Section 7.5.2.1). 
7.4.10 Other Clinical Assessments 
7.4.10.1 
Spirometry 
Spirometry with and without a short-acting bronchodilator will be done at the Screening Visit 
to evaluate inclusion/exclusion criteria (the post-bronchodilator results). At screening, 
spirometry without bronchodilator will be done first, and then, spirometry with 
bronchodilator. At screening, spirometry has to be conducted at least 1 hour after smoking. 
Furthermore, spirometry without bronchodilator will be performed prior to product use at 
Day 0 (baseline values), on Day 6, and Day 90 Visit (Day 91) (for comparison with the 
baseline values). 
Spirometry will follow the 2005 testing and quality recommendations by the American 
Thoracic Society/European Respiratory Society Joint Task Force on the standardization of 
spirometry along with the electronic data submission and documentation processes. 
Spirometry predicted values will be standardized to the NHANES III predicted set. 
All personnel performing lung function testing should have the appropriate training and 
quality control (QC) 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). 
The FEV1 and FVC will be recorded. 
The subject will be submitted to a spirometry with maximum voluntary ventilation 
measurement. 

 
 
 
 
 
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For spirometry, assessed parameters will include: 
• FEV1. 
• FVC. 
• FEV1/FVC. 
7.4.10.2 
Electrocardiogram 
An Electrocardiogram (ECG) will be recorded at Screening, on Day 6, at Day 30 Visit (Day 
30), Day 60 Visit (Day 60), and at 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 10 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. 
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. 
7.4.10.3 
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. 
7.5 Biomarker Assessment 
All bioanalytical assays and laboratory assessments will be carried out using validated 
methods (see 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. 

 
 
 
 
 
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7.5.1 Biomarker of Exposure  
7.5.1.1 Exhaled CO and Carboxyhemoglobin 
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. (Section 6.5.4). 
CO Breath Test 
Carbon monoxide in exhaled breath will be measured using the Smokerlyzer® device such as 
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 
four 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 at 
between 08:00 AM-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 
COHb measurement will be performed in all 3 study arms at a local laboratory. 
Carboxyhemoglobin will be assessed on a daily basis from Day-1 until Day 5. 
On Day -1 to Day 4: one blood sample will be collected in the evening between 8:00 PM-
09:30 PM. 
On Day 5: one blood sample will be collected within 15 minutes prior first product use. The 
three other blood samples will be collected as described in Section 9. 
For subjects in the SA arm from Day 1 onwards, the first COHb will be done between 
08:00AM-09:30 AM. The three other blood samples will be collected as described in 
Section 9. 

 
 
 
 
 
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On Day 30 Visit (Day 30), Day 60 Visit (Day 60)and Day 90 Visit (Day 90): for all study 
arms, one blood sample will be collected during the visit, irrespective of the time of product 
use. 
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 both on 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-09:30 PM. 
• Nicotine/cotinine Pharmacokinetic (PK) Profile on Day 5 and Day 6 (THS 2.2 Menthol 
and mCC arms only): 
In total, nine blood samples will be drawn on Day 5. The first blood sample on Day 5 will 
be drawn within 15 minutes prior 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 eight 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 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 
eight 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 will be taken in the evening between 
8:00 PM-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. 

 
 
 
 
 
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7.5.1.3 Other Biomarkers of Exposure 
BoExp will be measured as per the Schedule of Events (see Appendix 1): 
• in 24-hour urine collection samples during the confinement period from Day -1 onwards 
to Day 5.  
• in 24-hour urine collection during the ambulatory period collected on Day 30 Visit, on 
Day 60 Visit, and on Day 90 Visit.  
The following BoExps 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 samples. 
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, 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 there 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 vitals signs 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, homocystein, LDL, HDL 

 
 
 
 
 
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at the mentioned timepoints. The results on blood glucose, TG, and TC from the safety 
laboratory panel on Day 0, Day 31, Day 61, and Day 91 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 on Day 0, and Day 90 Visit (Day 91). 
Samplings will be planned to measure HbA1c at the mentioned timepoints. 
• sICAM-1 measured 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 and Day 5 and in 24-hour urine collection on Day 30 Visit, Day 60 Visit , and 
Day 90 Visit. Samplings will be planned to measure 8-epi-PGF2α and 11-DTX-B2 at the 
mentioned timepoints. The results will be normalized to creatinine and express as 
concentration adjusted to 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: to be assessed as risk markers on Day-2 on Day 90 
Visit (Day 91)as evaluated as part of the clinical examination (see Section 7.4.8). 
7.5.2.2 CYP1A2 activity test 
CYP1A2 activity will be measured on Day 0, Day 5, and Day 90 Visit (Day 90). 
Measurement of enzyme activity will be based on the post-dose PX and CAF plasma molar 
concentrations approximately 6 hours (±15 minutes) after the intake of one Tomerumin® 
(LionCorp.) caffeine tablet (around 170mg caffeine) with 150 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 (the blood sample will be taken 6 hours [±15 minutes] after the intake of the tablet) 
must be recorded. CYP1A2 activity will be assessed by measuring PX and CAF and 
calculating the PX/CAF molar metabolic ratio (Faber et al., 2004). 
7.5.2.3 CYP2A6 activity 
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 and cotinine (Jacob et al., 2011). 

 
 
 
 
 
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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 on 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.  
7.6 Laboratory Assessments 
A list of laboratories is provided in Appendix 2. 
7.6.1 Clinical Chemistry, Hematology, and Urine Analysis for 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 (see 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 and p24 antigen) 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 and at Admission to the clinic (Day -2) 
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 Breath Test 
Subjects will have a breath alcohol test at the Screening Visit and at Admission to the clinic 
(Day -2) using an alcometer device. 
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 31), Day 60 Visit (Day 61), 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 will inform the subject about the risks associated with 
smoking during pregnancy. In the event of an unclear urine pregnancy test, absence of 
pregnancy should be confirmed by a serum follicle stimulating hormone level >20 IU/l. 
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 
sample and the safety laboratory panel which will be tested at a local laboratory (see 
Appendix 2). The urine test for 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 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. 
7.7.1 Blood samples 
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 around 290 ml, which includes 50 ml for safety and repeated analysis, 30 ml of 
blood for long term storage of the bio-banking samples for further anaylsis of BoExp and risk 
markers (only if additional consents are given) and 15 ml for long-term storage bio-banking 

 
 
 
 
 
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samples for further analysis of transcriptomics (only if additional consents are given) (see 
Section 7.7.3). 
The blood sampling for transcriptomics and the data related to these samples will be 
anonymized. Anonymised 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. 
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 the confinement period: 
For the 24-hour urine collection, subjects will empty their bladders shortly before 06:30 AM 
on the study day indicated in the Schedule of Events (Appendix 1). The collection period 
starts at 06:30 AM and ends on the following day at 06:29 AM. 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. 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 the ambulatory period: 
Twenty four-hour urine fraction will be collected on Day 30 Visit, Day 60 Visit, and Day 90 
Visit) at site.  
Subject will be asked to come at site at around 08:00 AM on Day 30, Day 60 and Day 90 and 
will remain overnight on site until respectively Day 31, Day 61, and Day 91. Subject will be 
asked to empty his bladder on Day 30, Day 60, and Day 90 shortly before 09:00 AM minutes 
(this urine will be discarded). Then collection period will start at 09:00 AM ± 20 minutes. 
After nearly 24-hours of urine collection the day later at 08:59 AM ± 20 minutes, subjects 
will empty their bladder again and this urine will be used as the final portion of the 24-hour 
urine sample. 
For both confinement and ambulatory periods; 
All urine passed during the sampling period 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 

 
 
 
 
 
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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 collaborators.  
For assessment of urine BoExp, creatinine for normalization of urine BoExp, 8-epi-PGF2α 
and 11-TBX-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 (see 
Appendix 1), the dot corresponds to the day on which the 24-hour urine collection period 
starts. For example, for NEQ measured at Day 30 Visit in the 24-hour urine collection that 
starts on Day 30 and ends later on Day 31. 
7.7.3 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, 
additionnal samples of urine (from the 24-hour urine collection) and serum/plasma (30 ml of 
blood in total) will be collected as follows: 
• Samples from the 24 hour urine will be collected from the urine collections that started 
on Day 0, Day 5, and Day 90 Visit (10 tubes of 10 ml each per time points). 
• Serum/plasma will be collected on Day 0, Day 6, and Day 90 Visit (30 ml of blood in 
total with 2 tubes of 5 ml of blood drawn per timepoint: from one tube two x 1 ml plasma 
and from the second tube 2 x 1 ml of serum will be collected and stored). 
If a subject gives consent for sample biobanking of whole blood for further transcriptomics  
analysis, a total of 15 ml of blood will be collected as follows: 
Blood will be collected on Day 0, Day 6, and Day 90 Visit (15 ml in total with 5 ml per 
timepoint. The 5 ml will be split into two tubes of 2.5 ml each). 
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. 
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. 

