A Randomized, Controlled, Open-label, 3-arm Parallel Group, Single-center Study to Demonstrate Reductions in Exposure to Selected Smoke Constituents in Smoking, Healthy Subjects Switching to the Tobacco Heating System 2.2 (THS 2.2) or Smoking Abstinence, Compared to Continuing to Use Conventional Cigarettes, for 5 Days in Confinement.
Phase: NA
Conditions: Smoking
Sponsor: Philip Morris Products S.A.

 
 
 
 
 
 
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Clinical Study Protocol 
ZRHR-REXC-03-EU 
 
Study title: 
A randomized, controlled, open-label, 3-arm parallel group, 
single-center study to demonstrate reductions in exposure to 
selected smoke constituents in smoking, healthy subjects switching 
to the Tobacco Heating System 2.2 (THS 2.2) or smoking 
abstinence, compared to continuing to use conventional cigarettes, 
for 5 days in confinement 
Short study title: 
Reduced exposure study in smokers using THS 2.2 with 5 days in a 
confinement setting  
Registration number: Not assigned 
Product name: 
Tobacco Heating System 2.2 (THS 2.2)  
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Version number: 
Final  
Revision date: 
25 April 2013 
Authors: 
 PhD, Manager Clinical Science 
, MEng MSc, Biostatistician  
, MD, Medical Safety Officer 
, Medical Writer 

 
 
 
 
 
 
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SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Name of Product: 
Tobacco Heating System 2.2 (THS 2.2) 
Study Title: 
A randomized, controlled, open-label, 3-arm parallel group, single-center study to 
demonstrate reductions in exposure to selected smoke constituents in smoking, healthy 
subjects switching to the Tobacco Heating System 2.2 (THS 2.2) or smoking abstinence, 
compared to continuing to use conventional cigarettes, for 5 days in confinement 
Short Study Title: 
Reduced exposure study in smokers using THS 2.2 with 5 days in a confinement setting 
Study Number: 
ZRHR-REXC-03-EU 
Primary Objective 
The primary objective of this study is: 
 To demonstrate the reduction of primary biomarkers of exposure (BoExp) in smokers 
switching from conventional cigarettes (CC) to THS 2.2 as compared to smokers 
continuing to smoke CC. 
Secondary Objectives 
The secondary objectives of this study are: 
 To determine the reduction of secondary BoExp on Day 5 in smokers switching from 
CC to THS 2.2 as compared to smokers continuing to smoke CC. 
 To describe the levels of primary and secondary BoExp over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers continuing to smoke 
CC. 
 To determine the levels of nicotine on Day 5 in smokers switching from CC to THS 
2.2 as compared to smokers continuing to smoke CC and to describe their levels over 
the exposure period from Day 1 to Day 5. 
 To describe the levels of primary, secondary BoExp, and BoExp to nicotine over the 
exposure period in smokers switching from CC to THS 2.2 as compared to smokers 
switching from CC to smoking abstinence (SA). 
 To describe the pharmacokinetic profiles of the nicotine and cotinine in smokers 
switching from CC to THS 2.2 as compared to smokers continuing to smoke CC. 

 
 
 
 
 
 
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 To describe the changes in Cytochrome P450 1A2 enzymatic activity on Day 5 in 
smokers switching from CC to THS 2.2, switching from CC to SA, and continuing to 
smoke CC. 
 To describe the daily THS Tobacco Stick/CC consumption over the exposure period 
in smokers switching from CC to THS 2.2 as compared to smokers continuing to 
smoke CC. 
 To monitor the safety profile during the study. 
 
Exploratory Objectives 
The exploratory objectives of this study are:  
 To describe the following parameters in smokers switching from CC to THS 2.2 as 
compared to smokers continuing to smoke CC and smokers switching from CC to SA: 
• Excretion of mutagenic material in urine. 
• Subjective effects of smoking. 
• CYP2A6 activity, and 
• Selected risk markers. 
 
 To evaluate in smokers switching from CC to THS 2.2, smokers continuing to smoke 
CC and smokers switching from CC to SA the relationship between: 
• Nicotine equivalents (NEQ) and primary and secondary BoExp. 
• Selected risk markers and primary, secondary BoExp, and NEQ. 
 
 To describe the following parameters over the course of the study in smokers 
switching from CC to THS 2.2 as compared to smokers continuing to smoke CC: 
• Product evaluation. 
• Smoking pattern. 
 
 To describe the following parameter over the course of the study in smokers switching 
from CC to THS 2.2: 
• Potential combustion occurrences in tobacco plugs.  
• Filter analysis. 
 

 
 
 
 
 
 
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Study Hypotheses: 
The hypothesis to be tested for each of the primary and secondary BoExp is that the 
geometric mean level on Day 5 of the biomarker for THS 2.2 is lower relative to CC. 
 
Study Endpoints: 
The primary and secondary BoExp measured in this study are presented in Table S1. 
Table S1: 
 
Biomarkers of Exposure (BoExp) 
Harmful and 
potentially harmful 
constituents 
(HPHCs) 
Matrix 
Primary BoExp 
monohydroxybutenyl mercapturic 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 
Secondary BoExp 
carbon monoxide  
CO 
Exhaled breath 
total 1-hydroxypyrene (1-OHP) 
pyrene 
Urine 
total N-nitrosonornicotine (NNN) 
N-nitrosonornicotine 
Urine 
4-aminobiphenyl (4-ABP) 
4-aminobiphenyl  
Urine 
1-aminonaphthalene (1-NA) 
1-aminonaphthalene 
Urine 
2-aminonaphthalene (2-NA) 
2-aminonaphthalene 
Urine 
o-toluidine (o-tol) 
o-toluidine 
Urine 
2-cyanoethylmercapturic acid (CEMA) 
acrylonitrile 
Urine 
2-hydroxyethyl mercapturic acid (HEMA) 
ethylene oxide 
Urine 
3-hydroxy(a)benzopyrene 
benzo(a)pyrene 
Urine 
3-hydroxy-1-methylpropylmercapturic acid 
(HMPMA) 
crotonaldehyde 
Urine 
S-benzylmercapturic acid (S-BMA) 
toluene 
Urine 
total 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanol (NNAL) 
4 -
(methylnitrosamino)-
1-(3-pyridyl)-1-
butanone (NNK) 
Urine 

 
 
 
 
 
 
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BoExp to nicoitne 
nicotine equivalents (NEQ) 
free nicotine, nicotine-glucuronide, free 
cotinine, cotinine-glucuronide, free trans-3’-
hydroxycotinine, trans-3’-hydroxycotinine-
glucuronide 
nicotine 
Urine 
nicotine 
nicotine 
Plasma 
cotinine 
nicotine 
Plasma 
 
Primary Endpoints: 
 To demonstrate the reduction of primary BoExp in smokers switching from CC to 
THS 2.2 as compared to those continuing to smoke CC. 
• Monohydroxybutenyl mercapturic acid, 3-hydroxypropylmercapturic acid, 
S-phenylmercapturic acid (concentration adjusted to creatinine) in 24-hour urine, 
and carboxyhemoglobin in blood (expressed as % saturation of hemoglobin) as 
measured on Day 5. 
 
Evaluation Criterion: The study will be considered successful if the study demonstrates a 
50% reduction or more for all four primary BoExp in the THS 2.2 arm compared to the 
CC arm (as measured on Day 5). 
 
Secondary endpoints: 
 To determine the reduction of secondary BoExp on Day 5 in smokers switching from 
CC to THS 2.2 as compared to smokers continuing to smoke CC. 
 BoExp listed as secondary (Table S1) for the comparison of levels between 
smokers switching from CC to THS 2.2 and smokers continuing to smoke CC as 
measured on Day 5 as follows: 
 Carbon monoxide (CO) (expressed as ppm) in exhaled breath.  
 Urinary BoExp (expressed as quantity excreted and concentration adjusted to 
creatinine) in 24-hour urine. 
 
 To describe the levels of primary and secondary BoExp over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers continuing to smoke 
CC. 
 BoExp listed as primary and secondary (Table S1) for the comparison of levels 
between smokers switching from CC to THS 2.2 and smokers continuing to 
smoke CC as measured from Day 1 to Day 5. 

 
 
 
 
 
 
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 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 on Day 5 in smokers switching from CC to THS 
2.2 as compared to smokers continuing to smoke CC and to describe their levels over 
the exposure period from Day 1 to Day 5. 
 NEQ (expressed in quantity excreted and concentration adjusted to 
creatinine) (Table S1) in 24-hour urine on Day 5 and from Day 1 to Day 5. 
 Nicotine and cotinine in plasma on Day 5 and from Day 1 to Day 5. 
 
 To describe the levels of primary, secondary BoExp, and BoExp to nicotine over the 
exposure period in smokers switching from CC to THS 2.2 as compared to smokers 
switching from CC to SA. 
 BoExp listed as primary and secondary (Table S1) from Day 1 to Day 5 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 describe the PK profiles of the nicotine and cotinine in smokers switching from CC 
to THS 2.2 as compared to smokers continuing to smoke CC.  
 Peak (highest concentration value along the day) on Day 5 in plasma. 
 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 changes in CYP1A2 enzymatic activity on Day 5 in smokers 
switching from CC to THS 2.2, switching from CC to SA, and continuing to smoke 
CC.  
 Molar metabolic ratio of paraxanthine (PX)/caffeine (CAF) in plasma on 
Day 5. 
 

 
 
 
 
 
 
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 To describe the daily THS Tobacco Stick/CC consumption over the exposure period 
in smokers switching from CC to THS 2.2 as compared to smokers continuing to 
smoke CC: 
 Number of THS Tobacco Sticks and CC used each day for each subject from 
Day 1 to Day 5. 
 
 To monitor the safety profile during the study: 
 AEs/ SAEs and device events including THS 2.2 malfunction/misuse. 
 Respiratory symptoms: cough assessment by visual analogue scale (VAS), 
Likert scales, and one open question. 
 Vital signs. 
 Spirometry. 
 Electrocardiogram (ECG). 
 Clinical chemistry, hematology, and urine analysis safety panel. 
 Physical examination. 
 Concomitant medications. 
 
Exploratory Endpoints 
 To describe the following parameters in smokers switching from CC to THS 2.2 as 
compared to smokers continuing to smoke CC and to smokers switching from CC to 
SA: 
 Excretion of mutagenic material in urine: Ames Mutagenicity test 
(YG1024+S9) on Day 5 in 24-hour urine. 
 Subjective effects of smoking: Questionnaire of Smoking Urges (brief 
version) (QSU-brief); Minnesota Nicotine Withdrawal Scale, revised version 
on Day 5. 
 CYP2A6 enzymatic activity: in plasma on Day 6, using the molar metabolic 
ratio of trans-3’-hydroxycotinine/cotinine.  
 Selected risk markers: 8-epi-prostaglandine F2 (8 epi-PGF2α) and 11 
dehydro thromboxane B2 (11-DTX-B2) measured in 24-hour urine on Day 
5. 
 
 To evaluate in smokers switching from CC to THS 2.2, smokers continuing to smoke 
CC, and smokers switching from CC to  SA the relationship between: 
 NEQ and primary and secondary BoExp in 24-hour urine on Day 5. 

 
 
 
 
 
 
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 Primary, secondary BoExp, NEQ, and risk markers (8 epi-PGF2α and 11-
DTX-B2) in 24-hour urine. 
 
 To describe the following parameters over the course of the study in smokers 
switching from CC to THS 2.2 as compared to smokers continuing to smoke CC: 
 Product evaluation: Modified Cigarette Evaluation Questionnaire (MCEQ). 
 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 CC to THS 2.2: 
 Potential combustion occurrences in tobacco plugs: visual inspection of the 
tobacco plugs. 
 Filter analysis: smoke nicotine in filter and UV absorbance at 310 nm. 
Study Design: 
A randomized, controlled, open-label, 3-arm, parallel group, single-center study with a 
stratified randomization by sex and average daily cigarette consumption over the last 
4 weeks as reported during the Screening Visit (smokers smoking 10 to 19 CC and 
smokers smoking >19 CC per day) (Figure S1). 
This is an ad libitum smoking study. In general, smoking during confinement will be 
allowed between 06:30 AM and 11:00 PM.  
During the confinement period, compliance to product/regimen allocation (exclusive use 
of THS 2.2 and CC in THS 2.2 and CC arms respectively, and full abstinence from 
smoking in the SA arm) will be ensured by strict distribution of each Tobacco Stick/CC 
on demand of the subject. 

 
 
 
 
 
 
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Day -1, Day 0
Day -2
Admission
Baseline
Day 6 to Day 13
9 days in confinement
CC 
ad libitum
Safety
follow-up
ad libitum use 
of tobacco products
Day 1 to Day 5
Screening
*Screening 
within 1-4 weeks 
prior to admission
THS 2.2
Discharge (Day 6)
Smoking abstinence
CC
Figure S1: Study Design
Abbreviations: THS 2.2 = Tobacco Heating System 2.2; CC =  conventional cigarettes.
 
• Screening period over 4 weeks (Day -30 to Day -3) prior to admission to the 
clinic (Day -2): 
A demonstration of the THS 2.2 product will be done by the site staff during the 
Screening Visit. Subjects will be in a confinement setting for 9 days from Day -2 
onwards. Screening procedures do not necessarily have to be conducted on the 
same day. 
• 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 (use of up to 3 THS 2.2 Tobacco 
Sticks). In female subjects, the THS 2.2 product test may 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. 
• Baseline period (from Day -1, 06:30 AM until Day 1, 06:29 AM): 
All subjects will continue smoking their single preferred brand of CC and 

 
 
 
 
 
 
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baseline values will be recorded. On Day 0, subjects will be randomized to one of 
the 3 study arms in a 2:1:1 ratio using a stratified randomization: 
 THS 2.2 Arm: 80 subjects, ad libitum use of the product. 
 CC Arm: 40 subjects, ad libitum use of their preferred CC brand. 
 SA Arm: 40 subjects who will abstain from smoking. 
Subjects will be informed of their randomized study arm by the study site staff on 
Day 1 prior to 06:30 AM.  
• Exposure period (from Day 1, 06:30 AM until Day 5, 11:00 PM): 
The exposure period will consist of 5 days of ad libitum use of the assigned 
product between 06:30 AM and 11:00 PM in the THS 2.2 and CC arms. Use of 
any tobacco/nicotine-containing product other than the assigned product will not 
be allowed and may, at the discretion of the Investigator or designee, result in the 
subject withdrawal from the study. 
Subjects in the SA arm will be asked to abstain from smoking any 
nicotine/tobacco-containing product and will not be provided with medication to 
support SA. Subjects will be provided with psychological support during the 
period of smoking abstinence. 
The end of the 24-hour urine collection period for Day 5 will end in the morning 
on Day 6 prior to Discharge. 
• Day of Discharge (Day 6) (from Day 5, 11:01 PM to time of Discharge): 
Procedures of Discharge, including but not limited to laboratory parameters, will 
be conducted to discharge the subject from the clinic after 9 days in a confined 
setting. Use of CC will be allowed on Day 6, but only after spirometry has been 
performed.  
• Safety follow-up period (from Day 6, time of Discharge to Day 13): 
After time of Discharge, subject will enter a 7-day safety follow-up during which 
there will be recording of spontaneously reported new adverse events 
(AEs)/serious adverse events (SAEs) and the active follow-up of ongoing 
AEs/SAEs by the study site. In general, all AEs will be actively followed 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 6 plus 7-day follow-up period. 
During the study, any subjects who want to quit smoking will receive appropriate 
medical advice and will be referred to a smoking cessation councilor. 

 
 
 
 
 
 
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Study Population and Main Criteria for Inclusion: 
One hundred and sixty female or male smoking, healthy Caucasian adult subjects meeting 
the following main inclusion criteria: 
 Subject is aged from 21 to 65 years (inclusive). 
 Subject is Caucasian. 
 Smoking, healthy subject as judged by the Investigator or designee. 
 Subject smokes at least 10 commercially available non-menthol CCs 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. 
 The subject is ready to accept 5 days of smoking abstinence. 
 The subject is ready to accept using the THS 2.2 product. 
Subjects who do not complete the study after randomization will not be replaced. 
Investigational Product; Dose; and Mode of Use: 
Test Product: Tobacco Heating System 2.2 (THS 2.2) 
Reference product: The reference product to the THS 2.2 during the randomized exposure 
period is the subject’s own preferred commercially available single brand of non-menthol 
CC 
Reference Point: SA 
Duration of Study: 
The entire study duration per subject will be 17 to 44 days, including a Screening period 
of up to 4 weeks prior to baseline (Day -30 to Day -3), a 9-day confinement period (from 
Day -2 to time of Discharge on Day 6), followed by a 7-day safety follow-up period (until 
Day 13). 
Statistical Methods: 
Statistical Analysis: 
Analysis of BoExp will be conducted on the natural log scale. The transformed 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. Estimates of differences between 
groups will be back-transformed to provide relative effects. Assumptions of the analysis 
of variance model will be tested. Markedly non-lognormally distributed BoExp data will 
be transformed or analyzed by appropriate non-parametric methods. 
Unless stated otherwise, all statistical tests will be two-sided and conducted at the 5% 

 
 
 
 
 
 
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level, and all quoted confidence intervals (CIs) will be two-sided 95%CIs. 
Sample Size: 
A total of 160 subjects (80 in the THS 2.2 arm, 40 in the CC arm, and 40 in the SA arm) 
will be randomized. This sample size is needed to attain 80% power to show demonstrate 
a reduction of at least 50% on four primary BoExps in smokers switching from CC to 
THS 2.2 as compared to those continuing to smoke CC, using one-sided test with 2.5% 
type I error probability. 

