A Randomized, Controlled, Open-label, 2-arm Parallel Group, Single Center Study to Demonstrate Reductions in Exposure to Selected Smoke Constituents in Healthy Smokers Switching to the Carbon Heated Tobacco Product 1.2 (CHTP 1.2), Compared to Continuing to Use Combustible Cigarettes, for 5 Days in Confinement Followed by 85 Days in an Ambulatory Setting.
Phase: NA
Conditions: Smoking
Sponsor: Philip Morris Products S.A.

 
 
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Clinical Study Protocol 
P2R-REXA-07-EU 
 
Study Title: 
A randomized, controlled, open-label, 2-arm parallel group, 
single center study to demonstrate reductions in exposure to 
selected smoke constituents in healthy smokers switching to the 
Carbon Heated Tobacco Product 1.2 (CHTP 1.2), compared to 
continuing to use combustible cigarettes, for 5 days in 
confinement followed by 85 days in an ambulatory setting.  
Short Title 
Reduced exposure study using the CHTP 1.2 with 5 days in a 
confinement setting followed by 85 days in an ambulatory 
setting. 
EUDRACT Number: 
Not applicable 
Product Name: 
Carbon Heated Tobacco Product 1.2 (CHTP 1.2) 
Study Number 
P2R-REXA-07-EU 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Version Number: 
FINAL VERSION 5.0 
Revision Date: 
05 December 2016 
Authors: 
, Lead Clinical Scientist 
, Clinical Scientist 
, Biostatistician 
 Medical Safety Officer 
 
 

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Summary of Changes 
Clinical Study Protocol 
P2R-REXA-07-EU 
 
 
Version 
Date 
Amendment 
Current protocol 
Final Version 5.0 
05 December 2016 
N°2 
First amended protocol  
Final Version 4.0 
13 June 2016 
N°1 
Second updated protocol  
Final Version 3.0 
07 December 2015 
Non-substantial 
amendment 
First updated protocol 
Final Version 2.0 
02 November 2015 
Non-substantial 
amendment 
Original protocol 
Final Version 1.0 
22 October 2015 
 
 
 
INTRODUCTION 
The main purpose of this summary of changes is to summarize:  
 the substantial and administrative changes between the first amended protocol P2R-
REXA-07-EU (Final Version 4.0) dated 13 June 2016 and the current protocol version 
(Final Version 5.0) dated 05 December 2016 which is to be referred to Amendment 
N°2. 
 the substantial and administrative changes between the second updated protocol P2R-
REXA-07-EU (Final Version 3.0) dated 07 December 2015 and the first amended 
protocol (Final Version 4.0) dated 13 June 2016 which is to be referred to Amendment 
N0 1. 

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 the administrative changes between the first updated clinical study protocol P2R-
REXA-07-EU (Final Version 2.0) dated 02 November 2015 and the second updated 
protocol (Final Version 3.0) dated 07 December 2015. 
 the correction of the name of the investigational products in a few tables between the 
first updated clinical study protocol P2R-REXA-07-EU (Final Version 2.0) dated 02 
November 2015 and the second updated protocol (Final Version 3.0) dated 07 
December 2015. 
 the main changes between the clinical study protocol P2R-REXA-07-EU (Final 
Version 1.0) dated 22 October 2015 and its updated version (Final Version 2.0) dated 
02 November 2015. 
More precise details on the protocol sections changed are provided. For identification of the 
changes, the previous and the amended texts are provided. The new text has been highlighted 
in bold (e.g. new text) and deleted text has been crossed out (e.g. deleted text). 
Section 
 
Changes 
From Final 4.0 to Final 5.0 
The current version (Final Version 5.0) dated 05 December 2016 is to be referred to 
Amendment No 2 
From Final 3.0 to Final 4.0 
The first amended protocol version (Final Version 4.0) dated 13 June 2016 is to be referred 
to Amendment No 1 
From Final 2.0 to Final 3.0 
 
General 
The version number and the revision date were updated 
accordingly to the most current version and date. 
 
General  
Replacement of the current responsible Medical Safety 
Officer 
. 
The Medical Safety Officer duties have been assumed by 
the responsible Medical Safety Officer 
, 
MD. 
13.1.2 
Sponsor 
Amended text:  

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without the written consent of Philip Morris Products S.A. 
 
Medical Safety 
Officer 
Phone: +41 
 
Mobile: +41 
 
E-mail: 
@pmi.com  
 
Old text: 
 
 
 
Medical Safety 
Officer 
Phone: +41 
 
E-mail: 
.pmi.com 
 
Reason to change: The phone number and the e-mail 
address of the Sponsor’s MSO have been accordingly 
adapted to the change of the MSO. 
Synopsis  
Sample Size;: 
Title of Table 1 
Amended text: Expected Mean Ratios and Coefficients of 
Variation for CHTP 1.2/CC after 5 Days or 90 Days of 
exposure 
 
Old text: Expected Mean Ratios and Coefficients of 
Variation for THS 2.2 Menthol/mCC after 5 Days or 90 
Days of exposure 
 
Reason to change:  Correction of the names of the 
respective investigational products. 
12.2 
Determination 
of Sample Size 
and Power 
Consideration; 
Title of Table 
20; Title of 
Table 21 
Amended text:  
Table 20: Expected Mean Ratios and Coefficients of 
Variation for CHTP 1.2/CC after 5 Days of exposure 
Table 21: Expected Mean Ratios and Coefficients of 
Variation for CHTP 1.2/CC after 90 Days of exposure 
 
Old text:  

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Table 20: Expected Mean Ratios and Coefficients of 
Variation for THS 2.2 Menthol/mCC after 5 Days of 
exposure 
Table 21: Expected Mean Ratios and Coefficients of 
Variation for THS 2.2 Menthol/mCC after 90 Days of 
exposure 
 
Reason to change:  Correction of the names of the 
respective investigational products. 
From Final 1.0 to Final 2.0 
7.6.1 
Blood Samples 
Amended text: “The maximal total volume of blood 
drawn for each subject will be around 303 mL, …, about 
36 mL for long-term storage of the bio-banking samples of 
biomarkers, clinical risk endpoints and other circulating 
proteins (…), and about 57 mL for long-term storage bio-
banking samples for transcriptomics, lipidomics and DNA 
methylation sequencing analyses (only if additional 
consent is given)…”.   
 
Old text: “The maximal total volume of blood drawn for 
each subject will be around 452 mL, …, about 114 mL for 
long-term storage of the bio-banking samples of 
biomarkers, clinical risk endpoints and other circulating 
proteins (…) and 60 mL for long-term storage bio-banking 
samples for transcriptomics, lipidomics and DNA 
methylation sequencing analyses (only if additional 
consent is given)…”.  
 
Reason to change:  To correct blood volumes to be drawn 
which were overcalculated. 
7.6.3 
Bio-Banking 
for Long-Term 
Storage of 
Blood and 
Urine 
Amended text:  This is to obtain and store 2 x 1 mL of 
serum, 2 x 1 mL of plasma and 2 x 1 mL whole blood. 
Old text:  This is to obtain and store 2 x 1 mL of serum, 2 
x 1 mL of serum and 2 x 1 mL whole blood. 
Reason to change:  To correct an error in writing. 
 

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without the written consent of Philip Morris Products S.A. 
Amended text: “…and serum/plasma/whole blood 
(approx. 36 mL of blood in total) will be collected as 
follows:” .  
Old text: “…and serum/plasma/whole blood (36 mL of 
blood in total) will be collected as follows:”.  
 
Amended text: Serum/whole blood will be collected on 
Day -1, Day 6 and Visit 4, respectively (approx. 36 mL of 
blood in total with approx. 12 mL of blood draw per time 
point. 
Old text: Serum/whole blood will be collected on Day -1, 
Day 6 and Visit 4, respectively (36 mL of blood in total 
with 12 mL of blood draw per time point. 
 
Amended text: ”… and whole blood for DNA methylation 
sequencing approx. 57 mL of blood will additionally be 
collected in total.” 
Old text: “… and whole blood for DNA methylation 
sequencing an additional 60 mL of blood will be collected 
in total.” 
 
Amended text: On Day 1, Day 6 and at Visit 4, approx. 
15 mL blood in total will be collected for 
transcriptomics… 
Old text: On Day 1, Day 6 and at Visit 4, 15 mL blood in 
total will be collected for transcriptomics… 
 
Amended text:  For lipidomics analyses, approx. 12 mL 
blood in total will be collected on Day -1,… 
Old text:  For lipidomics analyses, 12 mL blood in total 
will be collected on Day -1,… 
 
Amended text:  For DNA methylation sequencing, 
approx. 30 mL blood in total will be collected on Day -
1,… 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
Old text:  For DNA methylation sequencing, 30 mL blood 
in total will be collected on Day -1,… 
 
Reason to change: Slight deviations in amount of blood 
during blood drawings are taken into consideration.  

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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without the written consent of Philip Morris Products S.A. 
SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Name of Product: 
Carbon Heated Tobacco Product 1.2 (CHTP 1.2) 
Study Title: 
A randomized, controlled, open-label, 2-arm parallel group, single center study to 
demonstrate reductions in exposure to selected smoke constituents in healthy smokers 
switching to the Carbon Heated Tobacco Product 1.2 (CHTP 1.2), compared to continuing 
to use combustible cigarettes, for 5 days in confinement and prolonged by 85 days in an 
ambulatory setting. 
Study Number: 
P2R-REXA-07-EU, no acronym 
Study Short Title: 
Reduced exposure study using the CHTP 1.2 with 5 days in a confinement setting and 85 
days in an ambulatory setting. 
Primary Objectives and Endpoints: 
1. To demonstrate the reduction of biomarkers of exposure (BoExp) to selected harmful 
and potentially harmful constituents (HPHCs) in smokers switching from combustible 
cigarettes (CC) to CHTP 1.2 as compared to smokers continuing to use CC for 5 days 
Endpoints (Day 5): 
 
BoExp to HPHCs in urine (expressed as concentration adjusted for creatinine in 24-
hour urine): 
 
BoExp to 1,3-butadiene: monohydroxybutenylmercapturic acid (MHBMA) 
 
BoExp to acrolein: 3-hydroxypropylmercapturic acid (3-HPMA) 
 
BoExp to benzene: S-phenylmercapturic acid (S-PMA) 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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without the written consent of Philip Morris Products S.A. 
 
BoExp to HPHCs in blood (expressed as % of saturation of hemoglobin): 
 
BoExp to carbon monoxide (CO): carboxyhemoglobin (COHb) 
2. To demonstrate the reduction of total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
(total NNAL) in smokers switching from CC to CHTP 1.2 as compared to smokers 
continuing to use CC for 90 days 
Endpoint (Visit 4): 
 
BoExp to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK): total NNAL 
level (expressed as concentration adjusted for creatinine in 24-hour urine) 
Secondary Objectives and Endpoints: 
1. To evaluate self-reported nicotine/tobacco product use throughout the entire exposure 
period, including dual-use in an ambulatory setting in smokers switching from CC to 
CHTP 1.2 as compared to smokers continuing to use CC 
Endpoint (measured daily): 
 
Number of CC or CHTP 1.2 used daily as reported on the usage log during the 
confinement period, and self-reported number of any nicotine/tobacco product use 
on a daily basis as reported on the product use diary during the ambulatory period 
2. To determine the reduction of various BoExp to HPHCs in smokers switching from CC 
to CHTP 1.2 as compared to smokers continuing to use CC for 5 days and for 90 days 
Endpoints (Day 5 to Visit 4): 
 
BoExp to HPHCs in urine (expressed as quantity excreted or concentration adjusted 
for creatinine in 24-hour urine): 
 
MHBMA (Visit 4 only) 
 
3-HPMA (Visit 4 only) 
 
S-PMA (Visit 4 only) 
 
Total NNAL (Day 5 only) 
 
BoExp to benzo(a)pyrene: 3-hydroxybenzo(a)pyrene (Day 5, Visit 4) 
 
BoExp to pyrene: total 1-hydroxypyrene (total 1-OHP) (Day 5, Visit 4) 
 
BoExp to N-nitrosonornicotine: total N-nitrosonornicotine (total NNN) (Day 5, 
Visit 4) 
 
BoExp to 4-aminobiphenyl: 4-aminobiphenyl (4-ABP) (Day 5, Visit 4) 
 
BoExp to 1-aminonaphthalene: 1-aminonaphthalene (1-NA) (Day 5, Visit 4) 
 
BoExp to 2-aminonaphthalene: 2-aminonaphthalene (2-NA) (Day 5, Visit 4) 

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 
BoExp to o-toluidine: o-toluidine (o-tol) (Day 5, Visit 4) 
 
BoExp to acrylonitrile: 2-cyanoethylmercapturic acid (CEMA) (Day 5, Visit 4) 
 
BoExp to ethylene oxide: 2-hydroxyethylmercapturic acid (HEMA) (Day 5, 
Visit 4) 
 
BoExp to crotonaldehyde: 3-hydroxy-1-methylpropyl-mercapturic acid (3-
HMPMA) (Day 5, Visit 4) 
 
BoExp to CO: 
 
CO in exhaled breath (expressed as ppm) (Day 5, Visit 4) 
 
COHb in blood (expressed as % of saturation of hemoglobin) (Visit 4 only) 
3. To describe the levels of BoExp over the entire exposure period in smokers switching 
from CC to CHTP 1.2 as compared to smokers continuing to use CC 
Endpoints (Day 1 to Visit 4): 
 
BoExp to CO: 
 
CO in exhaled breath (expressed as ppm) 
 
COHb in blood (expressed as % of saturation of hemoglobin) 
 
BoExp to HPHCs in urine (expressed as quantity excreted and concentration adjusted 
for creatinine in 24-hour urine): 
 
MHBMA 
 
3-HPMA 
 
S-PMA 
 
Total NNAL 
 
Total 1-OHP 
 
Total NNN 
 
4-ABP 
 
1-NA 
 
2-NA 
 
o-tol 
 
CEMA 
 
HEMA 
 
3-hydroxybenzo(a)pyrene 
 
HMPMA 

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4. To describe the levels of nicotine over the entire exposure period in smokers switching 
from CC to CHTP 1.2 as compared to smokers continuing to use CC 
Endpoints (Day 1 to Visit 4): 
 
Nicotine equivalents (NEQ = molar sum of free nicotine, nicotine-glucuronide, free 
cotinine, 
cotinine-glucuronide, 
free 
trans-3’-hydroxycotinine, 
trans-3’-
hydroxycotinine-glucuronide), expressed as concentration adjusted for creatinine in 
24-hour urine 
 
Nicotine and cotinine plasma concentrations 
5. To determine the changes over the entire exposure period in lung functions in smokers 
switching from CC to the CHTP 1.2 as compared to those continuing to use CC 
Endpoint (Day 6 and Visit 4): 
 
Spirometry (pre- and post-bronchodilator): forced expiratory volume in 1 second 
(FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow (FEF 25-
75) 
Endpoint (Day 1 to Visit 4): 
 
Cough assessment by Visual Analog Scale (VAS) and Likert Scales and one open 
question 
6. To monitor selected cardiovascular clinical risk endpoints over the entire exposure 
period in smokers switching from CC to CHTP 1.2 as compared to smokers continuing 
to use CC 
Endpoints (Day 6 to Visit 4): 
 
Systolic and diastolic blood pressure on Day 6, at Visit 2, Visit 3, and Visit 4 
 
High sensitive C-reactive protein (hs-CRP), blood glucose, myeloperoxidase (MPO), 
low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (TG), 
and total cholesterol (TC) in serum at Visit 2, Visit 3, and Visit 4 
 
Fibrinogen, homocysteine in plasma at Visit 2, Visit 3, and Visit 4 
 
Hemoglobin A1c (HbA1c) in blood at Visit 4 
 
Apolipoprotein A1 (Apo A1) and apolipoprotein B (Apo B) in serum at Visit 4 
 
Soluble inter-cellular adhesion molecule-1 (sICAM-1) in serum on Day 6, at Visit 2, 
Visit 3, and Visit 4 
 
White blood cell (WBC) and platelet counts in blood on Day 6, at Visit 2, Visit 3, 
and Visit 4 

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 
11-dehydro-thromboxane B2 (11-DTX-B2) in 24-hour urine on Day 5, at Visit 2, 
Visit 3, and Visit 4 (expressed as concentration adjusted for creatinine) 
 
Body weight and waist circumference at Visit 4 
7. To evaluate the changes in levels of selected clinical risk endpoints related to oxidative 
stress over the entire exposure period in smokers switching from CC to CHTP 1.2 as 
compared to smokers continuing to use CC 
Endpoints (Day 5 to Visit 4): 
 
Epi-prostaglandin F2α (8-epi-PGF2α) in 24-hour urine on Day 5, at Visit 2, Visit 3, 
and Visit 4 (expressed as concentration adjusted for creatinine) 
 
Ratio of 8-epi-prostaglandin F2α (8-epi-PGF2α) to prostaglandin F2α (PGF2α) in 
plasma on Day 5 and at Visit 4 
 
8-Hydroxy-2’-deoxyguanosine (8-OHdG) in 24-hour urine on Day 5, at Visit 2, 
Visit 3, and Visit 4 (expressed as concentration adjusted for creatinine) 
 
4-Hydroxy-2-nonenal (4-HNE) in serum on Day 5 and at Visit 4 a 
 
Total anti-oxidant capacity (TAC) in serum on Day 5 and at Visit 4 
a 
Samples for 4-HNE analysis have been collected but will not be analyzed due to the failure to develop a 
selective and quantitative assay. 
8. To describe the change in cytochrome P450 1A2 (CYP1A2) enzymatic activity in 
smokers switching from CC to the CHTP 1.2 as compared to smokers continuing to use 
CC 
Endpoint (Day 5 and Visit 4): 
• Molar metabolic ratio of paraxanthine/caffeine in plasma 
9. To monitor the safety profiles associated with CHTP 1.2 and CC during the study 
Endpoints: 
 
Adverse events (AEs) / serious adverse events (SAEs) and incidence of CHTP 1.2 
malfunctions and misuse, 
 
 
Vital signs 
 
Electrocardiogram (ECG) 
 
Clinical chemistry, hematology, and urine analysis safety panel 
 
Physical examination 
 
Concomitant medications 

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Exploratory Objectives and Endpoints: 
1. To describe the following parameters in smokers switching from CC to CHTP 1.2 as 
compared to smokers continuing to use CC 
• Excretion of mutagenic material in 24-hour urine: Ames mutagenicity test 
(YG1024+S9): Day 5 and Visit 4. 
 
Subjective effects of smoking: 
 
Questionnaire of Smoking Urges (QSU), (brief version): Day 1 to Visit 4 
 
Fagerström Test for Nicotine Dependence (FTND), (revised version): Visit 4 
 
Product evaluation: Modified Cigarette Evaluation Questionnaire (MCEQ): Day 
1 to Visit 4 
 
Cytochrome P450 2A6 (CYP2A6) enzymatic activity:  
 
the molar metabolic ratio of trans-3’-hydroxycotinine/cotinine: Day 6 and Visit 
4 
 
Intent to Use of CHTP 1.2: 
 
Intent to Use of CHTP 1.2 Questionnaire (ITUQ): only in smokers switching from 
CC to CHTP 1.2: Day 6 and Visit 4 
2. To describe the CHTP 1.2 use over the entire exposure period according to the product 
preference of the subject 
Endpoint (daily): 
 
Number of CC or CHTP 1.2 used daily as reported on the usage log during the 
confinement period and self-reported number of any nicotine/tobacco product use on 
a daily basis as reported on the product use diary during the ambulatory period 
according to product preference 
3. To assess the smokers’ mental state for the intention to quit 
Endpoint (Visit 4): 
 
Prochaska “Stage of Change” Questionnaire 
4. To monitor BoExp and clinical risk endpoints in subjects who attempt to quit using 
tobacco products according to the time since they quit b 
Endpoints: 

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 
BoExp: MHBMA, S-PMA, 3-HPMA, COHb, and total NNAL 
 
CO (expressed as ppm) in exhaled breath 
 
Selected clinical risk endpoints (hs-CRP, homocysteine, blood glucose, LDL, 
HDL, TG, TC, fibrinogen, HbA1c, sICAM-1, WBC, platelet count, Apo A1, Apo 
B, 11-DTX-B2, and clinical risk endpoints related to oxidative stress) in 
respective body matrix 
b 
The reporting of the objective will be the subject of an appendix to the main clinical study report. 
Study Hypothesis: 
The hypothesis to be tested is that the geometric means of each of the BoExp levels for the 
CHTP 1.2 is lower relative to CC. For BoExp measured as primary endpoints, this hypothesis 
will be tested after 5 days of exposure for MHBMA, 3-HPMA, S-PMA, and COHb, and 
after 90 days of exposure for total NNAL. 
Evaluation Criterion: 
The study is designed to be able to detect a reduction of 50% or more in the levels of 
MHBMA, 3-HPMA, S-PMA, and COHb after 5 days of exposure, and in total NNAL after 
90 days of exposure in smokers switching from CC to the CHTP 1.2 as compared to smokers 
continuing to use CC, using a one-sided test with 2.5% type I error probability. 
Study Design 
A randomized, controlled, open-label, 2-arm, parallel group, study design with a stratified 
randomization by sex and average daily CC consumption over the last 6 weeks as self-
reported at Admission (smoking 10 to 19 CC/day vs. > 19 CC/day) (Figure 1). 
 

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Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXA-07-EU  
FINAL VERSION 5.0 / 05 December 2016 
Page 16 of 166 
 
 
 
 
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without the written consent of Philip Morris Products S.A. 
discontinued. After the sample for CYP2A6 activity has been taken, and the product test 
has been performed, smokers will be allowed to smoke their single preferred brand of 
CC ad libitum until 11.00 PM. Use of any tobacco/nicotine containing product other than 
CC and CHTP 1.2 for the product test will not be allowed after Admission. 
 
The Baseline Period (from Day -2, 06:30 AM until Day 1, 06:29 AM): 
All subjects will continue smoking their CC ad libitum. Twenty four-hour urine 
collection for Day -2 will start in the morning of Day -2 ending in the morning of Day -1. 
Twenty four-hour urine collection for Day -1 will start in the morning of Day -1 ending 
in the morning of the Day 1. On Day -2 and Day -1, smoking will be allowed from 
06:30 AM until around 11:00 PM. However, on Day -2, smoking will be allowed only 
after the Cough Questionnaire has been completed. 
On Day -1, subjects will be randomized to 1 of the 2 study arms in a 2:1 ratio using a 
stratified randomization. 
 
CHTP 1.2 arm: ~80 subjects, ad libitum use of CHTP 1.2 
 
CC arm: ~40 subjects, ad libitum use of their own preferred CC brand 
Subjects will be informed about their randomized study arm by the study site staff on 
Day 1 prior to 06:30 AM. 
 
The Exposure Period (from Day 1, 06:30 AM until Discharge at Visit 4): 
The exposure period will include both the exposure period in confinement, and the 
exposure period in the ambulatory setting: 
 
The Exposure Period in the Confinement Setting (from Day 1, 06:30 AM until the 
time of Discharge on Day 6): 
The exposure period in confinement consists of 5 days of ad libitum use of the 
assigned product from 06:30 AM until around 11:00 PM each day in the CHTP 1.2 
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 Principal Investigator (PI), result in 
the subject’s discontinuation from the study. 
Twenty four-hour urine will be collected from Day 1 to Day 5 on site ending in the 
morning of Day 6. On Day 1, product use must not start prior to the end of urine 
collection of Day -1. The end of the 24-hour urine collection period for Day 5 will 
end in the morning of Day 6 prior to Discharge. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXA-07-EU  
FINAL VERSION 5.0 / 05 December 2016 
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Procedures on Day 6 will be conducted before discharge of the subject from the clinic 
after 9 days in a confined setting. Use of products will be allowed on Day 6 according 
to product allocation, but only after the sample for CYP2A6 activity has been taken, 
the cough assessment has been completed, and spirometry has been performed.  
Subjects will be instructed to continue their assigned product/regimen in an 
ambulatory setting for 85 days. 
 
The Exposure Period in the Ambulatory Setting (from Discharge on Day 6 until 
Discharge at Visit 4): 
Subjects will be required to make three visits (Visit 2, Visit 3, and Visit 4) to the 
investigational site. Each visit will cover 2 consecutive days on site. For Visit 2 and 
Visit 3, the subject will check-in in the morning on the first day of the respective visit 
and will check-out on the second day of the visit. For Visit 4, the subject will check-
in in the morning on the first day of the visit, and will be discharged on the second 
day of the visit after having performed all the safety examination procedures. 
Twenty four-hour urine will be collected at each visit (Visit 2, Visit 3, and Visit 4) at 
the site. The collection of 24-hour urine will start on the first day of the respective 
visits and will end 24 hours later on the following day. On the first day of Visit 2, 
Visit 3, and Visit 4, subjects in the CHTP 1.2 and CC arms will be allowed to use 
their assigned product from the time of check-in until 11:00 PM. On the second day 
of Visit 2 and Visit 3, product use will be allowed from 06:30 AM onwards. The 
exposure period to the assigned IP will end at 11:00 PM on the first day of Visit 4.  
On the second day of Visit 4 (Day 91), subjects who wish to smoke CC or use other 
nicotine/tobacco-containing products will be allowed to do so, but only after the end 
of 24-hour urine collection and after spirometry and sampling for CYP2A6 activity 
have been performed. 
During the visits, the dispense and use of CHTP 1.2 will be strictly forbidden for 
subjects in the CC arm. 
Subject will not be discontinued from the study for the use of nicotine/tobacco 
containing products other than the assigned product/regimen during the ambulatory 
period. Subjects will record in a product use diary any use of CC (menthol or non-
menthol), nicotine replacement therapy (NRT), or other nicotine/tobacco-containing 
products on a daily basis. 
During the confinement and ambulatory settings: 
 
Any subject, who wants to attempt to quit using any tobacco products during the 
study (e.g., CHTP 1.2 and CC) will be encouraged to do so and will be referred to 

Philip Morris Products SA 
Clinical Study Protocol 
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P2R-REXA-07-EU  
FINAL VERSION 5.0 / 05 December 2016 
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without the written consent of Philip Morris Products S.A. 
appropriate medical services. This will not affect subject’s financial compensation, 
and the subject will remain in the study. 
 