 
 
 
 
 
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7.8 Other Study Procedures 
7.8.1 Product Use 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 Day 90 11:00 PM Subjects will be trained by the study collaborators in the use of this 
electronic diary during the confinement period at the time the diary is delivered to the subject 
by the study collaborator (Day 6). 
7.8.2 Human Smoking Topography Assessment 
Human smoking topography (HST) involves the measurement of each smoker’s unique way 
of smoking mCCs or using Menthol Tobacco Sticks using the HST SODIM® device. The 
HST SODIM® device, model SPA/M (SODIM® Instrumentation, Fleury les Aubrais, France) 
is a device which is used to measure smoking topography (see Appendix 5). 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 THS Tobacco Stick being 
smoked/used. The holder is connected by two narrow tubes to a portable data 
logger/recording system (see Appendix 5) 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 SODIM® device 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 non-slim mCCs. 
The Sponsor will provide training on the use of the HST SODIM® device to the study 
collaborators. The study collaborators will, in turn, provide training to the subjects. All HST 
SODIM® devices will be returned to the sponsor after completion of the study. 

 
 
 
 
 
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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 below. From the per-puff parameters (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 the per-cigarette parameters will be part 
of the study database and will be analyzed. 
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 

 
 
 
 
 
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Description 
Variable 
Formula 
Unit 
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 
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 tobacco plugs collected during the study will be sent to the Sponsor for subsequent visual 
inspection to determine whether combustion occurred during product use. 
7.8.2.3 THS Filter Analysis 
All filters from used Menthol Tobacco Sticks will be sent to an external laboratory for 
analysis. All filters from used THS Menthol Tobacco sticks will be collected from Day 1 to 
Day 5. No filter analysis will be done during the ambulatory period. 
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 and instructions will be provided 
in the subject’s local language. The questionnaires and the VAS will be reviewed for 
completeness by the study collaborators 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 questionnaire 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 collaborators, 
using open, non-directive questions (see Section 8.2). 

 
 
 
 
 
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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 
product use/smoking and no later than 10:00 AM. On Day 30 Visit and Day 60 Visit, 
assessment of cough will be conducted irrespective of the time of product use but no later 
than 10:00 AM. On Day 90 Visit (Day 91), assessment of cough will be conducted prior to 
smoking 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, three 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. 

 
 
 
 
 
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Finally, subjects will be asked with an open question if they want to share any other 
important observations with the study collaborators 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). 
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 two scales: a ‘self-report scale’ and an ‘observer scale.’ 

 
 
 
 
 
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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 60 Visit and Day 90 Visit. 
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 Vist (Day 31), and Day 60 Visit (Day 
61), assessment of MNWS will be conducted irrespective of the time of product use but no 
later than 10:00 PM. On Day 91, Assessment of MNWS will be conducted prior to smoking 
but no later than 10:00 AM 
7.8.3.6 HST Questionnaire 
A specific questionnaire, used for exploratory purposes has been developed toevaluate the 
impact of the utilization of the HST SODIM® device on smoker’s smoking/inhalation 
experience in terms of ritual disruption. 
This is a questionnaire with five items to be rated on a 5-point scale and open questions. 
Subjects will be asked by the Investigator to complete the HST questionnaire at: 
• On Day 0 for all subjects smoking mCC compatible with the HST device (i.e.,non-slim 
mCC) 
• On 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). 
7.8.3.7 Socio-econonomic Status Questionnaire  
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 

 
 
 
 
 
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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. This questionnaire will allow the Sponsor to assign the subject household’s 
SES. 
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 socio-economic status questionnaire. Subjects will be asked a 
series of questions related to their education, occupation, size and monthly income of their 
household. 

 
 
 
 
 
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8 ADVERSE EVENTS 
8.1 Definitions 
8.1.1 Adverse Events 
The FDA MRTP guidelines (FDA, 2011) specify the following definition for adverse events 
for tobacco products: an AE is any health-related event associated with the use of tobacco 
product in humans, which is adverse or unfavorable, whether or not it is considered related to 
the tobacco product, as defined by the MRTP guidelines. 
An AE is defined as any untoward medical occurrence in a subject, or clinical investigation 
subject administered an IP, which does not necessarily have a causal relationship with the IP. 
An AE can therefore be any unfavorable and unintended sign (including a clinically relevant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
IP, whether or not related to the IP. 
8.1.2 Serious Adverse Events 
An 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 SAEs (they will be recorded only as AEs). However, any AE that occurs during 
this pre-planned hospitalization will be considered according to the above definitions. 

 
 
 
 
 
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8.2 Assessment of Adverse Events 
The Investigator is responsible for obtaining, assessing and documenting all AEs during the 
study. 
8.2.1 Collection of Information 
Adverse event information will be collected from the time of signature of the ICF onwards 
until End of Study (EOS) either by the Investigator via spontaneous reporting or by the use of 
consistent, open, non-directive questions from study site collaborator (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, the collection of AE information may also be 
triggered from his/her review of the subject questionnaires and the VAS. However, the main 
source for AE collection will be the face-to-face interview 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 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 
case report form (eCRF) and on a separate SAE report form (see Section 8.3). 
8.2.2 Period of Collection 
From the signature of the ICF onwards until EOS, all AEs (includes SAEs) will be collected 
by the Investigators and study site collaborator as described below. 

 
 
 
 
 
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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 collaborators 
and assessed by the Investigator in order to establish relationship or relatedness in respect to 
study procedures. Only the study procedures-related AEs will be reported in the clinical 
study report and in accordance with respective regulatory guidelines. 
8.2.4 Admission Day until the End of Study 
From Admission onwards until Day of Discharge, all AEs will be actively collected by the 
study collaborators.  
Any new, clinically relevant, abnormal finding or worsening of a pre-existing 
condition/concomitant disease detected during the study 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. SAEs 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 on behalf of the Sponsor (see 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 activities of daily living 
(ADL). 
Moderate:  
The AE interferes with ADL, but the subject is still able to function. 
Severe:  
The AE is incapacitating and requires medical intervention. 

 
 
 
 
 
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8.2.6 Relationship to Investigational Product and Relationship to Study 
Procedures 
According to the Council for International Organizations of Medical Sciences VI Working 
Group, there are no definitive methods for distinguishing most adverse drug reactions (i.e., 
events that are causally attributed to the IP) from clinical AEs that occur as background 
findings in the population and have only temporal association with the IP.  
In general, all AEs and/or SAEs will be assessed by the Investigator 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 shall document a potential relationship of the clinical 
event to any particular study procedure. 
Not related: The temporal relationship of the clinical event to IP administration or a study 
procedure 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 or a 
certain study procedure 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/or has not been previously observed 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 of Serious Adverse Events 
Any SAEs reported or observed during the study after signature of the ICF until the end of 
the safety follow-up period (i.e. up to 28 days after study Discharge), whether or not 
attributable to the IP, to any other medication or to any study procedures, must be reported by 
the Principal Investigator within 24 hours after first awareness by any party to 
 
 and to the Sponsor, and the head of the Investigational site. 
An SAE report form must be faxed or e-mailed as attachment to: 

 
 
 
 
 
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Phone number: 
 
Toll-free fax: 
 
E-mail: 
 
 
Address: 
 
 
 
 
Sponsor: 
Contact: 
  
 
 
Phone number: 
+41
 
E-mail: 
 
 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube 
5 Quai Jeanrenaud 
2000 Neuchâtel 
Switzerland 
The Principal Investigator/the head of the investigational site is responsible for local 
reporting (e.g. to the IRB) of SAEs that occur during the study, according to local 
regulations. 
Any follow-up information will be detailed in a subsequent SAE Report Form and sent to 
 and the Sponsor. 
The follow-up SAE report form must include the minimum information required for form 
completion and only changed/new information needs to be specified. Information provided in 
the follow-up SAE report form supersedes any information that is initially reported. 
All SAEs will be followed-up by the Investigator until 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. chronic condition). 
The SAE report form to be used in this study is provided as a separate document. All SAEs 
will be recorded on the relevant eCRF page, in addition to the SAE report form. 