 
 
 
 
 
 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS .........................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................17 
1 
ETHICS AND REGULATIONS .....................................................................................23 
1.1 
Independent Ethics Committee Approval ..............................................................23 
1.2 
Ethical Conduct of the Study .................................................................................23 
1.3 
Subject Information and Consent...........................................................................24 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................25 
2 
INTRODUCTION ...........................................................................................................26 
2.1 
Background ............................................................................................................26 
2.2 
Purpose of the Study ..............................................................................................28 
2.3 
Anticipated Benefits and Risks ..............................................................................28 
3 
STUDY OBJECTIVES ....................................................................................................30 
3.1 
Primary Objective ..................................................................................................30 
3.2 
Secondary Objectives.............................................................................................30 
3.3 
Exploratory Objectives ..........................................................................................30 
3.4 
Study Endpoints .....................................................................................................31 
4 
INVESTIGATIONAL PLAN ..........................................................................................36 
4.1 
Overall Study Design and Plan ..............................................................................36 
4.2 
Rationale for Study Design and Control Groups ...................................................38 
4.3 
Appropriateness of Measurements .........................................................................39 
4.4 
Study Duration .......................................................................................................40 
5 
STUDY POPULATION ..................................................................................................41 
5.1 
Selection of Study Population ................................................................................41 
6 
INVESTIGATIONAL PRODUCTS ...............................................................................48 
6.1 
Description of Investigational Products .................................................................48 
6.2 
Use of Investigational Product(s)...........................................................................49 
6.3 
Method for Assigning Subjects to Study Arms .....................................................51 
6.4 
Blinding..................................................................................................................51 
6.5 
Investigational Product Accountability and Compliance ......................................52 
6.6 
Restrictions ............................................................................................................53 
6.7 
Concomitant Medication ........................................................................................54 

 
 
 
 
 
 
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7 
STUDY PROCEDURES .................................................................................................58 
7.1 
Informed Consent...................................................................................................58 
7.2 
Advice on the Risk of Smoking and Debriefing ....................................................58 
7.3 
Support for the Smoking Abstinence Arm.............................................................59 
7.4 
Clinical Assessments .............................................................................................59 
7.5 
Biomarker Assessment...........................................................................................62 
7.6 
Laboratory Assessments ........................................................................................65 
7.7 
Sample Handling and Storage ................................................................................67 
7.8 
Other Study Procedures .........................................................................................69 
8 
ADVERSE EVENTS .......................................................................................................74 
8.1 
Definitions..............................................................................................................74 
8.2 
Assessment of Adverse Events ..............................................................................74 
8.3 
Reporting and Follow-Up of Serious Adverse Events ...........................................77 
8.4 
Reporting of Other Events Critical to Safety Evaluations .....................................78 
8.5 
Reporting and Follow-Up of Pregnancies..............................................................79 
8.6 
Adverse Events Leading to Withdrawal ................................................................80 
8.7 
Investigational Device Misuse ...............................................................................80 
8.8 
Investigational Device Malfunction .......................................................................80 
9 
STUDY ACTIVITIES .....................................................................................................82 
9.1 
Screening Visit .......................................................................................................82 
9.2 
Confinement Period (Days -2 to Day 6) ................................................................83 
9.3 
Safety Follow-up Period ......................................................................................101 
9.4 
Early Termination Procedures .............................................................................101 
10 CONTROL AND QUALITY ASSURANCE ...............................................................102 
10.1 
Monitoring ...........................................................................................................102 
10.2 
Training of Staff ...................................................................................................102 
10.3 
Audits and Inspections .........................................................................................103 
11 DATA MANAGEMENT ACTIVITIES........................................................................104 
11.1 
Data Capture ........................................................................................................104 
11.2 
Data Handling ......................................................................................................105 
12 PLANNED STATISTICAL METHODS ......................................................................107 
12.1 
General Considerations ........................................................................................107 
12.2 
Determination of Sample Size and Power Consideration ....................................108 

 
 
 
 
 
 
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12.3 
Analysis Population .............................................................................................111 
12.4 
Primary Analysis ..................................................................................................112 
12.5 
Secondary Analysis ..............................................................................................113 
12.6 
Exploratory Analysis ...........................................................................................114 
12.7 
Demographics and Baseline Characteristics ........................................................114 
12.8 
Interim Analysis ...................................................................................................114 
13 ADMINISTRATIVE CONSIDERATIONS ..................................................................115 
13.1 
Investigators and Study Administrative Structure ...............................................115 
13.2 
Subject Confidentiality ........................................................................................116 
13.3 
Access to Source Documentation ........................................................................116 
13.4 
Record Retention .................................................................................................117 
13.5 
Clinical Study Report ...........................................................................................118 
13.6 
Financial Disclosure.............................................................................................119 
13.7 
Publication and Disclosure Policy .......................................................................119 
14 REFERENCE LIST .......................................................................................................120 
 
LIST OF IN-TEXT TABLES 
Table 1 
Measured aerosol fractions for the THS Tobacco Sticks ..........49 
Table 2. 
Examples of Medications with Effects on CYP1A2 and CYP2A6 
Activity 
56 
Table 3. 
Clinical Laboratory Parameters for Safety Panel.......................................66 
Table 4. 
Human Smoking Topography - Per-Puff Parameters ................................70 
Table 5. 
Human Smoking Topography - Per-Cigarette Parameters ........................70 
Table 6. 
Time Schedule - Screening Visit ...............................................................82 
Table 7. 
Time Schedule - Day -2 .............................................................................84 
Table 8. 
Time Schedule - Day -1 .............................................................................85 
Table 9. 
Time Schedule - Day 0 ..............................................................................87 
Table 10. 
Time Schedule - Day 1 ..............................................................................89 
Table 11. 
Time Schedule - Day 2 ..............................................................................91 
Table 12. 
Time Schedule - Day 3 ..............................................................................93 
Table 13. 
Time Schedule - Day 4 ..............................................................................95 
Table 14. 
Time Schedule - Day 5 ..............................................................................96 
Table 15. 
Time Schedule - Day 6 ............................................................................100 
Table 16. 
Coefficients of Variation (YVD-CS01-EU study) ...................................109 

 
 
 
 
 
 
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Table 17. 
Coefficients of Variation (ZRHX‐EX‐01 study) .....................................110 
Table 18. 
Expected power (YVD-CS01-EU and ZRHX‐EX‐01 studies 
assumptions) ..............................................................................................................111 
 
LIST OF IN-TEXT FIGURES 
Figure S1: Study Design ....................................................................................................36 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events ...................................................................................125 
Appendix 2 
Participating Laboratories ........................................................................129 
Appendix 3 
Investigational Product and Instructions for Use .....................................130 
Appendix 4 
SODIM® Device Description ...................................................................131 
Appendix 5 
Abnormal Laboratory Values ..................................................................132 
 

 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
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 
11-DTX-B2 
11-dehydro-thromboxane B2  
ADL 
Activities of daily living 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BoExp 
Biomarker(s) of exposure 
BUN 
Blood urea nitrogen 
CAF 
Caffeine 
CC 
Conventional cigarette(s) 
CD 
Compact Disc 
CEMA 
2-cyanoethylmercapturic acid 
CI 
Confidence interval 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE  
Common Terminology Criteria for Adverse Event and Common Toxicity 
Criteria 

 
 
 
 
 
 
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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 
EOS 
End of Study  
ePRO 
Electronic patient 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 
Hb 
Hemoglobin 
HbsAg 
Hepatitis B surface antigen 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
HEMA 
2-hydroxyethyl mercapturic acid 
HIV 
Human immunodeficiency virus 
HMPMA 
3-hydroxy-1-methylpropylmercapturic acid 
HPHCs 
Harmful and potentially harmful constituents 
HST 
Human smoking topography 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  

 
 
 
 
 
 
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IEC 
Independent Ethics Committee 
IP 
Investigational Product 
ISO 
International Organization for Standardization 
IV 
Intravenous 
IWRS 
Interactive Web and Voice Response System 
LDH 
Lactic dehydrogenase 
LLN 
Lower limit of the normal range 
LLOQ 
Lower limit of quantification 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCEQ 
Modified Cigarette Evaluation Questionnaire  
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 
n 
Modified risk tobacco product 
number of subjects 
NEQ 
Nicotine equivalents 
NNAL 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
NNK 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 
NNN 
N-nitrosonornicotine 
NRT 
Nicotine replacement therapy 
NSAID 
Nonsteroidal anti-inflammatory drugs 
o-tol 
o-toluidine 
PK 
Pharmacokinetic(s) 
PMI 
Philip Morris International 
PP 
Per-protocol 

 
 
 
 
 
 
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PX 
Paraxanthine 
QC 
Quality control 
QSU-brief 
Questionnaire of Smoking Urges (brief version) 
RBC 
Red blood cell 
RNA  
Ribonucleic acid 
SA 
Smoking abstinence 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
S-BMA 
S-benzylmercapturic acid 
SHM 
Sample Handling Manual 
SOP 
Standard Operating Procedure 
S-PMA 
S-phenylmercapturic acid 
THS 2.2 
Tobacco Heating System 2.2 
U 
Urine 
 
 
UK 
United Kingdom 
ULN 
Upper limit of the normal range 
ULOQ 
Upper limit of quantification 
VAS 
Visual analogue scale 
WBC 
White blood cell 
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. 
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. 

 
 
 
 
 
 
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CC 
The term ‘conventional cigarette’ refers to manufactured and 
commercially available cigarettes and excludes hand-rolled 
cigarettes, cigars, pipes, bidis, and other nicotine-containing 
products. 
CC incompatible with 
HST device 
All CCs that are incompatible with the HST device (e.g. slim CC). 
Day of Discharge 
Day 6  
End of the study 
End of Study is defined as the time of discharge on Day 6 plus 7-
day follow-up period. 
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 THS 2.2 (the test of THS 2.2 is the last 
assessment prior to enrolment). 
Exposure period  
06:30 AM of Day 1 until 11:00 PM of Day 5. 
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, a 7-day safety follow-up will be done 
for the recording of spontaneously reported new adverse events 
(AEs)/serious adverse events (SAEs) and the active follow-up of 
ongoing AEs/SAEs. In general, any AE will be actively 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/subject information sheet) signature to the time of 
enrolment will be considered a screening failure and will be 
replaced by other subjects. 

 
 
 
 
 
 
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Time of Discharge 
The time of day the subject is discharged on Day of Discharge. 
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). 
Tobacco Heating 
Device  
The Device comprises everything in THS 2.2 except the Tobacco 
Stick 
Tobacco Heating 
System 2.2 (THS 2.2) 
THS 2.2 comprises the following components:  Tobacco Stick, 
Holder, Charger, a Cleaning Tool, a mains power supply, and a 
USB cable. 
THS Tobacco Stick 
(Tobacco Stick) 
The THS Tobacco Stick (Tobacco Stick) (product code C3) 
contains tobacco which, when heated, generates an aerosol. It is 
custom-designed to be used with the Holder. 

 
 
 
 
 
 
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1 
ETHICS AND REGULATIONS 
1.1 
Independent Ethics Committee Approval 
Prior to the start of the study, the clinical study protocol, together with its associated 
documents (informed consent form [ICF], subject information sheet, subject recruitment 
procedures [e.g., advertisements], written information including questionnaires and 
instructions to be provided to the subjects, Investigator’s Brochure [IB], available safety 
information, the Investigator’s curriculum vitae and/or other evidence of qualifications, and 
any other documents requested by the Independent Ethics Committee [IEC]), will be 
submitted for review and approval to the relevant IEC. The IEC shall be appropriately 
constituted and perform its functions in accordance with the International Conference on 
Harmonization (ICH) Tripartite Guidance for Good Clinical Practice (GCP) and local 
requirements, as applicable. 
In accordance with GCP, a written confirmation of the IEC approval should be provided to 
the Sponsor. This should identify the study (Investigator’s name, study number, and title) and 
the documents that have been approved by the IEC, with dates and version numbers, as well 
as the date of approval. The composition of the IEC, including the name and occupation of 
the chairperson, should be supplied to the Sponsor together with a GCP compliance 
statement. 
The written approval from the IEC will be filed in the Investigator file, and a copy will be 
filed in the Study Master File at the Sponsor or designated organization. The study must not 
start at a site before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the respective IEC. 
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the Investigator or designee. All amendments will 
be submitted to the IEC, and substantial amendments will only be implemented after 
approval by the IEC. 
These requirements for approval should in no way prevent any action from being taken by 
the Investigator (or designee) or by the Sponsor in order to eliminate immediate hazards to 
the subjects. If such a change to the protocol is felt to be necessary by the Investigator or 
designee, and is implemented for safety reasons, the Sponsor and the IEC should be informed 
immediately. 
Relevant safety information will be submitted to the IEC 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 applicable regulatory 
principles. 

 
 
 
 
 
 
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The Investigator or designee agrees to conduct the clinical study in compliance with the 
protocol agreed upon with the Sponsor and approved by the IEC. The Investigator or 
designee 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 
Informed Consent Form/Subject Information Sheet for Participation to the 
Study 
Before or at the Screening Visit, the Investigator or person designated by the Investigator 
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/subject information sheet by the date and signature of both the subject 
and the person who conducted the informed consent discussion. No study-specific procedures 
will be performed before the ICF/subject information sheet has been signed. 
The original, dated and signed ICF(s)/subject information sheet must be kept in the 
Investigator file at the site, and a signed copy must be given to the subject. 
The subject will be informed that additional data analyses not mentioned in the protocol or 
the statistical analysis plan might be performed with the collected data at a later time. If any 
additional analyses will be performed, they will fully be covered by data confidentiality, as 
for the main analyses described in this protocol.  
1.3.2 
Informed Consent Form/Subject Information Sheet for Long-Term Bio-
Banking  
1.3.2.1 
Bio-banking 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 pharmacogenomics 
testing will be done on these samples. 
1.3.2.2 
Bio-banking for Transcriptomics (Pharmacogenomics) 
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 as 

 
 
 
 
 
 
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compared to smokers continuing to smoke CC 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 or designee 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 person who conducted the 
informed consent discussion. The subject’s consent to storage of any samples in a bio-bank 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. 
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/ 
subject information sheet. If revision of the ICF/subject information sheet is necessary, the 
Investigator or designee will, with the support of the Sponsor, ensure that the documents 
have been reviewed and approved by a relevant IEC before subjects are required to re-sign 
the ICF/subject information sheet. 
1.4 
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation, 
and documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator or designee abide by the principles of the ICH guidelines on 
GCP. These guidelines apply specifically to pharmaceutical development, but nevertheless 
provide a robust and ethical framework for conducting clinical studies of tobacco products. 
In addition, the Investigator or designee will carry out the clinical study in accordance with 
applicable national and local laws of the pertinent regulatory authorities. 

 
 
 
 
 
 
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2 
INTRODUCTION 
2.1 
Background 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy 
Cigarette smoking causes pulmonary and cardiovascular diseases and other serious diseases 
in smokers (U.S. Department of Health and Human Services, 2010). There is no safe 
cigarette and the best way for smokers to reduce the adverse health consequences of smoking 
is to quit. Despite the risks which are attributable to smoking, some smokers cannot refrain 
from smoking or decide to continue smoking. To those smokers who are not able or not 
willing to quit, Philip Morris International (PMI) is developing alternative approaches by 
developing products with the potential to reduce the risks of tobacco-related diseases. These 
products are now referred to by the United States Food and Drug Administration (FDA) as 
modified risk tobacco products (MRTPs) (Food and Drug Administration, 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 conventional cigarettes [CC]). Philip Morris International is developing 
candidate MRTPs that provide an inhalation experience without combustion. The novel 
approach to achieve this is by heating tobacco at significantly lower temperatures than 
required for CC. 
Philip Morris International’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 (SA) 
as the reference point for assessing the risk reduction potential of its candidate MRTPs. The 
Institute of Medicine refers to smoking cessation as the “gold standard” for assessing risk 
reduction, and that “the closer risks and exposures from the MRTP are to cessation products, 
the more confident a regulator can be of achieving a net public health benefit” (Institute of 
Medicine, 2012). Philip Morris International has 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 reduction of individual risk in smokers and reduction of 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 (Rodgman and Perfetti, 
2009), and more than 100 of them have been categorized as harmful and potentially harmful 

 
 
 
 
 
 
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constituents (HPHCs) (Food and Drug Administration, 2011). There is no convincing 
evidence that selective reduction of smoke constituents can reduce tobacco related diseases 
(Hatsukami et al, 2007). Philip Morris International’s focus has been the development of 
products that do not combust tobacco but which replicate the “smoking experience” 
traditionally obtained with CC, as much as possible. Our approach limits pyrolysis and 
combustion, by heating tobacco at significantly lower temperatures than CC. Philip Morris 
International believes that such products present the best opportunity for reducing harm 
because they produce vastly lower levels of HPHCs and are more likely to be accepted by 
smokers as substitutes for CCs. Important to this effort has been providing nicotine in a way 
that closely parallels CC. 
The product developed by PMI, and to be assessed in this study, is the Tobacco Heating 
System 2.2 (THS 2.2). 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 is composed of the ‘THS Tobacco Stick Holder’, dedicated special Tobacco Sticks 
made of conventional tobacco, a Charger, and different accessories. The energy of the THS 
Tobacco Stick Holder is sufficient to maintain approximately a 6 minute session. Unlike CC, 
the Tobacco Sticks do not burn down during their consumption and their lengths remain 
constant after use. 
The non-clinical assessment of THS 2.2 and its predecessors including THS 1.0 supports the 
initiation of the clinical studies described in this Investigator’s Brochure (PMI, 2013a). 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 were increased compared to the CC. 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 in these biological models. Further details are given in 
the Investigator’s’ Brochure (PMI, 2013a). 
Several clinical studies have been conducted on THS 1.0, 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.  
The previous version of THS 2.2, namely THS 2.1 was tested in two exploratory clinical 
studies to measure the nicotine plasma kinetic profile (PK) (clinical trial.gov identifier: 
NCT01780688) and to assess the reduction of exposure to HPHCs (clinical trial dot. gov 
identifier: NCT01780714) when switching from CC to THS 2.1. 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. Clinical studies conducted so far revealed 
no safety concern for either of the previous version of THS 2.2 tested. Further details on the 
clinical data are provided in the Investigators’ Brochure (PMI, 2013a). 

 
 
 
 
 
 
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2.2 
Purpose of the Study 
The overall goal of the study is to show that the ad libitum use of THS 2.2 for 5 days by adult 
healthy smokers results in a reduction in selected BoExp to HPHCs (except BoExp to 
nicotine) in a well-controlled environment and to obtain information about safety in subjects 
using the THS 2.2 product as compared to smokers continuing smoking their own preferred 
brand of CC. Smokers who are asked to abstain from using any nicotine/tobacco containing 
products will be used as a reference point to THS 2.2 to evaluate how similar is the reduced 
exposure in the THS 2.2 arm as compared to smoking abstinence. The subjects allocated to 
the THS 2.2 and CC arms will be allowed to use their assigned product ad libitum. 
Additional parameters will be explored on selected variables (e.g., Cytochrome P450 2A6 
[CYP2A6]/Cytochrome P450 1A2 [CYP1A2] enzymatic activity, pharmacokinetic [PK] 
profile of nicotine and cotinine, product evaluation, product use and related subjective 
effects, human smoking topography [HST], and selected risk markers). 
2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
Research conducted by the United Kingdom (UK) National Health Service has shown that up 
to 75% of smokers want to quit. Despite associated health risks, however, only 2% of 
smokers make a smoking cessation attempt each year. Advice on health risks associated with 
smoking and smoking cessation will be provided at Screening, at Admission, and at the Day 
of Discharge. 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 and 
without short-acting bronchodilator at Screening) per study protocol and scientifically 
accepted standards. 

 
 
 
 
 
 
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2.3.3 
Anticipated Foreseeable Risks due to Investigational Product (THS 2.2/CC) 
 Change in smoking habits due to study requirements and related concomitant symptoms, 
(e.g., craving, withdrawal symptoms). 
All risks related to study procedures, IP, or support for SA will be explained in detail to the 
subjects. Mitigation will include, but will not be limited to: 
 Close monitoring and medical evaluation of potential safety signals throughout the study 
and follow-up. 
 Using accepted research and scientific standards, (e.g., blood samples not to exceed local 
blood donation standards). 
 Management and follow-up of adverse events (AEs)/serious adverse events (SAEs). 
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 objective of this study is: 
 To demonstrate the reduction of primary biomarkers of exposure (BoExp) in smokers 
switching from conventional cigarettes (CC) to THS 2.2 as compared to smokers 
continuing to smoke CC. 
3.2 
Secondary Objectives 
The secondary objectives of this study are: 
 To determine the reduction of secondary BoExp on Day 5 in smokers switching from CC 
to THS 2.2 as compared to smokers continuing to smoke CC. 
 To describe the levels of primary and secondary BoExp over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers continuing to smoke 
CC. 
 To determine the levels of nicotine on Day 5 in smokers switching from CC to THS 2.2 
as compared to smokers continuing to smoke CC and to describe their levels over the 
exposure period from Day 1 to Day 5. 
 To describe the levels of primary, secondary BoExp, and BoExp to nicotine over the 
exposure period in smokers switching from CC to THS 2.2 as compared to smokers 
switching from CC to smoking abstinence (SA). 
 To describe the pharmacokinetic profiles of the nicotine and cotinine in smokers 
switching from CC to THS 2.2 as compared to smokers continuing to smoke CC. 
 To describe the changes in Cytochrome P450 1A2 enzymatic activity on Day 5 in 
smokers switching from CC to THS 2.2, switching from CC to SA, and continuing to 
smoke CC. 
 To describe the daily THS  Tobacco Stick/CC consumption over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers continuing to smoke 
CC. 
 To monitor the safety profile during the study. 
3.3 
Exploratory Objectives 
The exploratory objectives of this study are:  
 To describe the following parameters in smokers switching from CC to THS 2.2 as 
compared to smokers continuing to smoke CC and smokers switching from CC to SA: 
• Excretion of mutagenic material in urine. 

 
 
 
 
 
 
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• Subjective effects of smoking. 
• CYP2A6 activity, and 
• Selected risk markers. 
 