The Safety Follow-up Period (from Discharge at Visit 4 until the End of the Safety 
Follow-up Period): 
After Discharge at Visit 4 or the date of early termination, subject will enter a 28-day 
Safety Follow-up Period during which there will be recording of spontaneously reported 
new AEs/SAEs and the active follow-up of ongoing AEs/SAEs by the study site. In 
general, all AEs will be followed-up until resolved, stabilized (i.e., no worsening of the 
event), or a plausible explanation for the event has been found until the end of the study. 
At the end of the Safety Follow-up Period, all ongoing AEs will be documented as 
“ongoing” and will not be followed-up by the Investigator. At the discretion of the 
Investigator, the subject will be referred to his General Practitioner for follow-up on 
ongoing AEs. 
AEs with onset after the end of the Safety Follow-Up Period and considered related to 
the IP might be reported to the Sponsor. Such AEs may not be part of the study report. 
SAEs spontaneously reported to the PI after the end of the Safety Follow-Up Period and 
considered related to the IP must also be reported to the Sponsor. Such SAEs may not be 
part of the study. 
The individual end of study (EOS) date for a subject is defined as either the Discharge at 
Visit 4 or the date of early termination followed by the 28-day Safety Follow-up Period. 
The EOS of the entire study is the last individual EOS time point during the study. 
Study Population and Main Criteria for Inclusion/Exclusion: 
Approximately 120 smoking, healthy Caucasian female or male adult subjects meeting the 
following main inclusion criteria: 
 
Subject is at least 28 years old 
 Subject is Caucasian 
 Subject is healthy, as judged by the Investigator 
 Subject has smoked on average at least 10 commercially available non-menthol CCs per 
day (no brand restrictions) at least for the last 6 weeks prior to the Screening Visit and 
Admission, respectively, based on self-reporting 
 Subject has smoked at least for the last 10 years 
 Subject does not plan to quit smoking in the next 6 months 
 Subject is ready to comply with the study procedures (e.g., to use CHTP 1.2 for the 
duration of the study) 

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Clinical Study Protocol 
Confidential 
P2R-REXA-07-EU  
FINAL VERSION 5.0 / 05 December 2016 
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Subjects who do not complete the study after randomization will not be replaced. 
Investigational Products; Dose; and Mode of Administration: 
 Carbon Heated Tobacco Product 1.2 (CHTP 1.2). CHTP 1.2 will be provided by the 
Sponsor 
 Subject’s own preferred commercially available non-menthol single brand of CC 
Duration of Study: 
The entire study duration per subject will be 128 to 169 days, including a Screening Period 
of up to 42 days prior to Admission on Day -3, a 9-day confinement setting (Day -3 to 
Discharge on Day 6) followed by a 85-day ambulatory setting (from the Discharge on Day 
6 to the Discharge at Visit 4), and a 28-day Safety Follow-up Period. The EOS of the entire 
study is the last individual EOS time point during the study. 
Statistical Methods: 
Analysis of BoExp will be conducted on the natural log scale. The Day 5- or Visit 4-BoExp 
levels will be analyzed by means of a generalized linear model using randomized arm as 
covariate adjusting for the following Baseline information: sex, average cigarette 
consumption over the previous 6 weeks prior to Admission (value at Admission for 
stratification), and Baseline value of the BoExp. Relative effects will be provided. 
Assumptions of the analysis of variance (ANOVA) model will be tested. Markedly non-log 
normally distributed BoExp data will be transformed or analyzed by appropriate non-
parametric methods. 
Unless stated otherwise, all statistical tests will conducted using a one-sided test with 2.5% 
type I error probability, and all quoted confidence intervals (CIs) will be two-sided 95% CIs.  
 
Sample Size: 
The analysis set to analyze the primary endpoints will be the Per-Protocol (PP) population. 
It is assumed that a minimal number of subjects will be excluded from the PP set in 
confinement for both arms and CC in ambulatory, whereas at least 50% will remain in the 
PP set in ambulatory for CHTP 1.2, therefore a 2:1 randomization ratio was chosen. Using 
the below assumptions, a total of 120 subjects (~80 in the CHTP 1.2 arm, and ~40 in the CC 
arm) will be randomized.). 
 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXA-07-EU  
FINAL VERSION 5.0 / 05 December 2016 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Table 1 
Expected Mean Ratios and Coefficients of Variation for CHTP 
1.2/CC after 5 Days or 90 Days of exposure  
Timepoint 
of 
assessment 
 
Primary 
endpoint 
CHTP 1.2/CC 
MR (CV) 
Day 5 
COHb 
0.40 (0.32) 
Day 5 
3-HPMA 
0.30 (0.50) 
Day 5 
MHBMA 
0.15 (0.70) 
Day 5 
S-PMA 
0.20 (0.70) 
Day 90 
Total 
NNAL 
0.30 (0.60) 
Abbreviations: 3-HPMA = 3-hydroxypropylmercapturic acid; CC = Combustible cigarettes; COHb = Carboxyhemoglobin; 
CV = Coefficients of variation; MHBMA = Monohydroxybutenyl mercapyuric acid; MR = Mean ratios; S-PMA = S-
phenylmercapturic acid; Total NNAL = Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; CHTP 1.2 = Carbon Heated 
Tobacco Product 1.2. 
This sample size is needed to attain 80% power to detect a 50% reduction or more in the 
levels of MHBMA, 3-HPMA, S-PMA, and COHb in the CHTP 1.2 arm compared to the CC 
arm after 5 days of exposure, and in the levels of total NNAL in the CHTP 1.2 arm compared 
to the CC arm after 90 days of exposure, using a one sided test with 2.5% type I error 
probability. The overall type I error will be protected by using a closed testing procedure 
(i.e., testing the four above listed endpoints simultaneously 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXA-07-EU  
FINAL VERSION 5.0 / 05 December 2016 
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TABLE OF CONTENTS 
SYNOPSIS ...................................................................................................................................... 8 
TABLE OF CONTENTS ............................................................................................................. 21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................... 26 
1 
ETHICS AND REGULATIONS ........................................................................................ 32 
1.1 
Independent Ethics Committee (IEC) Approval ...................................................... 32 
1.2 
Ethical Conduct of the Study .................................................................................... 33 
1.3 
Subject Information and Consent ............................................................................. 33 
1.4 
Good Clinical Practice and Regulatory Requirements ............................................ 34 
2 
INTRODUCTION ............................................................................................................... 36 
2.1 
Background ................................................................................................................ 36 
2.2 
Purpose of the Study .................................................................................................. 37 
2.3 
Anticipated Benefits and Risks ................................................................................. 37 
3 
STUDY OBJECTIVES ....................................................................................................... 39 
3.1 
Primary Objectives and Endpoints ........................................................................... 39 
3.2 
Secondary Objectives and Endpoints ....................................................................... 39 
3.3 
Exploratory Objectives and Endpoints ..................................................................... 43 
4 
INVESTIGATIONAL PLAN ............................................................................................. 45 
4.1 
Overall Study Design and Plan ................................................................................. 45 
4.2 
Rationale for Study Design ....................................................................................... 49 
4.3 
Appropriateness of Measurements ........................................................................... 52 
4.4 
Study Duration ........................................................................................................... 53 
5 
STUDY POPULATION ...................................................................................................... 54 
5.1 
Inclusion Criteria ....................................................................................................... 54 
5.2 
Exclusion Criteria ...................................................................................................... 55 
5.3 
Discontinuation of Subjects from the Study ............................................................ 57 
5.4 
Lost to Follow-up ...................................................................................................... 59 
5.5 
Violation of Selection Criteria .................................................................................. 59 
6 
INVESTIGATIONAL PRODUCTS .................................................................................. 60 
6.1 
Description of Investigational Products ................................................................... 60 
6.2 
Packaging and Labeling ............................................................................................ 60 

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Clinical Study Protocol 
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6.3 
Use of Investigational Product(s) ............................................................................. 61 
6.4 
Method for Assigning Subjects to Study Arms ....................................................... 62 
6.5 
Blinding ...................................................................................................................... 63 
6.6 
Investigational Product Accountability and Compliance ........................................ 63 
6.7 
Restrictions ................................................................................................................. 65 
6.8 
Concomitant Medication ........................................................................................... 67 
7 
STUDY PROCEDURES ..................................................................................................... 72 
7.1 
Informed Consent ...................................................................................................... 72 
7.2 
Smoking Cessation Advice and Debriefing ............................................................. 72 
7.3 
Clinical Assessments ................................................................................................. 72 
7.4 
Biomarker Assessment .............................................................................................. 77 
7.5 
Laboratory Assessments ............................................................................................ 80 
7.6 
Sample Handling, Storage, and Shipment................................................................ 82 
7.7 
Other Study Procedures ............................................................................................. 85 
8 
ADVERSE EVENTS ........................................................................................................... 90 
8.1 
Definitions .................................................................................................................. 90 
8.2 
Collection, Assessment and Follow-up of Adverse Events .................................... 91 
8.3 
Reporting of Serious Adverse Events....................................................................... 93 
8.4 
Abnormal Results of Laboratory Tests .................................................................... 94 
8.5 
Collection, Follow-Up and Reporting of Pregnancies ............................................ 95 
8.6 
Adverse Events Leading to Discontinuation ............................................................ 96 
8.7 
Investigational Product Malfunction and Misuse .................................................... 96 
9 
STUDY ACTIVITIES ......................................................................................................... 97 
9.1 
Screening Visit ........................................................................................................... 97 
9.2 
Confinement Period (Day -3 to Day 6) .................................................................... 99 
9.3 
Ambulatory Period (from Time of Discharge on Day 6 to the Day 91 (the 
Second Day of Visit 4) ............................................................................................ 116 
9.4 
Safety Follow-Up Period ......................................................................................... 124 
9.5 
Early Termination Procedures ................................................................................ 124 
10 QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 126 
10.1 
Monitoring................................................................................................................ 126 

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10.2 
Training of Collaborators ........................................................................................ 127 
10.3 
Audits and Inspections ............................................................................................ 127 
11 DATA MANAGEMENT ACTIVITIES .......................................................................... 128 
11.1 
Data Capture ............................................................................................................ 128 
11.2 
Data Handling .......................................................................................................... 129 
12 PLANNED STATISTICAL METHODS ......................................................................... 131 
12.1 
General Considerations ........................................................................................... 131 
12.2 
Determination of Sample Size and Power Consideration ..................................... 132 
12.3 
Analysis Populations ............................................................................................... 134 
12.4 
Primary Endpoints ................................................................................................... 135 
12.5 
Secondary Safety Endpoint(s)................................................................................. 136 
12.6 
Exploratory Analysis ............................................................................................... 137 
12.7 
Demographics and Baseline Characteristics .......................................................... 138 
12.8 
Interim Analysis ....................................................................................................... 138 
13 ADMINISTRATIVE CONSIDERATIONS .................................................................... 139 
13.1 
Investigator’s and Study Administrative Structure ............................................... 139 
13.2 
Subject Confidentiality ............................................................................................ 140 
13.3 
Access to Source Documentation ........................................................................... 141 
13.4 
Record Retention ..................................................................................................... 141 
13.5 
Clinical Study Report .............................................................................................. 143 
13.6 
Financial Disclosure ................................................................................................ 143 
13.7 
Publication and Disclosure Policy .......................................................................... 143 
13.8 
Insurance .................................................................................................................. 144 
14 REFERENCE LIST ........................................................................................................... 145 
 
LIST OF IN-TEXT TABLES 
Table 1 
Expected Mean Ratios and Coefficients of Variation for CHTP 1.2/CC 
after 5 Days or 90 Days of exposure ............................................................ 20 
Table 2 
Description of Blinded Study Personnel ...................................................... 63 
Table 3 
Examples of Medications with Effects on CYP1A2 and CYP2A6 
Activity .......................................................................................................... 68 

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Table 4 
Hematology and Clinical Chemistry Parameters (Safety) .......................... 81 
Table 5 
Time Schedule – Screening Visit (Day -45 to Day -4) ............................... 97 
Table 6 
Time Schedule – Admission (Day -3)........................................................ 100 
Table 7 
Time Schedule – Day -2 ............................................................................. 101 
Table 8 
Time Schedule – Day -1 ............................................................................. 102 
Table 9 
Time Schedule – Day 1 ............................................................................... 105 
Table 10 
Time Schedule – Day 2 ............................................................................... 106 
Table 11 
Time Schedule – Day 3 ............................................................................... 109 
Table 12 
Time Schedule – Day 4 ............................................................................... 110 
Table 13 
Time Schedule – Day 5 ............................................................................... 112 
Table 14 
Time Schedule – Day of Discharge (Day 6) .............................................. 113 
Table 15 
Time Schedule –The First Day of Visit 2 (Day 30), The First Day of 
Visit 3 (Day 60) ........................................................................................... 116 
Table 16 
Time Schedule – The Second Day of Visit 2 (Day 31), The Second 
Day of Visit 3 (Day 61) .............................................................................. 118 
Table 17 
Time Schedule – The First Day of Visit 4 (Day 90) ................................. 119 
Table 18 
Time Schedule – The Second Day of Visit 4 (Day 91) ............................ 121 
Table 19 
Time Schedule - Early Termination Procedures ....................................... 124 
Table 20 
Expected Mean Ratios and Coefficients of Variation for CHTP 1.2/CC 
after 5 Days of exposure ............................................................................. 133 
Table 21 
Expected Mean Ratios and Coefficients of Variation for CHTP 1.2/CC 
after 90 Days of exposure ........................................................................... 133 
Table 22 
Expected Power ........................................................................................... 134 
Table 23 
Test-Wise Power ......................................................................................... 134 
Table A1 
Study Assessments (Separate Table [Table A2] Shown for 24-hour 
Urine Collections) ....................................................................................... 150 
Table A2 
Schedule for 24-hour Urine Collection Assessments................................ 157 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design.................................................................................................. 15 
Figure 2 
Study Design.................................................................................................. 45 

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without the written consent of Philip Morris Products S.A. 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Events ...................................................................................... 150 
Appendix B 
Participating Laboratories ........................................................................... 158 
Appendix C 
Prochaska “Stage of Change” Questionnaire ............................................ 159 
Appendix D 
Summary of Biomarkers of Exposure to HPHC ....................................... 161 
Appendix E 
Abnormal Laboratory Values ..................................................................... 163 
 

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Clinical Study Protocol 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
1-NA 
1-aminonaphthalene 
2-NA 
2-aminonaphthalene 
3-HMPMA 
3-hydroxy-1-methylpropyl-mercapturic acid 
3-HPMA 
3-hydroxypropylmercapturic acid 
4-ABP 
4-aminobiphenyl 
4-HNE 
4-hydroxy-2-nonenal 
8-epi-PGF2α 
8-epi-prostaglandin F2α 
8-OHdG 
8-hydroxy-2’-deoxyguanosine 
11-DTX-B2 
11-dehydro-thromboxane B2 
ADL 
Activities of daily living 
AE 
Adverse event 
ANOVA 
Analysis of variance 
Apo A1 
Apolipoprotein A1 
Apo B 
Apolipoprotein B 
ATS 
American Thoracic Society 
BMI 
Body mass index 
BoExp 
Biomarker of exposure 
CAF 
Caffeine 
CC 
Combustible cigarette(s) 
CD 
Compact disc 
CEMA 
2-cyanoethylmercapturic acid 
CI 
Confidence interval 
CHTP 
Carbon Heated Tobacco Product 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case report form 

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CRO 
Contract research organization 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events and Common 
Toxicity Criteria 
CTMS 
Clinical trial management system 
CV (documentation) 
Curriculum vitae 
CV (statistics) 
Coefficient of variation 
CVD 
Cardiovascular diseases 
CYP1A2 
Cytochrome P450 1A2 
CYP2A6 
Cytochrome P450 2A6 
DMP 
Data management plan 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ENDs 
Electronic nicotine devices 
EOS 
End of study 
ERS 
European Respiratory Society 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FEF 
Forced expiratory flow 
FEV1  
Forced expiratory volume in 1 second 
FTND 
Fagerström Test for Nicotine Dependence (revised version) 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HDL 
High density lipoprotein 
HEMA 
2-hydroxyethylmercapturic acid 
HIV 
Human immunodeficiency virus 
HMPMA 
3-hydroxy-1-methylpropyl-mercapturic acid 
HPHCs 
Harmful and potentially harmful constituents  

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hs-CRP 
High sensitive C-reactive protein 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IEC 
International Ethic Committee 
IP 
Investigational product 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
ITUQ 
Intent to Use Questionnaire 
IU 
International unit 
IV 
Intravenous 
IxRS 
Interactive web/voice response system 
LDL 
Low density lipoprotein 
LLN 
Lower limit of the normal range 
LLOQ 
Lower limit of quantification 
LPO 
Lipid peroxidation 
MCEQ 
Modified Cigarette Evaluation Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHBMA 
Monohydroxybutenylmercapturic acid 
MPO 
Myeloperoxidase 
MR 
Mean ratio 
MRTP 
Modified risk tobacco product 
n 
Number of subjects 
NEQ 
Nicotine equivalents: molar sum of free nicotine, nicotine-
glucuronide, free cotinine, cotinine-glucuronide, free trans-3’-
hydroxycotinine, trans-3’-hydroxycotinine-glucuronide 
NNK 
4-(methylnitrosamino)-1-(3-pyridyl)-1butanone 
NRT 
Nicotine replacement therapy 
NSAID 
Nonsteroidal anti-inflammatory drugs 
o-tol 
o-toluidine 

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PGF2α 
Prostaglandin F2α 
PGHSs 
Prostaglandin-endoperoxide synthases 
PI 
Principal Investigator 
PMI 
Philip Morris International 
PP 
Per protocol 
PUFAs 
Polyunsaturated fatty acids 
PX  
Paraxanthine 
QC 
Quality control 
QSU-brief 
Questionnaire of Smoking Urges 
ROS 
Reactive oxygene species 
RRP 
Reduced risk products 
S-PMA 
S-phenylmercapturic acid 
SA 
Smoking abstinence 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Smoking cessation 
SD 
Standard deviation 
SES 
Socio-Econonomic Status Questionnaire 
SHM 
Sample handling manual 
sICAM-1 
Soluble inter-cellular adhesion molecule-1 
SMF 
Study master file 
SMP 
Safety management plan 
SOP 
Standard operating procedure 
SRO 
Subject reported outcome(s) 
T 
Time point 
T0 
Time point of first product use during study day 
t½ 
Half-life 
TAC 
Total anti-oxidant capacity 
TC 
Total cholesterol 

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TG 
Triglycerides 
Total 1-OHP 
Total 1-hydroxypyrene 
Total NNAL 
Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
Total NNN 
Total N-nitrosonornicotine 
 
 
ULN 
Upper limit of the normal range 
ULOQ 
Upper limit of quantification 
VAS 
Visual Analogue Scale 
vWF 
von-Willebrand factor 
WBC 
White blood cell (count) 
WHO 
World Health Organization 
 

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Explanation of Terms 
The following special terms are used in this protocol: 
Combustible cigarette 
(CC) 
The term “combustible cigarette” refers to commercially available 
cigarettes (manufactured) and excludes cigars, pipes, bidis, and 
other nicotine-containing products. 
Carbon Heated 
Tobacco Product 1.2 
(CHTP 1.2) 
CHTP 1.2 is a non-menthol tobacco stick which is comparable in 
shape and form, and is used in a similar manner to a combustible 
cigarette except that the tobacco contained in the CHTP 1.2 is 
heated by a Carbon Heat Tip and not burned like in a combustible 
cigarette.. 
End of study (EOS) 
The individual end of the study (EOS) for a subject is defined as 
either the Discharge at Visit 4 or the date of early termination 
followed by the 28-day Safety Follow-up Period. 
The EOS of the entire study is the last individual EOS time point 
during the study. 
Randomization  
Allocation of the respective product at any time on Day -1 utilizing 
an interactive web and voice response system (IxRS). On Day 1, 
the subjects will be individually informed about the product they 
are randomized to prior to the first product use. 
Screening failure 
All subjects that are not enrolled are considered as screen failures. 
Re-screening of subjects who did not meet any entry criteria will 
not be permitted. 

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1 
ETHICS AND REGULATIONS 
1.1 
Independent Ethics Committee (IEC) Approval 
Prior to the start of the study, the clinical study protocol, together with its associated documents 
(informed consent form [ICF], 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) [1] 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 (SMF) at the Sponsor or designated organization. No assessment can 
be performed on the subjects before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IEC. 
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the Investigator. 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. 
The Investigator is responsible for local reporting (e.g., to the IEC) of serious adverse events 
(SAEs) that occur during the study, according to local regulations. 
Relevant safety information will be submitted to the IEC during the course of the study in 
accordance with national regulations and requirements. 
Medically qualified study personnel will be available during the study. Separate ICFs will be 
signed by the subject for the collection and storage of bio-banking samples and their 
subsequent analysis. 

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hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
1.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki [2] and is consistent with applicable regulatory principles of ICH/GCP. 
The Investigator or designee agrees to conduct the clinical study in compliance with the 
protocol agreed with the Sponsor and approved by the IEC. The Investigator and the Sponsor 
must sign the protocol (and protocol amendments, if applicable) to confirm this agreement. A 
copy of the Declaration of Helsinki [2] is located in the Investigator’s study file. 
1.3 
Subject Information and Consent 
1.3.1 
Informed Consent Form for Study Participation 
Before or at V1, the Investigator or designee will ensure that each subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and benefits of 
the study, and the Investigator 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 the necessary information, and if he/she agrees to participate, 
this will be documented in the ICF by the date, time and signature of both the subject and the 
Investigator who conducted the informed consent discussion during Screening Visit. Any 
procedures specifically described in and related to the study protocol and study conduct, will 
not be performed before the ICF has been signed (including date and time). 
The personally signed and dated original ICF(s) must be kept by the Investigator and filed in 
the Investigator study file at the site or with the subject’s files and a copy must be given to the 
subject. The subject will be informed that if he/she discontinues from the study, the data 
collected until the point of discontinuation will be maintained as part of the study data and the 
samples collected prior to discontinuation will be analyzed, unless he/she refuses in writing. 
The subject will be informed that additional data analysis not mentioned in the protocol or in 
the statistical analysis plan (SAP) might be performed with the collected data at a later time. 
Any additional analysis performed will be covered by data confidentiality, as for the main 
analysis described in this protocol. 
1.3.2 
Informed Consent Form for Long-Term Bio-Banking 
Separate ICFs will be signed and dated by the subject for the collection of samples and their 
long-term bio-banking storage. The subject’s participation in the study does not depend on 
his/her consent to these separate ICFs. 

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without the written consent of Philip Morris Products S.A. 
 
One separate ICF to obtain consent for serum/plasma and urine collection and long-term 
storage for subsequent analysis of biomarkers of exposure, clinical risk endpoints and other 
circulating proteins, following completion of this study. No genetic, transcriptomics and/or 
lipidomics testing will be done on these samples. 
 
One separate ICF to obtain consent for collection and long-term storage of blood/plasma 
samples for further transcriptomics and lipidomics analyses. 
 