 
 
 
 
 
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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 and assessed for clinical relevance. If the Investigator considers 
the abnormal result to be of clinical relevance, then it must be recorded as a concomitant 
disease at Screening, or if not present at Screening, as an AE during the study. 
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 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 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 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 must report this worsening as an AE. 
• Where there is no grading available, the abnormal laboratory value will be evaluated by 
the Investigator, 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, be reviewed and assessed. 
Even if they do not meet the criteria of the CTCAE grading scheme (please see above), 
the Investigator 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. 

 
 
 
 
 
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8.4.2 Abnormal Results of Other Tests or Investigations 
An ongoing medical condition or clinically relevant finding detected during the Screening 
Visit (including elevated laboratory parameters), will be considered a concomitant disease 
and the subject’s eligibility for admission to the study will be reviewed. 
Any new, clinically relevant, abnormal finding or worsening of a pre-existing condition 
detected during the study after Screening until the end of the study will be documented as an 
AE. 
Any new onset of symptoms or worsening of pre-existing symptoms identified through the 
study questionnaires may be documented as AEs at the discretion of the Investigator. 
8.5 Reporting and Follow-Up of Pregnancies 
For pregnancies detected during the Screening period 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.  
All pregnancies occurring after signature of the ICF and diagnosed after first exposure to the 
IP until completion of the study must be reported by the Investigator.  
Any pregnancy potentially associated to exposure to the IP, including pregnancies 
spontaneously reported to the Investigator after the EOS must be reported by the Investigator 
and followed-up. Potential association with exposure to the IP is defined as the conception 
date being calculated before the last exposure to the IP. 
The Investigator 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 (see Section 8.3). In addition, each pregnancy has to be 
reported as a non-serious AE. No invasive procedures, including drawing of blood, must be 
done in such subjects after the discovery of pregnancy.  
United BioSource Corporation Safety will follow-up pregnancies only if they were detected 
after first product use (i.e., after THS 2.2 Menthol 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 complications, 
adverse pregnancy outcomes, or maternal complications will be recorded. 

 
 
 
 
 
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The Principal Investigator/head of the investigational site 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 EOS 
procedures, as described for the Day of Discharge, as soon as possible and will enter the 
period of safety follow-up. The Investigator 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 the 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 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 Charger, applying any chemicals, using 
conventional cigarettes, mechanical damage of the unit, etc.) that result in hazards must 
be documented and reported by the Investigator.  
According to FDA medical Device Regulation, data should be collected regarding the use-
related hazards that have occurred with device and when information pertaining to device use 
safety is extensive, it is helpful to provide it in summary form that highlights the most 
important issues, considerations, resolutions, and conclusions. The level of detail of device 
use documentation submitted should be consistent with the level of concern of use-related 
hazards for the device. 
8.8 Investigational Device Malfunction  
Any occurrences of malfunction of the Tobacco Stick Holder or Charger will be documented 
by the Investigator using a Device Issue Log. 

 
 
 
 
 
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Furthermore, any malfunctions of the Tobacco Stick Holder or 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 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 assessments 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-bankings 
 
 
 
Advice on the risk of smoking and debriefing 
 
 
 
Demographic data collected 
 
 
 
Identification of current mCC brand 
 
 
 
Medical history/concomitant disease 
 
 
 
Prior (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 
 
 
 
Willingness to quit smoking within the next 
3 months and to abstain from smoking for up 
to 90 days 
 
 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to measurement 
 
√ 
Clinical laboratory parameters (hematology, 
urine analysis, clinical chemistry) 
To be done after at least 10 
hours of fasting 
 
 
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 breath test screen 
 
 
 
Fagerström Test for Nicotine Dependence 
(FTND) 
 
 
 
Spirometry first without then with short-
acting bronchodilator 
Has to be done at least 1 hour 
after smoking 
 
 
ECG 
At least 10 minutes in supine 
position prior to recording 
 
 
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 purpose. The sequence will 
be at the discretion of the site after signature of ICF. 

 
 
 
 
 
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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. Subjects will attend the investigational site in at least 10-hour fasting state for 
clinical laboratory to be assessed. 
Table 8 shows the assessments 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 
All day 
Time of admission-
06:30 PM 
 
Urine pregnancy test (all females only) 
 
Time of admission-
06:30 PM 
 
Advice on the risk of smoking and 
debriefing  
 
Time of admission-
06:30 PM 
 
Smoking history  
 
Time of admission-
06:30 PM 
 
Willingness to abstain from smoking for up 
to 90 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 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 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 
 
Inclusion/exclusion criteria 
 
Time of admission-
06:30 PM 
 
Identification of current mCC brand 
 

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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Final 3.0/ 07 April 2014 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Admission 
 
Time of admission-
06:30 PM 
 
Product test of 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 
 
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 
 
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 show the assessments that will be performed at baseline (Day -1 and 
Day 0, respectively): 

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
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 
06:30 AM+/-20min 
 
Start collection of 24-hour urine to Day -1 
sampling bottle 
The subject must empty his 
bladder and discard the urine 
prior o the start of urine 
collection 
 
 
CO breath test 
Within 15 minutes before first 
mCC 
06:30 AM 
 
Beginning of smoking 
 
Before 10:00 AM 
 
Breakfast 
 
Before 11:30 AM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position 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 
 
Evening until 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 
QSU-brief questionnaire 
 
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. 

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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Final 3.0/ 07 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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
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 
06:29 AM+/-20min 
 
End of 24-hour urine collection andsamples 
to be taken from the 24-hour urine after the 
final portion of urine has been added to 
Day -1 sampling bottle.  
BoExps (primary secondary 
and NEQ) and creatinine  
 
06:30 AM+/-20min 
 
Start collection of 24-hour urine to Day 0 
sampling bottle 
 
 
 
√ 
CYP2A6 activity in plasma 
Has to be done prior to 
smoking 
 
 
Spirometry without short-acting 
bronchodilator 
Has to be done prior to 
smoking 
 
 
Assessment of cough 
Has to be done prior to 
smoking but no later than 
10:00 AM 
 
 
MNWS questionnaire 
Has to be done prior to 
smoking but no later than 
10:00 AM 
 
 
CO breath test 
Within 15 minutes before first 
smoking event.  
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 
Has to be done after at least 
10 hours of fasting. 
Blood glucose, TG, TC, 
WBC, platelet count from 
safety will be evaluated also 
as risk markers 

 
 
 
 
 
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Final 3.0/ 07 April 2014 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
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without the written consent of Philip Morris Products S.A. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Baseline Day 0 
 
 
√ 
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 
 
 
Urine safety analysis 
 
Before 10:00 AM 
 
Breakfast 
 
Before 11:30 AM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to measurement 
Systolic and diastolic BP to 
be evaluated also as risk 
markers 
10:00 AM-11:30 
AM 
 
A caffeine tablet containing approximately 
170 mg of caffeine + 150 ml water ± 10 ml 
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 the caffeine tablet 
04:00 PM-05:30 
PM 
 
CO breath test 
 
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 
 
08:00PM-11:00 PM 
 
HST questionnaire  
If compatible mCC are 
smoked 
08:00 PM-11:00 
PM 
 
MCEQ questionnaire,  
QSU-brief questionnaire 
 

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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Final 3.0/ 07 April 2014 
Page 110 of 181 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Baseline Day 0 
 