 To evaluate in smokers switching from CC to THS 2.2, smokers continuing to smoke CC 
and smokers switching from CC to SA the relationship between: 
• Nicotine equivalents (NEQ) and primary and secondary BoExp. 
• Selected risk markers and primary, secondary BoExp, and NEQ. 
 
 To describe the following parameters over the course of the study in smokers switching 
from CC to THS 2.2 as compared to smokers continuing to smoke CC: 
• Product evaluation. 
• Smoking pattern. 
 
 To describe the following parameter over the course of the study in smokers switching 
from CC to THS 2.2: 
• Potential combustion occurrences in tobacco plugs.  
• Filter analysis. 
 
3.4 
Study Endpoints 
The primary and secondary BoExp measured in this study are presented in Table S1. 
Table S1: 
 
Biomarkers of Exposure (BoExp) 
HPHCs 
Matrix 
Primary 
BoExp 
monohydroxybutenyl mercapturic 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 
Secondary 
BoExp 
carbon monoxide  
CO 
Exhaled 
breath 
total 1-hydroxypyrene (1-OHP) 
pyrene 
Urine 
total N-nitrosonornicotine (NNN) 
N-nitrosonornicotine 
Urine 

 
 
 
 
 
 
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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-hydroxyethyl mercapturic acid (HEMA) 
ethylene oxide 
Urine 
3-hydroxy(a)benzopyrene 
benzo(a)pyrene 
Urine 
3-hydroxy-1-methylpropylmercapturic acid (HMPMA) 
crotonaldehyde 
Urine 
S-benzylmercapturic acid (S-BMA) 
toluene 
Urine 
total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
(NNAL) 
4-(methylnitrosamino)-1-
(3-pyridyl)-1-butanone 
(NNK) 
Urine 
BoExp to nicotine 
NEQ 
free nicotine, nicotine-glucuronide, free cotinine, 
cotinine-glucuronide, free trans-3’-hydroxycotinine, 
trans-3’-hydroxycotinine-glucuronide 
nicotine 
Urine 
nicotine 
nicotine 
Plasma 
cotinine 
nicotine 
Plasma 
 
3.4.1 
Primary Endpoints 
 To demonstrate the reduction of primary BoExp in smokers switching from CC to THS 
2.2 as compared to those continuing to smoke CC. 
• Monohydroxybutenyl 
mercapturic 
acid, 
3-hydroxypropylmercapturic 
acid, 
S-phenylmercapturic acid (concentration adjusted to creatinine) in 24-hour urine, 
and carboxyhemoglobin in blood (expressed as % saturation of hemoglobin) as 
measured on Day 5. 
 
Evaluation Criterion: The study will be considered successful if the study demonstrates a 
50% reduction or more for all four primary BoExp in the THS 2.2 arm compared to the CC 
arm (as measured on Day 5). 
 
3.4.2 
Secondary Endpoints 
 To determine the reduction of secondary BoExp on Day 5 in smokers switching from CC 
to THS 2.2 as compared to smokers continuing to smoke CC. 

 
 
 
 
 
 
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 BoExp listed as secondary (Table S1) for the comparison of levels between smokers 
switching from CC to THS 2.2 and smokers continuing to smoke CC as measured 
on Day 5 as follows: 
 Carbon monoxide (CO) (expressed as ppm) in exhaled breath.  
 Urinary BoExp (expressed as quantity excreted and concentration adjusted to 
creatinine) in 24-hour urine. 
 
 To describe the levels of primary and secondary BoExp over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers continuing to smoke 
CC. 
 BoExp listed as primary and secondary (Table S1) for the comparison of levels 
between smokers switching from CC to THS 2.2 and smokers continuing to smoke 
CC as measured from Day 1 to Day 5. 
 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 on Day 5 in smokers switching from CC to THS 2.2 
as compared to smokers continuing to smoke CC and to describe their levels over the 
exposure period from Day 1 to Day 5. 
 NEQ (expressed in quantity excreted and concentration adjusted to creatinine) 
(Table S1) in 24-hour urine on Day 5 and from Day 1 to Day 5. 
 Nicotine and cotinine in plasma on Day 5 and from Day 1 to Day 5. 
 
 To describe the levels of primary, secondary BoExp, and BoExp to nicotine over the 
exposure period in smokers switching from CC to THS 2.2 as compared to smokers 
switching from CC to SA. 
 BoExp listed as primary and secondary (Table S1) from Day 1 to Day 5 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. 
 

 
 
 
 
 
 
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 To describe the PK profiles of the nicotine and cotinine in smokers switching from CC to 
THS 2.2 as compared to smokers continuing to smoke CC.  
 Peak (highest concentration value along the day) on Day 5 in plasma. 
 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 changes in CYP1A2 enzymatic activity on Day 5 in smokers switching 
from CC to THS 2.2, switching from CC to SA, and continuing to smoke CC.  
 Molar metabolic ratio of paraxanthine (PX)/caffeine (CAF) in plasma on Day 5. 
 
 To describe the daily THS Tobacco Stick/CC consumption over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers continuing to smoke 
CC: 
 Number of Tobacco Sticks and CC used each day for each subject from Day 1 
to Day 5. 
 
 To monitor the safety profile during the study: 
 AEs/ SAEs and device events including THS 2.2 malfunction/misuse. 
 Respiratory symptoms: cough assessment by visual analogue scale (VAS), 
Likert scales, and one open question. 
 Vital signs. 
 Spirometry. 
 Electrocardiogram (ECG). 
 Clinical chemistry, hematology, and urine analysis safety panel. 
 Physical examination. 
 Concomitant medication. 
 
3.4.3 
Exploratory Endpoints 
 To describe the following parameters in smokers switching from CC to THS 2.2 as 
compared to smokers continuing to smoke CC and to smokers switching from CC to SA: 
 Excretion of mutagenic material in urine: Ames Mutagenicity test 
(YG1024+S9) on Day 5 in 24-hour urine. 

 
 
 
 
 
 
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 Subjective effects of smoking: Questionnaire of Smoking Urges (brief version) 
(QSU-brief); Minnesota Nicotine Withdrawal Scale, revised version on Day 5. 
 CYP2A6 enzymatic activity: in plasma on Day 6, using the molar metabolic 
ratio of trans-3’-hydroxycotinine/cotinine.  
 Selected risk markers: 8-epi-prostaglandine F2 (8-epi-PGF2α) and 
11-dehydro-thromboxane B2 (11-DTX-B2) measured in 24-hour urine on 
Day 5. 
 
 To evaluate in smokers switching from CC to THS 2.2, smokers continuing to smoke CC, 
and smokers switching from CC to  SA the relationship between: 
 NEQ and primary and secondary BoExp in 24-hour urine on Day 5. 
 Primary, secondary BoExp, NEQ and risk markers (8-epi-PGF2α and 11-DTX-
B2) in 24-hour urine. 
 
 To describe the following parameters over the course of the study in smokers switching 
from CC to THS 2.2 as compared to smokers continuing to smoke CC: 
 Product evaluation: Modified Cigarette Evaluation Questionnaire (MCEQ). 
 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 CC to THS 2.2: 
 Potential combustion occurrences in tobacco plugs: visual inspection of the 
tobacco plugs. 
 Filter analysis: smoke nicotine in filter and UV absorbance at 310 nm. 

 
 
 
 
 
 
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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
A randomized, controlled, open-label, 3-arm, parallel group, single-center study with a 
stratified randomization by sex and average daily CC consumption over the last 4 weeks as 
reported during the Screening Visit (smokers smoking 10 to 19 CC and smokers smoking 
>19 CC per day) (Figure S1). 
This is an ad libitum smoking study. In general, smoking during confinement will be allowed 
between 06:30 AM and 11:00 PM.  
During the confinement period, compliance to product/regimen allocation (exclusive use of 
THS 2.2 and CC in the THS 2.2 and CC arms respectively, and full abstinence from smoking 
in the SA arm) will be ensured by strict distribution of each Tobacco Stick/CC on demand of 
the subject. 
 
Figure S1: Study Design  
Day -1, Day 0
Day-2
Admission
Baseline
Day 6 to Day 13
9 days in confinement
CC 
ad libitum
Safety
follow-up
ad libitum use 
of tobacco products
Day 1 to Day 5
Screening
*Screening 
within 1-4 weeks 
prior to admission
THS 2.2
Discharge (Day 6)
Smoking abstinence
CC
 
Abbreviations: THS 2.2 = Tobacco Heating System 2.2;  CC = conventional cigarettes. 

 
 
 
 
 
 
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 Screening period over 4 weeks (Day -30 to Day -3) prior to admission to the clinic (Day -
2): 
A demonstration of the THS 2.2 product will be done by the site staff during the 
Screening Visit. Subjects will be in a confinement setting for 9 days from Day -2 
onwards. Screening procedures do not necessarily have to be conducted on the same day. 
 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 (use of up to 3 THS Tobacco Sticks). In female 
subjects, the THS 2.2 product test may 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. 
 Baseline period (from Day -1, 06:30 AM until Day 1, 06:29 AM): 
All subjects will continue smoking their single preferred brand of CC and baseline values 
will be recorded. On Day 0, subjects will be randomized to one of the 3 study arms in a 
2:1:1 ratio using a stratified randomization: 
 THS 2.2 Arm: 80 subjects, ad libitum use of the product. 
 CC Arm: 40 subjects, ad libitum use of their preferred CC brand. 
 SA Arm: 40 subjects who will abstain from smoking. 
Subjects will be informed of their randomized study arm by the study site staff on Day 1 
prior to 06:30 AM.  
 Exposure period (from Day 1, 06:30 AM until Day 5, 11:00 PM): 
The exposure period will consist of 5 days of ad libitum use of the assigned product 
between 06:30 AM and 11:00 PM in THS 2.2 and CC arms. Use of any 
tobacco/nicotine-containing product other than the assigned product will not be allowed 
and may, at the discretion of the Investigator or designee, result in the subject withdrawal 
from the study. 
Subjects 
in 
the SA arm will be asked to 
abstain 
from smoking any 
nicotine/tobacco-containing product and will not be provided with medication to support 
SA. 
The end of the 24-hour urine collection period for Day 5 will end in the morning on Day 
6 prior to Discharge. 
 Day of Discharge (Day 6) (from Day 5, 11:01 PM to time of Discharge): 
Procedures of Discharge, including but not limited to laboratory parameters, will be 
conducted to discharge the subject from the clinic after 9 days in a confined setting. Use 
of CC will be allowed on Day 6, but only after spirometry has been performed.  
 Safety follow-up period (from Day 6, time of Discharge to Day 13): 

 
 
 
 
 
 
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After time of Discharge, subject will enter a 7-day safety follow-up 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 actively followed until 
resolved, stabilized (i.e., no worsening of the event), or a plausible explanation for the 
event has been found. The end of study (EOS) is defined as the time of Discharge on Day 
6 plus 7-day follow-up period. 
During the study, subjects in the CC and THS 2.2 arms who want to quit smoking will 
receive appropriate medical advice and will be referred to a smoking cessation councilor. 
 
4.2 
Rationale for Study Design and Control Groups 
This clinical study aims to demonstrate reduction in exposure to selected HPHCs (except 
nicotine) in smokers switching to the THS 2.2, a candidate MRTP (see IB, Error! Reference 
source not found.). 
The main reference product in this study will be smokers who continue to smoke CC. 
Smokers who stop smoking (the SA arm) will be used as a reference point.  
The exposure period in confinement will provide information on exposure reductions in a 
well-controlled environment and will allow full control of daily CC consumption. The choice 
of HPHCs to be assessed in this study is derived from the WHO (Ashley et al, 2008) and the 
draft guidance on Reporting Harmful and Potentially Harmful Constituents in Tobacco 
Products and Tobacco Smoke (Food and Drug Administration, 2012b).  
In the WHO list, 9 HPHCs (acrolein, CO, 1-3 butadiene, benzene, N-nitrosonornicotine 
[NNN], 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 
[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 lowering (Ashley et al, 2008). Exposure to 4 HPHCs (acrolein, CO, 1,3-butadiene, 
and benzene) among these 9 priority HPHCs will be assessed by measuring their respective 
BoExp as primary endpoints after 5 days of exclusive use of THS 2.2, CC, 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 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 tested candidate MRTP for 
5 days, similarly to that observed in smokers who stopped smoking (data on file from a 
previous study. 

 
 
 
 
 
 
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In addition to the 9 HPHCs recommended to be measured by WHO list, the FDA has 
required an additional 9 HPHCs for reporting to FDA (in total 18 HPHCs in cigarette smoke) 
(Food and Drug Administration, 2012b). From the WHO and FDA list, exposure to 
additional 9 HPHCs ( acrylonitrile, 4-aminobiphenyl [4-ABP], 1-aminonaphthalene [1-NA], 
2-aminonaphthalene [2-NA], benzo[a]pyrene, crotonaldehyde, NNK, NNN, and toluene) will 
be assessed by measuring the respective BoExp as secondary endpoints after 5 days of 
exclusive use of THS 2.2, CC, or SA.  
Cytochrome P450 1A2 activity, which is well known to be increased by smoking and to be 
decreased upon SA, will be measured in this study to evaluate the effect of THS 2.2 use on 
the activity of this enzyme (Faber and Fuhr, 2004) and data on file from a previous study 
(PMI, 2009). 
Additional risk markers will be assessed in this study as exploratory endpoints to understand 
if the reduced exposure results in biological changes. The risk markers have been selected 
based on their changes shown in smoking cessation studies as well as their believed 
association to health risks. The risk markers are: 
 Prostaglandin 8-epi-PGF2α is a well-established marker of oxidative stress, a pathway 
which is involved in atherosclerosis. F2-isoprostanes are bioactive prostaglandin-like 
compounds that are produced from arachidonic acid through a non-enzymatic process of lipid 
peroxidation catalyzed by oxygen free-radicals. On smoking cessation, the level of 8-epi-
PGF2decreases rapidly within 1 to 2 weeks to the levels seen in non-smoker plasma, 
serum, and urine (Pilz et al, 2000). 
 11-DTX-B2 (a major stable metabolite of thromboxane A2, which elicits mainly platelet 
aggregation). This risk marker was reported to decrease upon smoking cessation 
(Benowitz et al, 1993, Morita et al, 2005). 
All subjects will be asked to provide their own CC 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 used questionnaires, except the cough and HST questionnaires, are either available as a 
validated questionnaire in the local language or will be forward-translated and back-
translated with subsequent independent verification. 

 
 
 
 
 
 
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4.4 
Study Duration 
The entire study duration per subject will be 17 to 44 days, including a Screening period of 
up to 4 weeks days prior to baseline (Day -30 to Day -3), a 9-day confinement period 
(afternoon of Day -2 to time of Discharge at Day 6), followed by a 7-day safety follow-up 
period (until Day 13) for the recording of spontaneously reported new AEs/SAEs, and the 
follow-up of ongoing AEs/SAEs by the site. 
The 9-day confinement period consists of: 
 The run-in period: defined as from the admission to the clinic until 06:29 AM of Day -1. 
 The baseline period: defined as 06:30 AM at Day -1 until 06:29 AM of Day 1. 
 The 5-day exposure period during confinement: defined as from 06:30 AM of Day 1 until 
11:00 PM of Day 5. 
 The Day of Discharge defined as (Day 6) (from Day 5, 11:01 PM to time of discharge). 

 
 
 
 
 
 
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5 
STUDY POPULATION 
5.1 
Selection of Study Population 
In total, 160 female or male smoking, but healthy Caucasian subjects who smoke per day at 
least 10 non-menthol CC 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. The maximum number of CC is not limited. Subjects must have a smoking history of 
at least 3 years of consecutive smoking prior to the Screening Visit. There will be no brand 
restrictions. Subjects can smoke different non-menthol brands until Admission to the clinic. 
From Admission to the clinic onwards, however, they must restrict themselves to one 
preferred, non-menthol CC brand. The smoking status will be verified with a urinary cotinine 
test (cotinine ≥200 ng/ml). Each sex and each of the smoking strata should have a quota 
applied to ensure they represent at least 40% of the study 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 21 to 65 years 
(inclusive). 
Safety 
X 
 
3. Subject is of Caucasian origin. 
Effect 
X 
 
4. Smoking, but healthy subject as 
judged by the Investigator or designee 
based on all available assessments 
from the Screening period/Day of 
Admission (e.g., safety laboratory*, 
spirometry* Forced expiratory 
volume in 1 second [(FEV1) / Forced 
vital capacity (FVC) >0.7 at 
post-bronchodilator spirometry, 
post-bronchodilator FEV1 >80% 
predicted value, and 
Safety  
X 
X 

 
 
 
 
 
 
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document may be publicly disclosed without the written consent of Philip Morris Products S.A. 
Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
post-bronchodilator FVC >80% 
predicted value], vital signs, physical 
examination, electrocardiogram 
[ECG], chest X-ray, and medical 
history). 
5. Subject is a current smoker (based on 
self-reporting), who for the last 4 
weeks has smoked at least 10 
commercially available non-menthol 
CCs per day (no brand restrictions) 
with a maximum yield of 1 mg 
nicotine ISO per cigarette, as labeled 
on the cigarette package. 
Furthermore, the subject has smoked 
for at least the last 3 consecutive 
years. The smoking status will be 
verified with a urinary cotinine test 
(cotinine ≥200 ng/ml). 
Effect 
X 
X 
6. The subject is a current smoker who 
does not plan to quit smoking in the 
next 3 months. 
Safety 
X 
 
7. The subject is ready to accept 5 days 
of SA. 
Safety 
X 
X 
8. The subject is ready to accept using 
the THS 2.2 product. 
Effect  
 
X 
* Safety laboratory and spirometry with bronchodilator will be used for eligibility at 
screening only 

 
 
 
 
 
 
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document may be publicly disclosed without the written consent of Philip Morris Products S.A. 
5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the 
study: 
Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
1. As per Investigator or designee 
judgment, the subject cannot 
participate in the study for any reason 
(e.g., medical, psychiatric, and/or 
social reason). 
Safety  
X 
X 
2. A subject who is legally incompetent, 
physically or mentally incapable of 
giving consent (e.g., emergency 
situation, under guardianship, subject 
in a social or sanitary establishment, 
prisoners or subjects who are 
involuntarily incarcerated). 
Administrative 
X 
 
3. The subject has a 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 or 
designee. 
Safety 
X 
X 
4. The subject has a body mass index 
(BMI) <18.5 or ≥32 kg/m2. 
Safety 
X 
X 
5. As per Investigator or designee 
judgment, the subject has medical 
conditions which require or will 
Effect 
X 
X 

 
 
 
 
 
 
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document may be publicly disclosed without the written consent of Philip Morris Products S.A. 
Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
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 CC 
(either tobacco-based products or 
nicotine replacement therapy [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 5 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 or 
designee if these can potentially 
interfere with the study objectives or 
subject’s safety. 
Effect  
X 
X 
9. Concomitant use of nonsteroidal 
anti-inflammatory drugs (NSAIDs) or 
acetylsalicylic acid. 
Effect 
X 
X 
10. The subject has a positive alcohol test 
and/or the subject has a history of 
alcohol abuse that could interfere 
Administrative 
X 
X 

 
 
 
 
 
 
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document may be publicly disclosed without the written consent of Philip Morris Products S.A. 
Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
with the subject’s participation in the 
study. 
11. The subject has a positive urine drug 
test. 
Administrative 
X 
X 
12. Positive serology test for human 
immunodeficiency virus (HIV)1/2, 
hepatitis B surface antigen (HbsAg), 
or hepatitis C virus (HCV). 
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, or 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, or 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 
and at Admission) or is breast 
feeding. 
Safety 
X 
X 

 
 
 
 
 
 
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document may be publicly disclosed without the written consent of Philip Morris Products S.A. 
Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
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 the electronic 
Case Report Form (eCRF). 
When a subject withdraws or is removed from the study, the whole 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. Subject will be informed that the 
whole examination procedure on Day 6 should be done for their safety but subjects will be 
free not to do it.  
After the time of withdrawal, the subject will enter into the 7-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), at 
the discretion of the Investigator or designee. 
 Positive pregnancy testing (any invasive procedures, including the drawing of blood 
MUST NOT be performed after diagnosis of pregnancy, see Section 8.5). 
 The Sponsor or Investigator or designee terminates the study.  
 Withdrawal is considered to be in the best interest of the subject or the other subjects. 
Subjects may be discontinued from the study for any of the following reasons: 
 Lost to follow-up. 