One separate ICF to obtain consent for collection and long-term storage of whole blood 
samples for further analysis of DNA methylation sequencing. 
1.3.3 
Informed Consent Form for Additional Research Related to the Bioanalytical 
Method for 8-epi-PGF2α and PGF2α Analysis   
During the course of the study, the most recent development of the assay to measure the 8-epi-
PGF2α to PGF2α ratio showed that the ratio is not an effective endpoint for the determination 
of oxidative stress (Celerion Laboratory, unpublished data) in contrast to what was published 
(see section 4.2). IRB was informed on the 2nd of June that blood samples dedicated to this 
analysis were no longer collected as from 1st of June for subjects who have not still completed 
the study.  
However, blood samples collected up to June 1st will be analyzed for the purpose of the study, 
and the results will be included in the clinical study report as part of the main study.  
All subjects will be informed and asked to sign and date a separate ICF to consent for use of 
the 8-iso-PGF2α/ PGF2α analysis performed on already collected samples for bioanalytical 
research purposes.The subject’s participation in the study does not depend on his/her consent 
to this separate ICF. 
1.3.4 
Amendment to the Informed Consent Form 
If a protocol amendment is required, an amendment may be required to the ICF. If a revision 
of the ICF is necessary, the Investigator or designee will, with the support of the Sponsor, 
ensure that the documents have been reviewed and approved by the relevant IEC before 
subjects are informed and sign and personally date the amended ICF (including date and time). 
1.4 
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator and designee abide by the principles of the ICH guidelines on 
GCP as applicable to the study. These guidelines apply specifically to pharmaceutical 
development, but nevertheless provide a robust and ethical framework for conducting a clinical 

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study on candidate reduced risk products. The study will also be conducted in accordance with 
the general ethical principles outlined in the Declaration of Helsinki [2]. 
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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without the written consent of Philip Morris Products S.A. 
2 
INTRODUCTION 
2.1 
Background 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy 
Cigarette smoking causes pulmonary diseases, cardiovascular diseases (CVD) and other 
serious diseases in smokers [3]. 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. For those smokers not willing to quit, Philip Morris International (PMI) is developing 
products with the potential to reduce the risks of tobacco-related diseases (reduced risk 
products [RRP]). These products are referred by the Food and Drug Administration (FDA) as 
modified risk tobacco products (MRTP) [4]. 
PMI develops candidate RRPs with the objective to substantially reduce the exposure to 
harmful and potentially harmful constituents (HPHCs) while providing an acceptable option 
to smokers as substitutes for CC. In this way, PMI can substantially reduce or eliminate a large 
spectrum of HPHCs. PMI’s product development approaches achieve this, for example, by 
heating tobacco at significantly lower temperatures than CC. PMI believes that such products 
present the best opportunity for reducing harm because they produce vastly lower levels of 
HPHCs and are more likely to be accepted by smokers as substitutes for CC. Important to this 
effort, has been the development of a product with the potential to provide nicotine, taste, ritual 
and sensory experience in a way that closely parallels CC. 
2.1.2 
Description of the Product and Scientific Findings 
Thousands of smoke constituents are formed when tobacco is burned or combusted. More than 
6,000 of these smoke constituents have been identified [5], and more than 90 of them have 
been categorized as HPHCs [6]. 
The product developed by PMI, and being assessed in this study, is the Carbon Heated Tobacco 
Product 1.2 (CHTP 1.2). With this product, the heating of the tobacco does not exceed a well-
defined temperature profile during use, which ensures heating without combustion of the 
tobacco, and at the same time provides an acceptable consumer experience in a consistent 
manner. 
CHTP 1.2 is a non-menthol tobacco stick which has similar appearance, and is used in a similar 
manner to a CC. To use CHTP 1.2, the consumer removes the protective cap and uses regular 
matches or lighter to ignite the carbon heat source, except that this process should be done 
while holding CHTP 1.2 in the hand, rather than in the mouth (like for a CC). After a short 

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pause to allow the tobacco to become heated, the aerosol generated by the heating process is 
inhaled by placing the filter of CHTP 1.2 in the mouth (or on the lips) and drawing air through 
CHTP 1.2. 
The non-clinical assessment of CHTP 1.2 described in the Investigator’s Brochure supports 
the initiation of the clinical studies [7]. No new or increased toxicological hazard in the 
product’s aerosol was detected compared with CC smoke.  
The non-clinical assessment of CHTP 1.2 is described in the IB and supports the clinical 
assessment of CHTP 1.2 [7]. 
One clinical study (ClinicalTrials.gov Identifier: NCT00812279) has been conducted in Poland 
with CHTP 0.1, an earlier and non-menthol prototype version of CHTP 1.2. After 5 days of 
exposure marked reductions in exposure to HPHCs in the CHTP 0.1 arm and smoking 
abstinence (SA) arm compared to subjects continuing smoking CC were observed, and no 
safety concern was revealed. No clinical studies have been conducted with CHTP 1.2. One  
randomized, controlled, 2-period, 2-sequence, single-use crossover study with CHTP 1.1 M 
(Carbon Heated Tobacco Product 1.1 Menthol) is ongoing in Japan (ClinicalTrials.gov 
Identifier: NCT02466412) [8]. One randomized, controlled, open-label, 2-arm, parallel group, 
single-center study with CHTP 1.0 is currently ongoing in Poland (ClinicalTrials.gov 
Identifier: NCT02503254) [9]. 
2.2 
Purpose of the Study 
The overall goal of the study is to demonstrate reduction in the levels of BoExp to selected 
HPHCs and to obtain safety information in healthy subjects using the CHTP 1.2 as compared 
to smokers continuing smoking CC in a confinement setting for 5 days (exclusive use) 
followed by an ambulatory setting of 85 days. 
Importantly, the study will provide information on biological and functional changes in clinical 
risk endpoints, in particular, endpoints on oxidative stress upon use of CHTP 1.2. Furthermore 
product evaluation, assessment of product use and subjective effects of smoking will be 
performed. 
2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
Information on health risks associated with smoking and smoking cessation advice will be 
provided at the Screening Visit, Admission, at Discharge on Day 6, and at Visits 2, 3 and 4. 
The advice will follow the recommendations of the World Health Organization (WHO) 
“Evidence based Recommendations on the Treatment of Tobacco Dependence” [10]. Subjects 

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who are motivated to quit smoking during the study will be encouraged to do so, and will be 
referred to appropriate medical services for necessary support and counselling. Subjects who 
participate in this study will also benefit from repeated and detailed health check-ups. 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures 
 
Risks related to blood sampling, e.g., excessive bleeding, fainting, hematoma, paresthesia, 
or infection, and the total amount of blood taken over a period of time 
 
Risks related to chest X-rays, (e.g., a small increase of risk to develop cancer later in life) 
 
Risks related to drug applications as part of testing procedures (i.e., spirometry, and short-
acting bronchodilator at the Screening Visit) per study protocol and scientifically accepted 
standards 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product 
 
Change in smoking habits due to study requirements and related concomitant symptoms 
(e.g., craving) 
 
Using commonly accepted research and scientific standards (e.g., blood samples not to 
exceed blood donation standards) 
All risks related to the IP will be explained in detail to the subjects. 
Risk mitigation will include: 
 
Medical assessment, management of all study participants with follow-up of those who 
have experienced an AE(s)/SAE(s) 
2.3.4 
Unforeseeable Risks 
The possibility of unforeseeable events/risks will be explained in detail to study participants. 
Unexpected malfunction of CHTP 1.2 may lead to unforeseeable risk. Subjects will be 
informed that CHTP 1.2 is not demonstrated to be less harmful than CC. Mitigation will 
include close monitoring and medical supervision to detect any unforeseeable risk or safety 
signals at the earliest time possible. 

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without the written consent of Philip Morris Products S.A. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objectives and Endpoints 
The primary objectives of this study are: 
1. To demonstrate the reduction of biomarkers of exposure (BoExp) to selected harmful and 
potentially harmful constituents (HPHCs) in smokers switching from combustible 
cigarettes (CC) to CHTP 1.2 as compared to smokers continuing to use CC for 5 days 
Endpoints (Day 5): 
 
BoExp to HPHCs in urine (expressed as concentration adjusted for creatinine in 24-
hour urine): 
 
BoExp to 1,3-butadiene: monohydroxybutenylmercapturic acid (MHBMA) 
 
BoExp to acrolein: 3-hydroxypropylmercapturic acid (3-HPMA) 
 
BoExp to benzene: S-phenylmercapturic acid (S-PMA) 
 
BoExp to HPHCs in blood (expressed as % of saturation of hemoglobin): 
 
BoExp to carbon monoxide (CO): carboxyhemoglobin (COHb) 
2. To demonstrate the reduction of total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total 
NNAL) in smokers switching from CC to CHTP 1.2 as compared to smokers continuing 
to use CC for 90 days 
Endpoint (Visit 4): 
 
BoExp to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK): total NNAL level 
(expressed as concentration adjusted for creatinine in 24-hour urine) 
3.2 
Secondary Objectives and Endpoints 
The secondary objectives of this study are: 
1. To evaluate self-reported nicotine/tobacco product use throughout the entire exposure 
period, including dual-use in an ambulatory setting in smokers switching from CC to CHTP 
1.2 as compared to smokers continuing to use CC 
Endpoint (measured daily): 
 
Number of CC or CHTP 1.2 used daily as reported on the usage log during the 
confinement period, and self-reported number of any nicotine/tobacco product use on 
a daily basis as reported on the product use diary during the ambulatory period 

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2. To determine the reduction of various BoExp to HPHCs in smokers switching from CC to 
CHTP 1.2 as compared to smokers continuing to use CC for 5 days and for 90 days 
Endpoints (Day 5 to Visit 4): 
 
BoExp to HPHCs in urine (expressed as quantity excreted or concentration adjusted for 
creatinine in 24-hour urine): 
 
MHBMA (Visit 4 only) 
 
3-HPMA (Visit 4 only) 
 
S-PMA (Visit 4 only) 
 
Total NNAL (Day 5 only) 
 
BoExp to benzo(a)pyrene: 3-hydroxybenzo(a)pyrene (Day 5, Visit 4) 
 
BoExp to pyrene: total 1-hydroxypyrene (total 1-OHP) (Day 5, Visit 4) 
 
BoExp to N-nitrosonornicotine: total N-nitrosonornicotine (total NNN) (Day 5, 
Visit 4)  
 
BoExp to 4-aminobiphenyl: 4-aminobiphenyl (4-ABP) (Day 5, Visit 4) 
 
BoExp to 1-aminonaphthalene: 1-aminonaphthalene (1-NA) (Day 5, Visit 4) 
 
BoExp to 2-aminonaphthalene: 2-aminonaphthalene (2-NA) (Day 5, Visit 4) 
 
BoExp to o-toluidine: o-toluidine (o-tol) (Day 5, Visit 4) 
 
BoExp to acrylonitrile: 2-cyanoethylmercapturic acid (CEMA) (Day 5, Visit 4) 
 
BoExp to ethylene oxide: 2-hydroxyethylmercapturic acid (HEMA) (Day 5,       
Visit 4) 
 
BoExp to crotonaldehyde: 3-hydroxy-1-methylpropyl-mercapturic acid (3-
HMPMA) (Day 5, Visit 4) 
 
BoExp to CO: 
 
CO in exhaled breath (expressed as ppm) (Day 5, Visit 4) 
 
COHb in blood (expressed as % of saturation of hemoglobin) (Visit 4 only) 
3. To describe the levels of BoExp over the entire exposure period in smokers switching from 
CC to CHTP 1.2 as compared to smokers continuing to use CC 
Endpoints (Day 1 to Visit 4): 
 
BoExp to CO: 

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 
CO in exhaled breath (expressed as ppm) 
 
COHb in blood (expressed as % of saturation of hemoglobin) 
 
BoExp to HPHCs in urine (expressed as quantity excreted and concentration adjusted for 
creatinine in 24-hour urine): 
 
MHBMA 
 
3-HPMA 
 
S-PMA 
 
Total NNAL 
 
Total 1-OHP 
 
Total NNN 
 
4-ABP 
 
1-NA 
 
2-NA 
 
o-tol 
 
CEMA 
 
HEMA 
 
3-hydroxybenzo(a)pyrene 
 
HMPMA 
4. To describe the levels of nicotine over the entire exposure period in smokers switching 
from CC to CHTP 1.2 as compared to smokers continuing to use CC 
Endpoints (Day 1 to Visit 4): 
 
Nicotine equivalents (NEQ = molar sum of free nicotine, nicotine-glucuronide, free 
cotinine, 
cotinine-glucuronide, 
free 
trans-3’-hydroxycotinine, 
trans-3’-
hydroxycotinine-glucuronide), expressed as concentration adjusted for creatinine in 
24-hour urine 
 
Nicotine and cotinine plasma concentrations 
5. To determine the changes over the entire exposure period in lung functions in smokers 
switching from CC to the CHTP 1.2 as compared to those continuing to use CC 
Endpoint (Day 6 and Visit 4): 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
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FINAL VERSION 5.0 / 05 December 2016 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
Spirometry (pre- and post-bronchodilator): forced expiratory volume in 1 second 
(FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow (FEF 25-75) 
Endpoint (Day 1 to Visit 4): 
 
Cough assessment by Visual Analog Scale (VAS) and Likert Scales and one open 
question 
6. To monitor selected cardiovascular clinical risk endpoints over the entire exposure period 
in smokers switching from CC to CHTP 1.2 as compared to smokers continuing to use CC 
Endpoints (Day 6 to Visit 4): 
 
Systolic and diastolic blood pressure on Day 6, at Visit 2, Visit 3, and Visit 4 
 
High sensitive C-reactive protein (hs-CRP), blood glucose, myeloperoxidase (MPO), 
low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (TG), and 
total cholesterol (TC) in serum at Visit 2, Visit 3, and Visit 4 
 
Fibrinogen, homocysteine in plasma at Visit 2, Visit 3, and Visit 4 
 
Hemoglobin A1c (HbA1c) in blood at Visit 4 
 
Apolipoprotein A1 (Apo A1) and apolipoprotein B (Apo B) in serum at Visit 4 
 
Soluble inter-cellular adhesion molecule-1 (sICAM-1) in serum on Day 6, at Visit 2, 
Visit 3, and Visit 4 
 
White blood cell (WBC) and platelet counts in blood on Day 6, at Visit 2, Visit 3, and 
Visit 4 
 
11-dehydro-thromboxane B2 (11-DTX-B2) in 24-hour urine on Day 5, at Visit 2, Visit 
3, and Visit 4 (expressed as concentration adjusted for creatinine) 
 
Body weight and waist circumference at Visit 4 
7. To evaluate the changes in levels of selected clinical risk endpoints related to oxidative 
stress over the entire exposure period in smokers switching from CC to CHTP 1.2 as 
compared to smokers continuing to use CC 
Endpoints (Day 5 to Visit 4): 
 
Epi-prostaglandin F2α (8-epi-PGF2α) in 24-hour urine on Day 5, at Visit 2, Visit 3, 
and Visit 4 (expressed as concentration adjusted for creatinine) 
 
Ratio 8-epi-prostaglandin F2α (8-epi-PGF2α) to prostaglandin F2α (PGF2α) in plasma 
on Day 5 and at  Visit 4 

Philip Morris Products SA 
Clinical Study Protocol 
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P2R-REXA-07-EU  
FINAL VERSION 5.0 / 05 December 2016 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
8-Hydroxy-2’-deoxyguanosine (8-OHdG) in 24-hour urine on Day 5, at Visit 2, Visit 3, 
and Visit 4 (expressed as concentration adjusted for creatinine) 
 
4-Hydroxy-2-nonenal (4-HNE) in serum on Day 5 and at Visit 4 a 
 
Total anti-oxidant capacity (TAC) in serum on Day 5 and at Visit 4 
a 
Samples for 4-HNE analysis have been collected but will not be analyzed due to the failure to develop a 
selective and quantitative assay. 
8. To describe the change in cytochrome P450 1A2 (CYP1A2) enzymatic activity in smokers 
switching from CC to the CHTP 1.2 as compared to smokers continuing to use CC 
Endpoint (Day 5 and Visit 4): 
 Molar metabolic ratio of paraxanthine/caffeine in plasma 
9. To monitor the safety profiles associated with CHTP 1.2 and CC during the study 
Endpoints: 
 
Adverse events (AEs) / serious adverse events (SAEs) and incidence of CHTP 1.2 
malfunctions and misuse, 
 
 
Vital signs 
 
Electrocardiogram (ECG) 
 
Clinical chemistry, hematology, and urine analysis safety panel 
 
Physical examination 
 
Concomitant medications 
3.3 
Exploratory Objectives and Endpoints 
The exploratory objectives of this study are: 
1. To describe the following parameters in smokers switching from CC to CHTP 1.2 as 
compared to smokers continuing to use CC 
 
Excretion of mutagenic material in 24-hour urine: Ames mutagenicity test 
(YG1024+S9):  Day 5 and Visit 4 
 
Subjective effects of smoking: 
 
Questionnaire of Smoking Urges (QSU), (brief version): Day 1 to Visit 4 
 
Fagerström Test for Nicotine Dependence (FTND), (revised version): Visit 4 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXA-07-EU  
FINAL VERSION 5.0 / 05 December 2016 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
Product evaluation: Modified Cigarette Evaluation Questionnaire (MCEQ): Day 1 
to Visit 4 
 
Cytochrome P450 2A6 (CYP2A6) enzymatic activity: the molar metabolic ratio of 
trans-3’-hydroxycotinine/cotinine: Day 6 and Visit 4 
 
Intent to Use of CHTP 1.2: 
 
Intent to Use of CHTP 1.2 Questionnaire (ITUQ): only in smokers switching from 
CC to CHTP 1.2: Day 6, and Visit 4 
2. To describe the CHTP 1.2 use over the entire exposure period according to the product 
preference of the subject 
Endpoint (daily): 
 
Number of CC or CHTP 1.2 used daily as reported on the usage log during the 
confinement period and self-reported number of any nicotine/tobacco product use on a 
daily basis as reported on the product use diary during the ambulatory period according 
to product preference 
3. To assess the smokers’ mental state for the intention to quit 
Endpoint (Visit 4): 
 
Prochaska “Stage of Change” Questionnaire 
4. To monitor BoExp and clinical risk endpoints in subjects who attempt to quit using tobacco 
products according to the time since they quit b 
Endpoints: 
 
BoExp: MHBMA, S-PMA, 3-HPMA, COHb, and total NNAL 
 
CO (expressed as ppm) in exhaled breath 
 
Selected clinical risk endpoints (hs-CRP, homocysteine, blood glucose, LDL, HDL, 
TG, TC, fibrinogen, HbA1c, sICAM-1, WBC, platelet count, Apo A1, Apo B, 
11-DTX-B2, and clinical risk endpoints related to oxidative stress) in respective body 
matrix 
b 
The reporting of the objective will be the subject of an appendix to the main clinical study report. 

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Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXA-07-EU  
FINAL VERSION 5.0 / 05 December 2016 
Page 46 of 166 
 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
The Screening Period (from Day -45 until Admission on Day -3): 
The Screening Period covers 6 weeks prior to Admission to the site. A demonstration of 
CHTP 1.2 (without product use) will be done by the site collaborators during the Screening 
Visit. At the Screening Visit, spirometry needs to be done at least 1 hour after having 
stopped smoking. Use of any tobacco/nicotine containing product other than CC will not 
be allowed after the Screening Visit. At the end of the Screening Visit, subject will be 
instructed not to smoke in the morning prior to the admission to the site on the Admission 
Day. 
 
The Admission Day (from Admission on Day -3 until 06:29 AM of Day -2): 
Subjects will be in a confinement setting for 9 days from Day -3 onwards. 
On Day -3 (Admission), after all inclusion/exclusion criteria are checked, all eligible 
subjects will be enrolled and then perform a product test using up 5 CHTPs 1.2. However, 
before smoking and the product testing, the sample for CYP2A6 activity has to be taken. 
After the product test, subjects not willing and ready to use the CHTP 1.2 will be 
discontinued. All subjects that are not enrolled are considered as screen failures. After the 
sample for CYP2A6 activity has been taken, and the product test has been performed, 
smokers will be allowed to smoke their single preferred brand of CC ad libitum until 11.00 
PM. Use of any tobacco/nicotine containing product other than CC and CHTP 1.2 for the 
product test will not be allowed after Admission. 
 
The Baseline Period (from Day -2, 06:30 AM until Day 1, 06:29 AM): 
All subjects will continue smoking their CC ad libitum. Twenty four-hour urine collection 
for Day -2 will start in the morning of Day -2 ending in the morning of Day -1. Twenty 
four-hour urine collection for Day -1 will start in the morning of Day -1 ending in the 
morning of the Day 1. On Day -2 and Day -1, smoking will be allowed from 06:30 AM 
until around 11:00 PM. However, on Day -2, smoking will be allowed only after the Cough 
Questionnaire has been completed. 
On Day -1, subjects will be randomized to 1 of the 2 study arms in a 2:1 ratio using a 
stratified randomization. 
 
CHTP 1.2 arm: ~80 subjects, ad libitum use of CHTP 1.2. 
 
CC arm: ~40 subjects, ad libitum use of their own preferred CC brand. 
Subjects will be informed about their randomized study arm by the study site staff on Day 1 
prior to 06:30 AM. Subjects who do not complete the study after randomization will not 
be replaced. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXA-07-EU  
FINAL VERSION 5.0 / 05 December 2016 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
The Exposure Period (from Day 1, 06:30 AM until Discharge at Visit 4): 
The exposure period will include both the exposure period in confinement, and the exposure 
period in the ambulatory setting: 
 
The Exposure Period in the Confinement Setting (from Day 1, 06:30 AM until the time 
of Discharge on Day 6): 
The exposure period in confinement consists of 5 days of ad libitum use of the assigned 
product (CHTP 1.2 or CC, exclusively) from 06:30 AM until around 11:00 PM each 
day. Subjects who are willing to attempt quitting using any tobacco products during the 
study will be encouraged to do so and will be referred to a smoking cessation aid 
service. 
Use of any tobacco/nicotine containing product other than the assigned product will not 
be allowed and may, at the discretion of the Investigator, result in the subject’s 
discontinuation from the study. 
24-hour urine will be collected from Day 1 to Day 5 on site ending in the morning of 
Day 6. On Day 1, product use must not start prior to the end of urine collection of 
Day -1. The end of the 24-hour urine collection period for Day 5 will end in the morning 
of Day 6 prior to Discharge. 
Procedures on Day 6 will be conducted before discharge of the subject from the clinic 
after 9 days in a confined setting. Use of products will be allowed on Day 6 according 
to product allocation, but only after the sample for CYP2A6 activity has been taken, the 
cough assessment has been completed, and spirometry has been performed.  
Subjects will be instructed to continue their assigned product/regimen in an ambulatory 
setting for 85 days. 
 
The Exposure Period in the Ambulatory Setting (from Discharge on Day 6 until 
Discharge at Visit 4): 
At the end of the confinement period prior to Discharge on Day 6, subjects will be 
instructed to continue their assigned product/regimen in an ambulatory setting for 85 
days. 
Subjects will be required to make three visits (Visit 2, Visit 3 and Visit 4) to the 
investigational site. Each visit will cover 2 consecutive days on site. For Visit 2 and 
Visit 3, the subject will check-in in the morning on the first day of the respective visit 
and will check-out on the second day of the visit. For Visit 4, the subject will check-in 
in the morning on the first day of the visit, and will be discharged on the second day of 
the visit after having performed all the safety examination procedures. 

Philip Morris Products SA 
Clinical Study Protocol 
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FINAL VERSION 5.0 / 05 December 2016 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Twenty four-hour urine will be collected at each ambulatory visit (Visit 2, Visit 3, and 
Visit 4) at the site. The collection of 24-hour urine will start on the first day of the 
respective visits and will end 24 hours later on the following day. On the first day of 
Visit 2, Visit 3, and Visit 4, subjects in the CHTP 1.2 and CC arms will be allowed to 
use their assigned product from the time of check-in until 11:00 PM. On the second day 
of Visit 2 and Visit 3 product use will be allowed from 06:30 AM onwards. The 
exposure period to the assigned IP will end at 11:00 PM on the first day of Visit 4.  
On the second day of Visit 4 (Day 91), subjects who wish to smoke CC or use other 
nicotine/tobacco-containing products will be allowed to do so, but only after the end of 
24-hour urine collection and after spirometry and sampling for CYP2A6 activity have 
been performed. 
During the visits, the dispense and use of CHTP 1.2 will be strictly forbidden for 
subjects in the CC arm. 
Subject will not be discontinued from the study for the use of nicotine/tobacco 
containing products other than the assigned product/regimen during the ambulatory 
period. Subjects will record in a product use diary any use of CC (menthol or non-
menthol), Nicotine replacement therapy (NRT), or other nicotine/tobacco-containing 
products on a daily basis. 
During the confinement and ambulatory settings: 
 
Any subject, who wants to attempt to quit using any tobacco products during the study 
taking into account the outcome from the Prochaska “Stages of Change” Questionnaire, 
will be encouraged to do so and will be referred to appropriate medical services. This 
will not affect subject’s financial compensation and the subject will remain in the study. 
 
The Safety Follow-up Period (from Discharge at Visit 4 until the end of the Safety Follow-
up Period): 
After Discharge at Visit 4 or the date of early termination, subject will enter a 28-day Safety 
Follow-up Period during which there will be recording of spontaneously reported new 
AEs/SAEs and the active follow-up of ongoing AEs/SAEs by the study site. In general, all 
AEs will be followed-up until resolved, stabilized (i.e., no worsening of the event), or a 
plausible explanation for the event has been found until the end of the study. At the end of 
the Safety Follow-up Period, all ongoing AEs will be documented as “ongoing” and will 
not be followed-up by the Investigator. At the discretion of the Investigator, the subject will 
be referred to his General Practitioner for follow-up on ongoing AEs. 

Philip Morris Products SA 
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FINAL VERSION 5.0 / 05 December 2016 
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without the written consent of Philip Morris Products S.A. 
AEs with onset after the end of the Safety Follow-Up Period and considered related to the 
IP might be reported to the Sponsor. Such AEs may not be part of the study report. 
SAEs spontaneously reported to the PI after the end of the Safety Follow-Up Period and 
considered related to the IP must also be reported to the Sponsor. Such SAEs may not be 
part of the study. 
The individual end of study (EOS) date for a subject is defined as either the Discharge at 
Visit 4 or the date of early termination followed by the 28-day Safety Follow-up Period. 
The EOS of the entire study is the last individual EOS time point during the study. 
4.2 
Rationale for Study Design 
This clinical study aims to demonstrate the reduction of BoExp to selected HPHCs in smokers 
switching from CC to CHTP 1.2, a candidate RRP. The comparator in this study will be CC. 
The exposure period in confinement will provide information on exposure reductions 
achieveable in a well-controlled environment with full control on daily CHTP 1.2/CC 
consumption. The exposure period in the ambulatory setting will provide information on 
reduction of BoExp to selected HPHCs and related changes in selected clinical risk endpoints 
and functional endpoints when CHTP 1.2 is used in a real world setting. The choice of HPHCs 
to be assessed in this study is derived from the WHO [11] and the draft guidance on “Reporting 
Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke” [12]. 
In the WHO list, 9 HPHCs (acrolein, CO, 1-3 butadiene, benzene, NNN, NNK, acetaldehyde, 
benzo[a]pyrene, and formaldehyde) with evidence of carcinogenicity, respiratory, and cardiac 
toxicity were recommended to be measured as priority in the smoke chemistry for mandated 
lowering [11]. Exposure to 5 HPHCs (acrolein, CO, 1,3-butadiene, benzene, and NNK) among 
these 9 priority HPHCs will be assessed by measuring their respective BoExp as primary 
endpoints. 
The BoExp for acrolein, CO, 1,3-butadiene, and benzene will be tested after 5 days of exclusive 
use of CHTP 1.2 and CC. The following characteristics apply to these selected BoExp: 
 
They are several-fold higher in smokers than in smokers abstinent from smoking [13]. 
 
They exhibit, on average, an elimination half-life (t1/2) of ≤ 24-hours. Therefore, the 5 days 
of exposure are sufficient to reach the steady state with CHTP 1.2. 
 