11:00 PM 
 
End of smoking 
 
06:30 AM-11:15 
PM 
 
Collection of all mCC butts 
For accountability 
Abbreviations: AE = adverse event; BoExps = 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; WBC = white blood cell count. 
* Platelet count, WBC, blood glucose, triglycerides, and total cholesterol from safety will also be assessed as risk markers  
9.2.3 Exposure Period in Confinement (Days 1 06: 30 AM to time of 
Discharge on Day 6) 
The tables in this Section show the assessments that will be performed during the 
confinement period (Day 1 to Day 5). Table 11 shows the assessments 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+/-20min 
 
End of 24-hour urine collection and samples 
to be taken from the 24-hour urine after final 
portion of urine has been added to Day 0 
sampling bottle.  
BoExps (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)  

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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Final 3.0/ 07 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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 1 
 
Must be prior to first product 
use of Day 1 
06:30 AM+/-20min 
 
Start collection to Day 1 sampling bottle 24-
hour urine  
 
 
 
Assessment of cough (VAS) 
To be done prior to product 
use but no later tha 10:00 PM 
 
 
MNWS questionnaire 
To be done prior to product 
use but no later tha 10:00 PM 
 
 
CO breath test 
Within 15 minutes before 
first product use  (for THS 
2.2 Menthol and mCC arms) 
or between 08:00 AM-09:30 
AM (SA arm) 
06:30 AM-11:00 
PM 
 
HST 
In THS 2.2 Menthol and 
mCC arms, it should be done 
for all smoking events with 
HST SODIM® device, if 
compatible mCCs are smoked 
06:30 AM 
 
Beginning of product use 
 
Before 10:00 AM 
 
Breakfast 
 
10:00 AM-11:30 
AM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position 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 
 
08:00PM-11:00 PM 
 
MCEQ questionnaire (THS 2.2 Menthol and 
mCC arms only),  
QSU-brief questionnaire 
 
11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
Collection of used mCC butts 
For accountability 

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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Final 3.0/ 07 April 2014 
Page 112 of 181 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 1 
 
6:30 AM-11:15 PM 
 
Collection of all tobacco plugs and filters 
from Menthol Tobacco Sticks  
For accountability and further 
analysis 
Abbreviations: AE = adverse event; BoExps = 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; SAE 
= serious adverse event; THS = tobacco heating system. 
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+/-20min 
 
End of 24-hour urine collection andsamples to 
be taken from the 24-hour urine after the final 
portion of urine has been added to Day 1 
sampling bottle. 
BoExps (primary, 
secondary, and NEQ) and 
creatinine 
 
6:30 AM+/-20min 
 
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-09:30 
AM (SA arm) 
6:30 AM 
 
Beginning of product use 
 
Before 10:00 AM 
 
Breakfast 
 

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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Final 3.0/ 07 April 2014 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 2 
 
Before 11:30 AM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to 
measurement  
12:00 PM-01:30 
PM 
 
CO breath test  
 
Before02:30 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 
 
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 and filters from 
Menthol Tobacco Sticks  
For accountability and 
further analysis 
Abbreviations: AE = adverse event; BoExps = 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; SAE = serious adverse event; 
THS = tobacco heating system. 
Table 13 shows the assessments that will be performed on Day 3 of the confinement period: 

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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Final 3.0/ 07 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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
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+/-20min 
 
End of 24-hour urine collection and samples to 
be taken after final portion of urine has been 
added to Day 2 sampling bottle 
BoExps (primary, 
secondary, and NEQ)and 
creatinine  
 
6:30 AM+/-20min 
 
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 
 
 
CO breath test 
Within 15 minutes before 
first product use for THS 2.2 
Menthol and mCC arms or 
between 08:00 AM-09:30 
AM (SA arm) 
6:30 AM 
 
Beginning of product use 
 
Before 10:00 AM 
 
Breakfast 
 
10:00 AM-11:30 
AM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position 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 
 
CO breath test 
 

 
 
 
 
 
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Clinical Study Protocol 
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Final 3.0/ 07 April 2014 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 3 
 
PM 
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 
 
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 and filters from 
Menthol Tobacco Sticks 
For accountability and 
further analysis 
Abbreviations: AE = adverse event; BoExps = 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; SAE = serious adverse event; 
THS = tobacco heating system. 
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+/-20min 
 
End of 24-hour urine collection andsamples to 
be taken from 24-hour urine after final portion 
of urine has been added to Day 3 sampling 
bottle. 
BoExps (primary, secondary, 
and NEQ) and creatinine  
 
 
6:30 AM+/-20min 
 
Start collection to Day 4 sampling bottle 24-
hour urine 
 

 
 
 
 
 
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Final 3.0/ 07 April 2014 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 4 
 
 
 
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-09:30 
AM (SA arm) 
06:30 AM-11:00 
PM 
 
HST  
In THS 2.2 Menthol and 
mCC arms, HST SODIM® 
device has to be used for all 
product use if compatible 
mCCs are smoked 
6:30 AM 
 
Beginning of product use 
 
Before 10:00 AM 
 
Breakfast 
 
Before 11:30 AM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position 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 
√ 
Nicotine, cotinine in plasma 
 
08:00 PM-09:30 
 
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 
 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-07-JP 
Final 3.0/ 07 April 2014 
Page 117 of 181 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 4 
 
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 and filters from all 
Menthol Tobacco Sticks butts 
For accountability and further 
analysis 
Abbreviations: AE = adverse event; BoExps = 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; 
SAE = serious adverse event; THS = tobacco heating system. 

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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Final 3.0/ 07 April 2014 
Page 118 of 181 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
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 during smoking abstinence (SA arm 
only) if needed 
All day 
6:29 AM+/-20min 
 
End of 24-hour urine collection and samples 
to be taken from 24-hour after final portion of 
urine has been added to Day 4 sampling 
bottle. 
BoExps (primary secondary 
and NEQ) and creatinine 
 
6:30 AM+/-20min 
 
Start collection to Day 5 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-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-09:30 
AM (SA arm) 

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 5 
 
 
√ 
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 betweent 08:00  
PM-09:30 PM  
6:30 AM 
 
Beginning of product use 
 
Before 10:00 AM 
 
Breakfast 
 
Before 11:30 AM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to measurement 
10:00 AM-11:30 
AM 
 
A caffeine tablet containing around 170 mg 
of caffeine + 150 ml water ± 10 ml 
The time of the tablet  intake 
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 
Aftenoon 
 
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 
 

 
 
 
 
 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 5 
 
08:00 PM-11:00 
PM 
 
MCEQ questionnaire (THS 2.2 Menthol and 
mCC arms only),  
QSU-brief questionnaire 
 
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 and filters from  
Menthol Tobacco Sticks  
For accountability and 
frutrher analysis 
Abbreviations: AE = adverse event; BoExps = 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; sICAM-1 = soluble inter-cellular adhesion molecule; THS = tobacco 
heating system; WBC = white blood cell count. 
Table 16 shows the assessments that will be performed on Day 6, prior to Discharge from the 
study unit: 
Table 16. 
Time Schedule – Day 6 
Time 
Blood 
sample 
Procedure 
Additional information 
Start of procedure 
 
Day of Discharge Day 6 
 
 
AE/SAE recording; Concomitant medication 
All day until discharge 
 
 
Support during smoking abstinence (SA arm 
only) if needed 
All day until discharge 
 
√ 
Nicotine, cotinine - blood sampling: PK 
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 between 08:00 
AM-09:30 AMmin 

 
 
 
 
 
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Time 
Blood 
sample 
Procedure 
Additional information 
Start of procedure 
 
Day of Discharge Day 6 
 
6:29 AM+/-20min 
 
End of 24-hour urine collection and samples 
to be taken from the 24-hour urine  after final 
portion of urine has been added to Day 5 
sampling bottle 
BoExps (primary, secondary, 
and NEQ) and creatinine, and 
Ames mutagenicity 
Risk markers: 11-DTX-B2, 
8-epi-PGF2α, 
Biobanking 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 late.r than 10:00 
AM 
 
 
MNWS questionnaire 
To be done prior to product 
use but no late.r than 10:00 
AM 
 
 
Spirometry without short-acting 
bronchodilator 
Has to be done prior to 
product use 
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 
marker 
 
√ 
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 
 Before 09:00 AM 
 
Breakfast 
 
Prior to discharge 
of Day 6 
 
Physical examination, and weight and 
calculated BMI 
 
Prior to discharge 
of Day 6 
 
CO breath test 
 
Prior to discharge 
of Day 6 
 
Urine safety analysis 
 

 
 