 
 
 
 
 
 
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 Concomitant treatment with non-authorized medication as defined in the context of this 
study (in general, any concomitant medication should be discussed with the Contract 
Research Organization [CRO] Medical Monitor on an ongoing basis). 
 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 or 
designee to decide whether or not to withdraw the subject from the study. 
 Non-compliance to the study procedures. 
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 enrolment and will be replaced by 
other subjects. 
Subjects who violate the entry criteria prior to enrolment, but who were 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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document may be publicly disclosed without the written consent of Philip Morris Products S.A. 
6 
INVESTIGATIONAL PRODUCTS 
6.1 
Description of Investigational Products 
6.1.1 
Test Product 
THS 2.2 comprises the following components:  Tobacco Stick, Holder, Charger, a Cleaning 
Tool, a mains power supply, and a USB cable: 
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 
Tobacco 
Stick 
(Tobacco Stick): 
The Tobacco Stick (product code C3) contains tobacco which, 
when heated, generates an aerosol. It is custom-designed to be used 
with the Holder. 
 
The overall objective of the product design is to provide an acceptable experience in which 
the HPHC levels in the aerosol are substantially reduced in comparison with CC. 
 
The THS 2.2 will be provided by the Sponsor. 
Per cigarette/Tobacco Stick tar, nicotine, and carbon monoxide yields are normally 
determined by standardized 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 1 below lists the commonly reported measures (PMI, 2013a). 
 

 
 
 
 
 
 
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Table 1 Measured aerosol fractions for the THS Tobacco Sticks 
Constituent (mg/THS Tobacco Stick) 
ISO 1 
Health Canada  Intense 
regime 2 
Tar/NFDPM 
4 
10.3 
Nicotine  
0.5 
1.32 
Carbon monoxide 
1 
0.6 
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 non-menthol CC. Subjects 
are not allowed to roll their own CC.  
The reference product to the THS 2.2 during the randomized exposure period is the subject’s 
own preferred commercially available single brand of non-menthol CC.  
All eligible subjects will be asked to purchase their own preferred single brand CC prior to 
Admission and provide his/her anticipated amount of CC for a total of 9 days plus 4 extra 
packs on Day -2 (Admission Day) to the site staff. The CCs will not be provided by the 
Sponsor. 
6.1.3 
Packaging and Labeling 
At Admission, all study subjects will provide the anticipated amount of CC in sealed packs to 
the study site staff. The CC packs provided by the subjects should not be opened and the 
cellophane wrapper should be intact. 
Each pack of CC provided by the subject will be labeled to identify which subject the CCs 
belong to (labels should be affixed to the cellophane wrapper of the lower part of the pack). 
Each pack of CCs will be labeled to identify necessary information to match the subject with 
its suppliers. 
For the Tobacco Sticks, the packs will be printed with the necessary information including 
but not limited to health warning, tar/nicotine/CO ISO levels, product code. 
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 

 
 
 
 
 
 
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confinement period, smoking will generally be allowed between 06:30 AM to 11:00 PM. 
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. 
6.2.1 
Run-in Period 
Smoking ad libitum will be allowed prior to admission and throughout the day except during 
the procedures. All subjects will be allowed to continue smoking ad libitum their single 
preferred brand of usual CC. All subjects (except women with a positive pregnancy test at 
Screening or at Admission) will undergo a THS 2.2 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. 
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 non-menthol CC. 
6.2.3 
Exposure Period 
Subjects will not be allowed to smoke any CC or use any nicotine/tobacco-containing 
products other than their assigned product/regimen. 
6.2.3.1 
THS 2.2 Arm 
Subjects randomized to the THS 2.2 arm will use exclusively THS 2.2 from Day 1, 
06:30 AM onwards until Day 5, 11:00 PM.  
6.2.3.2 
Conventional Cigarette Arm 
Subjects randomized to the CC arm will continue smoking their CC from Day 1, 06:30 AM 
onwards until Day 5, 11:00 PM.  
6.2.3.3 
Smoking Abstinence Arm 
Subjects randomized to the SA study arm will be instructed to abstain from smoking from 
Day 1, 06:30 AM onwards until Day 5, 11:00 PM. They will not be provided with 
medication supportive for smoking abstinence.   
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 or designee. 

 
 
 
 
 
 
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6.2.5 
Safety Follow-up Period 
During the safety follow-up period (after discharge at Day 6 until Day 13), all subjects are 
free to smoke their own CC ad libitum. Subjects in the SA arm, who wish to continue their 
SA, or any subject who wish to stop smoking will be referred for further treatment as per the 
standard of care in the country in which the study is conducted, if requested by the subject.  
6.3 
Method for Assigning Subjects to Study Arms 
When all the eligibility criteria have been met, randomization will be done through the 
Interactive Web and Voice Response System on Day 0 at any time during the day. Subjects 
will be informed of their randomized study arm in the morning of Day 1, prior to 06:30 AM. 
Subjects will be randomized to one of the 3 study arms: THS 2.2:CC:SA in a 2:1:1 ratio. 
Stratified randomization will be conducted by sex and by average daily CC consumption in 
the 4 weeks prior to the Screening Visit as reported by the subject (those smoking 10 to 19 
CC and those smoking >19 CC per day). In each arm, each sex and each of the smoking 
strata should have a quota applied to ensure they represent at least 40% of the population. 
6.4 
Blinding 
This is an open-label study; therefore, the subjects and Investigators or designees 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. 
Abbreviations: CRO =  Contract Research Organization; PMI = Philip Morris International. 
(*) As part of the PMI quality control (QC) activity, data listings will be reviewed by PMI before database lock, 
with no access to the randomization arm information. 
Any PMI and CRO personnel who are not listed in the above table will be unblinded by 
default.  

 
 
 
 
 
 
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6.5 
Investigational Product Accountability and Compliance 
6.5.1 
Dispensing Investigational Product 
From Day-2 onwards, each CC will be dispensed to the subjects.  Subjects in the THS 2.2 
arm will be provided by the site personnel with Tobacco Sticks from Day 1 to Day 5. One 
CC/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 
(CC/THS 2.2) use has to be documented from Day -1 for CC and from Day 1 for Tobacco 
Sticks onwards. The subject must not take a puff of the Tobacco Stick during the pre-heating 
time. The product will not be promoted for commercial distribution or test market.  
6.5.2 
Storage and Accountability 
The THS 2.2 and CC 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 
staff. Subjects will return each butt of CC and any used Tobacco Stick immediately after use. 
This will be documented in appropriate log. 
The filters and tobacco plugs of all used Tobacco Sticks will be collected from Day 1 to 
Day 5, using dedicated vials for accountability and subsequent analysis of both nicotine and 
tar assessments in the filters and identification of potential combustion occurrences in the 
tobacco plugs. 
6.5.3 
Investigational Product Retention 
The study site will destroy or return to the Sponsor any unused Tobacco Sticks and will 
return to the Sponsor the THS 2.2 product components upon study completion. 
Irrespective of the study arm on the time of Discharge from the clinic, the site staff will 
return to the subjects any remaining CCs given by them on the Day of Admission. 
6.5.4 
Compliance to Investigational Product(s) 
Compliance for all study arms will be ensured by strict distribution of the products (product 
by product) and collection of Tobacco Sticks, and CC butts will be documented in 
appropriate log. 
In addition, in the SA arm, compliance will be chemically verified using an exhaled CO 
breath test. The cut-off point for the CO breath test value to distinguish tobacco use vs. no 
tobacco use will be 10 ppm (Benowitz et al, 2002). 

 
 
 
 
 
 
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6.6 
Restrictions 
6.6.1 
Smoking Restrictions and Restrictions to the Smoking Abstinence Arm 
To avoid cross smoke contamination between the 3 study arms, subjects must use THS 2.2 
and CC 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 study arm. 
In the THS 2.2 and SA arms, subjects will not be allowed to smoke any CC or use any 
nicotine/tobacco-containing products (including NRT) from Day 1 (06:30 AM) until Day 5 
(11:00 PM). In CC arm, subjects will not be allowed to use THS 2.2, any 
nicotine/tobacco-containing products and other CCs than collected to the site by the subject. 
During the confinement period, smoking will generally only be allowed during the 
designated smoking times, from 06:30 AM to 11:00 PM. Subjects will not have free access to 
their CC or THS 2.2; these will be dispensed by the study site staff individually as described 
in Section 6.5.1. 
Smoking will not be allowed during assessments on the Admission Day at the discretion of 
the site. Smoking will also not be allowed from Day 5, 11:01 PM until the spirometry has 
been performed on Day 6.  
In general, the performance of scheduled procedures has priority over the wish of a subject to 
smoke. However, this is different on Day 5 due to the assessment of the nicotine profile. If 
the subject wants to smoke on Day 5 around the time of the blood draw, he/she should 
inhale/smoke first and the blood will be drawn after the Tobacco Stick/CC has been 
inhaled/smoked. 
6.6.2 
Dietary Restrictions 
A standard diet will be designed by a dietician for the whole confinement period. For each 
meal, the caloric and fat content should be controlled in order to avoid a “high-fat” diet. The 
FDA guidance on food-effect studies for bioequivalence testing identifies a “high-fat” diet as 
a diet which maintains approximately 50 % of total caloric content of the meal and is high in 
calories (approximately 800 to 1000 calories) (Food and Drug Administration, 2002).  
In order to avoid any effect on assessment of BoExp, grilled or pan-fried meat, pre-cooked 
meats (e.g., tuna, ham, corned beef, and smoked meats), bacon, and sausage will not be 
permitted (Smith et al, 1996). 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 and Fuhr, 2004) except when the subject is asked to drink a cup of 
coffee for CYP1A2 measurement. Consumption of quinine-containing drinks (e.g., tonic 
water) is not allowed. 

 
 
 
 
 
 
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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 
snacks, 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. 
Fasting state has to be observed for at least 8 hours prior to blood draws for the safety 
laboratory at the Screening Visit, on Day 0, and Day 6,for the serum/plasma bio-banking 
samples on Day 0 and Day 6, and blood biobanking for transcriptomics (pharmacogenomics) 
on Day 0 and Day 6.  
6.7 
Concomitant Medication 
No medication should be taken during the study from the Screening until the end of the study 
(time of discharge plus 7-day safety follow-up period) without prior informing the 
Investigator or designee. However, the Investigator is responsible for the medical care of the 
subjects during their participation in this study. Any decisions regarding the prescribing of 
medication will be made in the best interests of the subject. 
Concomitant use of NSAID and acetylsalicylic acid (including over-the counter products) is 
not allowed, as all of them could interfere with the levels of 11-DTX-B2 and possibly other 
risk markers. Paracetamol will be allowed at a daily total dose of up to 1500 mg. Any 
medication with an impact on the CYP1A2 and CYP2A6 metabolism (as prescription and 
over-the-counter products) as shown in Table 2 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 eCRF (for details, see Section 6.7). 
Concomitant medications should be followed-up with the CRO Medical Monitor on an 
ongoing basis. 
The drugs and substances shown in Table 2 are a selection of drugs considered to have an 
impact on CYP1A2 and/or CYP2A6 activity (Chang and Kam, 1999; Ingelman-Sundberg et 
al, 1999; Lacy et al, 2007). Prior to database lock, 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 14 days 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. It is at the 
discretion of the Investigator or designee to assess if the termination of such medication at 
Screening is medically justified and safe for the subject. 

 
 
 
 
 
 
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Estrogens for contraception and for hormone replacement therapy, even though known to be 
CYP1A2 inhibitors, will be allowed in this study. The use of estrogensmust be documented 
on the eCRF. 

 
 
 
 
 
 
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Table 2. 
Examples of Medications with Effects on CYP1A2 and CYP2A6 Activity 
Drug name 
Substance Class 
Fluoroquinolones, including ciprofloxacin and 
ofloxacin, nafcillin, rifampicin 
Antibiotic 
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, losartan 
Antihypertensive 
Drosperinone, estrogens 
Hormonal contraceptives,  
Agents for 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 (substance class 
Furocoumarins) 
Modafinil, diclofenac, rofecoxib 
Analgesic 
Insulin 
Anti-diabetic 
Sildenafil 
Phosphodiesterase-Inhibitor (e.g., used 
for treatment of Erectile dysfunction) 

 
 
 
 
 
 
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Quinine 
Crystalline alkaloid 
St. John’s Wort 
Over-the-counter (herbal remedy) 
antidepressant 
Psoralen 
Anti-psoriatic (substance class 
Furocoumarins) 
Pilocapine 
Cholinergic agonists (e.g., used for 
Glaucoma Therapy) 
Data sources: Chang and Kam, 1999; Ingelman-Sundberg et al, 1999; Lacy et al, 2007. The list is not exhaustive. 
The list of drugs provided in Table 2- Examples of Medications with Effects on CYP1A2 and 
CYP2A6 Activity - is intended to provide guidance for the Investigator or designee; 
however, should not be considered exhaustive. 

 
 
 
 
 
 
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7 
STUDY PROCEDURES 
Personnel performing study measurements or recordings must have the appropriate training 
fully documented. Quality control (QC) measures have to be in place. An overview of all 
study procedures is shown in the Schedule of Events (Appendix 1). In this section, only the 
expected/planned time points for the various measurements are described. As not all subjects 
can undergo a procedure at the same time, adequate time windows are given for each study 
procedure and each time point (see Section 9). Site personnel will adhere to the site’s 
Standard Operating Procedures (SOPs) for all activities. Appropriate medical advice will be 
provided to the subject in case of any medial findings requiring health care. 
7.1 
Informed Consent 
Prior any study assessments is performed, the subject will be asked to provide his consent to 
participate to the study (ICF/subject information sheet for study participation) section 1.3. 
In addition to the ICF/subject information sheet for study participation, the subject will be 
asked to provide his separate consent for two kinds of biobanking section 1.3 .  
 ICF/subject information sheet to the additional bio-banking of serum/plasma/urine 
samples for further measurements of BoExp and risk markers.  
 ICF/subject information sheet to the additional bio-banking of blood sample for further 
transcriptomics (pharmacogenomics) analysis.  
The subject’s participation in the study does not depend on their providing consent for 
sample bio-banking. The consent for both bio-banking (for BoExp and risk markers and for 
transcriptomics 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 and Debriefing 
Each subject will be given advice on the risks of smoking 3 times during the study: at the 
Screening Visit, at Admission (Day -2), and at Day 6. 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 designee, and may additionally be given in a group session. 
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 THS 2.2. 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. 

 
 
 
 
 
 
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7.3 
Support for the Smoking Abstinence Arm 
All subjects in the SA arm will be closely monitored by the site staff for possible signs and 
symptoms of nicotine withdrawal. This includes clinical monitoring, (e.g., vital signs, 
physical examination, and body weight). It will also involve close monitoring of the subject’s 
behavior, mood, and any AEs. A psychologist may be contacted and will be available upon 
the subject’s request, or if considered necessary, upon the request of the Investigator, 
designee, or site staff. 
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 (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 or designee needs to check if inclusion 
criterion No. 04 is still fulfilled.  
7.4.1 
Demographic Data 
Demographic data (sex, date of birth/age, and race) will be recorded at the Screening Visit. 
7.4.2 
Identification of the Current Cigarette Brand 
Identification of the current CC 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 CC brand(s) to the site. On Day -2, subjects will hand their CC supply for the entire 
confinement period to the site staff. The site staff will document the brand name and yields. 
A photograph of the front and the side of the CC pack supplied by the subject (bearing the 
tar, nicotine, and CO yields) will be taken by the study site staff in addition to recording the 
brand name and yields. 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 Disc [CD]). 
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 3 consecutive years, to determine the number of CC smoked during the 
previous 4 weeks, and to evaluate if the CCs smoked during the previous 4 weeks were 
non-menthol CCs. 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 CC (either 

 
 
 
 
 
 
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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 
willing to abstain from smoking for at least 5 days (as required in the study protocol 
inclusion criteria). 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 Product Test of the THS 2.2 
All subjects will be shown a demonstration of the THS 2.2 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 product (use of up to 3 THS Tobacco Sticks). 
In female subjects, the THS 2.2 product test may 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 those subjects who are willing 
and able to use the product can participate in the study. The product test will be the last 
assessment prior to enrolment. 
7.4.5 
Medical History, Concomitant Disease, Previous and Ongoing Medications 
Relevant medical history as well as any concomitant diseases will be documented at the 
Screening Visit. Medical history is defined as any condition that started 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 within 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 captured in the eCRF. 
7.4.6 
Physical Examination 
A physical examination will be conducted at the Screening Visit, at Admission (Day -2), and 
at Day 6.  
Appropriate medical advice will be provided to the subject in case of any medical findings 
requiring health care. 

 
 
 
 
 
 
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7.4.7 
Body Height and Weight 
Body weight will be recorded at all time points at the Screening Visit, at Admission (Day -2), 
and at Discharge on at Day 6. Body height will be measured only at the Screening Visit.  
Body mass index will be calculated from the body weight and height using the following 
formula: 
BMI =  
weight in kilograms 
————————     ( kg/m² ) 
height in meters² 
 
7.4.8 
Vital Signs 
Systolic and diastolic blood pressure, pulse rate, and respiratory rate will be measured at the 
Screening Visit, at Admission (Day -2), and in the morning of every day of the confinement 
period (i.e., Day -1 to Day 6). 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. 
7.4.9 
Other Clinical Assessments 
7.4.9.1 
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. Furthermore, spirometry without bronchodilator will be performed at Day 0 
(baseline values), and at Day 6 (for comparison with the baseline values). Spirometry has to 
be done prior to smoking the first CC of the day on Day 0 and Day 6. 
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 National Health and Nutrition 
Examination Survey III predicted set. 
All personnel performing lung function testing should have the appropriate training and 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. 

 
 
 
 
 
 
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The subject will be submitted to a spirometry with maximum voluntary ventilation 
measurement. 
For spirometry, assessed parameters will include: 
 FEV1. 
 FVC. 
 FEV1/FVC. 
7.4.9.2 
Electrocardiogram 
An ECG will be recorded at Screening and at Day 6. Electrocardiogram 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 QT 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 in 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. 
7.4.9.3 
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 nicotine or CO. 
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 
CO in all 3 study arms. The CO breath test should be conducted in timely conjunction with 

 
 
 
 
 
 
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the blood sampling for COHb, where applicable. In the SA arm, the CO breath test will serve 
as a verification of compliance (see Section 6.5.4).  
Carbon Monoxide Breath Test 
Carbon monoxide in exhaled breath will be measured using the Smokerlyzer® e.g. Micro+™ 
Smokerlyzer® or similar device.  
On Days -1 to Day 5, the CO breath test will be conducted 4 times per day. The first test 
should be conducted within 15 minutes prior to the first product use. The other 3 tests should 
be conducted as defined in section 9. 
On Days 1 to Day 5, for subjects in the SA arm, the first CO breath test will be done between 
08:00 AM and 10:00 AM. The other 3 tests should be conducted as defined in section 9. 
On Day -2 and Day 6, the CO breath tests will be conducted once. 
Carboxyhemoglobin 
Assessment for COHb will be performed at the local laboratory. Carboxyhemoglobin in 
blood will be assessed on a daily basis, starting from Day -1 until Day 5. 
On Day -1 to Day 4: one blood sample as defined in section 9. 
On Day 5: one blood sample will be collected within 15 minutes prior to the first product use.  
The three other blood sample will be collected as defined in section 9. 
For subjects in the SA arm, the first COHb will be done between 08:00 AM-10:00 AM. The 
three  other blood samples will be collected as defined in section 9. 
7.5.1.2 
Plasma Nicotine and Cotinine 
Nicotine and cotinine concentrations will be measured in plasma to evaluate the exposure to 
nicotine. For subjects in the SA arm, blood samples will be collected on Day 0 to Day 4, at 
comparable time points. No nicotine PK profile will be done for subjects in the SA arm on 
Day 5 and Day 6. 
 On Day 0 to Day 4 (all study arms): 
One blood sample for nicotine and cotinine will be drawn each day 08:00 PM-10:00 PM. 
 Nicotine/cotinine PK profile on Day 5 and Day 6 (THS 2.2 and CC arms only): 
In total, 9 blood samples will be drawn on Day 5. The first blood sample on Day 5 will be 
drawn within 15 minutes prior to the first product use (T0). On Day 5, T0 will serve as a 
reference for the time to peak concentration. An additional 8 blood samples will be drawn in 
2 hour intervals after T0. The last blood sample should be drawn no later than 11:00 PM, 
corresponding to the end of the product use. At all time points, if the subject wants to smoke 
around the time of the blood draw, he/she should smoke first and the blood will be drawn 
after the product has been used. Depending on the time of the first product use, it may be that 
fewer than 8 blood samples will be collected from a subject after T0. 