They were decreased in smokers who switched to an earlier prototype of CHTP 1.2 for 5 
days, similarly to that observed in smokers who stopped smoking (data on file from a 
previous study with the ClinicalTrials.gov Identifier: NCT00812279). 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
The BoExp for NNK, i.e., total NNAL was selected as primary endpoint after 90 days of 
exposure to CHTP 1.2 and CC because: 
 This BoExp is tobacco specific [14], and exhibits, on average, an elimination half-life of 
10 to 15 days. Therefore, the 90 days of exposure are sufficient to reach the steady state 
with CHTP 1.2 and CC (4 to 5 times the half-life will lead to less than 5% of the original 
exposure levels after 90 days). 
In addition to the 9 mandated lowering HPHCs recommended to be measured by WHO list, 
the FDA has listed 9 additional HPHCs for reporting to FDA (in total 18 HPHCs in cigarette 
smoke) [12]. From the WHO and FDA list, exposure to additional 9 HPHCs (acrylonitrile, 4-
ABP, 1-NA, 2-NA, benzo[a]pyrene, crotonaldehyde, NNK, NNN, and toluene) will be 
assessed by measuring the respective BoExp as secondary endpoints over the entire exposure 
period of exclusive use of CHTP 1.2 and CC. 
Although the systemic responses to exposure to HPHCs in the cigarette smoke often result in 
elevation of the corresponding BoExp levels, the role of individual smoke constituents and 
their related BoExp on the development of smoking-related diseases has not been fully 
understood [15]. The missing link to a better understanding of elevated BoExp levels might be 
found if any association between elevated BoExp levels and changes in clinical risk endpoints, 
functional endpoints, and/or the pathogenesis of smoking related diseases could be shown. 
Recently, it has been shown that several of the low-grade systemic clinical risk endpoints of 
oxidative stress and inflammation are positively correlated with BoExp such as COHb, 3-
HPMA, NEQ, and total NNAL after exposure to the HPHCs in the cigarette smoke in adult 
cigarette smokers [15]. 
Oxidative stress and inflammation are pathophysiological networks related to various smoking 
related diseases such as arteriosclerosis, hypertension [16], chronic inflammatory lung diseases 
such as asthma and chronic obstructive pulmonary disease (COPD) [17, 18]. 
There is evidence indicating that smoking enhances oxidative stress, not only through the 
production of reactive oxygene species (ROS) in smoke but also through weakening of the 
adequate counterbalancing antioxidant defense systems pushing and sustaining the 
pathogenetic pair of oxidative stress and inflammation [19]. 
The following biomarkers of oxidative stress have been selected in order to evaluate the extent 
of oxidative stress in the CHTP 1.2 arm as compared to the CC arm: 
 
8-Hydroxy-2’-deoxyguanosine (8-OHdG) 
Deoxyguanosine is one of the constituents of the deoxyribonucleic acid (DNA). Under 
conditions of oxidative stress, it is oxidized and converted to 8-OHdG. Urinary 8-OHdG is 
a biomarker of generalized cellular oxidative stress reflecting the result of DNA lesions 

Philip Morris Products SA 
Clinical Study Protocol 
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FINAL VERSION 5.0 / 05 December 2016 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
[20]. It has been shown that levels of 8-OHdG are increased in smokers [21], and 8-OHdG 
excretion declined upon smoking cessation [22]. 
 The ratio of 8-epi-prostaglandin F2α (8-epi-PGF2α; oxidized form of prostaglandin F2α) 
to prostaglandin F2α (PGF2α; non-oxidized form of prostaglandin F2α). 
8-epi-PGF2α and PGF2α are prostaglandin-like compounds, known as isoprostanes, and 
are formed from the peroxidation of arachidonic acid, an ubiquitous polyunsaturated fatty 
acid, in membrane phospholipids [23]. The biosynthesis of 8-epi-PGF2α in humans occurs 
via excessive chemical lipid peroxidation (> 99%), and in a very small part, via enzymatic 
lipid peroxidation by prostaglandin-endoperoxide synthases. Using the ratio of 8-epi-
PGF2α to PGF2α can help to distinguish biomarker synthesis pathways and thus to confirm 
the potential change in oxidative stress [24].  
 4-Hydroxy-2-nonenal (4-HNE). 
Oxidative degradation of polyunsaturated fatty acids (PUFAs) occurs under conditions of 
oxidative stress when the cellular antioxidant defense mechanisms are overwhelmed 
leading to the formation of electrophilic lipid peroxidation products such as 4-HNE. Study 
results reported in the literature show that levels of 4-HNE are elevated in smokers and 
decrease significantly following smoking cessation [25]. 
 Total anti-oxidant capacity (TAC). 
Decreased total anti-oxidant capacity is indicative of conditions associated with oxidative 
stress or increased susceptibility to oxidative damage [26]. The combined activity of all the 
compounds in biological fluids with chain breaking antioxidant activity, excluding the 
contribution of antioxidant enzymes and metal binding proteins, will be assessed in a TAC 
assay. It has been reported in several studies that the assay of TAC is able to discriminate 
smoking status and demonstrates reversibility upon smoking cessation [27]. 
Cytochrome P450 1A2 activity, which is well known to be increased by smoking and to be 
decreased upon smoking abstinence (SA), will be measured in this study to evaluate the effect 
of CHTP 1.2 use on the activity of this enzyme [28]. Cytochrome P450 2A6 activity, the 
enzyme involved in nicotine metabolism, will be assessed in this study to evaluate if the use 
of CHTP 1.2 impacts the activity of this enzyme. 
Some clinical risk endpoints and functional endpoints have been selected in order to evaluate 
biological changes in the CHTP 1.2 arm as compared to the CC arm. Among the ones selected, 
some are well-known to be affected by smoking and to be reversible upon SA as follows: 
 
11-DTX-B2 (a major stable metabolite of thromboxane A2, which elicits mainly platelet 
aggregation) was decreased after 1 week of SA [29] and after 5 days of use of another 
candidate MRTP [30]. 

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without the written consent of Philip Morris Products S.A. 
 
Blood pressure, hs-CRP, fibrinogen, homocysteine, fasting blood glucose, LDL, HDL, TG, 
TC, hemoglobin A1c (HbA1c), waist circumference, sICAM-1, WBC count, Apo A1, Apo 
B, and 8-epi-PGF2α will be evaluated as risk markers [31, 32] for cardiovascular 
monitoring purposes. According to the literature, some of these clinical risk endpoints are 
known to be sensitive to smoking cessation: the levels of HDL increase when the levels of 
sICAM-1, WBC count, and 8-epi-PGF2α decrease following 1 to 3 months of smoking 
cessation [31, 33]. 
 
Body weight as a mean increase of 4.5 kg is observed after 12 months of smoking 
abstinence with the most weight gain occurring within the first 3 months of quitting [34]. 
 
Lung function including forced expiratory volume in 1 second (FEV1), force vital capacity 
(FVC), maximum expiratory flow (25-75), and respiratory symptoms such as cough will 
be assessed in this study, as it has been shown that some of these parameters may be 
improved and are markers correlating with early but still reversible changes occurring in 
distal airway upon smoking [35, 36]. 
Among others, clinical risk endpoints such as 8-epi-PGF2α, 11-DTX-B2, WBC, hs-CRP, 
fibrinogen, have been found related, i.e., to coronary atherosclerosis [15]. 
Other parameters such as product evaluation, and subjective effects related to smoking 
including smoking urges and withdrawal symptoms, and the intent to use, will be evaluated. 
Twenty-four hour-urine collection conducted in this study is the standard method to measure 
the levels of excretion of BoExp. 
As part of the characterization of the study population it is important to measure variables that 
have been shown to be related to nicotine dependence and product reinforcing value. Based on 
prior tobacco research these factors include age, gender, ethnicity, educational and socio-
economic status, tobacco use history, expectations of the effects of the products tested, nicotine 
exposure. In order to capture, these data, subjects will be asked questions about their socio-
economic status on Day 4. Such data would allow comparing populations across studies. 
All subjects will be asked to buy their own CC according to their anticipated needs for the 
study in order to minimize any changes in their smoking behavior. 
4.3 
Appropriateness of Measurements 
The HPHCs and their respective BoExp measured in this study were selected based on the 
following criteria: 
 
HPHCs to be assessed in this study are derived from the list of HPHCs recommended for 
lowering in cigarette smoke as defined by the WHO [11] and the draft guidance on 

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hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
”Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and 
Tobacco Smoke” [12] 
 
The HPHC should be specific to the source of exposure with other sources being minor or 
non-existent 
 
The BoExp to an HPHC should be easily detectable using validated, reliable, reproducible, 
precise analytical methods 
 
The HPHC should reflect a specific toxic exposure or be a reliable surrogate of exposure 
to HPHCs 
 
The list of HPHCs should include HPHCs from both gas and particulate phase 
 
The list of HPHCs should include a broad variety of chemical classes and organ toxicity 
classes (carcinogen, cardiovascular toxicant, respiratory toxicant, reproductive and 
development toxicant, addiction potential) and 
 
BoExp represent HPHCs formed at different temperature levels 
All questionnaires used for this study, except the Cough-VAS Questionnaire, are available as 
validated questionnaires or linguistically validated questionnaires. 
4.4 
Study Duration 
The entire study duration per subject will be 128 to 169 days, including a Screening Period of 
up to 42 days prior to Admission on Day -3, a 9-day confinement setting (Day -3 to Discharge 
on Day 6) followed by a 85-day ambulatory setting (from Discharge on Day 6 to Discharge at 
Visit 4), and a 28-day Safety Follow-up Period. The EOS of the entire study is the last 
individual EOS time point during the study. 

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5 
STUDY POPULATION 
120 smoking healthy Caucasian female or male subjects who has smoked at least 10 non-
menthol CCs per day for the last 6 weeks prior to Admission will be included in this study. 
Each sex and each of the smoking strata (smoking 10 to 19 CC/day vs. > 19 CC/day) will have 
a quota applied to ensure that they represent at least 40% of the study population. 
The maximum number of CC smoked daily is not limited. Subjects must have been smoking 
for at least 10 years of smoking prior to the Screening Visit. There will be no brand restrictions 
of non-menthol CC.  Smoking status will be verified with a urinary cotinine test (cotinine ≥200 
ng/mL).  
5.1 
Inclusion Criteria 
Subjects who meet all the following inclusion criteria can be enrolled into the study: 
Inclusion Criteria 
Rationale 
Screening Admission 
(Day -3) 
1. Subject has signed the ICF and is able to 
understand the information provided in the ICF. 
Administrative 
X 
 
2. Subject is aged ≥ 28 years. 
Safety 
X 
 
3. Subject is of Caucasian origin. 
Effect 
X 
 
4. Currently smoking, healthy subject as judged by 
the 
Investigator 
or 
designee 
based 
on 
assessments from the Screening Period (e.g., 
safety laboratory, spirometry, vital signs, physical 
examination, ECG, medical history, and X-ray). 
Safety 
X 
X 
5. Subject smokes at least 10 commercially 
available non-menthol CCs per day (no brand 
restrictions) with a maximum yield of 1 mg nicotine 
ISO/CC, as labelled on the cigarette package, at 
least for the last 6 weeks prior to the Screening 
Visit and Admission, respectively, based on self-
reporting. The smoking status will be verified 
based on a urinary cotinine test (cotinine ≥ 200 
ng/mL). 
Effect 
X 
X 
6. The subject has been smoking at least for the last 
10 years. 
Effect 
X 
X 

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Inclusion Criteria 
Rationale 
Screening Admission 
(Day -3) 
7. The subject does not plan to quit smoking in the 
next 6 months as assessed by Prochaska “Stage 
of Change” Questionnaire. 
Safety 
X 
 
8. The subject is ready to comply with the study 
protocol (e.g., to use CHTP 1.2). 
Effect 
X 
X 
5.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the study: 
Exclusion Criteria 
Rationale 
Screening 
Admission 
(Day -3) 
1. As per the 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. The subject is legally incompetent, physically 
or mentally incapable of giving consent (e.g., 
emergency situation, under guardianship, in a 
social or sanitary establishment, prisoner or 
involuntarily incarcerated). 
Administrative 
X 
 
3. Clinically significant gastrointestinal, renal, 
hepatic, 
neurological, 
hematological, 
endocrine, oncological, urological, pulmonary, 
immunological, psychiatric or cardiovascular 
disorders or any other conditions that in the 
opinion of the investigators would jeopardize 
the safety of the participant or affect the validity 
of the study results. 
Safety 
X 
 
4. Abnormal findings on physical examination, in 
the medical history, or in clinical laboratory test 
results assessed as Grade 2 and deemed 
clinically significant by investigators or Grade 3 
and higher (as per the Common Terminology 
Criteria for Adverse Events [CTCAE]). 
Safety 
X 
X 
5. The subject has (FEV1/FVC) < 0.7 and FEV1 < 
80% 
of 
the 
predicted 
value 
at 
post-
bronchodilator spirometry. 
Safety 
X 
 

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Exclusion Criteria 
Rationale 
Screening 
Admission 
(Day -3) 
6. The subject has (FEV1/FVC) < 0.75 (post-
bronchodilator) and reversibility in FEV1 (that is 
both > 12% and > 200 mL from pre- to post-
bronchodilator values). 
Safety 
X 
 
7. The subject has a body mass index (BMI) < 
18.5 or ≥ 32 kg/m2. 
Safety 
X 
 
8. As per the Investigator’s or designee’s 
judgment, the subject has medical conditions 
which require or will require in the course of the 
study, a medical intervention (e.g., start of 
treatment, surgery, hospitalization) which may 
interfere with the study participation and/or 
study results. 
Effect 
X 
X 
9. The subject has used nicotine-containing 
products other than commercially available CC 
(either tobacco-based products or nicotine 
replacement therapies), as well as electronic 
cigarettes and similar devices after the 
Screening Visit, i.e., within 6 weeks prior to 
Admission. 
Effect 
 
X 
10. The 
subject 
has 
received 
medication 
(prescription or over-the-counter) in Table 3 
(except for vitamins) within 14 days or within 5 
half-lives of the drug (whichever is longer) prior 
to Admission (Day -3) which has an impact on 
CYP1A2 or CYP2A6 activity. 
Effect 
 
X 
11. The subject has a positive alcohol test and/or 
the subject has a history of alcohol abuse that 
could interfere with the subject ’s participation 
in the study. 
Administrative 
X 
X 
12. The subject has a positive urine drug test. 
Administrative 
X 
X 
13.The subject has positive serology test for 
human immunodeficiency virus (HIV) 1/2, 
hepatitis B or hepatitis C. 
Safety  
X 
 
14.The subject has donated or received whole 
blood or blood products within 3 months prior to 
Admission. 
Safety 
 
X 

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Exclusion Criteria 
Rationale 
Screening 
Admission 
(Day -3) 
15. The subject is a current or former employee of 
the tobacco industry or their first-degree 
relatives (parent, sibling, child). 
Administrative 
X 
 
16. The 
subject 
is 
an 
employee 
of 
the 
investigational site or any other parties 
involved in the study or their first-degree 
relatives (parent, sibling and child). 
Administrative 
X 
 
17. The subject has participated in a clinical study 
within 3 months prior to the Screening Visit. 
Safety 
X 
 
18. The subject has been previously screened in 
this study. 
Administrative 
X 
 
19. For women only: 
Subject is pregnant (does have positive 
pregnancy tests at the Screening or at 
Admission) or is breast feeding. 
Safety 
X 
X 
20. For women only: 
Subject does not agree to use an acceptable 
method of effective contraception.* 
Safety 
X 
X 
* Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with spermicidal 
foam/gel/film/suppository, hormonal contraception, vasectomized partner(s), or true abstinence (periodic abstinence and 
withdrawal are not effective methods) from Screening until the end of the Safety Follow-up Period. Hysterectomy, tubal 
ligation, bilateral oophorectomy or post-menopausal status are reasons for not needing to use birth control. Post-menopausal 
status is defined as women who have not experienced menses for greater than 12 months. If a woman claims she’s post-
menopausal, but has had her menses within 12 months, a follicle stimulating hormone test must be performed and must be 
within acceptable limits. 
5.3 
Discontinuation of Subjects from the Study 
Discontinued subjects (i.e., enrolled subjects that do not complete the study) will include both 
subjects who withdraw from the study (subject’s decision) or subjects who are discontinued 
from the study by the decision of the Investigator. 
Subjects will be informed that they are free to withdraw from the study at any time. Subjects 
should be questioned for the reason of withdrawal from the study, although they are not obliged 
to disclose it. 
If the subject withdraws from the study he/she will be asked to confirm at least the following 
points and this information will be fully documented by the PI or designee: 

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 
The subject agrees to undertake the early termination procedures for safety assessments as 
defined in section 9.5, unless the subject refuses to perform the assessments. 
 
If applicable, the subject still consents for long-term biobanking (3 ICFs). 
 
The subject agrees that the samples collected up to the time of withdrawal will be analyzed 
and data collected up to the time of withdrawal will be used in the analysis and report. If 
the subject refuses he/she needs to document his disagreement in writing. 
Subjects must be discontinued from the study for any of the following reasons: 
 
Withdrawal of informed consent 
 
Subject becomes an employee of the investigational site or any other parties involved in 
the study or their first-degree relatives (parent, sibling and child) 
 
Any AE or condition (including clinically significant changes in a laboratory parameter) 
which at the discretion of the Investigator no longer justifies the subject’s participation in 
this study 
 
Positive pregnancy test (section 8.5) 
 
The Sponsor or Investigator terminates the study or the study terminates at a particular site. 
If the Sponsor or the Investigator decides to prematurely terminate the study, the subject 
will be promptly informed. The Investigator or designee should report the fact and the 
reason in writing to the IEC 
 
Discontinuation is considered to be in the best interest of the subject or the other subjects 
as judged by the Investigator 
 
Subject unwilling to use the product during the entire study duration after having done the 
product test 
Subjects may be discontinued from the study for the following reason: 
 
Non-compliance to the study procedures based on the judgment of the Investigator 
 
Violation of eligibility criteria 
During the exposure ambulatory period, subject will not be discontinued from the study for the 
use of nicotine/tobacco containing products other than the assigned product/regimen during 
the ambulatory period. 
Until randomization, subjects can be replaced, however subjects that discontinue the study 
after randomization will not be replaced. 

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5.4 
Lost to Follow-up 
Reasonable number of attempts to contact the subject (including written correspondence and 
phone calls) should be done and documented in the source documents by the site. When the 
PIs or designee(s) declare(s) a subject is lost to follow-up, the lost to follow-up date will be 
recorded.The date of of lost to follow up corresponds to the date of the end of study of the 
subject.  
If the site has lost track of the subject but the subject has reached the maximum number of 
study days (Day 169), then the PI(s) or designee(s) will declare the subject lost to follow-up at 
this date.
5.5 
Violation of Selection Criteria 
Any subjects who do not meet the entry criteria after signing the ICF and prior to Enrolment 
on Day -3 will be considered as screen failures. Re-screening of subjects is not permitted. 

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6 
INVESTIGATIONAL PRODUCTS 
6.1 
Description of Investigational Products 
 
CHTP 1.2 
CHTP 1.2 is a non-menthol tobacco stick which is comparable in shape and form, and is used 
in a similar manner to CC. To use CHTP 1.2, the consumer removes the protective cap and 
uses a conventional lighting method to ignite the heat source. After a short pause to allow the 
tobacco to become heated, the aerosol is generated by drawing air through CHTP 1.2. During 
use, the tobacco in CHTP 1.2 is heated and does not exceed a well-defined temperature profile 
which ensures heating without combustion of the tobacco and at the same time provides an 
acceptable consumer experience in a consistent manner. 
CHTP 1.2 will be provided by the Sponsor and its distribution will be limited to an 
appropriately trained study site collaborator. Additional information are provided in section 
2.1.2. 
The overall objective of CHTP 1.2 is to substantially reduce the exposure to HPHCs and 
provide an acceptable alternative and product use experience in comparison with CC. 
 
CC 
Commercially available non-menthol CC (no brand restrictions) with a maximum yield of 
1 mg nicotine ISO/CC, as labelled on the cigarette package, will be used. CC will not be 
provided by the Sponsor. 
All eligible subjects will be asked to purchase their own preferred single-brand of non-menthol 
CC prior to Admission. As randomization takes place at any time on Day -1, every study 
subject needs to buy his/her anticipated amount of CC for a total of 9 days plus 2 extra packs. 
6.2 
Packaging and Labeling 
At Admission, all study subjects will provide the anticipated amount of CC in sealed packs to 
the site collaborators. The CC packs provided by the subjects should not be opened and the 
cellophane 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 of the lower part of the pack). 
For CHTP 1.2, the packs and cartons will be labeled “for investigational use only” and 
according to any additional local regulatory requirements. 

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6.3 
Use of Investigational Product(s) 
Subjects will never be requested or forced to smoke or to use the CHTP 1.2 and will be free to 
stop smoking at any time during the study. The study is designed as an ad libitum use study. 
During the Screening Period, subjects will be allowed to smoke according to their smoking 
habits except during the procedures of the Screening Visit (section 9.1) At the end of the 
Screening Visit, subjects will be instructed not to smoke in the morning prior to Admission on 
Day -3. 
6.3.1 
Admission Day (Day -3) 
After Enrolment, all subjects will undergo a CHTP 1.2 product test. However, before smoking 
and the product testing, the sample for CYP2A6 activity has to be taken. If subject is not willing 
and ready to use CHTP 1.2 after the product test, he/she will be discontinued from the study 
and undergo early termination procedures, followed by a 28-day Safety Follow-up Period.  
After the sample for CYP2A6 activity has been taken, and the product test has been performed, 
smoking ad libitum will be allowed throughout the day until 11.00 PM. All subjects will be 
allowed to continue smoking ad libitum their single preferred brand of usual CC. 
6.3.2 
Baseline Period (Day -2 to Day 1) 
During the Baseline Period, all subjects will be allowed to continue smoking ad libitum their 
single preferred brand of non-menthol CC. 
6.3.3 
Exposure Period in Confinement (from Day 1 until the Discharge on Day 6) 
Subjects will not be allowed to use any nicotine/tobacco-containing products other than their 
assigned product. 
 
CHTP 1.2 arm 
Subjects randomized to the CHTP 1.2 arm will use exclusively CHTP 1.2 from Day 1, 
06:30 AM onwards until the time of Discharge on Day 6. 
 
CC arm 
Subjects randomized to the CC arm will continue smoking their CC from Day 1, 06:30 AM 
onwards until until the time of Discharge on Day 6. 
At the end of the confinement period prior to Discharge, subjects will be instructed to continue 
their assigned product/regimen in an ambulatory setting for 85 days. 

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6.3.4 
Exposure Period in the Ambulatory Setting (from Discharge on Day 6 until 
Discharge at Visit 4) 
On the first day of Visit 2, Visit 3, and Visit 4, subjects in the CHTP 1.2 and CC arms will be 
allowed to use their assigned product from the time of check-in until around 11:00 PM. On the 
second day of Visit 2 and Visit 3 product use will be allowed from 06:30 AM onwards. The 
exposure period to the assigned IP will end at 11:00 PM on the first day of Visit 4.  
On the second day of Visit 4 (Day 91), subjects who wish to smoke CC or use other 
nicotine/tobacco-containing products will be allowed to do so, but only after the end of 24-
hour urine collection and after spirometry and sampling for CYP2A6 activity have been 
performed. 
During the ambulatory visits (Visit 2, Visit 3, Visit 4) the use of CHTP 1.2 will be strictly 
forbidden for subjects in the CC arm. 
Subject will not be discontinued from the study for the use of nicotine/tobacco containing 
products other than the assigned product/regimen during the ambulatory period. 
6.3.5 
Safety Follow-up Period (from Discharge at Visit 4 until End of the Safety 
Follow-up Period) 
During the Safety Follow-up Period all subjects are free to smoke their own CC ad libitum. 
6.3.6 
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. 
6.4 
Method for Assigning Subjects to Study Arms 
At the end of the Baseline period enrolled subjects will be randomized using an interactive 
web and voice response system (IxRS) on Day -1 at any time during the day. Subjects will be 
informed of their randomized study arm in the morning of Day 1, prior to 06:30 AM (the start 
of the exposure period). Subjects will be randomized to one of the 2 study arms: CHTP 1.2 or 
CC in a 2:1 ratio. 
Stratified randomization will be conducted by sex and by average daily CC consumption over 
the last 6 weeks prior to Admission as self-reported (smoking 10 to 19 CC/day vs. > 19 
CC/day). In each arm, each sex and each of the smoking strata will have a quota applied to 
ensure they represent at least 40% of the population. 

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6.5 
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 contract research organization (CRO) 
personnel will be blinded to the randomized arm as summarized in Table 2: 
Table 2 
Description of Blinded Study Personnel 
Blinded Study Personnel 
End of Blinding Period 
PMI and CRO Study Statisticians 
After the SAP finalization or the database lock a whichever 
comes last.  
PMI Data Manager 
After the finalization of PMI blind database review a. 
PMI Clinical Scientist 
After the finalization of PMI blind database review a.  
a 
Data will be accessible blinded to randomization arm and to product use by means of a dummy randomization 
or masking. 
As part of the PMI quality control (QC) activity, data listings will be reviewed by the CRO and PMI before 
database lock, with no access to the randomization information. Full details will be available in the data 
review plan. 
Any PMI and CRO personnel who are not listed in the above table will be unblinded by default. 
6.6 
Investigational Product Accountability and Compliance 
6.6.1 
Dispensing Investigational Product 
During the confinement period from Day -3 to Discharge at Day 6, CC, and from Day 1 
onwards to Discharge at Day 6, CHTP 1.2, will be dispensed to the subjects stick by stick. One 
will be allowed at a time and documented in an appropriate log. 
On each day of the confinement period, the time of dispense and return for each product 
(CC/CHTP 1.2) use has to be documented from Day -3 until Discharge at Day 6. 
During the ambulatory period, subjects in the CHTP 1.2 arm will be provided with CHTP 1.2. 
Up to two extra deliveries of CHTP 1.2 in between two visits, e.g., between Visit 2 and Visit 
3, will be carried out. Subjects in the CC arm will buy their CCs and will not be reimbursed. 
Subjects will have free access to their assigned product (CC or CHTP 1.2) during Visit 2, Visit 
3 and the first day of Visit 4 of the ambulatory period.  
On the second day of Visit 4 (Day 91), subjects who wish to smoke CC or use other 
nicotine/tobacco-containing products will be allowed to do so, but only after the end of 24-

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hour urine collection and after spirometry and sampling for CYP2A6 activity have been 
performed. 
CHTP 1.2 will not be promoted for commercial distribution or test market. 
6.6.2 
Storage and Accountability 
CHTP 1.2 and CC will be stored in a secured storage site with access limited to authorized 
personnel only. The study collaborator designated by the PI will be responsible for the storage 
and accountability of the IPs in accordance to Sponsor’s requirements. CHTP 1.2 must be 
stored under controlled conditions (temperature and humidity), whereas CCs can be stored in 
normal conditions (at ambient temperature with no temperature or humidity control). 
During the confinement period subjects will return each used CHTP 1.2 or butt of each used 
CC immediately after use to the site collaborators for accountability. The time of return of the 
products will be documented in an appropriate log. 
During the ambulatory period subjects will record daily product use in the product use diary 
and return any unused packs, empty packs and partially used packs of CHTP 1.2 to the site for 
accountability after check-in at the investigational site at Visit 2, Visit 3 and Visit 4.  
On the first day of Visit 4, after the collection and check of empty/partially used CHTP 1.2 
packs for accountability, partially used packs will be returned and/or new packs will be handed 
out to the subjects, if requested, for use until 11:00 PM at the latest. All packs must be returned 
to study staff at the end of the first day of Visit 4.  
No IP accountability will be done for CC in the CC arm during the ambulatory period. 
Unused CCs given to the site collaborators at Admission will be given back to the subjects at 
Discharge on Day 6. 
6.6.3 
Investigational Product Retention 
Used and unused CHTP 1.2 will be destroyed or returned to the Sponsor upon study completion 
as per instructions which will be provided by the Sponsor in due time. 
6.6.4 
Adherence to Investigational Products 
During the confinement period, adherence to product allocation for both study arms will be 
ensured by strict distribution of the products (stick by stick) and collection of the CC butts and 
CHTP 1.2 after each use. Distribution and return of these products will be documented in 
appropriate logs. 