 
 
 
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Time 
Blood 
sample 
Procedure 
Additional information 
Start of procedure 
 
Day of Discharge Day 6 
 
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 prior to measurement 
Systolic and diastolic BP to 
be evaluated also as risk 
marker 
Prior to discharge 
of Day 6 
 
ECG 
At least 10 minutes in supine 
position prior to recording 
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. 
Prior to discharge 
of Day 6 
 
Advice on risk of smoking and debriefing 
 
Prior to discharge 
of Day 6 
 
Collection of all used Menthol Tobacco 
Sticks and smoked mCC butts  
 
For accountability 
Prior to discharge 
of Day 6 
 
Time of Discharge from confinement/-
beginning of the exposure ambulatory period 
 
Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse event; 
BMI = body mass index; BoExps = biomarkers of exposure; BP = blood pressure; mCC = 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 time of 
Discharge of Day 90 Visit on Day 91) 
For Day 30 Visit, and Day 60 Visit, a time window of +/- 3 days will be allowed with respect 
to Day 30 and Day 60 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 and Day 60 of the 
ambulatory period: 

 
 
 
 
 
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Table 17. 
Time Schedule – Day 30 Visit (from 08:00 AM on Day 30 to check-out of 
the subject on Day 31) and Day 60 Visit (from 08:00 AM to check out of 
the subject on Day 61) 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 30 and Day 60  
 
08:00 AM 
 
Opening of the Day 30 and Day 60 Visits 
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 08:00 
AM to 11:00 PM 
The use of THS 2.2 menthol 
in smokers allocated to mCC 
and SA arms will be forbidden 
 
 
Support for smoking cessation (SA arm only) 
if needed 
At any time of the day 
 
 
AE/SAE questioning; Concomitant 
medication 
At any time during the day 
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 with the assigned product 
of the subject 
09:00 AM ± 20 min 
 
Start of 24-hour urine collection to Day 30 
and Day 60 sampling bottles 
The subject must empty his 
bladder and discard the urine 
prior to  starting urine 
collection 
Before 10:00 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 

 
 
 
 
 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 30 and Day 60  
 
12:30 PM-01:30 
PM 
 
End of HST recording 
The HST should be recorded 
over a period of 4 hours ± 15 
minutes. 
HST recording will be done 
only on the subject’s assigned 
product 
Before 02.30 PM 
 
Lunch 
 
02:30 PM -07:00 
PM 
 
ECG 
At least 10 minutes in supine 
position prior to recording 
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 prior to measurement 
Systolic and diastolic BP 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 
08:00 PM-11:00 
PM 
 
MCEQ questionnaire (THS 2.2 Menthol and 
mCC arms only),  
QSU-brief questionnaire 
 
In the evening 
before 09:00 PM 
 
Dinner  
 
11:00 PM 
 
End of Product use 
 
08:00 AM-11:15 
PM 
 
Collection of empty/partially used Menthol 
Tobacco Stick packs 
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; BoExps = biomarkers of exposure; CO = 
carbon monoxide; COHb = carboxyhemoglobin;  HDL: high density lipoprotein; ; hs CRP: high sensitive C-reactive 
protein;  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. 
 

 
 
 
 
 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 31 and Day 61  
 
 
 
Support for smoking cessation (SA arm only) 
if needed 
At any time of the day 
 
 
AE/SAE questioning; Concomitant 
medication 
At any time during the day 
 
√ 
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 PM ± 20 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 
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 and pregnancy test 
 
Prior to check.out 
of the given visit 
 
Advice on the risk of smoking and debriefing 
 
Check-out  
 
End of the Visit 
 
Abbreviations: 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse event; BoExps = biomarkers of exposure; CO = 
carbon monoxide; COHb = carboxyhemoglobin;  HDL: high density lipoprotein; ; hs CRP: high sensitive C_reactive 
protein;  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. 
 
The procedures for the last visit which will be conducted on Day 90 Visit +/- 3 days of the 
study are shown in Table 18. 
The time of opening and end of the visit are given as an estimate.  

 
 
 
 
 
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Table 18. 
Time Schedule – Day 90 Visit (08:00 AM of Day 90 to time of discharge of 
Day 91) 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Day 90 
 
08.00 AM 
 
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 08:00 
AM to 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 cessation (SA arm 
only) if needed 
At any time of the day 
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 ± 20 
min 
 
Start of collection of 24-hour urine  to 
Day 90 sampling bottle 
The subject must empty his bladder 
and discard the urine prior to  
starting urine collection 
Before 10:00 
AM 
 
Breakfast with a caffeine tablet 
containing approximately 170 mg of 
caffeine + 150 ml water ± 10 ml 
The time of the 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 
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 HST recording 
The HST should be recorded over a 
period of 4 hours ± 15 minutes 
Before 02:30 
PM 
 
Lunch  
 

 
 
 
 
 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Day 90 
 
03:00 PM-04:00 
PM 
√ 
CYP1A2 activity in plasma 
6 hours ±15 minutes after intake of 
the caffeine tablet 
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 
 
In the evening 
before 09:00 
PM 
 
Dinner 
 
08:00 AM-
11:15 PM 
 
Collection of empty/partially used 
menthol THS tobacco stick packs  
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 Stick  
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; BoExps = 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 
 
 
 
AE/SAE questioning; Concomitant medication 
At any time during the day 
 
√ 
CYP2A6 activity in plasma 
Has to be done prior to 
smoking 

 
 
 
 
 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Day 91 
 
 
 
Assessment of cough 
To be done no later than 
10:00 AM 
Has to be done prior to 
smoking 
 
 
MNWS questionnaire 
To be done no later than 
10:00 AM 
Has to be done prior to 
smoking 
 
 
Spirometry without short-acting bronchodilator 
Has to be done prior to 
smoking 
08:59 PM ± 20 
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 90 sampling 
bottle 
BoExp (primary, secondary, 
and NEQ), creatinine, ames 
mutagenicity 
Urine biobanking  
Risk markers: 11-DTX-B2 
and 8-epi-PGF2α 
 
 
√ 
Clinical laboratory parameters (hematology, 
clinical chemistry)*, and risk markers (s-ICAM-
1, hs-CRP, fibrinogen, homocysteine, LDL, 
HDL, TG, HbA1c) 
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 
 
√ 
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 
Before10:00AM 
 
Breakfast  
 
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 

 
 
 
 
 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Day 91 
 
In the afternoon 
prior to 
discharge of 
Day 91 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to 
measurement 
At any time during the day 
Systolic and diastolic BP to 
be evaluated also as risk 
marker 
In the afternoon 
prior to 
discharge of 
Day 91t 
 
ECG 
At least 10 minutes in 
supine position prior to 
recording 
In the afternoon 
prior to 
discharge of 
Day 91 
 
Urine safety analysis and pregnancy test 
 
In the afternoon 
prior to 
discharge of 
Day 91 
 
Advice on the risk of smoking and debriefing 
 
 
 
Time of Discharge On Day 91 
 
Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse event;; 
BMI = body mass index; BoExps = 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. 
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.  

 
 
 
 
 
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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 safety assessments as described on Day 6 will be performed as early termination 
procedures (see Section 9.2.4). 