 
 
 
 
 
 
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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). 
 On Day 5 and Day 6 (SA arm only): 
On Day 5, one blood sample will be drawn 08:00 PM-10:00 PM. 
On Day 6, one blood sample will be drawn 08:00 AM-10:00 AM. 
7.5.1.3 
Other Biomarkers of Exposure 
The following BoExp will be measured in 24-hour urine collection samples as per the 
Schedule of Events (Appendix 1): 
 Primary BoExp: MHBMA, 3-HPMA, S-PMA.  
 Secondary BoExp: total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), 1-NA, 
total 1-hydroxypyrene (1-OHP), total NNN, 3-hydroxy(a)benzopyrene, 4-ABP, 2-NA, 
o-toluidine (o-tol), NEQ, 2-cyanoethylmercapturic acid (CEMA), 2-hydroxyethyl 
mercapturic acid (HEMA), S-benzylmercapturic acid (S-BMA), and 3-hydroxy-1-
methylpropylmercapturic acid (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 recorded/measured at the following time points: 
• 8-epi-PGF2α to be measured in 24-hour urine on Day 0 and Day 5. 
• 11-DTX-B2 to be measured in 24-hour urine on Day 0 and Day 5. 
 
7.5.2.2 
CYP1A2 Activity test 
Cytochrome P450 1A2 activity will be measured at Day 0 and at Day 5. Measurement of 
enzyme activity will be assessed through PX and CAF plasma molar concentrations 
approximately 6 hours (±15 minutes) after the intake of a cup of coffee made from 4.2 g 
(±10%) regular instant coffee (Nescafé Gold Instant; Nestlé; Deutschland; CAF content: 
72 mg/2 g) with 150 ml ±10 ml water. The CAF content will be approximately 150 mg CAF 
(Faber and Fuhr, 2004). The exact time of the intake of the cup of coffee in the morning and 
of the blood sampling (taken 6 hours [±15 minutes] after the intake of the coffee) must be 
recorded. Cytochrome P450 1A2 activity will be assessed by the measurement of the molar 
PX/CAF metabolic ratio (Faber and Fuhr, 2004). 

 
 
 
 
 
 
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7.5.2.3 
CYP2A6 activity 
Cytochrome P450 2A6 activity will be measured in plasma on Day 0, and on Day 6, using 
the molar metabolic ratio of trans-3’-hydroxycotinine/cotinine (Jacob et al, 2011). Blood 
sampling for CYP2A6 activity must be done prior to product use. 
Cytochrome P450 2A6 activity drives the hepatic 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 and 
on Day 5 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 
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, and at Day 6. Blood samples will be taken after at least 8 hours of fasting 
(see Section 6.6.2). The urine test will be performed semi-quantitatively as a urine dip-stick 
test. Parameters to be measured are listed in Table 3. 

 
 
 
 
 
 
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Table 3. 
Clinical Laboratory Parameters for Safety Panel 
Hematology 
Clinical Chemistry 
Urine analysis 
- Hematocrit (Hct) 
- Hemoglobin (Hb) 
- 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 HbsAg, HCV, and anti-HIV1/2 and p24 antigen will be done at Screening. In case 
of positive results, the subject will be referred to appropriate medical care. 
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. 

 
 
 
 
 
 
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7.6.4 
Urine Cotinine Screening 
A urine dip-stick cotinine test will be performed at Screening and at Admission (Day -2) in 
order to confirm the subject’s smoking status. The test must detect cotinine with a cotinine 
threshold of ≥200 ng/ml (i.e., One-Step Cotinine Test 008A086, Ultimed, Belgium). 
7.6.5 
Alcohol Breath Test 
Subjects will have a breath alcohol test at the Screening Visit and at Admission (Day -2) 
using an alcometer device (e.g., Alcotest 7410 Plus, Dräger). 
7.6.6 
Urine Pregnancy Testing 
All female subjects will undergo pregnancy testing at the Screening Visit, at Admission 
(Day -2), at Day 6. Female subjects with a positive pregnancy test at the Screening Visit or at 
Day -2 cannot be enrolled and will be considered a screening failure. The product test at 
Admission must be done only in female subjects with a negative urine pregnancy test. In any 
case of a positive urine pregnancy test, the Investigator or designee will inform the subject 
about the risks associated with smoking during pregnancy. 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 
Sample 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 dip-stick for the safety laboratory, urine pregnancy tests, urine drug 
screen, and urine cotinine tests will be done by personnel at the study sites. 
Detailed procedures for sample collection and handling of samples will be described in a 
separate Sample Handling Manual (SHM). Safety laboratory samples will be destroyed as 
per the laboratory’s standard procedures. All other samples (except bio-banking samples) 
will be destroyed after the Clinical Study Report (CSR) has been finalized. The facility/ies at 
which the samples are stored will be informed in writing by the Sponsor when destruction of 
the samples will be allowed. 
The bioanalytical lab(s) are listed in Appendix 2. 
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 be around 170 ml, which includes 20 ml for safety and repeated analysis, 20 ml 
of blood for long-term storage of the biobanking samples for further analysis of biomarkers 

 
 
 
 
 
 
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of exposure and risk markers (only if additional consents are given, see Section 7.7.3), and 
10 ml for long-term storage biobanking samples for further transcriptomics analysis (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 tests, and safety urinalysis.  
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. During the sampling 
period, all urine passed must be collected and put into the sampling bottle, with the exception 
of about 10 ml for the spot urine tests (described above). No urine must be passed into the 
toilet. The start and the end time of the 24-hour urine collection will be recorded by the study 
site staff. 
For assessment of urine BoExp, creatinine for normalization of urine BoExp, 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, 
NEQ measured at Day 5 in the 24-hour urine collection starts on Day 5 and ends later on Day 
6. 
At time of Discharge on Day 6, subjects will empty their bladder shortly before 06:29 AM. 
This will be the last urine portion for the 24-hour urine for the Day 5 dot mark in the 
Schedule of Events. 
7.7.3 
Long-Term Bio-banking Storage of Blood or Urine 
If a subject gives consent for sample bio-banking for BoExp/risk markers, additional samples 
of urine (from the 24-hour urine collection) and serum/plasma (20 ml of blood total) will be 
collected. 
 Samples from the 24-hour urine will be collected from the urine collections that started 
on Day 0 and on Day 5, respectively. 
 Serum/plasma will be collected on Day 0 and Day 6. 
These samples are intended for possible later analysis of additional BoExp/risk markers. No 
genetic or transcriptogenomics testing will be performed on these samples. 

 
 
 
 
 
 
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If a subject gives consent for sample bio-banking of whole blood for transcriptomics, a total 
of 10 ml of blood will be collected to that purpose at Day 0 and Day 6. 
The samples intended for sample bio-banking will be kept frozen according to the SHM, 
separate from the other samples collected, and will be shipped to a central storage facility. 
After the final CSR is signed, samples of plasma/serum 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 sample bio-banking. 
7.8 
Other Study Procedures 
7.8.1 
Human Smoking Topography Assessment 
Human smoking topography involves the measurement of each smoker’s unique way of 
smoking CCs or using THS 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 4). It consists of a 
special sample holder (containing a constriction in the middle) which is placed between the 
subject’s mouth and the filter of the CC or THS Tobacco Stick being smoked/used. The 
sample holder is connected by 2 narrow tubes to a portable data logger/recording system (see 
Appendix 4 for a description of the device). Any malfunction of the HST SODIM® portable 
device will be documented in appropriate log. 
At Day 0, the HST SODIM® device has to be used for all CC smoked for all subjects. On 
Day 1 and Day 4 of the confinement period, the HST SODIM® device has to be used for 
every product use for all subjects in the CC and THS 2.2 arms. 
Smoking topography with the HST SODIM® device will not be recorded for subjects 
smoking CC that are incompatible with the HST SODIM® device (e.g., slim CC). 
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 CCs at 
each cohort but not more than 40 subjects at each cohort.   
From Day 1, for subjects in the SA arm, no HST assessments will be performed. 
The Sponsor will provide training on the use of the HST SODIM® device to the study site 
staff. The study site staff will, in turn, provide training to the subjects. All HST SODIM® 
devices will be returned to the Sponsor after completion of the study. 

 
 
 
 
 
 
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7.8.1.1 
Human Smoking Topography Parameters: 
The HST SODIM® device measures and records the flow and other per-puff parameters 
listed in Table 4 below. From the per-puff parameters (Table 4), the per-cigarette parameters 
shown in Table 5 will be derived (representing average values or totals per cigarette). 
Prior to calculation of the per-cigarette parameters, the Sponsor’s 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 4. 
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 5. 
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) 
 
 
7.8.2 
THS Filter Analysis 
All filters from used Tobacco Sticks will be sent to an external laboratory for analysis. 
7.8.3 
Visual Inspection of THS Tobacco Plugs 
All THS tobacco plugs collected during the study will be sent for subsequent visual 
inspection to determine whether combustion occurred during product use.  
7.8.4 
Questionnaires 
The subject questionnaires and the VAS will be entered by the subject directly in the 
electronic patient reported outcomes (ePRO) device, or on paper copy. The questionnaires 
and the VAS will be reviewed for completeness by the study site staff and subjects will be 
requested to complete any missing information. 
Symptoms or worsening of symptoms documented on any of the questionnaires or the VAS 
do not need to be documented as additional AEs because the questionnaire and the VAS will 
be analyzed as part of the final report. However, it is at the discretion of the Investigator or 
designee to decide whether to document such symptoms as additional AEs. The main source 
for AE collection will be the face-to-face interview between the subject and study site staff, 
using open, non-directive questions (see Section 8). 
7.8.4.1 
Fagerström Test for Nicotine Dependence (Revised Version) 
Potential nicotine dependence will be assessed at Screening using the Fagerström Test for 
Nicotine Dependence (FTND) (Fagerström et al, 2012). 

 
 
 
 
 
 
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The questionnaire consists of 6 questions which will be answered by the subject 
himself/herself. The scores obtained on the test permit the classification of nicotine 
dependence into 3 levels: mild (0-3 points), moderate (4-6 points), and severe (7-10 points) 
(Fagerström et al, 2012). 
7.8.4.2 
Assessment of Cough 
Subjects will be asked to assess the respiratory symptom ‘cough’ on a VAS, on 3 Likert 
scales, and with an open question on a daily basis during the confinement period from Day 0 
to Day 6. On each day, cough assessment has to be done prior to product use. 
Subjects will be asked if they have experienced a regular need to cough, (e.g., whether they 
have coughed several times in the previous 24-hours prior to assessment). If the answer is 
‘yes’, subjects will be asked to complete a VAS, 3 Likert scales, and to answer the open 
question. 
On the VAS, subjects will assess how bothersome their cough was during the previous 
24-hours. The VAS ranges from ‘not bothering me at all’ to ‘extremely bothersome’. 
Furthermore, subjects will assess the intensity and frequency of cough and the amount of 
sputum production during the previous 24-hours on Likert scales. 
The intensity of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = very mild -   2 = mild - 3 = moderate - 4 = severe - 5 = very severe. 
The frequency of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = rarely - 2 = sometimes - 3 = fairly often - 4 = often  - 5 = almost always. 
The amount of sputum production will be assessed on a 4-point Likert scale ranging from 
0 to 3, with 0 = no sputum - 1 = a moderate amount of sputum - 2 = a larger amount of 
sputum - 3 = a very large amount of sputum. 
Finally, subjects will be asked with an open question if they want to share any other 
important observations with the staff about their coughing. 
7.8.4.3 
Modified Cigarette Evaluation Questionnaire  
Product evaluation will be assessed using the MCEQ (Cappelleri et al, 2007). The MCEQ 
assesses the degree to which subjects experience the reinforcing effects of smoking, by 
measuring: 
 Smoking satisfaction (satisfying, tastes good, enjoys smoking). 
 Psychological rewards (calms down, more awake, less irritable, helps concentrate, 
reduces hunger). 
 Aversion (dizziness, nauseous). 
 Enjoyment of respiratory tract sensations (single-item assessment). 
 Craving reduction (single-item assessment). 

 
 
 
 
 
 
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Only subjects who are randomized to the THS 2.2 and CC arms will complete this 
questionnaire. The subjects will complete the questionnaire by themselves. 
The MCEQ will be completed by subjects during the confinement period from Day -1 to 
Day 5. 
7.8.4.4 
Questionnaire of Smoking Urges brief version 
To assess the urge-to-smoke, all subjects will be asked to fill-in a 10-item brief version of the 
QSU-brief (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. 
7.8.4.5 
Minnesota Nicotine Dependence/Withdrawal Scale (revised version) 
The MNWS is a valid and reliable scale that has been used previously to examine signs and 
symptoms of withdrawal from cigarette smoking (Hughes and Hatsukami, 1986; Hughes and 
Hatsukami, 2008). It consists of two scales: a ‘self-report scale’ and an ‘observer scale’. 
For the purpose of this study, only the self-reporting scale will be used and filled-in by the 
subject. Furthermore, the subject’s weight will not be recorded for the purpose of the 
MNWS. At the end of the assessment of the questionnaire, the subject’s pulse rate will be 
recorded. 
Subjects will be asked to rate the items for the previous 24-hours on a scale ranging from 0 to 
4 (where 0 = none, 1 = slight, 2 = mild, 3 = moderate, 4 = severe). 
The MNWS (revised version) will be completed on a daily basis from Day 0 to Day 6. On 
each day, MNWS has to be asked prior to product use. 
7.8.4.6 
Human Smoking Topography Questionnaire 
A specific questionnaire, used for exploratory purposes, has been developed by PMI to 
evaluate the impact of the utilization of the HST SODIM® device on smoker’s smoking 
experience in terms of ritual disruption. 
This is a questionnaire with 5 items to be rated on a 5-point scale and open questions. 
Subjects will be asked by the Investigator or designee to complete the HST questionnaire at: 
 The end of the baseline period on Day 0 for all subjects smoking CC compatible with the 
HST SODIM® device (i.e., non-slim CC). 
 On Day 4 for all subjects in the THS 2.2 and for all subjects smoking CC compatible with 
the HST SODIM® device (i.e., non-slim CC). 
 

 
 
 
 
 
 
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8 
ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
The FDA MRTP guidelines specify the following definition for AEs 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 by 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 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/subject 
information sheet will not be recorded as SAEs, however, they will be recorded as AEs only. 
Any AE that occurs during this pre-planned hospitalization will be considered according to 
the above definitions. 
8.2 
Assessment of Adverse Events 
The Investigator or designee is responsible for obtaining, assessing, and documenting all AEs 
during the study.  

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

 
 
 
 
 
 
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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. 
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 site staff.  
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 or designee 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 or designee 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. 
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 or designee as either 
‘related’ or ‘not related’ to IP as described below. In addition to the assessment of the 
relationship of the clinical event to the IP, the Investigator or designee shall document a 
potential relationship of the clinical event to any particular study procedure. 
Not related: The temporal relationship of the clinical event to IP administration or a 
study procedure makes a causal relationship unlikely, or, concomitant 

 
 
 
 
 
 
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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 and Follow-Up of Serious Adverse Events 
Any SAEs reported or observed during the study after signature of the ICF/subject 
information sheet until the end of the safety follow-up period (i.e., up to 7 days after study 
Discharge) whether or not attributable to the IP, to any other medication or to any study 
procedures, or any SAE related to the product and spontaneously reported after the safety 
follow-up must be reported by the Investigator or designee or other study site staff within 24 
hours after first awareness by any party involved in the study to 
 
 and to the Sponsor. 
An SAE report form must be faxed or e-mailed as an attachment to: 
: 
Phone number: 
 
Fax number 
 
E-mail: 
 
 
Address: 
 
 
 
 
Sponsor: 
Contact: 
 
MD, Medical Safety 
Officer  
Phone number: 
 
E-mail: 
@pmi.com 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube 
Quai Jeanrenaud 5 

 
 
 
 
 
 
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2000 Neuchâtel 
Switzerland 
The Investigator or designee is responsible for local reporting (e.g., to the IEC) of SAEs that 
occur during the study, according to local regulations. 
Any additional/follow-up information that becomes available after the initial SAE report 
form has been completed will be forwarded to 
 and the Sponsor within 24 hours 
after first awareness by any person at the site using a follow-up to the existing SAE report 
form. 
The follow-up SAE report form must include the minimum information required for form 
completion and only changed/new information needs to be specified. Information provided in 
the follow-up SAE report form supersedes any information that was initially reported. 
All SAEs will be followed-up by the Investigator or designee and/or 
 until 
resolution or until the Investigator or designee considers the event to be stabilized (i.e., no 
worsening of condition), or an acceptable explanation has been found (e.g., a chronic 
condition). 
The SAE report form to be used in this study is provided as a separate document. All SAEs 
will be recorded on the eCRF, in addition to the SAE report form. 
8.4 
Reporting of Other Events Critical to Safety Evaluations 
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator or designee and assessed for clinical relevance. If the 
Investigator or designee 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 the Common Terminology Criteria for Adverse Event and 
Common Toxicity Criteria [CTCAE] version 4.03) will be used by the Investigator or 
designee to assess abnormal laboratory AEs as follows: 
 All Grade 1 abnormal laboratory values will be evaluated by the Investigator or designee 
with respect to baseline value and clinical relevance. If considered to be clinically 
relevant, the Investigator or designee must report it as an AE. All Grade 2 and higher 
abnormal laboratory values must be reported as or linked to an AE/concomitant disease. 
 If a subject has Grade 2 and higher abnormal laboratory values at Screening, it is at the 
discretion of the Investigator or designee to enroll the subject or not. This decision must 
be documented in the source documentation and captured in the eCRF. 
 If there is any worsening in grade from Grade 2 and above during the study, the 
Investigator or designee must report this worsening as an AE. 