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During the ambulatory period, from Discharge on Day 6 until Discharge at Visit 4, subjects in 
both study arms will capture the number of the product used (e.g., menthol and non-menthol 
CC, CHTP 1.2, or any other tobacco /nicotine-containing products including nicotine 
replacement therapy [NRT]) in the product use diary on a daily basis. The product use diary 
will be supplied by Sponsor and distributed to the subjects by the study site collaborators. The 
data captured in the product use diary will serve as the method to assess adherence in both 
arms. On Day 6, the adherence to the assigned product will be ensured using both the 
accountability log (from 06:30 AM until Discharge) and the product use diary (in the subjects 
daily report of product use). In case of discrepancy between the log and the diary entries, the 
diary will be considered as the primary source data. 
6.7 
Restrictions 
6.7.1 
Smoking Restrictions 
6.7.1.1 
Screening Visit and Confinement Period 
At the Screening Visit pre- and post-bronchodilator spirometry will be done at least 1 hour 
after having stopped smoking. At the end of the Screening Visit, subjects will be instructed not 
to smoke in the morning prior to Admission on Day-3. On the Admission Day, smoking will 
be allowed only after the blood drawing for CYP2A6 activity has been taken, on Day -2, only 
after the Cough Questionnaire has been completed, and on the Day of Discharge (Day 6) only 
after twenty four-hour urine collection of Day 5 and the Cough Questionnaire have been 
completed, and the blood drawing for CYP2A6 activity assessment has been performed. 
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 CHTP 1.2 which will be dispensed by the site 
collaborators individually as described in section 6.6.1. 
To avoid cross smoke contamination between the two study arms, subjects must use their 
assigned product (CHTP 1.2 or CC) in separate smoking rooms. 
Using CHTP 1.2 or smoking CC will not be allowed during study procedures. 
6.7.1.2 
Ambulatory Period 
Subjects in the CHTP 1.2 arm will be instructed to exclusively use CHTP 1.2. 
On the first day of Visit 2, Visit 3, and Visit 4, subjects in the CHTP 1.2 and CC arms will be 
allowed to use their assigned product from the time of check-in until around 11:00 PM. On the 

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second day of Visit 2 and Visit 3 product use will be allowed from 06:30 AM onwards. The 
exposure period to the assigned IP will end at 11:00 PM on the first day of Visit 4. On the 
second day of Visit 4 (Day 91), subjects who wish to smoke CC or use other nicotine/tobacco-
containing products will be allowed to do so, but only after the end of 24-hour urine collection 
and after spirometry and sampling for CYP2A6 activity have been performed. 
During the ambulatory visits (Visit 2, Visit 3, Visit 4) the use of CHTP 1.2 will be strictly 
forbidden for subjects in the CC arm.  
6.7.2 
Dietary Restrictions 
6.7.2.1 
Confinement Period 
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. A 
“high-fat” diet is defined as a diet which contains “approximately 50 percent of total caloric 
content of the meal [from fat] and is high in calories (approximately 800 to 1000 calories)” 
[37]. 
In order to avoid any effect on assessment of biomarkers of exposure, grilled or pan-fried meat, 
pre-cooked meats (e.g. tuna, ham, corned beef, and smoked meats), bacon and sausage will not 
be permitted. In addition, alcohol, broccoli, brussels sprouts, cauliflower, grapefruit and 
xanthine-containing foods and beverages (coffee, tea, chocolate, cocoa, mate, guarana, etc.) 
will not be allowed except when the subject will be asked to drink a cup of coffee for one of 
the assessment of CYP1A2). 
Subjects will not be allowed to bring their own food (including sweets or chewing gum, etc.) 
or beverages to the investigational site. Meals will be served according to the agreed schedules. 
Additional light snacks, fruits (with the exception of grapefruits), and raw vegetables can be 
distributed to the subjects without restrictions at any time during confinement as long as they 
comply with the dietician’s standard diet. Consumption of non-carbonated water is allowed, 
however, should be carefully monitored. Consumption of quinine-containing drinks (e.g., tonic 
water) is not allowed during the study. The same menu and meal schedule will be administered 
uniformly for all subjects in both study arms. 
In addition, for the purpose of the Ames test planned on Day -1 and Day 5, the menus served 
on Day -2 and Day 4 will be identical. 
A fasting state has to be observed for at least 10 hours prior to blood drawings for: 
 
Safety laboratory on Day -1 and Day 6 
 
Clinical risk endpoints’ assessments in serum/plasma/blood on Day -1 and Day 6 

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 
Serum/plasma bio-banking samples for BoExp, clinical risk endpoints and other circulating 
proteins on Day -1 and Day 6 
 
Blood bio-banking for further transcriptomics, lipidomics and DNA methylation 
sequencing analyses on Day -1 and Day 6 
6.7.2.2 
Ambulatory Period 
The above dietary restrictions are not applicable for the ambulatory period. 
One day prior to Visit 2, Visit 3, Visit 4, and during the visit on site, subjects will be asked by 
the site staff to refrain from consuming grapefruit or grapefruit-containing products, or 
quinine-containing drinks (e.g., tonic water). Alcohol, broccoli, brussels sprouts, cauliflower, 
chargrilled meat, xanthine-containing foods and beverages (e.g., coffee, tea, chocolate, cocoa, 
mate, guarana) will not be allowed on site during Visit 4. 
A fasting state has to be observed for at least 10 hours prior to blood drawing for: 
 
Safety laboratory at Visit 2, Visit 3 and Visit 4 
 
Clinical risk endpoints’ assessments in serum/plasma/blood at Visit 2, Visit 3 and Visit 4 
 
Serum/plasma bio-banking samples for BoExp, clinical risk endpoints and other circulating 
proteins, at Visit 4 
 
Blood bio-banking for transcriptomics, lipidomics and DNA methylation sequencing 
analyses at Visit 4 
6.8 
Concomitant Medication 
For the purpose of this study, no concomitant medication should be taken by the subjects from 
Screening until the end of the Safety Follow-up Period without informing the PI or designee. 
However, the PI 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 medication and prior medications will first be assessed at the Screening Visit. To 
be eligible for the study, any medication with impact on CYP1A2 and CYP2A6 metabolism 
must be discontinued at least 14 days or for at least 5 half-lives (whichever is longer) prior to 
admission to the site. It is at the discretion of the Investigator or designee to assess if the 
termination of such medication at the Screening Visit is medically justified and safe for the 
subject. 
Any medication (except medication containing estrogen) with an impact on the CYP1A2 and 
CYP2A6 metabolism (as prescription and over-the-counter products) as presented below in 

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Table 3 must be avoided and must not be used during the entire study until the Discharge at 
Visit 4. Prior to database lock, concomitant medication will be reviewed according to their 
potential impact on CYP1A2 and CYP2A6 activity and assessed for their potential impact on 
the study results. 
Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid 
(including over-the counter products) is not allowed, as all of them could interfere with clinical 
risk endpoints such as 11-DTX-B2. Acetaminophen will be allowed at a daily total dose of up 
to 3000 mg. 
If the use of a concomitant medication cannot be avoided for the subject’s safety, it must be 
fully documented in the source document and transcribed into the case report form [CRF] (for 
details, see section 7.3.6). Concomitant medications should be followed up with the PI on an 
ongoing basis. 
Estrogens for contraception and for hormone replacement therapy, even though known to be 
CYP1A2 inhibitors, will be allowed in this study. The use of estrogens must be documented 
on the CRF. 
Supplemental antioxidant nutrients such as β-carotene, α-carotene, lycopene, lutein, 
zeaxanthin, β-cryptoxanthin, vitamin E (α-tocopherol, γ-tocopherol), vitamin C and selenium 
with an impact on the clinical risk enpoints to oxidative stress must be avoided and should not 
be used during the entire study until the Discharge at Visit 4. 
Table 3 
Examples of Medications with Effects on CYP1A2 and CYP2A6 
Activity 
CYP1A2 Inhibitors [38] 
Pharmacologic Category 
Amlodipine 
Antihypertensive; calcium channel blocker  
Cimetidine 
Histamine H2 antagonist 
Ciprofloxacin 
Antibiotic, fluoroquinolone 
Fluvoxamine 
Antidepressant, selective serotonin reuptake inhibitor 
Fospropofol 
General anesthetic 
Gemfibrozil 
Antilipemic agent, fibric acid 
Ketoconazole 
Antifungal agent, topical 
Diclofenac 
NSAID 
Methoxsalen 
Psoralen 
Mexiletine 
Antiarrhythmic agent 
Miconazole 
Antifungal agent, topical 

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CYP1A2 Inhibitors [38] 
Pharmacologic Category 
Nifedipine 
Antihypertensive, calcium channel blocker 
Norfloxacin 
Antibiotic, fluoroquinolone 
Propofol 
Systemic general anesthetic 
Primaquine 
Aminoquinoline (antimalarial) 
Ofloxacin 
Antibiotic, fluoroquinolone 
Thiabendazole 
Antihelmintic agent 
Tranylcypromine 
Antidepressant, monoamine oxidase inhibitor 
Zileuton 
5-lipoxygenase inhibitor 
CYP1A2 Inducers [38] 
Drug Class 
Carbamazepine 
Anticonvulsant 
Phenobarbital 
Anticonvulsant, barbiturate 
Primidone 
Anticonvulsant, barbiturate  
Rifampin 
Antibiotic, antitubercular agent 
CYP1A2 Substrates [38] 
Drug Class 
Acenocoumarol 
Anticoagulant 
Alosetron 
Antiemetic, selective 5-HT3 receptor antagonist 
Aminophylline 
Phosphodiesterase enzyme inhibitor, nonselective  
Betaxolol 
Antihypertensive, beta-blocker 
Caffeine 
Central nervous system stimulant, phosphodiesterase 
enzyme inhibitor 
Clomipramine 
Antidepressant, tricyclic  
Clozapine 
Antipsychotic agent 
Cyclobenzaprine 
Skeletal muscle relaxant 
Dacarbazine 
Antineoplastic agent, alkylating agent 
Duloxetine 
Antidepressant, serotonin/norepinephrine reuptake inhibitor 
Flutamide 
Antineoplastic agent, antiandrogen 
Fluvoxamine 
Antidepressant, selective serotonin reuptake inhibitor  
CYP1A2 Substrates [38] 
Drug Class 
Guanabenz 
Antihypertensive, central Alpha-2 adrenergic agonist  
Mexiletine 
Antiarrhythmic agent, class Ib 

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Mirtazapine 
Antidepressant, alpha-2 antagonist 
Olanzapine 
Antimanic agent, antipsychotic agent 
Pimozide 
Antipsychotic agent 
Propranolol 
Antihypertensive, beta-blocker  
Ramelteon 
Hypnotic 
Rasagiline 
Anti-Parkinson's agent, MAO type B inhibitor 
Riluzole 
Glutamate inhibitor 
Ropinirole 
Anti-Parkinson's agent, dopamine agonist 
Ropivacaine 
Local anaesthetic 
Tacrine 
Anti-Alzheimer agent, cholinesterase inhibitor 
Theophylline 
Phosphodiesterase enzyme inhibitor, nonselective 
Thiothixene 
Antipsychotic agent 
Tizanidine 
Alpha-2 adrenergic agonist 
Trifluoperazine 
Antipsychotic agent 
CYP2A6 Inhibitors [38] 
Drug Class 
Amiodarone 
Antiarrhythmic agent, class III 
Desipramine 
Antidepressant, tricyclic 
Isoniazid 
Antitubercular agent 
Ketoconazole 
Antifungal agent, topical 
Letrozole 
Antineoplastic agent, aromatase inhibitor 
Methoxsalen 
Psoralen 
Miconazole 
Antifungal agent, topical 
Tranylcypromine 
Antidepressant, monoamine oxidase inhibitor 
CYP2A6 Inducers [38] 
Drug Class 
Amobarbital 
Barbiturate 
Pentobarbital 
Anticonvulsant, barbiturate 
Phenobarbital 
Anticonvulsant, barbiturate  
Rifampin 
Antibiotic, antitubercular agent 
Secobarbital 
Barbiturate 
CYP2A6 Substrates [38] 
Drug Class 
Dexmedetomidine 
Alpha-2 adrenergic agonist, sedative 

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Ifosfamide 
Antineoplastic agent, alkylating agent 
The PI is responsible for the medical care of the subjects during their participation in this study. 
 
 

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7 
STUDY PROCEDURES 
Personnel performing or recording study assessments must have appropriate and fully 
documented training. Quality control (QC) measures have to be in place. An overview of all 
study assessments is shown in the schedule of events (Appendix A). 
7.1 
Informed Consent 
Prior any study assessments is performed, the subject will be asked to provide his/her written 
consent to participate to the study (ICF) (section 1.3). All assessments must start after ICF 
signature by the subject for study participation. 
In addition to the ICF for study participation, the subject will be asked to provide his/her 
separate consent for sample bio-banking (section 1.3.2). 
The subject’s participation in the study does not depend on his/her consent for sample bio-
banking and will be separated from the consent for study participation. The different consents 
will be captured in the CRF. 
Additionally, subjects will be asked to provide their separate consent for the use of the 8-iso-
PGF2α/ PGF2α analysis, performed on already collected samples, for bioanalytical research 
purposes (section 1.3.23). 
7.2 
Smoking Cessation Advice and Debriefing 
Each subject will be given advice on the risks of smoking, with smoking cessation (SC) advice, 
six times during the study: at the Screening Visit, at Admission on Day -3, at Discharge on 
Day 6, at Visit 2, Visit 3, and Visit 4. The form of a brief interview will be used according to 
current WHO recommendations [10]. Details of the interview will be recorded in the source 
document file. Information on the risk of smoking/SC advice will be given to the subjects on 
an individual basis during a face-to-face meeting between the subject and the Investigator and 
may additionally be given in a group session. 
In addition to the information of the risk of smoking/SC advice, a debriefing of subjects will 
be performed at Discharge from the study, together with information on the risk of smoking 
and SC advice to address any intended or unintended beliefs participants have about CHTP 1.2. 
The goal of the debriefing is to ensure that subjects exit the study with an accurate 
understanding of product risks including an understanding that CHTP 1.2 has not been 
demonstrated to be less harmful than CC. 
7.3 
Clinical Assessments 
The results of the clinical assessments described in this section will be recorded in the CRF. 

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7.3.1 
Demographic Data 
Demographic data (gender, age, and race) will be collected. 
See Appendix A for the time points of assessment. 
7.3.2 
Identification of the Current Cigarette Brand 
Identification of the current non-menthol CC brand smoked by the subject will be done at the 
Screening Visit and at Admission. Subjects will be asked to bring their own supply of current 
CC brand to the site and will have to hand their CC supply for the confinement period to the 
site collaborators. The site staff will document the brand name and yields in the source 
documentation. 
7.3.3 
Questions on Smoking Habits 
Subjects will be asked by the site collaborators the following questions about their smoking 
habits at the Screening Visit and on the Admission Day, and the answers will be recorded: 
1. Have you smoked for at least the past 10 years? (yes/no) 
2. How many years have you smoked? (numeric response, 2 digits) 
3. On average, how many cigarettes per day have you smoked over the last 6 weeks? (numeric 
response, 2 digits) 
3 a. How many are non-menthol (check all, or numeric response, 2 digits) 
4. On average, how many cigarettes per day have you smoked since you started smoking? 
(numeric response, 2 digits) 
5. Have you used nicotine-containing products other than commercially available non-
menthol/menthol CC until today? For example, any tobacco-based products or NRT, 
electronic cigarettes, or similar devices. 
6. On average, how would you describe your e-cigarette use over the last year? (check one) 
a. Daily 
i. How much use per day? (numeric response, 2 digits) 
b. Weekly 
i. How much use per week? (numeric response, 2 digits) 
c. Sporadically. (less than once per week) 
d. Tried e-cigarettes (between 1 – 10 uses) 

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e. Never tried e-cigarettes 
This self-reported CC daily consumption reported on the Admission Day will be used to assess 
eligibility. 
See Appendix A for the time points of assessment. 
7.3.4 
Product Preference 
In order to perform a complementary analysis on subjects’ preference, the following question 
will be asked to the subject; 
“Which product would you prefer to be randomized to?”: 
 
CHTP 1.2 
 
CC 
 
“No preference” 
This question will be asked to all subjects on Day -3 after Enrolment, but will have no influence 
on randomization. 
7.3.5 
Demonstration and CHTP 1.2 Test 
All subjects will have a demonstration of CHTP 1.2 at the Screening Visit. On Day -3 after 
Enrolment, subjects will have a product test using up to 5 sticks of CHTP 1.2. Subjects who 
are not willing and ready to use CHTP 1.2 will be discontinued from the study. 
7.3.6 
Medical History, Concomitant Disease, Previous and Ongoing Medications 
Relevant medical historywill be documented at the Screening Visit. Medical history is defined 
as any condition that started and ended prior to the Screening Visit. Any concomitant disease 
will be documented at the Screening Visit and on the Admission Day.  A concomitant disease 
is defined as any condition that started before and was going on at the time of ICF signature. 
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 as concomitant medication. Medication 
initiated after the Screening Visit is also referred to as concomitant medication. This applies to 
both prescription and over-the-counter products. 
Records of medication taken 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 frequency, the start and (if applicable), the stop date (day, month 

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and year). Any therapy changes (including changes of regimen) during the study are to be 
documented. 
7.3.7 
Physical Examination 
A physical examination will be conducted and the assessment recorded. 
See Appendix A for the time points of assessment. 
7.3.8 
Body Height and Weight 
Body weight and height will be recorded at the Screening Visit, body weight will also be 
recorded at Admission and Day 6, at Visit 2, Visit 3, and Visit 4. 
See Appendix A for the time points of assessment. 
The BMI will be calculated from the body weight and height using the following formula: 
BMI = weight in kilograms
height in meters2
= 𝑘𝑔
𝑚2 
7.3.9 
Vital Signs 
Systolic and diastolic blood pressure, pulse rate and respiratory rate will be measured in the 
morning at applicable visits. All measurements will be made after the subject has rested for at 
least 5 minutes in a supine position. 
Vital signs must be performed after a period of at least 15 minutes after having stopped using 
the allocated product. 
See Appendix A for the time points of assessment. 
7.3.10 
Other Clinical Assessments 
7.3.10.1 
Spirometry 
All personnel performing lung function testing must have the appropriate training according 
to local requirements with the record of the training. Quality control measures should be 
available and be properly documented. In a sitting position, the subject will be at rest for at 
least 15 minutes prior to lung function testing, i.e., pre- and post-bronchodilator application. 
All lung function maneuvers will be recorded with the subject in a sitting position throughout 
the study. 

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The spirometry test will be performed in accordance with the 2005 guideline of the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) Joint Task Force on the 
standardization of spirometry [39]. 
The spirometry tests will include the recording of FEV1, FVC, FEV1/FVC ratio, and FEF 25-
75. 
All spirometry testing must be performed at least 1 hour after having stopped using the 
allocated product (if applicable). 
See section 6.7.1 for the smoking restrictions associated spirometry. 
Pre- and post- bronchodilator spirometry tests will be performed. The ratio of FEV1/FVC will 
be calculated from the highest acceptable FEV1 and the highest acceptable FVC, respectively. 
All post-bronchodilator spirometry testing will be performed 15-30 minutes post 
administration of around 400 µg of salbutamol/albuterol (usually equivalent to 4 puffs 
assuming 100 g/puff). The time of salbutamol/albuterol inhalation and time of spirometry 
assessment will be recorded in the source document. 
The results from FEV1 and the ratio FEV1 to FVC at the Screening Visit will be used for 
eligibility criteria to assess spirometry and asthma conditions. 
For all the other visits, pre-bronchodilator spirometry will be used to describe the changes in 
pre-spirometry measurements over the duration of the study. 
See Appendix A for the time points of assessment. 
7.3.10.2 
Electrocardiogram 
Electrocardiogram (ECG) recording 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. QT interval will be corrected according to Federicia’s formula. Every ECG has to be 
assessed as normal, abnormal – clinically not significant, or abnormal - clinically significant. 
A diagnosis has to be provided on the CRF for all ECGs assessed as abnormal – clinically 
significant. 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 and signed by the PI or designee. 
See Appendix A for the time points of assessment. 

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7.3.10.3 
Chest X-ray 
A chest X-ray (anterior-posterior and left lateral views) will be assessed during the Screening 
Period to exclude subjects with relevant pulmonary diseases. Subjects will be referred to a 
radiology facility (within or outside the investigational site) 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. 
7.4 
Biomarker Assessment 
All bioanalytical assays and laboratory assessments (section 7.5) will be carried out using 
validated methods, except for the analysis of 8-iso-PGF2α and PGF2α in plasma. The 
bioanalytical methods used will be documented in the bioanalytical plans and reports. A list of 
laboratories is provided in Appendix B. 
Precautions should be taken during blood sampling and processing to prevent the 
contamination of samples with environmental nicotine or CO. 
7.4.1 
Biomarker of Exposure 
7.4.1.1 
Biomarker of Exposure to CO in Exhaled breath and Blood 
COHb measured in blood and exhaled CO will be investigated as a measure of exposure to 
CO. 
 
CO breath test: 
CO in exhaled breath will be measured using the Smokerlyzer® (e.g., Micro 4 
Smokerlyzer® device or similar). 
The CO breath test should be conducted in conjunction (i.e., within 30 minutes) with the 
blood sampling for COHb. 
See Appendix A for the time points of assessment. 
 
COHb test: 
Tests for COHb measurement will be performed at a designated laboratory. 
COHb assessments should be done in conjunction (i.e., within 30 minutes) with CO breath 
tests, where applicable. 
See Appendix A for the time points of assessment. 

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7.4.1.2 
Biomarker of Exposure to Nicotine in Plasma 
Nicotine and cotinine concentrations will be measured in plasma to evaluate the exposure to 
nicotine. 
See Appendix A for the time points of assessment. 
7.4.1.3 
Other Biomarkers of Exposure to HPHCs in Urine 
The following BoExp to HPHCs will be measured in 24-hour urine collection samples as per 
the schedule of events (Appendix A): 
 
Primary endpoints: MHBMA, 3-HPMA, S-PMA, and total NNAL 
 
Secondary endpoints: total 1-OHP, total NNN, 4-ABP, 1-NA, 2-NA, o-tol, CEMA, 
HEMA, 3-hydroxybenzo(a)pyrene, 3-HMPMA, NEQ 
BoExp to HPHCs in urine will be expressed as concentrations adjusted to creatinine. For 
normalization of BoExp to HPHCs, creatinine will also be measured in the 24-hour urine 
samples. 
7.4.2 
Clinical Risk Endpoints 
7.4.2.1 
Cardiovascular Clinical Risk Endpoints 
 
In blood: 
Blood samples will be drawn according to the sample handling manual and laboratory 
manual in order to measure: 
 
In serum: hs-CRP, LDL, HDL, Apo A1 and Apo B, sICAM-1, MPO 
 
In plasma: fibrinogen, homocysteine 
 
In blood: HBA1c 
No additional blood samples are required for the evaluation of blood glucose, TG, TC, 
WBC, and platelet count as clinical risk endpoints as they are measured as part of the safety 
parameters (section 7.5.1). As the analysis methods for hematology and clinical chemistry 
parameters are established and in use, no analytical plans and the respective analytical 
reports for platelet count, fasting glucose, total cholesterol and triglycerides will be 
generated, with the exception of WBC, for which the templates for the analytical plan and 
the respective report are already available. 
See Appendix A for the time points of assessment. 

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 
In urine: 
11-DTBX-B2 will be measured in 24-hour urine collection samples as per the schedule of 
events (Appendix A). 
For normalization, 11-DTBX-B2 will be expressed as concentrations adjusted to creatinine 
measured in 24-hour urine. 
7.4.2.2 
Clinical Risk Endpoints to Oxidative Stress 
 
In blood: 
Blood samples will be drawn according to the sample handling manual and laboratory 
manual in order to measure: 
 
In serum: 
4-HNE a and TAC 
 
In plasma: 
8-epi-PGF2 and PGF2  
See Appendix A for the time points of assessment. 
a 
Samples for 4-HNE analysis have been collected but will not be analyzed due to the failure to develop a 
selective and quantitative assay. 
 
 
In urine: 
8-OHdG and 8-epi-PGF2 will be measured in 24-hour urine collection samples as per the 
schedule of events (Appendix A). 
For normalization, 8-OHdG and 8-epi-PGF2 will be expressed as concentrations adjusted 
to creatinine measured in 24-hour urine.  
7.4.2.3 
Other Clinical Risk Endpoints 
 
CYP1A2 activity test: 
CYP1A2 activity will be assessed in plasma by measuring paraxanthine (PX) and caffeine 
(CAF) concentrations and calculating the PX/CAF molar metabolic ratio. Samples to 
measure PX and CAF will be drawn 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 [28]. 

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The exact time of intake of the cup of coffee in the morning and of the time of blood 
sampling 6 hours [±15 minutes] later must be recorded. 
See Appendix A for the time points of assessment. 
 
CYP2A6 activity test: 
CYP2A6 activity will be measured in plasma using the molar metabolic ratio of trans-3’-
hydroxycotinine to cotinine. CYP2A6 activity drives the metabolism of nicotine to cotinine 
and subsequent metabolites. CYP2A6 blood sampling has to be done prior to smoking. 
See Appendix A for the time points of assessment. 
7.4.3 
Ames Mutagenicity Test 
Urine mutagenicity, a biomarker for measuring mutagen load, will be measured 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. 
See Appendix A for the time points of assessment. 
7.5 
Laboratory Assessments 
A list of laboratories is provided in Appendix B. 
7.5.1 
Clinical Chemistry, Hematology, and Urine Analysis for Safety Panel 
Hematology, clinical chemistry, and urine analysis for the safety panel will be measured 
according to Appendix A for the timepoints of assessment. Blood will be taken after no less 
than the 10 hours of fasting except at the Screening Visit (section 6.7.2). Parameters to be 
measured are listed in Table 4. 
The hematology and clinical chemistry parameters total white blood cell count (WBC), platelet 
count, fasting glucose, total cholesterol, triglycerides are listed, among others, as selected 
cardiovascular clinical risk endpoints in secondary objectives.  
 