 
 
 
 
 
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10 CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
The Clinical Research Associate (“Monitor”) will be responsible for the monitoring of the 
study. Monitoring will be performed according to CRO’s Standard Operating Procedure 
(SOPs) and as per the agreed monitoring plan with the Sponsor. 
The Principal Investigator/head of the investigational site 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 will be detailed 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 collaborator 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 study collaborator 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 study collaborator 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 Study Collaborators 
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 the Investigator’s meeting will 
be described in the monitoring plan.  
In addition to the Investigator meeting, the PI will ensure that appropriate training relevant to 
the study is provided to all study collaborator involved in the study, and that any new 
information relevant to the performance of this study is forwarded to the study collaborator 
involved in a timely manner. The record of all individuals involved in the study will be 
maintained in the Site Investigator File. 
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 Principal Investigator/head of investigational site 
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 collaborator 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 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 and 
documents specified therein. 
11.1 Data Capture 
11.1.1 Case Report Forms and Study Records 
With the exception of the subject reported outcome data, all results from the clinical 
assessments will be recorded in the Source Documents by the Investigator or 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 the electronic patient reported outcomes 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 Principal Investigator has ultimate responsibility for the collection and reporting of all 
data related to the clinical study and ensuring that the data are accurate, authentic/original, 
legible, timely (contemporaneous), enduring, and available when required. The eCRF must 
be signed by the Investigator to attest that the data contained in the eCRF are true and 
accurate. Any corrections made to Source Documents must be clearly recorded, without 
obscuring the original values and be accompanied by the date of change, reason for change, 
and identification of the person making the change. The eCRF for each subject will be 
checked against the Source Documents at the study site by the CRA. Instances of missing or 
unclear data will be discussed with the Investigator for resolution. An eCRF will be 
generated for all subjects that sign the informed consent.  
For the ePRO device, all subject reported outcome data will be provided in English and 
instructions will be provided in the subject’s local language.  
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 

 
 
 
 
 
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considered and handled as important communication, documented and tracked as protocol 
deviations, as necessary. 
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 are described in the SOPs 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 CRO will prepare a DMP, to be 
reviewed and approved by the Sponsor, prior to the start of the study. 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 
and stored 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 reported as defined in DMP and Data Validation Plan. 
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, at time of 
coding the first entry: 

 
 
 
 
 
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Medical history: 
Medical Dictionary for Regulatory Activities (MedDRA®) 
Adverse events: 
MedDRA® 
Medications: 
WHO Drug Dictionary Enhanced and Anatomical Therapeutic 
and Chemical classification system 
THS 2.2 Menthol 
device issues 
 and/or malfunctions: 
C54451/Medical_Device_Problem_Codes_FDA_CDRH 
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 the data is reviewed by the Sponsor, resolution of all raised queries and QC of the 
changed data, database, or selected data upon Sponsor approval as applicable, is 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 documented in the database log file. 
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’s 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. 
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, 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 standard deviation. 
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. 
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 alpha level of 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.  

 
 
 
 
 
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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 BoExps 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 conventional cigarettes to 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. 
Table 19. 
Expected Mean Ratios and Coefficients of Variation for THS 2.2 
Menthol/mCC 
 
THS 2.2 Menthol /mCC 
MR (CV) 
THS 2.2 Menthol /SA 
MR (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; CC = conventional cigarettes; COHb = carboxyhemoglobin; 
CV = coefficients of variation; MHBMA = monohydroxybutenyl mercapyuric 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 the mCC control arm in Total NNAL on Day 90 based on 
data from a 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. 

 
 
 
 
 
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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 ratios; SA = smoking 
abstinence; THS 2.2 = Tobacco Heating System 2.2. 
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, 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. 
 
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; CC = conventional cigarettes; COHb = carboxyhemoglobin; 
CV = coefficients of variation; MHBMA = monohydroxybutenyl mercapyuric acid; MR = mean ratios; 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 Section12.4.2. 

 
 
 
 
 
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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 
 
Table 23 describes the expected power to demonstrate a reduction on all 5 primary BoExps 
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% confidence intervals for the ratio between 
(geometrical) mean levels of primary BoExps in THS 2.2 Menthol and SA with upper and 

 
 
 
 
 
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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 standard deviation 
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 standard deviation 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), FDA 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. 
Although subjects 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 THS2.2 Menthol arm might be exclusively using THS2.2 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, using the reported number of cigarettes and/or Menthol Tobacco Sticks 
consumption since time of Discharge,  
• on Day 60, using the reported number of cigarettes and/or Menthol Tobacco Sticks 
consumption after Day 30 and  
• on Day 90, using the reported number of cigarettes and/or Menthol Tobacco Sticks 
consumption after Day 60. 

 
 
 
 
 
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Figure 2 presents a detailed overview on the definition of the product use categories: 
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 BoExp 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 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 BoExp 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 to creatinine. For non-smokers CEMA and CEMA 
concentration adjusted to 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. To 
evaluate the robustness of the interpretation of safety and the study level safety conclusions 
an additional subset of the safety analyses will also be presented on the full safety population, 
as specified in Section12.6.5. Safety will be summarized and 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 

 
 
 
 
 
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non-safety assessment (THS 2.2 Menthol, mCC, SA arms). Subjects that were enrolled at the 
site that was terminated due to ICH/GCP uncompliance will be excluded from the FAS. 
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 if randomized to THS 2.2 Menthol or SA 
arms. Non-compliance will be defined over a period ( confinement period, ]Day6-Day 
30 Visit], ]Day 30 Visit-Day 60 Visit], ]Day 60 Visit-Day 90 Visit] and will be defined 
as having smoked than 3 CC during a single day in that period or having smoked on 
average over that period more that, not including 0.5 cigarettes per day.  
• 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. Although subjects that were enrolled at the site that was 
terminated due to ICH/GCP uncompliance will be excluded from the safety population, they 
will be summarized within the Full Safety Population (see Section 12.4.4). 
12.4.4 Full Safety Population 
The full 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 full safety population will be 
analyzed according to actual exposure.  
12.4.5 Compliant Population 
The compliant population will be a subset of the PP 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 12.3 or 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 

 
 
 
 
 
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• 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 BoExps in the THS 2.2 Menthol arm compared to the CC arm, using a 
one-sided test test with 2.5% type I error probability. 
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 PP. 
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 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL) according to the primary 
and secondary objectives.  
Analysis of BoExp will be conducted on the natural log scale. In order to test the follow 
hypothesis: 
 
Null hypothesis (H0):  
 
m1≥m2 
 
Alternative hypothesis (H1): m1<m2 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A. 
 
Where m1 and m2 are the is the geometric means of the biomarker levels on Day 5 or on 
Day 90 for THS 2.2 Menthol and mCC respectively. 
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 vs mCC is significant. Estimates 
of differences between groups will be back-transformed to provide relative effects.  
Assumptions of the ANOVA model will be tested. Markedly non-lognormally distributed 
BoExp data will be transformed or analyzed by appropriate non-parametric methods. 
Should more than 20% of the subjects be excluded from the PP, would the above 
confirmatory analysis be repeated on the Compliant Population. 
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. 
12.6.3 Descriptive Analysis 
In general, secondary endpoints will be summarized as described in Section 12.1.3 according 
to the populations as described in Section 12.4. 
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 (except Total NNAL). 

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
12.6.5 Safety Analysis  
In general, all safety data will be listed and tabulated on the safety population by product 
arm, using the approach described in Section 12.1.3. Safety variables collected during 
exposure periods will also be reported by product exposure. 
Adverse events 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); 
spirometry; 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), summarized for the safety population and the full 
safety population. 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 and the full 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. 
12.7.2 Descriptive Analysis 
In general, exploratory endpoints will be summarized as described in Section 12.1.3 
according to the populations as described in Section 12.4. 
12.7.3 Preference Analysis 
At admission, subjects will be aksed for their preferred product (THS 2.2 Menthol, mCC, no 
preference). A sensitivity analysis will be run for the exposure according to the subjects’ 
preferred product. 

 
 
 
 
 
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are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
12.8 Demographics and Baseline Characteristics 
Demographic and other baseline characteristics will be reported according to the populations 
as described in Section 12.4. 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. 

 
 
 
 
 
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13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Principal Investigators and Study Administrative Structure 
13.1.1 Principal Investigators 
Mamoru Oki M.D., Ph.D. 
Seishukai Clinic 
3-18-5, Matsugaya, Taitou-ku,  
Tokyo 111-0036 Japan 
Phone: 
 
Professor Masahiro Endo M.D. 
Osaki Hospital Tokyo Heart Center 
5-4-12, Kitashinagawa, Shinagawa-ku,  
Tokyo 141-0001 Japan  
Phone: 
 
Fax: 
 
e-mail:
 
 

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
13.1.2 Sponsor 
Sponsor: 
Philip Morris Products S.A, 
Quai Jeanrenaud 5, 
2000 Neuchâtel, 
Switzerland. 
Tel: + 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 
 
E-mail: 
@pmi.com 
, PhD 
Medical Writer 
Phone: +41 
 
E-mail: 
 
 
Clinical Study Manager 
Phone: +41 
 
Mobile: +41 
 
E-Mail: 
@pmi.com  
 

 
 
 
 
 
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are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
13.1.3 Other Responsibilities 
 
 is the local Contract Research Organization designated by PMI to manage and 
monitor the study: all duties and responsibilities transferred to 
 by PMI will be defined 
in the agreement signed between the two parties. 
 