 
 
 
 
 
 
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 Where there is no grading available, the abnormal laboratory value will be evaluated by 
the Investigator or designee, and assessed for clinical relevance. If considered to be 
clinically relevant, the Investigator or designee will report it as an AE. 
 Any other abnormal clinical laboratory result (including those that are not part of the core 
safety assessments) can, at the discretion of the Investigator or designee, be reviewed and 
assessed. Even if they do not meet the criteria of the CTCAE grading scheme (please see 
above), the Investigator or designee may consider them to be of clinical relevance and, if 
they are, must report them as AEs. 
 In general, laboratory values will be recorded as ‘increased <lab parameter>’ or 
‘decreased <lab parameter>’ to ensure consistency of recording/coding. 
All other information (e.g., relationship to IP, intensity, seriousness, outcome) will be 
assessed as for other AEs. 
8.5 
Reporting and Follow-Up of Pregnancies 
For pregnancies detected during the Screening period and prior to first THS 2.2 use, the 
subject will be considered as a screening failure and removed from the study. No Pregnancy 
Form will be completed, however, the diagnosed pregnancy must be captured in the Screen 
Failure eCRF.  
All pregnancies occurring after signature of the ICF/subject information sheet and diagnosed 
after first exposure to the IP until completion of the study must be reported by the 
Investigator or designee.  
Any pregnancy potentially associated to exposure to the IP, including pregnancies 
spontaneously reported to the Investigator or designee after the EOS must be reported by the 
Investigator or designee and followed-up. Potential association with exposure to the IP is 
defined as the conception date being calculated before the last exposure to the IP.   
The Investigator or designee will complete a Pregnancy Form (provided as a separate 
document) for all pregnancies diagnosed (including positive urine pregnancy tests). 
The procedure to report a pregnancy and provide any additional/follow-up information to 
 and the Sponsor must be followed in the same manner and within the same 
timelines as described for an SAE (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.  
 will follow-up pregnancies only if they were detected 
after first product use (i.e., after THS 2.2 product test on Admission Day). If pregnancies are 
to be followed-up, they will be followed-up until an outcome is reached (e.g., normal 
delivery, spontaneous abortion, or voluntary termination). Any pregnancy complications, 
adverse pregnancy outcomes, or maternal complications will be recorded. 

 
 
 
 
 
 
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The Investigator or designee is responsible for informing the IEC 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 procedures as 
described for the Day of Discharge, as soon as possible and will enter the period of safety 
follow-up. The Investigator or designee and/or 
 will follow-up these AEs until they have 
resolved, stabilized (i.e., no worsening of condition), or an acceptable explanation has been 
found. 
8.7 
Investigational Device Misuse 
Any occurrences of the Holder or Charger misuse (use not in accordance with its label and 
instruction) by a subject will be documented by the Investigator or his/her designated staff 
using a Device Issue Log.  
Investigational device misuse may result in use-related hazards. 
Use-related hazards are derived from the US Food and Drug Administration Medical Device 
Use-Safety Guidance (Food and Drug Administration, 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 device, etc.) that result in 
hazards must be documented and reported by the Investigator or designee”. 
According to FDA Medical Device Regulation, data should be collected regarding the 
use-related hazards that have occurred with the 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.  
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. Furthermore, any misuse of 
the Holder or Charger that lead to an AE/SAE will follow the same processes as described 
above. 
8.8 
Investigational Device Malfunction  
Any occurrences of malfunction of the Holder or Charger will be documented by the 
Investigator or his/her designated staff using a Device Issue Log. 

 
 
 
 
 
 
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Furthermore, any malfunctions of the 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 8-hour fasting state for 
clinical laboratory parameters to be assessed. Table 6 shows the assessments that will be 
performed at the Screening Visit. First, the ICF/subject information sheet should be given to 
the subject. When/if the ICF/subject information sheet 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 6. 
Time Schedule - Screening Visit 
Time 
(Day-30 to 
Day-3) 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Screening 
 
 
 
Informed consent/Subject Information Sheet 
and Informed consents/subject information 
sheets for the two bio-banking 
 
 
 
Advice on the risk of smoking and 
debriefing 
 
 
 
Demographic data collected 
 
 
 
Identification of current CC brand 
 
 
 
Medical history/concomitant disease 
 
 
 
Prior medication (4 weeks prior to Screening 
Visit) and concomitant medication 
 
 
 
Smoking history 
 

 
 
 
 
 
 
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Time 
(Day-30 to 
Day-3) 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Screening 
 
 
 
Willingness to quit smoking within the next 
3 months and to abstain from smoking for at 
least 5 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 8 hours 
of fasting 
 
√ 
HIV, hepatitis B and C 
 
 
 
Physical examination and  height, weight, 
calculation of BMI 
 
 
 
THS 2.2 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 
 
 
 
Urine pregnancy test (all females) 
 
 
 
FTND 
 
 
 
Spirometry without short-acting 
bronchodilator first, and then with 
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; CC = conventional cigarette(s); ECG = electrocardiogram; 
FTND = Fagerström Test for Nicotine Dependence; HIV = human immunodeficiency virus; SAE = serious adverse event; 
THS 2.2 = Tobacco Heating System 2.2. 
9.2 
Confinement Period (Days -2 to Day 6) 

 
 
 
 
 
 
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9.2.1 
Admission (Day -2) 
The procedures of Day -2 can be performed in order deemed most practical except product 
test which will be the last assessment prior to enrolment after all eligibility criteria have been 
met. Table 7 shows the assessments that will be performed at Admission (Day -2): 
 
Table 7. 
Time Schedule - Day -2 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Admission 
 
 
 
AE/SAE recording; concomitant medication,  All day 
 
 
Urine pregnancy test (all females only) 
 
 
 
Advice on the risk of smoking and 
debriefing 
 
 
 
Smoking history  
 
 
 
Willingness to abstain from smoking for at 
least 5 days 
 
 
 
Urine drug screen  
 
 
 
Urine cotinine screening test 
 
 
 
Alcohol breath test screen 
 
 
 
CO breath test   
 
 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to measurement 
 
 
Physical examination, weight, BMI 
 
 
 
Inclusion/exclusion criteria 
 
 
 
Identification of current CC brand and 
picture 
 
 
 
THS 2.2 product test 
 
Until 11:00 PM 
 
Smoking Period 
 
In the evening 
until 09:00 PM 
 
Dinner 
 
 
 
Enrolment 
Only after all eligibility criteria 
have been met 
11:00 PM 
 
End of study day 
 
Abbreviations: AE = adverse event; BMI = body mass index; CC = conventional cigarette(s); CO = carbon monoxide; SAE: 
serious adverse event; THS 2.2= Tobacco Heating System 2.2. 

 
 
 
 
 
 
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9.2.2 
Baseline Period (Day -1 to Day 0) 
Table 8 and Table 9 show the assessments that will be performed at baseline (Day -1 and 
Day 0, respectively). 
The start times given are for the first subject. All subsequent subjects should complete 
procedures within the time window given in the tables. 
 
Table 8. 
Time Schedule - Day -1 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Baseline Day -1 
 
 
 
AE/SAE recording; concomitant medication 
All day 
06:30 AM+/-
30min 
 
Start urine collection to Day -1 sampling 
bottle 
 
 
 
CO breath test 
To be done within 15 minutes 
prior to smoking 
06:30 AM 
 
Beginning of smoking period 
 
Before 10:00 
AM 
 
Breakfast 
 
before 12:00 
PM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to measurement 
12:00 PM-
02:00 PM 
 
CO breath test 
 
before 03:00 
PM 
 
Lunch 
 
04:00 PM-
06:00 PM 
 
CO breath test 
 
Afternoon 
 
Snacks 
 
In the evening 
until 09:00 PM 
 
Dinner 
 
08:00 PM-
10:00 PM 
 
CO breath test 
 
08:00 PM-
10:00 PM 
√ 
COHb in blood 
 
08:00 PM-
11:00 PM 
 
MCEQ questionnaire ,  
QSU-brief questionnaire 
 
11:00 PM 
 
End of smoking period 
 

 
 
 
 
 
 
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06:30 AM-
11:15 PM 
 
Collection of all smoked CC butts  
For accountability 
Abbreviations: AE = adverse event; CC = conventional cigarette(s); CO = carbon monoxide; COHb = carboxyhemoglobin; 
MCEQ = Modified Cigarette Evaluation Questionnaire; QSU-brief = Questionnaire of Smoking Urges (brief version); 
SAE= serious adverse event; THS 2.2 = Tobacco Heating System 2.2. 
 

 
 
 
 
 
 
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Table 9. 
Time Schedule - Day 0 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Baseline Day 0 
 
 
 
AE/SAE recording; concomitant 
medication 
All day 
 
 
Randomization 
At any time during the day after 
eligibility criteria have been met. 
Subjects are not to be informed of 
their assigned arm until Day 1.  
06:29 AM +/-30 
min 
 
Analysis sample to be taken after final 
portion of urine has been added to 
Day -1 sampling bottle.  
BoExp and creatinine in 24-hour 
urine 
06:30 AM +/-30 
min 
 
Start of urine collection to Day 0 
sampling bottle  
 
 
 
Assessment of cough (VAS) 
To be done prior to smoking but 
no later than 10:00 PM 
 
 
MNWS questionnaire 
To be done prior to smoking but 
no later than 10:00 PM 
 
 
Spirometry without short-acting 
bronchodilator 
To be done prior to smoking 
 
√ 
CYP2A6 activity in plasma 
To be done prior to smoking 
 
 
CO breath test 
To be done within 15 minutes 
prior to smoking 
 
 
HST 
HST SODIM® device has to be 
used for all product uses if 
compatible CCs are smoked 
06:30 AM 
 
Beginning of smoking period 
 
 
√ 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
To be done after  at least 8 hours 
of fasting 
 
√ 
Bio-banking for BoExp/ risk markers 
in serum/plasma (if consent is 
obtained) 
To be done after at least 8 hours 
of fasting 
 
√ 
Bio-banking for transcriptomics (if 
consent is obtained) 
To be done after at least 8 hours 
of fasting 
 
 
Urine safety analysis  
 
Before 10:00 AM 
 
Breakfast 
 

 
 
 
 
 
 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Baseline Day 0 
 
10:00 AM-12:00 
PM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to measurement 
10:00 AM-12:00 
PM 
 
A cup of coffee containing 
approximately 150 mg of CAF 
 
12:00 PM-02:00 
PM 
 
CO breath test 
 
before 3:00 PM 
 
Lunch 
 
04:00 PM-06:00 
PM 
 
CYP1A2 activity in plasma 
6 hours +/-15 minutes after intake 
of cup of coffee 
04:00 PM-06:00 
PM 
 
CO breath test 
 
afternoon 
 
Snacks 
 
In the evening 
until 09:00 PM 
 
Dinner 
 
08:00 PM-10:00 
PM 
 
CO breath test 
 
08:00 PM-10:00 
PM 
√ 
COHb in blood 
 
08:00 PM-10:00 
PM 
√ 
Nicotine, cotinine in plasma 
 
08:00 PM-11:00 
PM 
 
HST questionnaire 
 
08:00 PM- 11:00 
PM 
 
MCEQ questionnaire (THS 2.2 and 
CC arms only),  
QSU-brief questionnaire 
 
11:00 PM 
 
End of smoking period 
 

 
 
 
 
 
 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Baseline Day 0 
 
6:30 AM-11:15 
PM 
 
Collection of all CC butts  
For accountability 
Abbreviations: AE = adverse event; BoExp = biomarkers of exposure; CAF = caffeine; CC = conventional cigarette(s); CO 
= carbon monoxide; COHb = carboxyhemoglobin; CYP1A2 = Cytochrome P450 1A2; CYP2A6 = Cytochrome P450 2A6 
HST = human smoking topography; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = Minnesota Nicotine 
Withdrawal Scale (revised version); QSU-brief = Questionnaire of Smoking Urges (brief version); SAE = serious adverse 
event; THS 2.2= Tobacco Heating System 2.2; VAS = Visual analogue scale. 
9.2.3 
Exposure Period (Days 1 to 5) 
The tables in this section show the assessments that will be performed during the 
confinement period (Day 1 to Day 5). Table 10 shows the assessments that will be performed 
on Day 1: 
Table 10. 
Time Schedule - Day 1 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 1 
 
 
 
AE/SAE  recording; 
concomitant 
medication 
All day 
 
 
Support during 
smoking abstinence 
(SA arm only) if 
needed 
All day 
6:29 AM +/-30 min 
 
Analysis sample to be 
taken after final portion 
of urine has been added 
to Day 0 sampling 
bottle. Must be prior to 
first product use of Day 
1 
 
BoExp, creatinine, and Ames 
mutagenicity in 24-hour urine 
Risk markers: 8-epi-PGF2 and 11-
DTX-B2 
Bio-banking for BoExp/ risk markers 
in 24-hour urine (if additional consent 
is obtained) 
6:30 AM +/-30 min 
 
Start collection to Day 
1 sampling bottle  
 
 
 
Assessment of cough 
(VAS) 
To be done prior to product use but no 
later than 10:00 PM 
 
 
MNWS questionnaire 
To be done prior to product use but no 
later than 10:00 PM 

 
 
 
 
 
 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 1 
 
 
 
CO breath test 
To be done within 15 minutes prior 
first product use (for THS 2.2 and CC 
arms) or 08:00-10:00 AM (SA arm) 
6:30 AM 
 
Beginning of product 
use 
 
06:30 AM-11:00 PM 
 
HST 
In THS 2.2 and CC arms, HST 
SODIM® device has to be used for all 
product uses if compatible CCs are 
smoked 
Before 10:00 AM 
 
Breakfast 
 
10:00 AM-12:00 PM 
 
Vital signs (blood 
pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine position 
prior to measurement  
12:00 PM-02:00 PM 
 
CO breath test  
 
before 03:00 PM 
 
Lunch  
 
04:00 PM-06:00 PM 
 
CO breath test 
 
afternoon 
 
Snacks 
 
In the evening before 09:00 PM 
 
Dinner  
 
08:00 PM-10:00 PM 
 
CO breath test 
 
08:00 PM-10:00 PM 
√ 
COHb in blood  
 
08:00 PM-10:00 PM 
√ 
Nicotine, cotinine in 
plasma 
 
08:00 PM-11:00 PM 
 
MCEQ questionnaire 
(THS 2.2 and CC arms 
only)  
QSU-brief 
questionnaire 
 
11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
Collection of all used 
Tobacco Sticks and 
smoked CC butts 
Collection of all 
tobacco plugs and 
filters from all used 
Tobacco Sticks in 
dedicated vials 
For accountability 
 
 
For analysis of combustion occurrences 
and filter analysis 

 
 
 
 
 
 
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Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse event; 
BoExp = biomarkers of exposure; CC = conventional cigarette(s); CO = carbon monoxide; COHb = carboxyhemoglobin; 
HST = human smoking topography; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = Minnesota Nicotine 
Withdrawal Scale (revised version); QSU-brief= Questionnaire of Smoking Urges (brief version); SA = smoking abstinence; 
SAE = serious adverse event; THS 2.2 = Tobacco Heating System 2.2; VAS = visual analogue scale. 
 
Table 11 shows the assessments that will be performed on Day 2 of the confinement period: 
 
Table 11. 
Time Schedule - Day 2 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 2 
 
 
 
AE/SAE recording; 
concomitant 
medication 
All day 
 
 
Support during 
smoking abstinence 
(SA arm only) if 
needed 
All day 
6:29 AM +/-30 min 
 
Analysis sample to 
be taken after final 
portion of urine has 
been added to Day 
1 sampling bottle. 
Must be prior to 
first product use of 
Day 2 
 
BoExp and creatinine in 24-hour urine 
6:30 AM +/-30 min 
 
Start collection to 
Day 2 sampling 
bottle  
 
 
 
MNWS 
questionnaire 
To be done prior to product use but not 
later than 10:00 AM 
 
 
Assessment of 
cough (VAS) 
To be done prior to product use but not 
later than 10:00 AM 
 
 
CO breath test 
To be done within 15 minutes prior to 
first product use (for THS 2.2 and CC 
arms) or 08:00-10:00 AM (SA arm) 
6:30 AM 
 
Beginning of 
product use 
 
Before 10:00 AM 
 
Breakfast 
 

 
 
 
 
 
 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 2 
 
before 12:00PM 
 
Vital signs (blood 
pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine position 
prior to measurement  
12:00 PM-02:00 PM 
 
CO breath test 
 
before 03:00  PM 
 
Lunch  
 
04:00 PM-06:00 PM 
 
CO breath test 
 
afternoon 
 
Snacks 
 
In the evening before 09:00PM 
 
Dinner  
 
08:00 PM-10:00 PM 
 
CO breath test 
 
08:00 PM-10:00 PM 
√ 
COHb in blood  
 
08:00 PM-10:00 PM 
√ 
Nicotine, cotinine 
in plasma 
 
08:00 PM-11:00 PM 
 
MCEQ 
questionnaire (THS 
2.2 and CC arms 
only)  
QSU-brief 
questionnaire 
 
11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
Collection of all 
used Tobacco 
Sticks and smoked 
CC butts 
Collection of all 
tobacco plugs and 
filters from all used 
Tobacco Sticks in 
dedicated vials 
For accountability 
 
 
For analysis of combustion occurrences 
and filter analysis 
Abbreviations: AE = adverse event; BoExp = biomarkers of exposure; CC = conventional cigarette(s); CO = carbon 
monoxide; COHb = carboxyhemoglobin; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = Minnesota 
Nicotine Withdrawal Scale (revised version); QSU-brief = Questionnaire of Smoking Urges (brief version); SA = smoking 
abstinence; SAE = serious adverse event; THS 2.2 = Tobacco Heating System 2.2; VAS = visual analog scale. 
Table 12 shows the assessments that will be performed on Day 3 of the confinement period: 

 
 
 
 
 
 
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Table 12. 
Time Schedule - Day 3 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 3 
 
 
 
AE/SAE recording; 
concomitant medication 
All day 
 
 
Support during smoking 
abstinence (SA arm 
only) if needed 
All day 
6:29 AM +/-30min 
 
Analysis sample to be 
taken after final portion 
of urine has been added 
to Day 2 sampling bottle. 
Must be prior to first 
product use of Day 3 
BoExp and creatinine in 24-hour urine 
6:30 AM +/-30min 
 
Start collection to Day 3 
sampling bottle  
  
 
 
MNWS questionnaire  
To be done prior to product use but not 
later than 10:00 AM 
 
 
Assessment of cough 
(VAS) 
To be done prior to product use but not 
later than 10:00 AM 
 
 
CO breath test 
To be done within 15 minutes prior to 
first product use (for THS 2.2 and CC 
arms) or 08:00-10:00 AM (SA arm) 
6:30 AM 
 
Beginning of product 
use 
 
Before 10:00 AM 
 
Breakfast 
 
10:00 AM-12:00 PM 
 
Vital signs (blood 
pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine position 
prior to measurement  
12:00 PM-02:00 PM 
 
CO breath test  
 
before 03:00 PM 
 
Lunch  
 
04:00 PM-06:00 PM 
 
CO breath test 
 
afternoon 
 
Snacks 
 
In the evening before 09:00 PM 
 
Dinner  
 
08:00 PM-10:00 PM 
 
CO breath test 
 

 
 
 
 
 
 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 3 
 
08:00 PM-10:00 PM 
√ 
COHb in blood 
 
08:00 PM-10:00 PM 
√ 
Nicotine, cotinine in 
plasma 
 
08:00 PM - 11:00 PM 
 
MCEQ questionnaire 
(THS 2.2 and CC arms 
only)  
QSU-brief questionnaire 
 
11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
Collection of all used 
Tobacco Sticks and 
smoked CC butts 
Collection of all tobacco 
plugs and filters from all 
used Tobacco Sticks in 
dedicated vials 
For accountability 
 
 
For analysis of combustion occurrences 
and filter analysis 
Abbreviations: AE = adverse event; BoExp = biomarkers of exposure; CC = conventional cigarette(s); CO = carbon 
monoxide; COHb = carboxyhemoglobin; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = Minnesota 
Nicotine Withdrawal Scale (revised version); QSU-brief = Questionnaire of Smoking Urges (brief version); SA = smoking 
abstinence; SAE = serious adverse event; THS 2.2 = Tobacco Heating System 2.2; VAS = visual analog scale 
Table 13 shows the assessments that will be performed on Day 4 of the confinement period: 

 
 
 
 
 
 
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Table 13. 
Time Schedule - Day 4 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 4 
 
 
 
AE/SAE recording; 
concomitant medication 
All day 
 
 
Support during smoking 
abstinence (SA arm 
only) if needed 
All day 
6:29 AM +/-30 min 
 