 
 
 

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Table 4 
Hematology and Clinical Chemistry Parameters (Safety) 
Hematology 
Clinical Chemistry 
Urine Analysis 
- Hematocrit 
- Hemoglobin 
- Mean corpuscular 
hemoglobin 
- Mean corpuscular 
hemoglobin concentration 
- Mean corpuscular volume 
- Platelet count 
- Red blood cell count 
- White blood cell (WBC) 
count 
- Differential WBC count: 
 
Neutrophils 
 
Basophils 
 
Eosinophils 
 
Lymphocytes 
 
Monocytes 
- Albumin 
- Total protein 
- Alkaline phosphatase 
- Alanine aminotransferase 
- Aspartate aminotransferase 
- Blood urea nitrogen 
- Creatinine 
- Gamma-glutamyl transferase 
- Fasting glucose 
- Lactate dehydrogenase 
- Potassium 
- Sodium 
- Total bilirubin 
- Direct bilirubin 
- Total cholesterol 
- Triglycerides 
- pH 
- Bilirubin 
- Glucose 
- Nitrite 
- Red blood cell traces 
- Protein 
- Specific gravity 
- Urine sediment (to be 
performed only in case of 
abnormal urine analysis 
results) 
See Appendix A for the time points of assessment. 
7.5.2 
Serology 
A test for hepatitis B surface antigen, hepatitis C virus and human immunodeficiency virus 
(anti-HIV 1/2 and p24 antigen) will be done. In case of positive results, the subject will be 
referred to appropriate medical care. 
See Appendix A for the time points of assessment. 
7.5.3 
Urine Drug Screening 
The urine will be screened for the following drugs or class or drugs: amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine and opiates. 
See Appendix A for the time points of assessment. 
7.5.4 
Urine Cotinine Screening 
A urine dip-stick or casette cotinine test will be performed to confirm the subject’s smoking 
status. The test must detect cotinine with a cotinine threshold of ≥ 200 ng/mL, (e.g., One-Step 
Cotinine Test 008A086, Ultimed, Belgium). 

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See Appendix A for the time points of assessment. 
7.5.5 
Alcohol Breath Test 
Subjects will undertake a breath alcohol test using an alcometer device (e.g., Alcotest 7410 
Plus, Dräger). 
See Appendix A for the time points of assessment. 
7.5.6 
Serum/Urine Pregnancy Test 
All female subjects will have pregnancy testing. At the Screening Visit, pregnancy testing for 
all female subjects will be performed using the serum pregnancy test. At all other time points 
after the Screening Visit, pregnancy testing for all female subjects will be performed using the 
urine pregnancy test. Female subjects with a positive serum pregnancy test at the Screening 
Visit or a positive urine pregnancy test at Admission will not be enrolled and will be considered 
as screen failures. In case of any positive pregnancy test, the Investigator or designee will 
inform the subject about the risks associated with smoking during pregnancy. 
The post-menopause is formally defined as the time after which a woman has experienced 12 
consecutive months of amenorrhea (lack of menstruation) without a period. At the Screening 
Visit, if a woman claims she is post-menopausal, but has had her menses within 12 months, a 
follicle stimulating hormone test must be performed and must be within acceptable limits of 
the post-menopausal status. 
All pregnancies detected during the study must be reported and handled as described in 
section 8.5. 
See Appendix A for the time points of assessment. 
7.6 
Sample Handling, Storage, and Shipment 
All blood samples are to be tested at a central laboratory with the exception of the safety 
laboratory panel and the serum pregnancy test at the Screening Visit which will be tested at a 
local laboratory (see Appendix B). The urine dip-stick for the safety laboratory, urine 
pregnancy tests, urine drug screening, and urine cotinine tests will be done by personnel at the 
study sites. 
Detailed procedures for collection and handling of samples are described in a separate sample 
handling manual (SHM) and laboratory manual. Safety laboratory samples will be destroyed 
as per the laboratory’s standard procedures. All primary and back-up samples for the 
assessments of BoExp and clinical risk endpoints (except bio-banking samples) will be 
destroyed after the bioanalytical report has been finalized or the database has been locked, 

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whichever comes last. Personnel at the facility/-ies where samples are stored will be informed 
in writing by the Sponsor when destruction of the samples will be allowed. 
The bioanalytical laboratory(ies) are listed in the Appendix B. 
7.6.1 
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 303 mL, which includes about 40 mL for safety and repeated analysis, 
about 36 mL for long-term storage of the bio-banking samples of biomarkers, clinical risk 
endpoints and other circulating proteins (only if additional consent is given), and about 57 mL 
for long-term storage bio-banking samples for transcriptomics, lipidomics and DNA 
methylation sequencing analyses (only if additional consent is given) (section 7.6.3). 
The blood sampling for transcriptomics, lipidomics, and DNA methylation sequencing 
analyses, and the data related to these samples will be anonymized. Anonymized data and 
samples are initially single or double coded where the link between the subjects’ identifiers 
and the unique code(s) is subsequently deleted. 
7.6.2 
Urine Samples 
Spot urine samples will be used for the urine cotinine screening test,  urine drug screening, 
urine pregnancy test and safety urine analysis at the Screening Visit and on the Admission 
Day. 
7.6.2.1 
Confinement Exposure Period 
Twenty four-hour urine will be collected from Day -2 to Day 5 (which will end after 24 hours 
± 1 hour on Day 6) on site.  
Twenty four-hour urine sample collection for Day -2 will start approx. at 06:30 AM on Day -2 
after the first morning void which should be discarded and will end after 24 hours ±1 hour on 
Day -1.  On Day 1, product use must not start prior to the end of urine collection of Day -1. 
From Day -1 onwards, the 24-hour urine collection for the respective day will start after the 
end of 24-hour urine collection of the previous day (after 24 hours ±1 hour) (Appendix A). 
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. 

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7.6.2.2 
Ambulatory Exposure Period 
During the ambulatory visits, subjects will be asked by the site at their check-in of the first day 
of the respectives visits (Visit 2, Visit 3, and Visit 4) to empty their bladder shortly at 09:00 ± 
30 minutes. This urine will be discarded but the timing of the void will correspond to the start 
of urine collection. After nearly 24-hours of urine collection, subjects will empty their bladder 
again on the second day of the respective visit, and this urine will be used as the final portion 
of the 24-hour urine sample. 
7.6.2.3 
Confinement and Ambulatory Exposure Period 
During the collection period for both confinement and ambulatory exposure period, all urine 
passed must be collected and put into the sampling container, with the exception of about 10 
mL for the spot urine tests. 
Spot urine sample of the around 10 mL to measure urine pregnancy test and safety urine 
analysis, will be taken from the final portion of the 24-hour urine sample before putting this 
final portion into the sampling container. The amount of 10 mL for the spot urine tests should 
not be subtracted from the 24-hour urine sample. No urine must be passed into the toilet. The 
start and the end time of urine collection as well as the measurement of the volume of 24-hour 
urine will be recorded by the site in a log. 
For assessment of urine BoExp, creatinine for normalization of urine BoExp, sample bio-
banking and urine mutagenicity, clinical risk endpoints, aliquots from the 24-hour urine 
collection will be taken. In the schedule of events for the 24-hour urine collection (see 
Appendix A) the dot corresponds to the day on which the 24-hour urine collection period starts. 
For example, NEQ measured on Day 5 in the 24-hour urine collection, the 24-hour urine 
collection starts on Day 5 and ends in the morning of Day 6 prior to Discharge. 
See Appendix A for the time points of assessment. 
7.6.3 
Bio-Banking for Long-Term Storage of Blood and Urine 
If a subject gives consent for sample bio-banking for long-term storage for possible later 
analysis of additional biomarkers, additional samples of urine (from the 24-hour urine 
collection) and serum/plasma/whole blood (approx. 36 mL of blood in total) will be collected 
as follows: 
 
Serum/plasma/whole blood will be collected on Day -1, Day 6 and Visit 4, respectively 
(approx. 36 mL of blood in total with approx. 12 mL of blood draw per time point. This is 
to obtain and store 2 x 1 mL of serum, 2 x 1 mL of plasma and 2 x 1 mL whole blood). 
 
Samples from the 24-hour urine will be collected from the urine collections that started on 
Day -1, Day 5, and Visit 4, respectively (5 tubes of 10 mL urine for each time point). 

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These samples are intended for possible later analysis of additional biomarkers of exposure, 
clinical risk endpoints or any other circulating proteins. No genetic or transcriptomics testing 
will be performed on these samples. 
If a subject gives consent for sample bio-banking of whole blood/plasma for further 
transcriptomics, plasma for lipidomics analyses, and whole blood for DNA methylation 
sequencing approx. 57 mL of blood will additionally be collected in total. On Day-1, Day 6 
and at Visit 4, approx. 15 mL blood in total will be collected for transcriptomics with 5 mL 
each day. The 5 mL whole blood per each assessment will be split into 2 tubes of 2.5 mL each. 
For lipidomics analyses, approx. 12 mL blood in total will be collected on Day -1, Day 6 and 
at Visit 4 with 4 mL each day. The 4 mL of blood will be centrifuged, and the plasma aliquoted 
in 2 tubes of 500 l each. For DNA methylation sequencing, approx. 30 mL blood in total will 
be collected on Day -1, Day 6 and at Visit 4 with 10 mL each day. The 10 mL whole blood per 
each assessment will be split into 2 tubes of 5 mL each. 
The samples intended for sample bio-banking will be kept frozen and shipped to a central 
storage facility. After the final clinical study report (CSR) is signed, samples of 
plasma/serum/blood will be stored for a maximal period of 5 years and samples of urine will 
be stored for a maximal period of 2 years. The blood/plasma bio-banking for transcriptomics,  
lipidomics and DNA methylation sequencing analyses will be stored for a maximum period of 
5 years. 
If a subject withdraws his/her consent for sample bio-banking the facility at which the samples 
are stored will follow their procedures for destruction of banked samples as stated in 
section 7.6.3. 
See Appendix A for the time points of assessment. 
7.7 
Other Study Procedures 
7.7.1 
Product Use Diary 
A product use diary will be used for the documentation of the used CHTPs 1.2, CCs (menthol 
and non-menthol), used NRTs product, or the use of other nicotine/tobacco containing 
products. All subjects in both arms must complete this diary on a daily basis on and from Day 
6 until the time of Discharge at Visit 4. Subjects will be trained by site staff in the use of this 
diary during the confinement period at the time the diary is delivered to the subject. 
7.7.2 
Questionnaires 
The subject questionnaires listed in the following sections including the cough-VAS used in 
this study will be answered and assessed by the subject directly on the CRF Health device. All 

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subject-reported outcome data as well as instructions will be provided in the subject’s local 
language.  
Symptoms or worsening of symptoms documented on any of the questionnaires or on the VAS 
do not need to be documented as additional AEs because the questionnaires and the cough-
VAS will be analyzed as part of the final report. However, it is at the discretion of the 
Investigator or designee to decide whether such symptoms are additional AEs. The main source 
for AE collection will be the face-to-face interview between the subject and the site 
collaborators, using open, non-directive questions (section 8). 
See Appendix A for the time points of assessment. 
The questionnaires should be done at the same time for each visit. 
7.7.2.1 
Fagerström Test for Nicotine Dependence (Revised Version) 
Potential nicotine dependence will be assessed via a subject self-reported questionnaire using 
the Fagerström Test for Nicotine Dependence (FTND) in its revised version [40]. 
The questionnaire consists of six questions which will be answered by the subject 
himself/herself. The scores obtained on the test allow the classification of nicotine dependence 
in three different levels: mild (0-3 points), moderate (4-6 points), and severe (7-10 points) with 
regards to CC at the Screening Visit and the assigned product at Visit 4. . 
See Appendix A for the time points of assessment. 
7.7.2.2 
Assessment of Cough-VAS 
Subjects will be asked to self-report and to assess the respiratory symptom “cough” on a VAS, 
on three Likert scales, and with an open question. Assessment of cough reflecting the cough 
symptoms in the last 24 hours will be conducted irrespective of the time of 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 scale questions and 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. 

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The frequency of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = rarely – 2 = sometimes – 3 = fairly often – 4 = often – 5 = almost always. 
The amount of sputum production will be assessed on a 4-point Likert scale ranging from 0 to 
3, with 0 = no sputum – 1 = a moderate amount of sputum – 2 = a larger amount of sputum – 
3 = a very large amount of sputum. 
Finally, subjects will be asked to share any other important observations with the site 
collaborators about their coughing. 
See Appendix A for the time points of assessment. 
7.7.2.3 
Modified Cigarette Evaluation Questionnaire (MCEQ, Modified Version) 
Product evaluation will be assessed using the subject self-reported MCEQ [41]. The MCEQ 
assesses the degree to which subjects experience the reinforcing effects of smoking, by 
measuring: 
 
Smoking satisfaction (satisfying, tastes good, enjoy 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) 
See Appendix A for the time points of assessment. 
7.7.2.4 
Questionnaire of Smoking Urges (QSU-brief) 
To assess the urge-to-smoke, all subjects will be asked to complete a 10-item brief version of 
the QSU [42]. The QSU-brief is a subject 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 findings in this brief version were consistent with the expressions of craving found in the 
32-item version of the QSU [43]. The findings supported a multi-dimensional 
conceptualization of craving to smoke and demonstrated the utility of a brief multi-dimensional 
measure of craving [42]. 
See Appendix A for the time points of assessment. 

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7.7.3 
Intent to Use Questionnaire (ITUQ) 
The ITUQ is a self-report questionnaire that assesses subjects’ intention to use CHTP 1.2 in 
smokers switching from CC to CHTP 1.2. The ITUQ comprises 3 sets of items: 
 
1 item assessing the likelihood of using CHTP 1.2 regularly 
 
5 items assessing the likelihood of using CHTP 1.2 with or without other tobacco-nicotine 
products including CC. Only subjects who provide response to the item assessing the 
likelihood of using CHTP 1.2 regularly with “Very unlikely” to “Definitely” will be asked 
to answer these items 
Each item in these 2 sets will be rated on a 6-point scale ranging from “definitely not” to 
“definitely” with higher scores indicating greater likelihood to use CHTP 1.2 in the respective 
aspect. 
 
1 item assessing how soon the subject will begin to use CHTP 1.2. Only subjects who 
provide response to the item assessing the likelihood of using CHTP 1.2 regularly with 
“Very unlikely” to “Definitely” will be asked to answer this item 
This item will be rated on an ordinal scale with 6 timeframe categories ranging from “Within 
one week” to “Never”. 
See Appendix A for the time points of assessment. 
7.7.4 
Prochaska “Stage of Change” Questionnaire: Intention to Quit Smoking 
The Prochaska’s “Stage of Change” Questionnaire will be used to assess the smokers’ mental 
state for the intention to quit (Appendix C for staging algorithm; [44, 45]).There are 5 stages 
of change describing smokers and former smokers: 1. Precontemplation, 2. Contemplation. 3. 
Preparation. 4. Action. 5. Maintenance. 
 
In the “Precontemplation” stage, the individual does not recognize smoking as a problem 
 
In the “Contemplation” stage, the individual is gathering information about smoking, such 
as contacting a health care provider or a tobacco quit line for information on the effects of 
smoking or smoking cessation consequences. During this stage, the stress and 
inconvenience of quitting smoking is greater than the immediate and possible long-term 
health effects of continuing smoking 
 
In the “Preparation” stage, intention and behavior begin to come together and the subject 
is preparing to enter into action in the next 30 days. It is necessary for the subject to 
recognize the benefits of not smoking, before a subject can enter the “Action” stage and as 
a result, changes his/her smoking behavior 

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 
After six months of not smoking, the individual reaches the “Maintenance” stage when 
different skills may be needed to prevent relapse from smoking 
See Appendix A for the time points of assessment. 
7.7.5 
Socio-Economic Status (SES) 
As part of the characterization of the study population it is important to measure variables that 
have been shown to be related to nicotine dependence and tobacco product reinforcing value. 
Based on prior tobacco research these factors include age, gender, ethnicity, tobacco use 
history, educational as well as socio-economic status (SES). 
SES information is recorded in similar manner in the clinical program, in behavioral research 
and will be eventually assessed in post-marketing studies once the product is commercialized. 
In order to predict and to evaluate the effect of alternative, potentially less harmful tobacco 
product use might have in adult smokers the SES constitutes an important demographic 
characteristic. SES data will be reported across the randomized clinical studies and will be 
collected in observational pre- and post-marketing studies. 
At the Screening Visit the subjects will be notified about the SES assessments. 
Subjects will be asked a series of questions related to their education, occupational status, size 
and annual income of their household. These data will be used to create a measure for SES that 
categorizes subjects into low, moderate and high SES [46]. If the subject does not want to 
answer the questionnaire, he/she will not be discontinued from the study. 
See Appendix A for the time points of assessment. 

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8 
ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
According to ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting [47]), an AE is defined as any untoward medical occurrence in a 
subject administered an IP, which does not necessarily have a causal relationship with the IP. 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
IP, whether or not it is considered related to the IP. 
8.1.2 
Serious Adverse Events 
A SAE is defined as, but is not limited to, any untoward medical occurrence that an any dose: 
 
Is life-threatening 
 
Results in death 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity, or 
 
Is a congenital anomaly/birth defect 
“Life-threatening” means that the subject was at immediate risk of death from the event that, 
had it occurred in a more serious form, might have caused death. 
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, a 
SAE may jeopardize the subject or the subject may require medical or surgical intervention to 
prevent one of the outcomes listed in the above definitions. 
8.1.3 
Conditions Existent Before the Start of the Period of Collection (ICF 
Signature) 
Clinical conditions that existed before the start of the period of collection (concomitant 
disease), and whose severity or frequency remained unchanged after that point, should not be 
considered AEs and should not be captured as such. This includes medical therapies or surgical 
interventions that had been planned before the start of the period of collection regardless of 
involving admissions to hospital, if the medical condition to be addressed did not worsen after 

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the start of the collection period. Otherwise, any medical condition that existed before the start 
of the period of collection and whose severity or frequency increased after that point is to be 
captured as a non-serious AE or an SAE, depending on the seriousness criteria met. 
8.2 
Collection, Assessment and Follow-up of Adverse Events 
8.2.1 
Collection of Information 
Any non-serious AE occurrence during the study must be documented in the subject’s medical 
records in accordance with the Investigator’s normal clinical practice and on the AE page of 
the CRF. SAEs that occur during the study must be documented in the subject’s medical record, 
on the AE CRF, and on the SAE form. 
AEs should be collected mainly via face-to-face interview with the subject through 
spontaneous reporting or by the use of consistent, open, non-directive questions from the 
investigational site collaborators (e.g., “Have you had any health problems since you were last 
asked? or “How have you been feeling since you were last asked?”). 
Information recorded will include: verbatim description of the AE, start and stop dates, 
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, stabilized). 
Information to be recorded about an AE/SAE should include, whenever possible, the verbatim 
description of the AE/SAE, onset and resolution dates and times, circumstances leading up to 
the event, clinical elements such as clinical course, specific vital signs and test results that may 
explain the pathophysiology of the event, as well as alternative explanations to its occurrence. 
Whenever a medically meaningful diagnosis is available to comprise a set of reported signs 
and/or symptoms, it should be preferentially provided as the AE or SAE term, rather than the 
individual signs and/or symptoms. Otherwise, each one of those signs and/or symptoms should 
be reported separately as event terms. 
8.2.2 
Period of Collection 
Any AEs which occur during the Screening period will be captured by the study site staff and 
assessed by the PI(s) or designee(s) in order to establish relationship to study procedures. Only 
the study procedures-related AEs will be reported in the CSR and in accordance with respective 
regulatory guidelines. 
AEs (including SAEs) will be collected from the time of ICF signature until the EOS. 
During a 28-day Safety Follow-up Period 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, 

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all AEs will be followed-up until resolved, stabilized (i.e., no worsening of the event), or a 
plausible explanation for the event has been found until the end of the study. At the end of the 
Safety Follow-up Period, all ongoing AEs will be documented as “ongoing” and will not be 
followed-up by the Investigator. At the discretion of the Investigator, the subject will be 
referred to his General Practitioner for follow-up on ongoing AEs. 
Any AEs or SAEs that are ongoing at the end of the 28 days of the Safety Follow-up Period 
will be managed as described in section 8.2.6. 
Non-serious AEs with onset after the end of the Safety Follow-Up Period and considered 
related to the IP might be reported to the Sponsor. Such AEs may not be part of the study 
report. 
SAEs spontaneously reported to the PI after the end of the Safety Follow-Up Period and 
considered related to the IP must also be reported to the Sponsor. Such SAEs may not be part 
of the study report. 
8.2.3 
Intensity of Adverse Event 
The Investigator must assess the intensity of each reported AE according to the following 
grading scale: 
Mild: 
Easily tolerated, not interfering with normal everyday activities 
Moderate: 
Interferes with normal everyday activities, but the subject is still able to 
function 
Severe: 
Incapacitating and requires medical intervention 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures 
The Investigator must assess the causal relationship between the exposure to the IP and each 
of the reported AEs, using the classification system and the criteria described below. The same 
assessment must be made separately regarding the causal relationship between the study 
procedures and each of the reported AEs: 
Not related: The temporal relationship of the adverse event to IP administration makes a 
causal relationship unlikely, or concomitant medication, therapeutic 
interventions, or underlying conditions provide a sufficient explanation for the 
observed event. 
Related: 
The temporal relationship of the adverse to IP administration makes a causal 
relationship possible, and concomitant medication, therapeutic interventions, or 

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underlying conditions do not provide a sufficient explanation for the observed 
event. 
8.2.5 
Expectedness 
Any AE assessed as related to the IP will be assessed for its expectedness. An AE will be 
regarded as “unexpected” if its nature or severity is not consistent with information already 
recorded about the IP CHTP 1.2 in the current IB. The current IB provides further detail on 
signs or symptoms that might be expected with the use of the IP CHTP 1.2, including 
information relating to malfunction or misuse [51]. The assessment of expectedness with the 
IP CC will be based on the judgement of the PI relying on the available safety information on 
CC in the literature. 
8.2.6 
Follow-up of Non-Serious and Serious Adverse Events 
Any non-serious AE that is ongoing during the Safety Follow-Up Period will be actively 
followed-up by the Investigator during that period until it has been resolved, stabilized (i.e., no 
worsening of the condition), or an acceptable explanation has been found (e.g., a chronic 
condition). 
At the end of the Safety Follow-Up Period, all ongoing non-serious AEs will be documented 
as “ongoing” and no follow-up information will be sought for on them anymore by the 
Investigator. At that point, the Investigator will assess whether the subject should be referred 
to his/her General Practicioner to have their ongoing AEs addressed accordingly. 
All SAE will be followed up by the Investigator or designee, despite their continuation after 
the end of the Safety Follow-Up Period, until their resolution, stabilization (i.e., no worsening 
of the condition), or an acceptable explanation has been found (e.g., a chronic condition). 
8.3 
Reporting of Serious Adverse Events 
Any SAE observed during the period of collection by any of the parties involved in this study 
(including the Investigational site personnel) must be reported by that party within 24 hours of 
first awareness to 
. 
SAEs considered related to the IP CHTP 1.2 and observed by, or reported to, any of the parties 
involved in this study (including the Investigational site personnel) after the period of 
collection must also be reported by that party within 24 hours of first awareness to 
 
 for safety surveillance purposes. Such SAEs will not be included in the 
clinical study report. 
All the SAE report forms must be either faxed or sent as an attachment to an e-mail message 
to 
: 

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: 
Fax number: 
+41
 
E-mail: 
 
Address: 
 
 
Switzerland 
As further information regarding an already reported SAE becomes available to any of the 
parties involved in this study, such follow-up information should be reported on a new SAE 
report form, marked as a follow-up report and submitted to 
 according 
to the same timelines described above. The follow-up SAE report form must include the 
minimum information required for form completion and only changed/new information needs 
to be specified. Information provided in the follow-up SAE report form supersedes any 
information that was initially reported. 
The SAE report form to be used in this study is provided as a separate document. All SAEs 
will also be recorded on the relevant CRF page, in addition to the SAE report form. 
The PI or designee is responsible for submitting the relevant reports of SAEs that occur during 
the study to the local Independent Ethic Committee (IEC) according to local regulations. 
8.4 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the PI and assessed for clinical significance according to its severity. A clinically 
significant abnormal laboratory test result detected at the Screening Visit must be recorded as 
a concomitant disease. A clinically significant abnormal laboratory test result detected after 
the Screening Visit, but within the Screening Period, must be recorded as a concomitant disease 
or an AE based on the judgement of the PI. A clinically significant abnormal result detected 
after the Screening Period must be recorded as an AE (or linked to a concomitant disease), and 
handled according to the directions in sections 8.2 and 8.3. The severity of AEs representing 
clinically significant abnormal laboratory results should be assessed using the grading scheme 
shown in Appendix E. Whenever that grading scheme is not available for the laboratory result 
of concern, the PI should assess the severity and the clinical significance of that result using 
his/her medical judgment. 
The principles for assessing and reporting abnormal laboratory test results, emerging after the 
Screening Period, using the grading scheme shown in Appendix E, is the following: 
• All Grade 1 abnormal laboratory value will be evaluated by the Investigator taking into 
account the value of the test of concern at Baseline and its clinical significance. If 

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considered to be clinically significant, the Investigator must report it as an AE, or link it to 
a reported AE or to a concomitant disease. 
• All Grade 2 and higher abnormal laboratory value must be reported as an AE, or linked to 
an AE or a concomitant disease. 
If there is any worsening in grade, the Investigator must report this worsening 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 [45] (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. 
8.5 
Collection, Follow-Up and Reporting of Pregnancies 
8.5.1 
Period of Collection and Follow-up 
Pregnancies detected between the signature of the ICF and the Enrolment will lead to screen 
failure of the subject. In that situation, no pregnancy form will be filled. However the diagnosed 
pregnancy must be captured in the screen failure CRF. 
Any pregnancy that occurred after first exposure to the IP and is potentially associated with 
exposure to the IP, including pregnancies spontaneously reported to the PI or designee after 
the EOS of the subject, must be reported by the Investigator and followed-up until the 
pregnancy outcome is reached. 
Potential association with exposure to the IP is defined as the conception date being calculated 
to have been before the date of the last exposure to IP. 
8.5.2 
Reporting of Pregnancies 
A dedicated pregnancy form will be used to report reportable cases of pregnancy. The PI will 
complete that form (provided as a separate document) for all reportable pregnancies that are 
diagnosed (including positive serum or urine pregnancy tests). 
The procedure to report a pregnancy and provide any additional/follow-up information to 
 
 must be followed in the same manner and within the same timelines as 
described for a SAE (section 8.3). 