 
 
 
Responsible person (Clinical Pharmacology):  
 
 
 
Any SAEs or pregnancies will be handled by: 
 
 
 
 
Phone: 
 
Fax:  
 
E-mail: 
 
Details of the laboratories conducting the clinical safety laboratory services, 
biopharmaceutical analyses and the analyses of BoExp are shown in Appendix 2. 
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. 

 
 
 
 
 
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are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
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, health 
insurance ID card, medical chart number, etc.). The assignment of a subject number/code for 
subject identification will be based on the appropriate data protection rules. 
Any documents that allow full identification of the subject (e.g. the subject’s signed ICF) 
must be maintained in confidence by the 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, 
health insurance ID card, 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/head of the investigational site and all study site collaborator 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 
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 
Principal Investigator/head of investigational 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 Article 41 of 
Ministerial Ordinance on GCP (Ministry of Health and Welfare, 1997). Essential documents 

 
 
 
 
 
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are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
must be retained by the Principal Investigator or the head of the investigational site 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, or 
• 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 identification code list, Screening Log and Enrolment Log (if applicable). 
• Record of all communications between the Principal 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 head of 
the investigational site has delegated significant study-related duties, together with their 
roles in the study. 
• Investigator Logs. 
• eCRFs, study specific questionnaires (and associated data/scoring), subject diaries. 
• Adverse event 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. 
• 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. 

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
It is the responsibility of the Sponsor to inform the Principal Investigator/head of 
investigational site as to when these documents no longer need to be retained. 
The Principal Investigator/head of investigational site must take measures to prevent 
accidental or premature destruction of these documents. 
If the head of the investigational site wishes to assign the study records to another party or 
move them to another location, the Sponsor must be notified in advance. 
The head of the investigational site must obtain written approval from the Sponsor before 
destruction of any records. Normally, these records will be held in the Investigator’s 
archives. If the head of the investigational site 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 this 
information if any relevant changes occur during the course of the investigation and for 
1 year following the completion of the study. 

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
13.7 Publication and Disclosure Policy 
This document contains data, information and trades secretes that are confidential and 
proprietary to the Sponsor. This document 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). 
13.8 Insurance 
The Sponsor is responsible for AEs and health damage of the subjects that are associated 
with the THS 2.2 Menthol product or with study procedures which are used during this study, 
except for AEs and health damage of the subjects caused by a negligent or an intentional 
misconduct and/or significant deviation to the Protocol of the Investigator or the clinical 
study site or the subjects. The Sponsor has taken out insurance to coverany bodily injury and 
property damage caused by the operations cried out by the insured. . 

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
14 REFERENCE LIST 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
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without the written consent of Philip Morris Products S.A. 
 
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without the written consent of Philip Morris Products S.A. 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
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without the written consent of Philip Morris Products S.A. 
 
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constituents:BaP, phénols, TSNA et amines aromatiques. 
PMI, 2012b 
Philip Morris International, 2012. In French. Work Instruction PMI_RD_WKI_000527: 
Guide d’utilisation de l’extracteur in situ, nettoyage des seringues, des pistons, des aiguilles 
et des pieges (R2540.M109). Version 3.0. 
PMI, 2013a 
Philip Morris International, Neuchatel, Switzerland, 2013. Investigator’s Brochure for 
Tobacco Heating System 2.2. 
PMI, 2013b 
Philip Morris International. 2013. David Ghosh. Experimental report: Identifying the 
appropriate technique to collect and extract water, nicotine and glycerin from the TPM to 
further characterize the tar of the ZURICH product. Version 1.0. 
PMI White Paper Docket 
Food and Drug Administration (FDA), Division of Dockets Management. Philip Morris’s 
International comments on the scientific evaluation of the modified risk tobacco product 
applications. Docket no. FDA-2011-N-0443. 
Raw et al., 2002 
Raw M, Anderson P, Batra A, Dubois G, Harrington P, Hirsch A et al. World Health 
Organization European Partnership Project to Reduce Tobacco Dependence. WHO Europe 
evidence based recommendations on the treatment of tobacco dependence. Tob Control. 
2002; 11 (1): 44-46. 

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
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without the written consent of Philip Morris Products S.A. 
 
Saareks et al., 2001 
Saareks V, Ylitalo P, Alanko J, Mucha I, Riutta A. Effects of smoking cessation and nicotine 
substitution on systemic eicosanoid production in man. Naunyn Schmiedebergs Arch 
Pharmacol. 2001 May; 363 (5): 556-61. 
Tiffany et al., 1991 
Tiffany ST, Drobes DJ. The development and initial validation of a questionnaire on 
smoking urges. British Journal of Addiction. 1991; 86: 1467-1476. 
U.S. Department of Health and Human Services, 2010 
U.S. Department of Health and Human Services. How Tobacco Smoke Causes Disease: The 
Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon 
General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease 
Control and Prevention, National Center for Chronic Disease Prevention and Health 
Promotion, Office on Smoking and Health, 2010. 
Available at: 
http://www.surgeongeneral.gov/library/tobaccosmoke/report/executivesummary.pdf 
Vasan, 2006 
Vasan RS. Biomarkers of cardiovascular disease: molecular basis and practical 
considerations. Circulation. 2006 May 16; 113 (19): 2335-62. 
YVD-CS01-EU study 
Philip Morris International, 2009. YVD-CS01-EU study. A Controlled, Randomised, Open-
Label, 3-Arm Parallel Single-Centre Confinement Study to Investigate Exposure to Selected 
Smoke Constituents in Smokers Switching From Conventional Cigarettes to SMAR 
Cigarettes for 5 Days (ClinicalTrials.gov: ID: NCT00812279).  
Available at: 
http://clinicaltrials.gov/show/NCT00812279 (accessed on 22 February 2013) 

 
 
 
 
 
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Appendix 1 
Schedule of Events 
Table A1  
 
Study Assessments (separate table [Table A2] shown for 24 hour urine collections) 
 
Screening 
Confinement Period 
Ambulatory Period  
Safety 
Follow-up v 
 
 
 
 
 
 
 
 
 
 
 
Day 30 
Visit ± 3 
days 
Day 60 
Visit ± 3 
days 
Day 90 
Visit ± 3 
days 
 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
30  
31 
60  
61 
90 
91 
91 to 119 
Informed consent for 
study participation and 
two informed consents for 
bio-bankings 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission/Discharge 
 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
Advice on the risk of 
smoking and debriefing 
● 
● 
 
 
 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
Monitoring/Intensive 
support for SA arm 
 
 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
Inclusion/exclusion 
criteria 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical 
history,  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant diseases 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 

 
 
 
 
 
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Screening 
Confinement Period 
Ambulatory Period  
Safety 
Follow-up v 
 
 
 
 
 
 
 
 
 
 
 
Day 30 
Visit ± 3 
days 
Day 60 
Visit ± 3 
days 
Day 90 
Visit ± 3 
days 
 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
30  
31 
60  
61 
90 
91 
91 to 119 
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 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U: Urine drug screen, 
urine cotinine screening 
test 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U: Pregnancy test 
● 
● 
 
 
 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
Alcohol breath test 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FTND 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 

 
 
 
 
 
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Screening 
Confinement Period 
Ambulatory Period  
Safety 
Follow-up v 
 
 
 
 
 
 
 
 
 
 
 
Day 30 
Visit ± 3 
days 
Day 60 
Visit ± 3 
days 
Day 90 
Visit ± 3 
days 
 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
30  
31 
60  
61 
90 
91 
91 to 119 
Smoking history  
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Willingness to quit 
smoking in the next three 
months  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Readiness to abstain from 
smoking up to 90 days 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Identification of mCC 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THS 2.2 Menthol 
demonstration 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THS 2.2 Menthol product 
test g 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of mCC butts 
for accountability 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
      
 
      
 
 