Analysis sample to be 
taken after final portion 
of urine has been added 
to Day 3 sampling 
bottle. Must be prior to 
first product use of Day 
4 
BoExp and creatinine in 24-hour urine  
 
6:30 AM +/-30 min 
 
Start collection to Day 4 
sampling bottle  
 
 
 
Assessment of cough 
(VAS) 
To be done prior to product use but not 
later than 10:00 AM 
 
 
MNWS questionnaire 
To be done prior to product use but not 
later than 10:00 AM 
 
 
CO breath test 
To be done within 15 minutes prior to 
first product use (for THS 2.2 and CC 
arms) or 08:00-10:00 AM (SA arm) 
6:30 AM 
 
Beginning of product 
use 
 
 
 
HST  
In THS 2.2 and CC arms, HST 
SODIM® device has to be used for all 
product uses if compatible CCs are 
smoked 
Before 10:00 AM 
 
Breakfast 
 
10:00 AM-12:00 PM 
 
Vital signs (blood 
pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine position 
prior to measurement  
12:00 PM-02:00 PM  
 
CO breath test  
 
before 03:00 PM 
 
Lunch  
 
04:00 PM-06:00 PM 
 
CO breath test 
 

 
 
 
 
 
 
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Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 4 
 
afternoon 
 
Snacks 
 
In the evening before 09:00 PM 
 
Dinner  
 
08:00 PM-10:00 PM 
 
CO breath test 
 
08:00 PM:10:00 PM 
√ 
COHb in blood  
 
08:00 PM:10:00 PM 
√ 
Nicotine, cotinine in 
plasma 
 
08:00 PM-11:00 PM 
 
HST questionnaire  
In THS 2.2 and CC arms only 
08:00 PM-11:00 PM 
 
MCEQ questionnaire 
(THS 2.2 and CC arms 
only)  
QSU-brief questionnaire 
 
11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
Collection of all used 
Tobacco Sticks and 
smoked CC butts 
Collection of all tobacco 
plugs and filters from all 
used Tobacco Sticks in 
dedicated vials 
For accountability 
 
 
For analysis of combustion occurrences 
and filter analysis 
Abbreviations: AE = adverse event;; BoExp = biomarkers of exposure; CC = conventional cigarette(s); CO = carbon 
monoxide; COHb = carboxyhemoglobin; HST = human smoking topography; MCEQ = Modified Cigarette Evaluation 
Questionnaire; MNWS = Minnesota Nicotine Withdrawal Scale (revised version); QSU-brief = Questionnaire of Smoking 
Urges (brief version); SA = smoking abstinence; SAE = serious adverse event; THS 2.2 = Tobacco Heating System 2.2; 
VAS = visual analog scale. 
Table 14 shows the assessments that will be performed on Day 5 of the confinement period: 
 
Table 14. 
Time Schedule - Day 5 
Time 
Blood sample 
Procedures 
Additional information 
Start of 
procedure 
 
Day 5 
 
 
 
AE/SAE recording; 
concomitant 
medication 
All day 

 
 
 
 
 
 
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Time 
Blood sample 
Procedures 
Additional information 
Start of 
procedure 
 
Day 5 
 
 
 
Support during 
smoking abstinence 
(SA arm only) if 
needed 
All day 
6:29 AM +/-30 
min 
 
Analysis sample to be 
taken after final 
portion of urine has 
been added to Day 4 
sampling bottle. Must 
be prior to first 
product use of Day 5 
BoExp and creatinine in 24-hour urine 
6:30 AM +/-30 
min 
 
Start collection to Day 
5 sampling bottle  
 
 
 
Assessment of cough 
(VAS) 
To be done prior to product use but not 
later than 10:00 AM 
 
 
MNWS questionnaire 
To be done prior to product use but not 
later than 10:00 AM 
 
 
CO breath test 
To be done within 15 minutes prior to 
first product use (for THS 2.2 and CC 
arms) or 08:00-10:00 AM (SA arm) 
 
√ 
COHb in blood 
To be done within 15 minutes prior to 
first product use (for THS 2.2 and CC 
arms) or 08:00 AM -10:00 AM (SA arm) 
6:30 AM 
 
Beginning of product 
use 
 
 
√ 
Nicotine, cotinine in 
plasma 
For THS 2.2 and CC 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: at 08:00 PM-10:00 PM 
Before 10:00 
AM 
 
Breakfast 
 
10:00 AM-
12:00 PM 
 
Vital signs (blood 
pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine position 
prior to measurement 

 
 
 
 
 
 
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Time 
Blood sample 
Procedures 
Additional information 
Start of 
procedure 
 
Day 5 
 
10:00 AM-
12:00 PM 
 
A cup of coffee 
containing 
approximately 150 mg 
of CAF 
 
12:00 PM-
02:00 PM 
 
CO breath test 
 
12:00 PM-
02:00 PM 
√ 
COHb in blood 
 
before 03:00 
PM 
 
Lunch 
 
04:00 PM-
06:00 PM 
 
CO breath test 
 
04:00 PM-
06:00 PM 
√ 
COHb in blood 
 
04:00 PM-
06:00 PM 
√ 
CYP1A2 activity in 
plasma 
6 hours +/-15 minutes after intake of cup 
of coffee 
afternoon 
 
Snacks 
 
In the evening 
before 09:00 
PM 
 
Dinner 
 
08:00 PM-
10:00 PM 
 
CO breath test 
 
08:00 PM-
10:00 PM 
√ 
COHb in blood 
 
08:00 PM-
11:00 PM 
 
MCEQ questionnaire 
(THS 2.2 and CC arms 
only)  
QSU-brief 
questionnaire 
 
11:00 PM 
 
End of product use 
 
6:30 AM-
11:15 PM 
 
Collection of all used 
Tobacco Sticks and 
smoked CC butts 
Collection of all 
tobacco plugs and 
filters from all used 
Tobacco Sticks in 
For accountability 
 
 
For analysis of combustion occurrences 
and filter analysis 

 
 
 
 
 
 
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Time 
Blood sample 
Procedures 
Additional information 
Start of 
procedure 
 
Day 5 
 
dedicated vials 
Abbreviations: AE = adverse event; BoExp = biomarkers of exposure; CAF = caffeine; CC = conventional cigarette(s); CO = 
carbon monoxide; COHb = carboxyhemoglobin; CYP1A2 = Cytochrome P450 1A2; MCEQ = Modified Cigarette Evaluation 
Questionnaire; MNWS = Minnesota Nicotine Withdrawal Scale (revised version); QSU-brief = Questionnaire of Smoking 
Urges (brief version); SA = smoking abstinence; SAE = serious adverse event; THS 2.2 = Tobacco Heating System 2.2; T0 = 
first product use; VAS = visual analog scale. 
9.2.4 
Day of Discharge (Day 6) 
Table 15 shows the assessments that will be performed on Day 6, prior to time of Discharge 
from the study unit: 

 
 
 
 
 
 
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Table 15. 
Time Schedule - Day 6 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Day of Discharge Day 6 
 
 
 
AE/SAE recording; concomitant medication 
All day until time of discharge 
 
 
Nicotine, cotinine in plasma  
20 hours and 24 hours blood 
sampling after T0 of Day 5 for 
THS 2.2 and CC arms. Each 
sample has a time window of +/-
5 minutes 
For SA arm:  08:00 AM-10:00 
AM 
06:29 AM+/-
30 min 
 
Analysis sample to be taken after final 
portion of urine has been added to Day 5 
sampling bottle  
BoExp, creatinine, and Ames 
mutagenicity in 24-hour urine 
Risk markers: 8-epi-PGF2 and 
11-DTX-B2 
Bio-banking for BoExp/ risk 
markers in 24-hour urine (if 
additional consent is obtained) 
 
 
Assessment of cough (VAS) 
To be done prior to smoking but 
not later than 10:00 AM 
 
 
MNWS questionnaire 
To be done prior to smoking but 
not later than 10:00 AM 
 
√ 
CYP2A6 activity in plasma 
To be done prior to smoking 
 
 
Spirometry without short-acting 
bronchodilator 
To be done prior to smoking  
 
 
Clinical laboratory parameters (hematology, 
clinical chemistry) 
To be done after at least 8 hours 
of fasting 
 
 
Bio-banking for BoExp/ risk markers in 
serum/plasma (if consent is obtained) 
To be done after at least 8 hours 
of fasting 
 
√ 
Bio-banking for transcriptomics (if 
consent is obtained) 
To be done after at least 8 hours 
of fasting 
Before 
discharge 
 
Urine safety analysis 
 
Before 
discharge 
 
Urine pregnancy test (all females) 
 
before 10:00 
AM 
 
Breakfast 
 

 
 
 
 
 
 
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Time 
Blood 
sample 
Procedures 
Additional information 
Before 
discharge 
 
CO breath test 
 
Before 
discharge 
 
Physical examination, and weight and 
calculated BMI 
 
Before 
discharge 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to measurement 
Before 
discharge 
 
ECG 
At least 10 minutes in supine 
position prior to recording 
Before 
discharge 
 
Advice on risk of smoking and debriefing 
 
 
 
Discharge 
 
Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse event; 
BMI = body mass index; BoExp = biomarkers of exposure; CO = carbon monoxide; CYP2A6 = Cytochrome P450 2A6 
ECG = electrocardiogram; MNWS = Minnesota Nicotine Withdrawal Scale (revised version); SA = smoking abstinence; 
SAE = serious adverse event; VAS = visual analog scale. 
9.3 
Safety Follow-up Period 
After subjects have completed the assessments at Day 6 (or if they are prematurely 
withdrawn from the study), they will enter a 7-day safety follow-up period after the time of 
Discharge. 
During the 7-day safety follow-up period, there will be spontaneous reporting by the subject 
of new AEs and new SAEs. Any ongoing AEs/SAEs will be actively followed-up by the site.  
Any AEs or SAEs that are ongoing at the end of the 7-day safety follow-up period will be 
handled as described in Section 8. 
9.4 
Early Termination Procedures 
The assessments of the Day of Discharge will be performed as early termination procedures 
(see Section 9.2.4). 
 

 
 
 
 
 
 
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10 
CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
A Clinical Research Associate (CRA; “Monitor”) not involved with the study site will be 
responsible for the monitoring of the study. Monitoring will be performed according to the 
study CROs SOP and as per the agreed monitoring plan with the Sponsor. 
The Investigator or designee 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 or designee shall access medical records for the Monitor in order that entries 
in the eCRFs may be verified. The Investigator or designee, 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. 
Communication by telephone, mail, and e-mail may be used as needed to supplement site 
visits. The Investigator or designee and study personnel will cooperate with the Monitor, 
provide all appropriate documentation, and will be available to discuss the study. 
The Monitor and the Sponsor’s personnel will be available between visits, should the 
Investigator or other staff at the sites need information and advice. 
Site visits will be made at regular intervals during the study. The frequency of the monitoring 
visits will be defined in the monitoring plan agreed with the Sponsor. 
The Investigator, or a designated member of the Investigator’s staff, must be available during 
the monitoring visit to review the data and resolve any queries, and to allow direct access to 
the subject’s records for source data verification. 
10.2 Training of Staff 
A formal meeting (Investigator’s meeting) will be conducted prior to site initiation. During 
this meeting, the Sponsor or its authorized representative will discuss the requirements of the 
clinical study protocol and related documents and will also provide training including a 
formal GCP 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 Investigator or designee will ensure that 
appropriate training relevant to the study is provided to all staff involved in the study, and 

 
 
 
 
 
 
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that any new information relevant to the performance of this study is forwarded to the staff 
involved in a timely manner. The Investigator or designee will maintain a record of all 
individuals involved in the study. 
10.3 Audits and Inspections 
Good Clinical Practice regulations require that there are independent inspections of clinical 
program activities. Such inspections may be performed at any time before, during, and/or 
after the study. 
Authorized representatives of the Sponsor, regulatory agencies, and/or an IEC may perform 
audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, ICH/GCP guidelines, and any 
applicable regulatory requirements. The Investigator or designee will contact the Sponsor or 
the authorized representative immediately, if contacted by a regulatory agency about an 
inspection at their site. 
The Investigator or designee and study staff are responsible for maintaining a comprehensive 
and accurate filing system of all study-related documentation that will be suitable for 
inspection at any time by the Sponsor, its authorized representative, and/or regulatory 
agencies. In signing this protocol, the Investigator or designee understands and agrees to 
provide access to the necessary documentation and files. 

 
 
 
 
 
 
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11 
DATA MANAGEMENT ACTIVITIES 
All Data Management Activities will be described in detail in the Data Management Plan 
(DMP) and documents specified therein. 
11.1 Data Capture 
11.1.1 Case Report Forms and Study Records 
With the exception of the subject reported outcome data, all results from the clinical 
assessments will be recorded in the Source Documents by the Investigator or their authorized 
designee and then captured in the eCRFs at the study site. The subject questionnaires and the 
VAS will be entered by the subject directly in the ePRO device or a paper copy. Trained 
study personnel will be responsible for capturing the data from the observations, tests, and 
assessments specified in the protocol in the Source Documents and then transferring the data 
into the eCRF according to the eCRF Completion Guidelines. 
The Investigator or designee 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 or designee 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 or designee for resolution. An eCRF will 
be generated for all subjects that sign the informed consent. 
11.1.2 Protocol Deviations 
All protocol deviations will be entered into the Clinical Trial Management System (CTMS) 
or other approved format. 
Information from the Source Documents will represent the primary source of protocol 
deviations. Information following site monitoring and other manual reviews will be 
documented in the site visit reports, follow-up letters, audit documentation, or other manual 
review and will be recorded and tracked in the CTMS or other approved format. 
Telecommunications and other verbal communications regarding deviations will be 
considered and handled as important communication, documented and tracked as protocol 
deviations, as necessary. 
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 

 
 
 
 
 
 
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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, concomitant disease, 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: 
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 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 

 
 
 
 
 
 
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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 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 SAP. Any changes to the planned 
statistical methods will be documented in the CSR. 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 Screening. 
 
12.1.2 
Definitions for Statistical Data Analysis 
In general, baseline is the last available time-point prior to Day 1, 06:30 AM. 
 
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by product arm and subject, unless otherwise 
specified. 
Descriptive statistics for continuous variables (number of subjects [n], number and percent of 
subjects with data, mean, standard deviation [SD], median, first and third quartiles, minimum 
and maximum for continuous data, and the n and absolute and relative [%] frequency for 
categorical data) will be presented by product arm and overall at each time point, where 
applicable. 
For BoExp, the geometric mean and coefficient of variation (CV) will be presented in 
addition to the mean and SD. 
 
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 
approach. 
For questionnaire data, total scores and domain or subscale scores may use a certain degree 
of imputation by averaging across individual item scores. 
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. 
Further details will be provided in the SAP. 

 
 
 
 
 
 
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document may be publicly disclosed without the written consent of Philip Morris Products S.A. 
 
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 (CIs) will be two-sided 95% CIs. 
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. 
Full details of this approach 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 4 selected primary BoExps in smokers switching from CC to THS 2.2 as compared 
to smokers continuing to smoke CC. 
Table 16 describes the expected coefficients of variation (CV) and mean ratios (MR) 
between THS 2.2 and the two control arms based on data from a controlled, randomized, 
open-label, 3-arm parallel single-center confinement study that investigated exposure to 
selected smoke constituents in smokers switching from CC to smoking article cigarettes for 
5 days, the YVD-CS01-EU study   (ClinicalTrials.gov: ID: NCT00812279) sponsored by 
PMI. 

 
 
 
 
 
 
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Table 16. 
Coefficients of Variation (YVD-CS01-EU study) 
 
THS 2.2 /CC 
MR (CV) 
THS 2.2 /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 17 describes the expected coefficients of variation (CV) and mean ratios (MR) 
between THS 2.2 and the CC control arm 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, but otherwise 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. 

 
 
 
 
 
 
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Table 17. 
Coefficients of Variation (ZRHX‐EX‐01 study) 
 
THS 2.2 /CC 
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, the power to demonstrate a reduction was computed. 
Table 18 describes the expected power to demonstrate a reduction on 4 primary BoExps in 
smokers switching from CC to THS 2.2 as compared to those continuing to smoke CC, using 
one-sided test with 2.5% type I error probability using the assumptions from YVD-CS01-EU 
and ZRHX‐EX‐01 and 160 smokers (80 in THS 2.2, 40 in CC, and 40 in the SA arm). 

 
 
 
 
 
 
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Table 18. 
Expected power (YVD-CS01-EU and ZRHX‐EX‐01 studies assumptions) 
Reduction 
Assumptions 
50% 
51% 
52% 
53% 
54% 
55% 
YVD-CS01-EU  
96% 
91% 
85% 
75% 
63% 
48% 
ZRHX‐EX‐01  
>99% 
>99% 
96% 
81% 
48% 
16% 
 
A total of 160 smokers (80 in THS 2.2, 40 in CC, and 40 in the SA arm) will be randomized 
to demonstrate to demonstrate a reduction of at least 50% on 4 primary BoExps in smokers 
switching from CC to THS 2.2 as compared to those continuing to smoke CC, using 
one-sided test with 2.5% type I error probability. 
Power considerations related to secondary endpoints of biological changes: 
The sample size is sufficient to obtain 95% CIs for the ratio between (geometrical) mean 
levels of primary BoExps in THS 2.2 and SA see Section 12.2 with upper and lower limits 
deviating  not more than 18% from the point estimates, with an 80% overall probability of 
achieving the desired precision of estimating the true mean. 
This study has 80% power using a one-sided test with 2.5% type I error probability: 
 To detect a 0.631 [ml/min/kg] (29%) difference between THS 2.2 and CC in CYP1A2 
activity, as measured by the CAF 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 and CC 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 is assumed to be about 90% of the effect of 
smoking cessation reported in the paper by Saareks et al, 2001. 
 
12.3 Analysis Population 
The main population for non-safety analysis will be the full analysis set (FAS) population. 
The per-protocol (PP) population will be used only for the analysis of the primary endpoint 
to examine the robustness of the primary analyses. 
Safety will be analyzed using the safety population. 
 
12.3.1 
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 or CC, and have at least one valid non-
safety assessment (THS 2.2, CC, SA arms). 

 
 
 
 
 
 
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12.3.2 
Per Protocol Population 
The PP population is a subset of FAS and includes all randomized subjects who fulfill key 
compliance criteria of the protocol, and have no major protocol deviation (to be further 
described in the SAP). 
 
12.3.3 
Safety Population 
The safety population consists of all the subjects who had at least one exposure to THS 2.2 
(product test at Admission Day). Subjects in the safety population will be analyzed according 
to actual exposure. 
12.4 Primary Analysis 
12.4.1 
Primary Endpoint Analysis Variables 
The primary endpoints are: 
• COHb on Day 5 
• MHBMA on Day 5 
• 3-HPMA on Day 5 
• S-PMA on Day 5. 
See section 3.4.1. 
Evaluation Criterion: The study will be considered successful if the study demonstrates a 
50% reduction or more for all four primary BoExp in the THS 2.2 arm compared to the CC 
arm (as measured on Day 5), using a one-sided test with 2.5% type I error probability. 
 
12.4.2 
Baseline Comparability 
Not applicable. 
 
12.4.3 
Descriptive Analysis 
Primary endpoints will be summarized as described in Section 12.1.3 on the FAS. 
Should more than 20% of the subjects be excluded from the FAS population, the above 
descriptive analysis will be repeated on the PP population. 
 
12.4.4 
Confirmatory Analysis 
The hypothesis to be tested for each of the primary and secondary biomarkers of exposure is 
that the geometric mean level on Day 5 of the biomarker for THS 2.2 is lower relative to CC. 