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The PI or designee is responsible for submitting to the local IEC any pregnancy report, 
according to local regulations. 
8.6 
Adverse Events Leading to Discontinuation 
Subjects who are discontinued from the study because of an AE, will undergo the early 
termination procedures as described in section 9.5 as soon as possible, and will enter the 28-day 
Safety Follow-up Period. The follow-up of these events will be performed according to section 
8.2.6. 
8.7 
Investigational Product Malfunction and Misuse 
During the confinement period, any occurrences of CHTP 1.2 malfunction (
 
) or misuse (use not in accordance with its label and instruction) by a subject, will be 
documented by the PI or his designee using a product issue log.  
During the ambulatory visits at site, the PI or his designee will also collect information about 
CHTP 1.2 malfunction or misuse having occurred during the ambulatory period days between 
the ambulatory visits. In case the site is aware of a device event having occurred during the 
ambulatory period and some information is missing, only the available information as best 
recalled by the subject will be recorded on the issue log.  
Investigational product misuse may result in use-related hazards. 
Furthermore, any misuse or malfunction of CHTP 1.2 that leads to an AE/SAE will be handled 
with the same processes as described above for the reporting of AE/SAE. 

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9 
STUDY ACTIVITIES 
A detailed schedule of assessments can be found in Appendix A. 
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 procedure is provided, then the procedure can be performed 
at any time during the day. 
Site personnel will adhere to the site’s standard operating procedures (SOPs) for all activities 
or otherwise specified by the protocol. Appropriate medical advise will be provided to the 
subject in case of any medical findings requiring health care. 
9.1 
Screening Visit 
The Screening Visit will be performed within 6 weeks (1 to 42 days) prior to Admission. First, 
the ICF along with study information should be given to the subject. When/if the ICF is signed, 
dated and timed, the other screening procedures can be performed in the order deemed most 
practical. The point of time of each screening procedure must be recorded in the source 
document. While it is recommended to complete as many screening procedures as possible in 
one day, it is permissible to complete those over more than one day. Smoking is allowed during 
the Screening Visit. 
Table 5 shows the procedures for the Screening Visit. The sequence of assessments/events is 
given just for illustrative purposes and will be at the discretion of the site after signature of the 
ICF. 
Table 5 
Time Schedule – Screening Visit (Day -45 to Day -4) 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of 
Procedure 
 
Screening 
 
Before any study 
procedure  
 
Informed consent for study 
participation and additional 
consents for bio-banking (if 
applicable) 
 

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Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of 
Procedure 
 
Screening 
 
During the visit 
√ 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
 
During the visit  
 
Safety urine analysis 
 
 
 
 
 
During the visit 
 
√ 
Serology (HIV, hepatitis B 
and C) 
 
During the visit 
 
Information on the risks of 
smoking, smoking cessation 
advice and debriefing. 
 
During the visit  
 
Demographic data and medical 
history collected 
 
During the visit  
 
Concomitant disease, prior and 
concomitant medication 
 
During the visit 
 
Prochaska Questionnaire (Intent 
to Quit) 
 
During the visit 
 
FTND Questionnaire 
 
During the visit 
 
Questions about smoking habits 
 
During the visit 
 
Identification of currently used CC 
brand 
 
During the visit 
 
ECG 
At least 10 minutes in 
supine position prior to 
recording 
During the visit 
 
Chest X-ray 
If not performed 6 months 
prior to Screening 
During the visit  
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in 
supine position, at least 
15 minutes after having 
stopped smoking 
During the visit  
√ 
Serum pregnancy test (all 
females) 
 
During the visit  
 
Physical examination, height 
and weight, and calculated BMI 
 
During the visit 
 
Urine drug screening 
 

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Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of 
Procedure 
 
Screening 
 
During the visit 
 
Urine cotinine screening  
 
During the visit  
 
Alcohol urine or breath test  
 
During the visit  
 
Spirometry pre- and post-
bronchodilatator (recording of 
FEV1, FVC, FEV1/FVC) 
Has to be done at least 1 
hour after having stopped 
smoking 
At rest in sitting position 
for at least 15 minutes 
prior to pulmonary 
function testing. 
In sitting position. 
All post-bronchodilator 
spirometry testing will be 
performed 15-30 minutes 
post administration of 
salbutamol 
During the visit  
 
AE/SAE recording 
If the Screening Visit is 
performed on two 
separate days, the 
AE/SAE questions will be 
asked again 
During the visit  
 
Inclusion/exclusion criteria  
See section 5 
During the visit  
 
CHTP 1.2 product 
demonstration  
 
Abbreviations: AE = Adverse event; CC = Combustible cigarette; CHTP 1.2 = Carbon Heated Tobacco Product 1.2; 
ECG = Electrocardiogram; FEV1= Force expiratory volume in 1 second; FVC = Forced vital capacity; FTND = Fagerström 
Test for Nicotine Dependence; HIV = Human immunodeficiency virus; SAE = Serious adverse event. 
9.2 
Confinement Period (Day -3 to Day 6) 
9.2.1 
Admission (Day -3) 
The procedures of Day -3 can be performed in order deemed most practical.  
Table 6 shows the assessments that will be performed on the day of Admission (Day -3). A 
subject is considered as being enrolled once he/she is declared for being enrolled in the IxRS. 

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Table 6 
Time Schedule – Admission (Day -3) 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of Procedure 
 
Admission (Day -3) 
 
During the visit  
 
Urine drug screening  
Prior to Enrolment  
During the visit 
 
Urine cotinine screening 
Prior to Enrolment 
During the visit 
 
Urine pregrancy test (female only) 
Prior to Enrolment 
During the visit 
 
Alcohol urine or breath test 
Prior to Enrolment 
During the visit 
 
Prior/concomitant medication 
Prior to Enrolment 
During the visit 
 
Questions about smoking habits 
Prior to Enrolment 
During the visit 
 
Identification of currently used CC 
brand 
Prior to Enrolment 
During the visit 
 
Inclusion/exclusion criteria 
All eligibility criteria must 
be checked. 
Prior to Enrolment 
During the visit 
 
Enrolment 
 
During the visit 
 
Physical examination, body 
weight, and calculated BMI 
After Enrolment 
During the visit 
 
Waist circumference  
After Enrolment 
Prior to 11:30 AM 
√ 
CYP2A6 activity in plasma 
After Enrolment. Prior to 
smoking and the 
product testing 
 
 
Product test for CHTP 1.2 (Use up 
to 5 CHTPs 1.2) 
After Enrolment. 
Subjects who are 
unwilling to use the 
product during the entire 
study duration will be 
discontinued from the 
study 
During the visit 
 
Vital signs (blood pressure, pulse 
rate, respiratory rate) 
At least 5 minutes in 
supine position 
 
 
 
 
During the visit 
 
CO breath test 
 

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Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of Procedure 
 
Admission (Day -3) 
 
During the visit 
 
Information on the risks of 
smoking, smoking cessation 
advice and debriefing. 
 
 
 
 
 
During the visit 
 
Question on Product Preference  
After Enrolment 
During the visit 
 
AE/SAE recording 
At any time of the day 
During the visit 
 
Collection of used CC butts 
For accountability 
During the visit 
 
Collection of CHTP 1.2 used for 
the product test  
For accountability 
Abbreviations: AE = Adverse event; BMI = Body mass index; CC = Combustible cigarette(s); CHTP 1.2 = Carbon Heated 
Tobacco Product 1.2; CO = Carbon monoxide; SAE = Serious adverse event. 
9.2.2 
Baseline Period (Day -2 and Day -1) 
Table 7 shows the assessments that will be performed on Day -2. 
The collection of 24-hour urine sample for Day -2 will start in the morning of Day -2 and will 
end in the morning of Day -1. 
Table 7 
Time Schedule – Day -2 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of 
Procedure 
 
Baseline Period (Day -2) 
 
6:30 AM 
 
Start of smoking CC 
 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Concomitant medications 
 
Prior to 11:30 AM 
 
Start of 24-hour urine sample 
collection for Day -2. 
The start of urine 
collection should start 
after the first morning 
void which should be 
discarded, and the 
end is in the morning 
of the following day. 

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Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of 
Procedure 
 
Baseline Period (Day -2) 
 
Prior to 11:30 AM 
 
Assessment of cough (VAS) 
Has to be done prior 
to smoking 
Prior to 11:30 AM  
 
Vital signs (blood pressure, pulse 
rate, respiratory rate) 
At least 5 minutes in 
supine position, at 
least 15 minutes after 
having stopped 
smoking 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
 
CO breath test  
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
√ 
COHb in blood 
 
8:00 PM - 11:00 PM 
 
ITUQ Questionnaire 
 
8:00 PM - 11:00 PM 
 
QSU brief Questionnaire 
 
8:00 PM - 11:00 PM 
 
MCEQ Questionnaire 
 
11:00 PM 
 
End of smoking period 
 
6:30 AM - 11:15 PM 
 
Collection of used CC butts  
For accountability  
Abbreviations: AE = Adverse event; CC = Combustible cigarette(s); CO = Carbon monoxide; COHb = Carboxyhemoglobin; 
ITUQ = Intent to Use Questionnaire; QSU–brief = Questionnaire of Smoking Urges (brief version); MCEQ = Modified 
Cigarette Evaluation Questionnaire; SAE = Serious adverse event. 
Table 8 show the assessments that will be performed on Day -1 
Table 8 
Time Schedule – Day -1 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Baseline Period (Day -1) 
 
6:30 AM 
 
Start of smoking 
 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Concomitant medications 
 

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hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Baseline Period (Day -1) 
 
Prior to 11:30 AM 
 
End of 24-hour urine sample 
collection for Day -2 
The urine is collected for 24 
hours ±1 hour. The end of 
the 24-hour urine collection 
should be prior to smoking 
the first CC. 
Prior to 11:30 AM 
 
Start of 24-hour urine sample 
collection for Day -1. 
The start of 24-hour urine 
collection of Day -1 should 
be subsequent to the end of 
24-hour urine collection of 
Day -2  
Prior to 11:30 AM 
 
Urine sample to be taken 
from the 24-hour urine of 
Day -2. 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 
Prior to 11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position 
Prior to 11:30 AM 
 
ECG 
At least 10 minutes in 
supine position prior to 
recording 
Prior to 11:30 AM 
 
Assessment of cough (VAS) 
Has to be done prior to 
smoking 
Prior to 11:30 AM 
√ 
Bio-banking for BoExp, 
clinical risk endpoints and 
other circulating proteins, 
and transcriptomics,  
lipidomics and DNA 
methylation sequencing 
If additional consent is 
signed. 
After at least 10 hours of 
fasting 
Prior to 11:30 AM 
√ 
Clinical laboratory 
parameters* (hematology, 
clinical chemistry) and 
cardiovascular clinical risk 
endpoints (hs-CRP, MPO, 
fibrinogen, homocysteine, 
LDL, HDL, HbA1c, sICAM-1, 
Apo A1, Apo B, 8-epi-
PGF2α, PGF2α), clinical risk 
endpoints of oxidative stress 
(4-HNE, TAC) 
After at least 10 hours of 
fasting. 
* Blood glucose, TG, TC, 
WBC, platelet count from 
safety will be also evaluated 
as clinical risk endpoints 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Baseline Period (Day -1) 
 
Prior to 11:30 AM  
 
Safety urine analysis  
 
Prior to 11:30 AM 
 
Intake of a cup of coffee 
made from 4.2 g (±10%) 
regular instant coffee; CAF 
content: 72 mg/2 g) with 150 
ml ±10 ml water.  
The time of intake of the cup 
of coffee must be recorded 
After 11:30 AM  
√ 
CYP1A2 activity in plasma 
6 hours ±15 minutes after 
intake of the the cup of 
coffee. 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
 
CO breath test  
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
√ 
COHb in blood 
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required. 
8:00 PM-11:00 PM 
 
QSU brief Questionnaire 
 
8:00 PM-11:00 PM 
 
MCEQ Questionnaire 
 
11:00 PM 
 
End of smoking period 
 
6:30 AM-11:15 PM 
 
Collection of used CC butts  
For accountability 
 
 
Randomization 
Day -1 
Abbreviations: 4-HNE = 4-hydroxy-2-nonenal; AE = Adverse event; Apo A1 = Apolipoprotein A1; Apo B = 
Apolipoprotein B; BoExp = Biomarker (s) of exposure; CC = Combustible cigarette(s); CHTP 1.2 = Carbon Heated 
Tobacco Product 1.2; CO = Carbon monoxide; COHb = Carboxyhemoglobin; CYP1A2 = Cytochrome P450 1A2; CYP2A6 
= Cytochrome P450 2A6; ECG = Electrocardiogram; HbA1C = Hemoglobin A1C; HDL = High density lipoprotein; hs-
CRP = High sensitive C-reactive protein; LDL = Low density lipoprotein; MCEQ = Modified Cigarette Evaluation 
Questionnaire; MPO = Myeloperoxidase; QSU–brief = Questionnaire of Smoking Urges (brief version); SAE = Serious 
adverse event; sICAM-1 = Soluble inter-cellular adhesion molecule-1; TAC = Total anti-oxidant capacity; TC = Total 
cholesterol; TG = Triglycerides; VAS = Visual Analogue Scale; WBC = White blood cell 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
9.2.3 
Exposure Period (Days 1 to 5) 
Table 9 shows the assessments that will be performed on Day 1. 
The collection of 24-hour urine of Day 1 starting on Day 1 will end on Day 2. 
Table 9 
Time Schedule – Day 1 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 1 
 
 
 
Allocation to study arm 
 
6:30 AM 
 
Start of use of IPs 
 
Prior to 11:30 AM 
 
AE/SAE recording 
 
Prior to 11:30 AM 
 
Concomitant medications 
 
Prior to 11:30 AM 
 
End of 24-hour urine sample 
collection for Day -1 
The urine is collected for 24 
hours ±1 hour. The end of 
the 24-hour urine collection 
should be prior to first use of 
IPs. 
Prior to 11:30 AM 
 
Start of 24-hour urine 
sample collection for Day 1.  
The start of 24-hour urine 
collection of Day 1 should be 
subsequent to the end of 24-
hour urine collection of 
Day -1 
Prior to 11:30 AM 
 
Urine sample to be taken 
from the 24-hour urine of 
Day -1 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 
Bio-banking for biomarkers 
(if additional consent is 
obtained) 
Prior to 11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position, at least 15 minutes 
after having stopped using IP 
Prior to 11:30 AM 
 
Assessment of cough (VAS) 
Has to be done prior to 
allocated IPs 

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Clinical Study Protocol 
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FINAL VERSION 5.0 / 05 December 2016 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 1 
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
 
CO breath test  
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
√ 
COHb in blood 
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required 
8:00 PM - 11:00 PM 
 
QSU brief Questionnaire 
 
8:00 PM - 11:00 PM 
 
MCEQ Questionnaire 
 
11:00 PM 
 
End of use of IPs 
 
6:30 AM - 11:15 PM 
 
Collection of used CC butts 
For accountability 
6:30 AM - 11:15 PM 
 
Collection of used CHTP 1.2 
For accountability 
Abbreviations: AE = Adverse event; BoExp = Biomarker (s) of exposure; CC = Combustible cigarette(s); 
CHTP 1.2 = Carbon Heated Tobacco Product 1.2; CO = Carbon monoxide; COHb = Carboxyhemoglobin; IP = 
Investigational product; MCEQ = Modified Cigarette Evaluation Questionnaire; QSU–brief = Questionnaire of Smoking 
Urges (brief version); SAE = Serious adverse event; VAS = Visual Analogue Scale 
Table 10 shows the assessments that will be performed on Day 2. 
The collection of 24-hour urine sample for Day 2 will start on Day 2 and will end on Day 3. 
Table 10 
Time Schedule – Day 2 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 2 
 
6:30 AM  
 
Start of use of IPs 
 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Concomitant medications 
 

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Clinical Study Protocol 
Confidential 
P2R-REXA-07-EU  
FINAL VERSION 5.0 / 05 December 2016 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 2 
 
Prior to 11:30 AM 
 
End of 24-hour urine sample 
collection for Day 1 
The urine is collected for 24 
hours ±1 hour.  
Prior to 11:30 AM 
 
Start of 24-hour urine sample 
collection for Day 2.  
The start of 24-hour urine 
collection of Day 2 should 
be subsequent to the end of 
24-hour urine collection of 
Day 1 
 
 
Urine sample to be taken 
from the 24-hour urine of Day 
1 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 
Prior to 11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position, at least 15 minutes 
after having stopped using 
IP 
Prior to 11:30 AM 
 
Assessment of cough (VAS)  
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
 
CO breath test 
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
√ 
COHb in blood 
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required 
8:00 PM - 11:00 PM 
 
QSU brief Questionnaire 
 
8:00 PM - 11:00 PM 
 
MCEQ Questionnaire 
 
11:00 PM 
 
End of use of IPs  
 
6:30 AM - 11:15 PM 
 
Collection of used CC butts 
For accountability 
6:30 AM - 11:15 PM 
 
Collection of used CHTP 1.2 
For accountability  
Abbreviations: AE = Adverse event; BoExp = Biomarker (s) of exposure; CC = Combustible cigarette(s); 
CHTP 1.2 = Carbon Heated Tobacco Product 1.2; CO = Carbon monoxide; COHb = Carboxyhemoglobin; IP = 

Philip Morris Products SA 
Clinical Study Protocol 
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P2R-REXA-07-EU  
FINAL VERSION 5.0 / 05 December 2016 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 2 
 
Investigational product; MCEQ = Modified Cigarette Evaluation Questionnaire; QSU–brief = Questionnaire of Smoking 
Urges (brief version); SAE = Serious adverse event; VAS = Visual Analogue Scale 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXA-07-EU  
FINAL VERSION 5.0 / 05 December 2016 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Table 11 shows the assessments that will be performed on Day 3. 
The collection of 24-hour urine sample for Day 3 will start on Day 3 and will end on Day 4. 
Table 11 
Time Schedule – Day 3 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 3 
 
6:30 AM 
 
Start of use of IPs 
 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Concomitant medications 
 
Prior to 11:30 AM 
 
End of 24-hour urine sample 
collection for Day 2 
The urine is collected for 24 
hours ±1 hour.  
Prior to 11:30 AM 
 
Start of 24-hour urine sample 
collection of Day 3.  
The start of 24-hour urine 
collection of Day 3 should 
be subsequent to the end of 
24-hour urine collection of 
Day 2 
Prior to 11:30 AM 
 
Urine sample to be taken from 
the 24-hour urine of Day 2 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 
Prior to 11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position, at least 15 minutes 
after having stopped using 
IP 
Prior to 11:30 AM 
 
Assessment of cough (VAS) 
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
 
CO breath test  
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
√ 
COHb in blood 
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required 
8:00 PM - 11:00 PM 
 
QSU brief Questionnaire 
 
8:00 PM - 11:00 PM 
 
MCEQ Questionnaire 
 

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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 3 
 
11:00 PM 
 
End of use of IPs 
 
6:30 AM - 11:15 PM 
 
Collection of used CC butts 
For accountability 
6:30 AM - 11:15 PM 
 
Collection of used CHTP 1.2 
For accountability 
Abbreviations: AE = Adverse event; BoExp = Biomarker (s) of exposure; CC = Combustible cigarette(s); 
CHTP 1.2 = Carbon Heated Tobacco Product 1.2; CO = Carbon monoxide; COHb = Carboxyhemoglobin; IP = 
Investigational product; MCEQ = Modified Cigarette Evaluation Questionnaire; QSU–brief = Questionnaire of Smoking 
Urges (brief version); SAE = Serious adverse event; VAS = Visual Analogue Scale 
Table 12 shows the assessments that will be performed on Day 4. 
The collection of 24-hour urine sample for Day 4 will start on Day 4 and will end on Day 5. 
Table 12 
Time Schedule – Day 4 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 4 
 
6:30 AM 
 
Start of use of IPs 
 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Concomitant medications 
 
During the visit 
 
SES Questionnaire 
 
Prior to 11:30 AM 
 
End of 24-hour urine sample 
collection for Day 3 
The urine is collected for 24 
hours ±1 hour. The end of 
the 24-hour urine collection 
should be prior to first use of 
IPs 
Prior to 11:30 AM 
 
Start of 24-hour urine sample 
collection of Day 4.  
The start of 24-hour urine 
collection of Day 4 should 
be subsequent to the end of 
24-hour urine collection of 
Day 3 

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Clinical Study Protocol 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 4 
 
Prior to 11:30 AM 
 
Urine sample to be taken 
from the 24-hour urine of Day 
3. 
Aliquots from 24-hour urine 
will be collected according to 
Table A2 
Prior to 11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position, at least 15 minutes 
after having stopped using 
IP 
Prior to 11:30 AM 
 
Assessment of cough (VAS) 
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
 
CO breath test 
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
√ 
COHb in blood 
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required 
8:00 PM - 11:00 PM 
 
QSU brief Questionnaire 
 
8:00 PM - 11:00 PM 
 
MCEQ Questionnaire 
 
11:00 PM 
 
End of use of IPs. 
 
6:30 AM - 11:15 PM 
 
Collection of used CC butts 
For accountability 
6:30 AM - 11:15 PM 
 
Collection of used CHTP 1.2 
For accountability  
Abbreviations: AE = Adverse event; BoExp = Biomarker (s) of exposure; CC = Combustible cigarette(s); 
CHTP 1.2 =Carbon Heated Tobacco Product 1.2; CO = Carbon monoxide; COHb = Carboxyhemoglobin; IP = 
Investigational product; MCEQ = Modified Cigarette Evaluation Questionnaire; QSU-brief = Questionnaire of Smoking 
Urges (brief version); SAE = Serious adverse event; SES = Socio-Economic Status Questionnaire; VAS = Visual Analogue 
Scale 
Table 13 shows the assessments that will be performed on Day 5. 
The collection of 24-hour urine sample for Day 5 will start on Day 5 and will end on Day 6. 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Table 13 
Time Schedule – Day 5 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 5 
 
6:30 AM 
 
Start of use of IPs 
 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Concomitant medications 
 
Prior to 11:30 AM 
 
End of 24-hour urine sample 
collection for Day 4 
The urine is collected for 24 
hours ±1 hour.  
Prior to 11:30 AM 
 
Start of 24-hour urine sample 
collection of Day 5.  
The start of 24-hour urine 
collection of Day 5 should 
be subsequent to the end of 
24-hour urine collection of 
Day 4  
Prior to 11:30 AM 
 
Urine sample to be taken 
from the 24-hour urine of Day 
4 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 
Prior to 11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position, at least 15 minutes 
after having stopped using 
IP 
Prior to 11:30 AM 
√ 
Cardiovascular clinical risk 
endpoints/Biomarkers of 
oxidative stress (8-epi-
PGF2α, PGF2α), clinical risk 
endpoints of oxidative stress 
(4-HNE, TAC) 
After at least 10 hours of 
fasting. 
 
Prior to 11:30 AM 
 
Assessment of cough (VAS) 
 
Prior to 11:30 AM 
 
Intake of a cup of coffee 
made from 4.2 g (±10%) 
regular instant coffee; CAF 
content: 72 mg/2 g) with 150 
ml ±10 ml water. 
The time of intake of the cup 
of coffee must be recorded 
04:00 PM - 06:00 PM 
√ 
CYP1A2 activity in plasma 
6 hours ±15 minutes after 
intake of the cup of coffee  
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour ) 
 
CO breath test  
 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 5 
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
√ 
COHb in blood 
 
In the evening prior 
to 9:30 PM (approx. 
8:00 PM ± 1.5 hour) 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required 
8:00 PM - 11:00 PM 
 
QSU brief Questionnaire 
 
8:00 PM - 11:00 PM 
 
MCEQ Questionnaire 
 
11:00 PM 
 
End of use of IPs 
 
6:30 AM - 11:15 PM 
 
Collection of used CC butts 
For accountability 
6:30 AM - 11:15 PM 
 
Collection of used CHTP 1.2 
For accountability  
Abbreviations: AE = Adverse event; BoExp = Biomarker (s) of exposure; CAF = Caffein; CC = Combustible cigarette(s); 
CHTP 1.2 = Carbon Heated Tobacco Product 1.2; CO = Carbon monoxide; COHb = Carboxyhemoglobin; IP = 
Investigational product; MCEQ = Modified Cigarette Evaluation Questionnaire; QSU–brief = Questionnaire of Smoking 
Urges (brief version); SAE = Serious adverse event; VAS = Visual Analogue Scale 
Table 14 shows the assessments that will be performed on Day 6, prior to Discharge from the 
study unit. 
Table 14 
Time Schedule – Day of Discharge (Day 6) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 6 
 
6:30 AM 
 
Start of use of IPs 
 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Concomitant medications 
 
 
 
End of 24-hour urine sample 
collection for Day 5 
The urine is collected for 24 
hours ±1 hour 

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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 6 
 
 
 
Urine sample to be taken 
from the 24-hour urine of 
Day 5 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 
Bio-banking for biomarkers 
(if additional consent is 
obtained) 
06:29 AM ± 1.5 
hour 
√ 
Clinical laboratory 
parameters* (hematology, 
clinical chemistry), 
cardiovascular clinical risk 
endpoint: sICAM-1 
After at least 10 hours of 
fasting 
* Blood glucose, TG, TC, 
WBC, platelet count from 
safety will be also evaluated 
as clinical risk endpoints 
06:29 AM ± 1.5 
hour 
√ 
CYP2A6 activity in plasma 
Has to be done prior to use 
of IPs 
06:29 AM ± 1.5 h 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required 
06:29 AM ± 1.5 
hour  
 
Spirometry pre- and post-
bronchodilatator (recording 
of FEV1, FVC, FEV1/FVC) 
Has to be done prior to use 
of IPs 
At rest in sitting position for 
at least 15 minutes prior to 
pulmonary function testing 
In sitting position 
All post-bronchodilator 
spirometry testing will be 
performed 15-30 minutes 
post administration of 
salbutamol 
Prior to 11:30 AM 
√ 
Bio-banking for BoExp, 
clinical risk endpoints and 
other circulating proteins, 
and transcriptomics, 
lipidomics and DNA 
methylation sequencing  
If additional consent is 
signed 
After at least 10 hours of 
fasting 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 6 
 
Prior to 11:30 AM  
 
Assessment of cough (VAS) 
 
Before Discharge 
 
ITUQ Questionnaire 
 
Before Discharge 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position, at least 15 minutes 
after having stopped using 
IP 
Before Discharge 
 
Physical examination, body 
weight, and calculated BMI 
 
Before Discharge 
 
Safety urine analysis 
 
Before Discharge 
 
Urine pregnancy test 
(females only) 
 
Before Discharge  
 
ECG 
At least 10 minutes in 
supine position prior to 
recording 
Before Discharge 
 
Information on the risks of 
smoking, smoking cessation 
advice and debriefing. 
 