Collection tobacco plugs 
of used Menthol Tobacco 
Sticks for further analysis  
 
 
 
 
● 
● 
● 
● 
● 
  
● 
 
● 
 
● 
 
 
Collection filters of used 
Menthol Tobacco Sticks 
for further analysis  
 
 
 
 
● 
● 
● 
● 
● 
 
 
 
 
 
 
 
 

 
 
 
 
 
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Screening 
Confinement Period 
Ambulatory Period  
Safety 
Follow-up v 
 
 
 
 
 
 
 
 
 
 
 
Day 30 
Visit ± 3 
days 
Day 60 
Visit ± 3 
days 
Day 90 
Visit ± 3 
days 
 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
30  
31 
60  
61 
90 
91 
91 to 119 
Collection filters of used 
Menthol Tobacco Sticks 
for accountability 
 
 
 
 
● 
● 
● 
● 
● 
● 
 
 
 
 
 
 
 
Collection of 
empty/partially used 
Menthol Tobacco Stick 
packs 
 
 
 
 
 
 
 
 
 
 
● 
 
● 
 
● 
 
 
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 
(primary and secondary, 
and BoExp to nicotine) j 
(see Table A2)  
 
 
● 
● 
● 
● 
● 
● 
● 
 
● 
 
● 
 
● 
 
 
B:Risk markers: hs-CRP, 
fibrinogen, homocysteine, 
LDL, HDL k 
 
 
 
● 
 
 
 
 
 
 
 
● 
 
● 
 
● 
 

 
 
 
 
 
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Screening 
Confinement Period 
Ambulatory Period  
Safety 
Follow-up v 
 
 
 
 
 
 
 
 
 
 
 
Day 30 
Visit ± 3 
days 
Day 60 
Visit ± 3 
days 
Day 90 
Visit ± 3 
days 
 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
30  
31 
60  
61 
90 
91 
91 to 119 
B: Risk Marker: s-ICAM-
1 l 
 
 
 
● 
 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
B: Risk Marker: HbA1c m 
 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
 
U: Risk markers: 8-epi-
PGF2α and 11-DTX-B2 
(see Table A2) n 
 
 
 
● 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
 
One caffeine tablet 
(170mg) 
 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
● 
 
 
B: CYP1A2 activity 
 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
● 
 
 
B: CYP2A6 activity 
 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
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 
 
 
 
● 
● 
● 
● 
● 
● 
● 
 
● 
 
● 
 
● 
 

 
 
 
 
 
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Screening 
Confinement Period 
Ambulatory Period  
Safety 
Follow-up v 
 
 
 
 
 
 
 
 
 
 
 
Day 30 
Visit ± 3 
days 
Day 60 
Visit ± 3 
days 
Day 90 
Visit ± 3 
days 
 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
30  
31 
60  
61 
90 
91 
91 to 119 
Preference product 
question 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE recording 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
U: Bio-banking for BoExp 
and risk markers  ( see 
Table A2) u 
 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
● 
 
 
B: Bio-banking for BoExp 
and risk markers u 
 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
B: Bio-banking for 
transcriptomics u 
 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse event; 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; 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 evaluated also 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), body weight and calculated BMI. Weight will be evaluated also as risk marker on Day 0 and Day 90 Visit (Day91) 
c: Waist circumference will be evaluated also as risk markers on Day -2 and Day 90 Visit (Day 91). 

 
 
 
 
 
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d: At screening, spirometry without bronchodilator will be done first, and then, spirometry with bronchodilator. At screening, spirormetry has to be conducted at least 1 hour after 
smoking. Furthermore, spirometry without bronchodilator will be performed prior to product use at Day 0 (baseline values), on Day 6, and Day 90 Visit (on Day 91 for comparison 
with the baseline values). 
e: WBC, 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 also ed 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. The first test should be conducted within 15 minutes prior to the first product use (for subjects in 
the Menthol 2.2 and mCC arms) and between  08:00 AM-09:30 AMfor 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 to Day 4: one blood sample in the evening between08:00 PM-09:30 PM. 
Day 5: one blood sample within 15 minutes prior to product use (for subjects in THS 2.2 Menthol and mCC arms) and between 08:00 AM_09:30 AM for subjects in the SA arm. 
The three other blood sampling will be conducted as described in section 9. 
Day 30 Visit (Day 30), Day 60 Visit (Day 60) and Day 90 Visit (Day 90): one blood sample to be collected during the visit, irrespective of the time of product use. 
j: Nicotine/cotinine; Day 0 to Day 4 (all study arms): one blood sample between 08:00 PM-09:30 PM. 
Day 5 and Day 6 (THS 2.2 Menthol and mCC arms): one sample within 15 minutes prior to the product use; eight blood samples after 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): on Day 5, one blood sample in the evening betwen 08:00 PM-09:30 on Day 5 and one blood sampling between 08:00 AM-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. 

 
 
 
 
 
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k:To be evaluated also as risk markers on Day 0, Day 30 Visit (Day 31), Day 60 Visit (Day 61) , and Da y 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 Da y 90 Visit (Day 91). 
m: To be evaluated also as risk markers on Day 0, and Da y 90 Visit (Day 91). 
n: To be evaluated also as risk markers on Day 0, Day 5, Day 30 Visit (Day 30), Day 60 Visit (Day 60), and Day 90 Visit (Day90). 
o: Daily during ambulatory period only (from time of Discharge on Day 6 to Day 90 only). Use of any tobacco/nicotine containing products will be captured in the e-diary. 
p: 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 no later than 10:00 AM, i.e. Day 30 Visit (Day 
31), and Day 60 Visit (Day 61) irrespective of time of product use and on Day 90 Visit (Day 91) prior to smoking. 
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). On Day -1 and Day 0, MCEQ will be aksed to all 
subjects. From Day 1, MCEQ will be asked to THS 2.2 Menthol and mCC arms only. 
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. Smoking topography with the HST 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 at every visit during the ambulatory period no later than 10:00 AM, 
i.e. Day 30 Visit (Day 31), and Day 60 Visit (Day 61) irrespective of time of product use and Day 90 Visit (Day 91) prior to smoking. 
u: Samples will only be taken if additional consent for bio-banking is given by the subject. 
v: Spontaneous reporting of new AEs/SAEs by the subject and active follow-up of ongoing AEs/SAEs by the site. 
 
 

 
 
 
 
 
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Table A2  
 
Schedule for 24 hour Urine Collection Assessments 
During the confinement and ambulatory periods, the dot corresponds to the start of 24-hour urine collection.  
 
Baseline period 
Confinement Exposure Period 
24-hour urine 
Ambulatory Exposure Period 
24-hour-urine 
 
 
Day -1 to  
Day 0 
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 and 8-epi-
PGF2α 
 
● 
 
 
 
 
● 
● 
● 
● 
Ames mutagenicity 
test 
 
● 
 
 
 
 
● 
 
 
● 
Bio-banking b 
 
● 
 
 
 
 
● 
 
 
● 
Abbreviations: Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2 
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 BoExp bio-banking is given by the subject.  
During the confinement and ambulatory periods, when the BoExp is mentioned to be assessed at Day x, it corresponds to the start of urine collection, For 
example, for NEQ assessed on Day 5, it will be the measurement of NEQ in the Day 5-Day 6 24-hour urine collection. 
 
 

 
 
 
 
 
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Appendix 2 
Participating Laboratories 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
  
More details will be found in the study laboratory manuals.  
For samples biobanking: 
 

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

 
 
 
 
 
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Appendix 4 
THS Package Labels 
The package label for the THS Menthol Tobacco Sticks: 

 
 
 
 
 
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The package label for the THS Menthol Tobacco Sticks carton: 

 
 
 
 
 
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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; 
>300 – 400; 
>400 - 500; 

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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Final 2.0/07 April 2014 
Page 179 of 181 
 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
 
(mmol/l) 
>ULN – 7.75 
>7.75 – 10.34 
>10.34 – 12.92 
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; 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. 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-07-JP 
Final 2.0/07 April 2014 
Page 180 of 181 
 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
 
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. 
Clinical Study Protocol 
Confidential 
ZRHM-REXA-07-JP 
Final 2.0/07 April 2014 
Page 181 of 181 
 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
 
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.