 
 
 
 
 
 
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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 
Where m1 and m2 are the geometric means of the biomarker levels on Day 5 for THS 2.2 
and CC respectively. 
The transformed 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. Estimates of 
differences between groups will be back-transformed to provide relative effects.  
Assumptions of the analysis of variance model will be tested. Markedly non-lognormally 
distributed BoExp data will be transformed or analyzed by appropriate non-parametric 
methods. 
Should more than 20% of the subjects be excluded from the FAS, would the above 
confirmatory analysis will be repeated on the PP population. 
12.5 Secondary Analysis 
12.5.1 
Secondary Endpoint Analysis Variables 
See section 3.4.2 
More details on derivation rules will be given in the SAP. 
 
12.5.2 
Baseline Comparability 
Not applicable. 
 
12.5.3 
Descriptive Analysis 
In general, secondary endpoints will be summarized as described in Section 12.1.3 on the 
FAS. 
 
12.5.4 
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 event data will serve as the primary assessment of safety. Other safety variables 
monitored in this study include: respiratory symptoms (cough assessment VAS and Likert 
scales); vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate); 
spirometry; ECG data; clinical chemistry, hematology, concomitant medications, and urine 
analysis safety panel; physical examination. 

 
 
 
 
 
 
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The number and percentage of subjects with AEs and SAEs will be tabulated by system organ 
class and preferred term. 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 will be tabulated by sequence 
for laboratory parameters. 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. 
12.6 Exploratory Analysis 
12.6.1 
Exploratory Endpoint Analysis Variables 
See section 3.4.3. 
 
12.6.2 
Baseline Comparability 
Not applicable. 
 
12.6.3 
Descriptive Analysis 
In general, exploratory endpoints will be summarized as described in Section 12.1.3 on the 
FAS. 
 
12.7 Demographics and Baseline Characteristics 
Demographic and other baseline characteristics will be reported for safety population. 
Summary statistics will be provided by exposure group and stratified by sex and by cigarette 
consumption. Formal statistical analysis will not be performed on baseline demographic data. 
 
12.8 Interim Analysis 
There are no planned interim analyses. 
 

 
 
 
 
 
 
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13 
ADMINISTRATIVE CONSIDERATIONS 
13.1 Investigators and Study Administrative Structure 
13.1.1 Investigator 
Principal Investigator: 
Katarzyna Jarus-Dziedzic, MD, PhD (PI) 
 
 
BioVirtus Research Site Sp. z o.o.  
  
 
 
     
 
 
 
13.1.2 Sponsor 
Sponsor: 
Philip Morris Products S.A., 
Quai Jean Renaud 5 
2000 Neuchâtel 
Switzerland 
Phone: + 41 (58) 242 2111 
Fax: + 41 (58) 242 2811 
, PhD 
Manager Clinical Science 
Phone: +41
 
Mobile: +41 
 
E-mail:
@pmi.com 
, MEng, 
MSc 
Biostatistician 
Phone: +41
 
Mobile: +41
 
E-mail:
@pmi.com 
, MD 
Medical Safety Officer 
 
Phone: +41 
 
Mobile: +41
 
Email:
@pmi.com 
, PhD 
Clinical Study Manager 
Phone: +41 
 
Mobile: +41
 
E-mail:
@pmi.com 
 
Phone: +41
 

 
 
 
 
 
 
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Medical Writer 
Mobile: +41
 
E-mail:
@pmi.com 
13.1.3 Other Responsibilities 
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. 
The confidentiality of data for subjects participating in this study will be maintained. 
Subjects will be identifiable by the Sponsor (or Sponsor’s authorized representative) on 
eCRFs and other documents by their subject (or randomization) number/code, sex, and date 
of birth, but not by name, initial, or any other details relating to identifiable person (e.g., 
address, social security number, medical chart number, etc). The assignment of a subject 
number/code for subject identification will be based on the appropriate data protection rules. 
Any documents that allow full identification of the subject (e.g., the subject’s signed subject 
information sheet and ICF) must be maintained in confidence by the Investigator or designee. 
If any document relating to this study shows a subject’s name or any other details relating to 
an identifiable person (e.g., address, social security number, medical chart number, etc.), the 
name or other identifiable details must be obscured before a copy of that document is 
supplied to the Sponsor or the Sponsor’s authorized representative. 
13.3 Access to Source Documentation 
Subjects will be informed that, during the course of the clinical study, the Sponsor, any 
authorized representatives of the Sponsor, IEC, or regulatory authorities may inspect their 
medical records to verify the information collected, and ensure that all personal information 

 
 
 
 
 
 
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made available for inspection is handled in the strictest confidence and in accordance with 
national and local data protection and privacy legislation. 
The Investigator or designee and all study site staff involved with the study must permit 
direct access to source data/documents for study related monitoring, audits, IEC review, and 
regulatory inspection(s). 
13.4 Record Retention 
All records of data, source data, and Source Documents (original records or certified copies), 
in any form (including, but not limited to, written, electronic, magnetic, optical records and 
scans, X-rays, and ECGs) that describe or record the methods, conduct, and/or results of the 
study, the factors affecting the study, and the actions taken will be maintained by the 
Investigator/study site for the study, as required by ICH GCP and any other applicable local 
or national regulations. For X-rays, at least the radiologist’s assessment is required as source 
documentation. If the actual image is available, it can be stored on CD, as well. 
Essential study documents/records, which individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced, are described in Section 8 of the 
ICH Tripartite Guideline for GCP (ICH Guideline for Good Clinical Practice E6 (R1), July 
1996). 
Essential documents must be retained by the Investigator or designee 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 
information sheet. 
• Subject identification code list, Screening Log, and Enrolment Log (if applicable). 
• Record of all communications between the Investigator or designee and the IEC, 
composition of the IEC. 
• Record of all communications/contact between the Investigator or designee, 
Sponsor, and its authorized representatives. 
• List of sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles 
in the study, curricula vitae, and their signatures. 

 
 
 
 
 
 
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• Investigator Logs. 
• eCRFs, study specific questionnaires (and associated data/scoring), and 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, and dispensing records. 
• Information regarding subjects’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the Investigator/study site as to when these 
documents no longer need to be retained. 
The Investigator/study site must take measures to prevent accidental or premature destruction 
of these documents. 
If an Investigator or designee wishes to assign the study records to another party or move 
them to another location, the Sponsor must be notified in advance. 
The Investigator or designee must obtain written approval from the Sponsor before 
destruction of any records. Normally, these records will be held in the Investigator’s 
archives. If an Investigator or designee 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 will 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 

 
 
 
 
 
 
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acceptable. Submission of the CSR to the IEC will be complied with as requested by local 
requirements. 
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. 
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. 
The Sponsor plans to disclose details of the study protocol on a web-based, publicly 
available, clinical trial register database (e.g., ClinicalTrials.gov). 
 

 
 
 
 
 
 
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14 
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secrets and confidential commercial information, and the legal protections provided to such trade secrets and 
confidential information are hereby claimed under the applicable provisions of applicable law. No part of this 
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confidential information are hereby claimed under the applicable 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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Jacob et al, 2011 
Jacob P 3rd, Yu L, Duan M, Ramos L, Yturralde O, Benowitz NL. Determination of the 
Nicotine Metabolites Cotinine and Trans-3'-Hydroxycotinine in Biologic fluids of Smokers 
and Non-smokers using Liquid Chromatography - Tandem Mass Spectrometry: Biomarkers 
for Tobacco Smoke Exposure and for Phenotyping Cytochrome P450 2A6 Activity. J 
Chromatogr B Analyt Technol Biomed Life Sci. 2011 Feb 1; 879 (3-4): 267-76. 
Lacy et al, 2007 
Lacy CF, Armstrong LL, Goldman MP, Lance LL. Drug Information Handbook 15th ed. 
Hudson, OH; LexiComp Inc. 2007: 1899-1912. 
Lindner et al, 2011 
Lindner D, Smith S, Leroy CM, Tricker AR. Comparison of Exposure to Selected Cigarette 
Smoke Constituents in Adult Smokers and Nonsmokers in a European, Multicenter, 
Observational Study. Cancer Epidemiol Biomarkers Prev. 2011;20:1524-36. Published 
OnlineFirst May 25, 2011. 
Morita et al, 2005 
Morita H, Ikeda H, Haramaki N, Eguchi H, Imaizumi T. Only two-week smoking cessation 
improves platelet aggregability and intraplatelet redox imbalance of long-term smokers. 
J Am Coll Cardiol. 2005 Feb 15; 45 (4):589-94. 
Pilz et al, 2000 
Pilz H, Oguogho A, Chehne F, Lupattelli G, Palumbo B, Sinzinger H. Quitting Cigarette 
Smoking Results in a Fast Improvement of in vivo Oxidation Injury (Determined via Plasma, 
Serum and Urinary Isoprostane. Thrombosis Research. 99 (2000) 209-21. 
PMI, 2009 
Philip Morris International. 2009. YVD-CS01-EU: Investigate the Exposure to Selected 
Smoke Constituents in Smokers Switching to Distillation Based Smoking Article. 
ClinicalTrials.gov: 
ID: 
NCT00812279. 
Sponsored 
by 
PMI. 
Available 
at 
http://clinicaltrials.gov/show/NCT00812279. 

 
 
 
 
 
 
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secrets and confidential commercial information, and the legal protections provided to such trade secrets and 
confidential information are hereby claimed under the applicable provisions of applicable law. No part of this 
document may be publicly disclosed without the written consent of Philip Morris Products S.A. 
PMI, 2012a 
Philip Morris International. 2013. Internally-modified method based on International 
Organization for standardization’s ISO 4387:2000. In French.  PMI_RD_WKI_000530: 
Détermination du TMP et CO et trappage de l’eau, nicotine, acide pyruvique et des smoke 
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): 44-6. 
Rodgman and Perfetti, 2009 
Rodgman A, Perfetti TA. The chemical components of tobacco and tobacco smoke (Taylor 
& Francis Group 2009). 
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. 
Smith et al, 1996 
Smith CJ, McKarns SC, Davis RA, Livingston SD, Bombick BR, Avalos JT, et al. Human 
urine mutagenicity study comparing cigarettes which burn or primarily heat tobacco. Mutat 
Res. 1996 Sep 26; 361 (1): 1-9. 
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 

 
 
 
 
 
 
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secrets and confidential commercial information, and the legal protections provided to such trade secrets and 
confidential information are hereby claimed under the applicable provisions of applicable law. No part of this 
document may be publicly disclosed without the written consent of Philip Morris Products S.A. 
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. 
(http://www.surgeongeneral.gov/library/tobaccosmoke/report/executivesummary.pdf). 
 
 

 
 
 
 
 
 
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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  
  
Safety 
Follow-Up 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
6-13 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
Admission/Discharge 
 
● 
 
 
 
 
 
 
 
● 
 
Advice on the risk of 
smoking and debriefing 
● 
● 
 
 
 
 
 
 
 
● 
 
Support for SA arm 
 
 
 
 
● 
● 
● 
● 
● 
 
 
Inclusion/exclusion 
criteria 
● 
● 
 
 
 
 
 
 
 
 
 
Enrolment 
 
● 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
● 
 
 
 
 
 
 
 
Demographics, medical 
history, concomitant 
diseases 
● 
 
 
 
 
 
 
 
 
 
 
Vital signs a 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Physical examination b 
● 
● 
 
 
 
 
 
 
 
● 
 
Spirometry c 
● 
 
 
● 
 
 
 
 
 
● 
 
Prior/concomitant 
medication 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
B/U: Hematology, clinical 
chemistry, urine analysis  
● 
 
 
● 
 
 
 
 
 
● 
 
Electrocardiogram 
● 
 
 
 
 
 
 
 
 
● 
 
Chest X-ray d 
● 
 
 
 
 
 
 
 
 
 
 
B: HIV, hepatitis B and C 
● 
 
 
 
 
 
 
 
 
 
 
U: Urine drug screen, 
urine cotinine screening 
test 
● 
● 
 
 
 
 
 
 
 
 
 
U: Pregnancy test 
● 
● 
 
 
 
 
 
 
 
● 
 
Alcohol breath test 
● 
● 
 
 
 
 
 
 
 
 
 
FTND 
● 
 
 
 
 
 
 
 
 
 
 
Smoking history 
● 
● 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
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Screening 
Confinement Period  
  
Safety 
Follow-Up 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
6-13 
Willingness to quit 
smoking e 
● 
● 
 
 
 
 
 
 
 
 
 
Identification of cigarette 
brand 
● 
● 
 
 
 
 
 
 
 
 
 
THS 2.2 demonstration 
● 
 
 
 
 
 
 
 
 
 
 
THS 2.2 product test f 
 
● 
 
 
 
 
 
 
 
 
 
CO breath test g 
 
● 
● 
(x4) 
● 
(x4) 
● 
(x4) 
● 
(x4) 
● 
(x4) 
● 
(x4) 
● 
(x4) 
● 
 
B: BoExp in blood: COHb 
h 
 
 
● 
● 
● 
● 
● 
● 
● 
(x4) 
 
 
B: Biomarker of exposure 
in plasma: nicotine, 
cotinine i 
 
 
 
● 
● 
● 
● 
● 
● 
● 
 
B: CYP1A2 activity 
 
 
 
● 
 
 
 
 
● 
 
 
B: CYP2A6 activity 
 
 
 
● 
 
 
 
 
 
● 
 
QSU-brief questionnaire j 
 
 
● 
● 
● 
● 
● 
● 
● 
 
 
MNWS (revised version) k 
 
 
 
● 
● 
● 
● 
● 
● 
● 
 
MCEQ (modified version; 
THS 2.2 and CC arms) l 
 
 
● 
● 
● 
● 
● 
● 
● 
 
 
HST (THS 2.2 and CC 
arms) m 
 
 
 
● 
● 
 
 
● 
 
 
 
HST questionnaire (THS 
2.2 and CC arms) m 
 
 
 
● 
 
 
 
● 
 
 
 
Assessment of cough 
 
 
 
● 
● 
● 
● 
● 
● 
● 
 
AE/SAE recording 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Collection of tobacco 
plugs and filters from all 
used Tobacco sticks for 
analysis of combustion 
occurrences and filter 
analysis and for 
accountability 
 
 
 
 
● 
● 
● 
● 
● 
 
 
Collection of used CC 
butts for accountability 
 
 
● 
● 
● 
● 
● 
● 
● 
 
 
B: Bio-banking for 
biomarkers of exposure 
and risk markers n  
 
 
 
● 
 
 
 
 
 
● 
 

 
 
 
 
 
 
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Screening 
Confinement Period  
  
Safety 
Follow-Up 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
6-13 
B: Bio-banking for 
transcriptomicsn 
 
 
 
● 
 
 
 
 
 
● 
 
Abbreviations: AE = adverse event; B = blood; BoExp = biomarker(s) of exposure; BMI = body mass index; CC = 
conventional cigarette(s); CO = carbon monoxide; COHb = carboxyhemoglobin; CYP1A2 = cytochrome P450 1A2; 
CYP2A6 = cytochrome P450 2A6;  FTND = Fagerström Test for Nicotine Dependence; HIV = human immunodeficiency 
virus; HST = human smoking topography; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = Minnesota 
Nicotine Withdrawal Scale (revised version); QSU -brief= Questionnaire of Smoking Urges (brief version); SA = smoking 
abstinence; SAE = serious adverse event; T0 = first product use; THS 2.2 = Tobacco Heating System 2.2; U = urine. 
a: Systolic and diastolic blood pressure, pulse rate, and respiratory rate 
b: Including height (only at Screening), body weight and calculated BMI. 
c: Spirometry has to be done prior to smoking on Day 0 and Day 6. At screening, spirometry needs to be done prior at least 
1 hour after smoking. 
d: Pre-study chest X-ray (with anterior-posterior and left lateral views) may be used, if performed within 6 months prior to 
Screening. 
e: Subjects will be asked if they plan to quit smoking within the next 3 months (at Screening only) and, in order to satisfy 
the protocol inclusion criteria, if they are ready to abstain from smoking for at least 5 days (at Screening and Day -2). 
f: THS 2.2 product test to be conducted as the last procedure of eligibility check at Day -2 (and after urine pregnancy test 
has been done in female subjects to exclude pregnancy). 
g: On Days -1 to Day 5, the CO breath test will be conducted 4 times per day. For subject in the THS 2.2 and CC arms, the 
first test should be conducted prior to the first product use. The other 3 tests should be conducted as described in section 9.  
On Days 1 to Day 5, the CO breath test will be conducted 4 times per day. for subjects in the SA arm, the first CO breath 
test will be done 08:00 AM-10:00 AM. The other three tests will be conducted as described in section 9.  
On Day -2 and Day 6, the CO breath tests will be conducted once.  
h: COHb; Assessments should be done in conjunction with CO breath tests, where applicable. Day -1 to Day 4: one blood 
sample in the evening as described in section 9. 
Day 5: four blood samples will be collected 4 times per day. one blood sample prior to the first product use (for subjects 
in the THS 2.2 and CC arms) and 08:00-10:00 AM for subjects in the SA arm, and the three remaining samples as 
described in section 9. 
i: Nicotine/cotinine; Day 0 to Day 4 (all study arms): one blood sample  08:00 PM:10:00 PM. 
Day 5 and Day 6 (THS 2.2 and CC arms): one sample within 15 minutes prior to the T0; eight blood samples after 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 08:00 PM-10:00 PM. On Day 6, one blood sample 
to be drawn 08:00 AM-10:00 AM. 
j: QSU-brief: Daily, from Day -1 to Day 5. 
k: MNWS daily from Day 0 to Day 6. 
l: MCEQ: Day -1 to Day 5 on a daily basis. 
m: On Day 0, HST and HST questionnaire will be done in all subjects smoking CC compatible with the HST SODIM® 
device. On Day 1 and Day 4, HST and HST questionnaire will be done in all subjects in the THS 2.2 and CC arms. 
Smoking topography with the HST SODIM® device will not be done in subjects smoking CC that are incompatible with 
the HST SODIM® device (e.g. slim CC). No HST assessments will be done in subjects in the SA arm. 
n: Samples will only be taken if additional consent for BoExp bio-banking is given by the subject.  

 
 
 
 
 
 
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document may be publicly disclosed without the written consent of Philip Morris Products S.A. 
 
Table A2   
Schedule for 24-hour Urine Collection Assessments 
 
Baseline period 
Confinement Exposure Period 
24 hour urine samples 
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 
BoExp in urine  
● 
● 
● 
● 
● 
● 
● 
Creatinine  
● 
● 
● 
● 
● 
● 
● 
Ames mutagenicity test, 11-DTX-B2 
and 8-epi-PGF2 
 
● 
 
 
 
 
● 
Bio-banking  
 
● 
 
 
 
 
● 
Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; BoExp = 
biomarker(s) of exposure. 
 
 
 

 
 
 
 
 
 
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document may be publicly disclosed without the written consent of Philip Morris Products S.A. 
Appendix 2 
Participating Laboratories 
1) Clinical safety laboratory services will be provided by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
2) The following laboratory will analyze urine, blood and plasma samples for the BoExp 
and risk markers: 
 
 
 
  
 
 
 
 
 
3) The urine samples for the BoExp, 4_ABP, 2-NA, total 1-OHP and o-tol will be analysed 
at the following laboratory: 
 
 
 
 
  
 
 
 
 
 
 

 
 
 
 
 
 
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document may be publicly disclosed without the written consent of Philip Morris Products S.A. 
 
Appendix 3 
Investigational Product and Instructions for Use 
The product user guide will be provided as a separate document. The site should insert the 
manual here in the protocol binder. 
 
 

 
 
 
 
 
 
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Appendix 5 
Abnormal Laboratory Values 
CTCAE 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 

 
 
 
 
 
 
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Cholesterol high** (1)                      
 
 
 
 
 
 
 
(mg/dl) 
(mmol/l) 
 
>ULN - 300; 
>ULN - 7.75 
 
>300-400; 
>7.75-10.34 
 
>400-500; 
>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. 

 
 
 
 
 
 
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document may be publicly disclosed without the written consent of Philip Morris Products S.A. 
CTCAE 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 Event and Common Toxicity Criteria (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. 

 
 
 
 
 
 
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CTCAE 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 Event and Common Toxicity Criteria (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.