Before Discharge  
 
Distribution of product use 
diary  
To be completed by the 
subject every day from time 
of Discharge on Day 6 until 
next visit. All CHTPs 1.2, 
CC and any 
tobacco/nicotine containing 
products have to be 
recorded 
6:30 AM - 
Discharge 
 
Collection of used CC butts 
For accountability 
6:30 AM - 
Discharge 
 
Collection of used CHTP 1.2 
For accountability 
 
 
Discharge at Day 6 
 
Abbreviations: 4-HNE = 4-hydroxy-2-nonenal; AE = Adverse event; Apo A1 = Apolipoprotein A1; Apo B = 
Apolipoprotein B; BMI = Body mass index; BoExp = Biomarker (s) of exposure; CC = Combustible cigarette(s); 
CHTP 1.2 = Carbon Heated Tobacco Product 1.2; CYP2A6 = Cytochrome P450 2A6; ECG = Electrocardiogram; FEV1 = 
Forced expiratory volume in 1 second; FVC = Forced vital capacity; HbA1C = Hemoglobin A1C; HDL = High density 
lipoprotein; hs-CRP = High sensitive C-reactive protein; IP = Investigational product; ITUQ = Intent to Use Questionnaire; 

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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 6 
 
LDL = Low density lipoprotein; SAE = Serious adverse event; sICAM-1 = Soluble inter-cellular adhesion molecule-1; 
TAC = Total anti-oxidant capacity; TC = Total cholesterol; TG = Triglycerides; VAS = Visual Analogue Scale; WBC = 
White blood cell 
9.3 
Ambulatory Period (from Time of Discharge on Day 6 to the Day 91 
(the Second Day of Visit 4) 
For Visit 2 (Day 30 and Day 31), Visit 3 (Day 60 and Day 61) and Visit 4 (Day 90 and Day 
91), a time window of +/- 5 days will be allowed with respect to the day of randomization. The 
time of opening and end of the visit are given as an estimate. 
Table 15 shows the assessments that will be performed on Day 30 (the first day of Visit 2) and 
Day 60 (the first day of Visit 3) of the ambulatory period. 
Table 15 
Time Schedule –The First Day of Visit 2 (Day 30), The First Day of 
Visit 3 (Day 60) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 30 / Day 60 
 
Prior to 8:30 AM 
 
Start of Day 30 (the first day 
of Visit 2) / Day 60 (the first 
day of Visit 3) 
No product use restriction 
prior to the opening of the 
visit 
Product use will be allowed 
on site in the CHTP 1.2 and 
CC arm from the time of 
check-in in the morning to 
around 11:00 PM 
The use of CHTP 1.2 in 
smokers allocated to CC is 
forbidden 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Concomitant medications 
 

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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 30 / Day 60 
 
09:00 AM ± 30 min 
 
Start of 24-hour urine sample 
collection for Day 30 (the first 
day of Visit 2) / Day 60 (the 
first day of Visit 3) 
The subject must empty 
his/her bladder and discard 
the urine prior to starting 
urine collection. The urine is 
collected for 24 hours ±1 
hour 
During the visit  
 
CO breath test 
Irrespective of the time of 
product use 
During the visit  
√ 
COHb in blood 
Irrespective of the time of 
product use 
During the visit  
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required 
During the visit  
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position, at least 15 minutes 
after having stopped using 
IP 
During the visit  
 
Physical examination, body 
weight, and calculated BMI 
 
During the visit  
 
Urine pregnancy test 
(females only) 
 
8:00 PM - 11:00 PM 
 
QSU brief Questionnaire 
 
8:00 PM - 11:00 PM 
 
MCEQ Questionnaire 
 
11:00 PM 
 
End of use of IPs 
 
During the visit  
 
Product use diary  
To be completed by the 
subject. All IPs used 
including CHTPs 1.2, CC, 
and any tobacco/nicotine 
containing products have to 
be recorded 
During the visit  
 
Collection of empty/partially 
used CHTP 1.2 packs for 
accountability 
At any time of the day 
Partially used packs will be 
returned to the subject 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 30 / Day 60 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; CC = Combustible cigarette(s); CHTP 1.2 = Carbon Heated 
Tobacco Product 1.2; CO = Carbon monoxide; COHb = Carboxyhemoglobin; IP = Investigational product; MCEQ = 
Modified Cigarette Evaluation Questionnaire; QSU-brief = Questionnaire of Smoking Urges (brief version); SAE = Serious 
adverse event 
Table 16 shows the assessments that will be performed on the second day of Visit 2 and of 
Visit 3 of the ambulatory period. 
Table 16 
Time Schedule – The Second Day of Visit 2 (Day 31), The Second 
Day of Visit 3 (Day 61) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 31 / Day 61 
 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Concomitant medications 
 
 
 
End of 24-hour urine sample 
collection for Day 30 (the first 
day of Visit 2) / Day 60 (the 
first day of Visit 3) 
The urine is collected for 24 
hours ±1 hour  
 
 
Urine sample to be taken 
from the 24-hour urine of Day 
30 (the first day of Visit 2) / 
Day 60 (the first day of Visit 
3) 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 
Prior to 11:30 AM 
√ 
Clinical laboratory 
parameters* (hematology, 
clinical chemistry) and 
cardiovascular clinical risk 
endpoints (hs-CRP, MPO, 
fibrinogen, homocysteine, 
LDL, HDL, sICAM-1) 
After at least 10 hours of 
fasting 
* Blood glucose, TG, TC, 
WBC, platelet count from 
safety will be also evaluated 
as clinical risk endpoints 
Prior to 11:30 AM 
 
Assessment of cough (VAS) 
Irrespective of the time of IP 
use 

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without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 31 / Day 61 
 
Before Discharge 
 
Safety urine analysis 
 
Before Discharge 
 
Information on the risks of 
smoking, smoking cessation 
advice and debriefing. 
 
Before Discharge 
 
Product use diary  
To be completed by the 
subject every day from time 
of Discharge until next visit. 
All IPs used including 
CHTPs 1.2, CC, and any 
tobacco/nicotine containing 
products have to be 
recorded. 
 
 
Discharge from Visit 2 / 
Visit 3 
 
Abbreviations: AE = Adverse event; CC = Combustible cigarette(s); CHTP 1.2 = Carbon Heated Tobacco Product 1.2; 
IP = Investigational product; SAE = Serious adverse event; VAS = Visual Analogue Scale 
Table 17 shows the assessments that will be performed on the first day of Visit 4 of the 
ambulatory period. 
Table 17 
Time Schedule – The First Day of Visit 4 (Day 90) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 90 
 
Prior to 8:30 AM 
 
Start of Day 90 (the first day 
of Visit 4) 
No product use restriction 
prior to the opening of the 
visit 
Product use will be allowed 
on site in the CHTP 1.2 and 
CC arm from the time of 
check-in in the morning to 
around 11:00 PM 

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without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 90 
 
The use of CHTP 1.2 in 
smokers allocated to CC is 
forbidden 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Concomitant medications 
 
09:00 AM ± 30 min 
 
Start of 24-hour urine sample 
collection for Day 90 (the first 
day of Visit 4) 
The subject must empty 
his/her bladder and discard 
the urine prior to starting 
urine collection. The urine is 
collected for 24 hours ±1 
hour 
Prior to 11:30 AM 
 
Intake of a cup of coffee 
made from 4.2 g (±10%) 
regular instant coffee; CAF 
content: 72 mg/2 g) with 150 
ml ±10 ml water. 
The time of intake of the cup 
of coffee must be recorded 
After 11:30AM  
√ 
CYP1A2 activity in plasma 
6 hours ±15 minutes after 
intake of the cup of coffee 
During the visit  
 
CO breath test 
Irrespective of the time of 
product use 
During the visit  
√ 
COHb in blood 
Irrespective of the time of 
product use 
During the visit  
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required 
8:00 PM - 11:00 PM 
 
Prochaska Questionnaire 
(Intent to Quit) 
 
8:00 PM - 11:00 PM 
 
QSU brief Questionnaire 
 
8:00 PM - 11:00 PM 
 
MCEQ Questionnaire 
 
8:00 PM - 11:00 PM 
 
FTND Questionnaire 
 
11:00 PM 
 
End of use of IPs 
 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 90 
 
During the visit  
 
Product use diary  
To be completed by the 
subject. All IPs used 
including CHTPs 1.2, CC, 
and any tobacco/nicotine 
containing products have to 
be recorded. 
During the visit  
 
Collection of empty/partially 
used CHTP 1.2 packs for 
accountability 
At any time of the day 
Partially used packs will be 
returned and/or new packs 
will be handed out to the 
subject for use until 11:00 
PM at the latest.  
End of day 
 
Collection of empty/partially 
used CHTP 1.2 packs used 
during the day for final 
accountability 
All packs must be returned 
to study staff at the end of 
Day 90. 
Abbreviations: AE = Adverse event; CAF = Caffein; CC = Combustible cigarette(s); CHTP 1.2 = Carbon Heated Tobacco 
Product 1.2; CO = Carbon monoxide; COHb = Carboxyhemoglobin; CYP1A2 = Cytochrome P450 1A2; FTND = 
Fagerström Test for Nicotine Dependence; IP = Ivestigational product; MCEQ = Modified Cigarette Evaluation 
Questionnaire; QSU-brief = Questionnaire of Smoking Urges (brief version); SAE = Serious adverse event 
Table 18 shows the assessments that will be performed on the second day of Visit 4 prior to 
Discharge from the ambulatory period. 
Table 18 
Time Schedule – The Second Day of Visit 4 (Day 91) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 91 
 
 
 
AE/SAE recording 
At any time of the day 
 
 
Concomitant medications 
At any time of the day 
 
 
End of 24-hour urine sample 
collection for Day 90 (the 
first day of Visit 4) 
The urine is collected for 24 
hours ±1 hour. The end of 
the 24-hour urine collection 
should be prior to smoking 

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without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 91 
 
the first CC/using other 
nicotine/tobacco-containing 
products. 
 
 
Urine sample to be taken 
from the 24-hour urine of 
Day 90 (the first day of Visit 
4) 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 
Bio-banking for biomarkers 
(if additional consent is 
obtained) 
Prior to 11:30 AM 
√ 
Clinical laboratory 
parameters* (hematology, 
clinical chemistry) and 
cardiovascular clinical risk 
endpoints (hs-CRP, MPO, 
fibrinogen, homocysteine, , 
LDL, HDL, HbA1c, sICAM-1, 
Apo A1, Apo B, 8-epi-
PGF2α, PGF2αǂ), clinical risk 
endpoints of oxidative stress 
(4-HNE, TAC) 
After at least 10 hours of 
fasting. 
* Blood glucose, TG, TC, 
WBC, platelet count from 
safety will be also evaluated 
as clinical risk endpoints 
ǂAs of 01 June 2016 blood 
samples for 8-epi-
PGF2α/PGF2α will no 
longer be collected. 
Prior to 11:30 AM 
√ 
Bio-banking for BoExp, 
clinical risk endpoints and 
other circulating proteins, 
and transcriptomics,  
lipidomics and DNA 
methylation sequencing 
If additional consent is 
signed 
After at least 10 hours of 
fasting 
Prior to 11:30 AM  
 
Spirometry pre- and post-
bronchodilatator (recording 
of FEV1, FVC, FEV1/FVC) 
Has to be done prior to use 
of CC or other 
nicotine/tobacco-containing 
products 
At rest in sitting position for 
at least 15 minutes prior to 
pulmonary function testing 
In sitting position 
All post-bronchodilator 
spirometry testing will be 
performed 15-30 minutes 

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without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 91 
 
post administration of 
salbutamol 
Prior to 11:30 AM  
√ 
CYP2A6 activity in plasma 
Has to be done prior to use 
of CC or other 
nicotine/tobacco-containing 
products  
Prior to 11:30 AM  
 
Assessment of cough (VAS) 
Irrespective of the time of CC 
or other nicotine/tobacco-
containing products use  
Before Discharge 
 
ITUQ Questionnaire 
 
Before Discharge 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position, at least 15 minutes 
after having stopped using 
CC or other 
nicotine/tobacco-containing 
products 
Before Discharge 
 
Physical examination, body 
weight, and calculated BMI 
 
Before Discharge 
 
Waist circumference 
 
Before Discharge 
 
Safety urine analysis 
 
Before Discharge 
 
Urine pregnancy test 
(females only) 
 
Before Discharge  
 
ECG 
At least 10 minutes in 
supine position prior to 
recording 
Before Discharge 
 
Information on the risks of 
smoking, smoking cessation 
advice and debriefing. 
 
 
 
Discharge from Visit 4 
 
Abbreviations: 4-HNE = 4-hydroxy-2-nonenal; AE = Adverse event; Apo A1 = Apolipoprotein A1; Apo B = 
Apolipoprotein B; BMI = Body mass index; BoExp = Biomarker (s) of exposure; CC = Combustible cigarette(s); CYP2A6 
= Cytochrome P450 2A6; ECG = Electrocardiogram; FEV1 = Forced expiratory volume in 1 second; FVC = Forced vital 
capacity; HbA1C = Hemoglobin A1C; HDL = High density lipoprotein; hs-CRP = High sensitive C-reactive protein; IP = 
Investigational product; ITUQ = Intent to Use Questionnaire; LDL = Low density lipoprotein; MPO = Myeloperoxidase; 

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without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 91 
 
SAE = Serious adverse event; sICAM-1 = Soluble inter-cellular adhesion molecule-1; TAC = Total anti-oxidant capacity; 
TC = Total cholesterol; TG = Triglycerides; VAS = Visual Analogue Scale; WBC = White blood cell 
9.4 
Safety Follow-Up Period 
All subjects participating in the product test on Day -3 will enter the 28-day Safety Follow-Up 
Period. 
After Discharge at Visit 4 or the date of early termination, subject will enter a 28-day Safety 
Follow-up Period during which there will be recording of spontaneously reported new 
AEs/SAEs and the active follow-up of ongoing AEs/SAEs by the study site.  
Any AEs or SAEs that are ongoing at the end of the 28 days of the Safety Follow-up Period 
will be managed as described in section 8.2.6. 
9.5 
Early Termination Procedures 
Early termination procedures will be as follows, unless the subject refuses to do so: 
Table 19 
Time Schedule - Early Termination Procedures 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Early Termination 
 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Concomitant medications 
 
During the visit 
√ 
Clinical laboratory 
parameters (hematology, 
clinical chemistry) 
After at least 10 hours of 
fasting 
 During the visit 
 
Spirometry pre- and post-
bronchodilatator (recording 
of FEV1, FVC, FEV1/FVC) 
Has to be done 1 hour of not 
smoking 
At rest in sitting position for 
at least 15 minutes prior to 
pulmonary function testing 
In sitting position 

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without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Early Termination 
 
All post-bronchodilator 
spirometry testing will be 
performed 15 - 30 minutes 
post administration of 
salbutamol 
During the visit 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position, at least 15 minutes 
after having stopped using IP 
During the visit 
 
ECG 
At least 10 minutes in supine 
position prior to recording 
During the visit 
 
Physical examination, body 
weight, and calculated BMI 
 
During the visit 
 
Safety urine analysis 
 
During the visit 
 
Urine pregnancy test 
(females only) 
 
During the visit 
 
Information on the risks of 
smoking, smoking cessation 
advice and debriefing. 
 
During the visit 
 
Discharge from the site 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; ECG = Electrocardiogram; FEV1 = Forced expiratory 
volume in 1 second; FVC = Forced vital capacity; SAE = Serious adverse event 

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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
The contract research organization (CRO) Clinical Research Associate (“Monitor”) will be 
responsible for the monitoring of the study. Monitoring will be performed according to the 
CRO’s SOPs and as per the agreed monitoring plan with the Sponsor. 
The PI 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 satisfactorily met. 
The PI or designee shall access medical records for the Monitor in order that entries in the 
CRFs may be verified. The Investigator or designee, as part of his/her 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 and included 
in the study, a site initiation visit will be conducted by the Monitor and, if necessary, with the 
Sponsor or its authorized representative. The purpose of the site initiation visit is described in 
the monitoring plan. 
During the study, the Monitor will have regular contact with the study site, including interim 
monitoring visits. The purpose of these visits is described in the monitoring plan. 
Communication by telephone, mail and e-mail may be used as needed to supplement site visits. 
The PI and study personnel will cooperate with the Monitor, provide all appropriate 
documentation and will be available to discuss the study. 
The Monitor and the Sponsor’s personnel will be available between visits, should the PI or 
other collaborators at the sites need information and/or 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 PI, or a designated member of the Investigator’s collaborators, must be available during 
the monitoring visit to review the data and resolve any queries and to allow direct access to the 
subject’s records for source data verification. 

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10.2 Training of Collaborators 
A formal meeting (Investigator’s meeting) will be conducted prior to site initiation. During 
this meeting, the Sponsor or its authorized representative will discuss the requirements of the 
clinical study protocol and related documents and will also provide training to the relevant 
systems and other study-specific procedures. The activities of this meeting will be described 
in the monitoring plan. 
Further to the Investigator’s meeting, the Investigator or designee will ensure that appropriate 
training relevant to the study is provided to all collaborators involved in the study, and that any 
new information relevant to the performance of this study is forwarded in a timely manner to 
the site collaborators. The PI or designee will maintain a record of all individuals involved in 
the study. 
10.3 Audits and Inspections 
Good Clinical Practice regulations require independent inspections of clinical program 
activities. Such inspections may be performed at any time before, during and/or after the study. 
Authorized representatives of the Sponsor, regulatory agencies and/or an IRB/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 and site collaborators 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. By signing 
this protocol, the PI or designee understands and agrees to provide access to the necessary 
documentation and files. 

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without the written consent of Philip Morris Products S.A. 
11 DATA MANAGEMENT ACTIVITIES 
All data management activities will be described in details in the data management plan (DMP) 
and documents specified therein. The electronic systems used, CRF and subject reported 
outcome (SRO), to collect subject data will be FDA 21 CFR Part 11 compliant. 
11.1 Data Capture 
11.1.1 
Case Report Forms and Study Records 
With the exception of the SRO data, all results from the clinical assessments will be recorded 
in the source documents by the PI(s) or authorized designee(s), and then captured in the CRFs 
at the study site. 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 
transferring the data to the CRF according to the CRF completion guidelines. 
The Investigator or designee has the 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 CRF must be 
signed by the Investigator or designee to attest that the data contained in the CRF are true and 
accurate. Any corrections made to source documents and/or CRFs must be recorded, without 
obscuring the original values, and must be accompanied by the date of change, reason for 
change and identification of the person making the change. The CRF data will be verified 
against the source documents at the study site by the Monitor. Instances of missing or unclear 
data will be discussed with the Investigator or designee for resolution. All SRO questionnaires 
will be provided to the subject in his/her local language. 
11.1.2 
Protocol Deviations 
Protocol deviations are defined as deviations from the study procedures as defined in this 
document, including but not limited to any violation of inclusion/exclusion criteria, 
assessments not performed or performed outside the scheduled time windows, or use of drugs 
that are known to affect study endpoints. 
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 

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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 CRF database but will not be formally reconciled with the CRF 
database (e.g., their description or occurrence date). The overall procedure for managing 
protocol deviations is described in the SOPs and/or agreed upon procedure of the CRO data 
management team. All deviations will be reviewed periodically, as determined at study start, 
to identify trends to improve monitoring and/or potential impact on the statistical analysis. 
11.2 Data Handling 
All study data will be managed by the data management (DM) CRO. The overall procedures 
for quality assurance of clinical study data are described in the SOPs of the DM-CRO. The 
DM- CRO will prepare a DMP, to be reviewed and approved by the Sponsor, prior to the start 
of data entry. This document will describe, in details, the data management-related procedures 
and processes. 
Data of all subjects enrolled including screening failures and AE during the study (from the 
time of informed consent to the end of the study of the subject) will be captured in the source 
documents and all AEs will be entered in the study database (CRF). 
All data collected during the study are declared property of the Sponsor, irrespective of the 
location of the database and the DM-CRO. 
Additional details are covered in the DMP. 
11.2.1 
Data Verification 
The data will be verified as defined in the DMP and data verification plan. Discrepancy will 
be generated electronically, and issued as queries to the site, as necessary. 
Data queries will be raised for discrepant or missing data. All changes to data will be captured 
in the database with a comprehensive audit trail. 
11.2.2 
Coding 
Adverse events, medical/surgical history, and prior/concomitant medication will be classified 
according to the terminology of the latest version of the following dictionaries, at time of 
coding the first entry: 

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Adverse events, concomitant 
disease, medical history: 
Medical Dictionary for Regulatory Activities (MedDRA®) 
Medications: 
WHO Drug Dictionary Enhanced and Anatomical 
Therapeutic and Chemical classification system 
11.2.3 
Database Lock 
When all outstanding data management issues have been resolved and quality review and 
cleaning activities are complete, the database or selected data is/are declared soft-locked. 
Access to change data in the soft-locked database or to change selected data at this time is 
limited. 
After data review by the Sponsor, resolution of all raised queries and QC of the changed data, 
the database or selected data thereof will be declared locked upon Sponsor approval, as 
applicable. 
Any changes to the database after that time can only be made by written agreement between 
the Sponsor and the DM-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 and defined in the data transfer agreement. The clinical database will be 
provided in the “Clinical Data Interchange Standards Consortium 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 clinical study report. The statistical evaluation 
will be performed using SAS®, version 9.2 or later. 
The data from this study could be used for the purpose of providing data for the design and 
interpretation of assessment studies of PMI candidate modified risk tobacco products. 
12.1.1 
Stratification Criteria 
For the analysis of the primary study endpoints, the following stratification criteria will be 
used: 
1. Gender (male; female) 
2. Average daily CC consumption over the 6 weeks prior to Admission as reported on the 
Admission Day (smoking 10 to 19 CC/day vs. > 19 CC/day) 
3. Product used category (to be further described in the SAP). 
12.1.2 
Definitions for Statistical Data Analysis 
Baseline: 
Unless specified, Baseline is defined as the last available time point prior to first product use 
in the Exposure Period. 
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by product arm and subject, unless otherwise 
specified. 
Descriptive statistics (number of subjects [n], number and percent of subjects with missing 
data, the arithmetic mean, arithmetic standard deviation (SD), median, first and third quartiles, 
minimum and maximum for continuous data, including geometric mean and coefficient of 
variation (CV) for data analyzed in the log scale; frequency counts and percentages for 
categorical data) will be presented overall and at each time point, where applicable. 
For BoExp, the geometric mean and CV will be presented in addition to the mean and SD. 

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without the written consent of Philip Morris Products S.A. 
12.1.4 
Handling of Missing Values and of Values outside the Detection Limits 
Descriptive summaries will be provided for the evaluable data with no imputation. 
Missing values for the endpoints analyzed via the mixed model method will not be directly 
imputed as they are handled within the analysis itself. 
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. If 50% or more data are below LLOQ or 
above ULOQ, only the number (%) of value below LLOQ or above ULOQ will be reported in 
the summaries, together with minimum and maximum of the observed values. 
For questionnaire data, total scores and domain or subscale scores may use a certain degree of 
imputation by averaging across individual item scores. 
Further details will be provided in the SAP. 
12.1.5 
Significance Level for Inferential Analysis 
Unless stated otherwise, all statistical tests will conducted using a one-sided test with 2.5% 
type I error probability, 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 the one-sided 2.5% type I error probability. 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 detect a reduction of 50% or more in the 
levels of MHBMA, 3-HPMA, S-PMA, and COHb on Day 5 and in total NNAL after  90 days 
in smokers switching from CC to the CHTP 1.2 as compared to smokers continuing to use CC, 
using a one-sided test with 2.5% type I error probability. 
Table 20 describes the expected coefficients of variation (CV) and mean ratios (MR) between 
CHTP 1.2 and the one control arm 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 20 
Expected Mean Ratios and Coefficients of Variation for CHTP 
1.2/CC after 5 Days of exposure  
 
CHTP 1.2/CC 
MR (CV) 
COHb 
0.40 (0.32) 
3-HPMA 
0.30 (0.50) 
MHBMA 
0.15 (0.70) 
S-PMA 
0.20 (0.70) 
Abbreviations: 3-HPMA = 3-hydroxypropylmercapturic acid; CC = Combustible cigarettes; COHb = Carboxyhemoglobin; 
CV = Coefficients of variation; MHBMA = Monohydroxybutenyl mercapyuric acid; MR = Mean ratios; S-PMA = S-
phenylmercapturic acid; CHTP 1.2 = Carbon Heated Tobacco Product 1.2. 
Table 21 describes the expected coefficients of variation (CV) and mean ratios (MR) in total 
NNAL after 90 days between CHTP 1.2 and the one control arm based on a randomized, 
controlled, forced-switching, open-label, parallel-group, single-center study in 90 male and 
female adult smokers to evaluate six biomarkers of tobacco smoke exposure over a 12-week 
period of unrestricted smoking in the participants' normal life setting [48]. 
Table 21 
Expected Mean Ratios and Coefficients of Variation for CHTP 
1.2/CC after 90 Days of exposure 
 
CHTP 1.2/CC 
MR (CV) 
Total NNAL 
0.30 (0.60) 
Abbreviations: Total NNAL = Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; MR = Mean ratio; CHTP 1.2 = Carbon 
Heated Tobacco Product 1.2; CC = Combustible cigarettes; CV = Coefficient of variation. 
The power to detect a reduction was computed. 
Table 22 describes the expected power to detect a reduction of 50% or more in the levels of 
MHBMA, 3-HPMA, S-PMA, and COHb in CHTP 1.2 arm compared to the CC arm after 5 
days of exposure and total NNAL after 90 days of exposure, with a one sided test with 2.5% 
type I error probability using the assumptions from YVD-CS01-EU and, and 120 randomized 
subjects in a 2:1 ratio (80 in CHTP 1.2 arm and 40 in CC arm). It is assumed that a minimal 
number of subjects will be excluded from the PP set in confinement for both arms and CC in 
ambulatory, whereas at least 50% will remain in the PP set in ambulatory for CHTP 1.2, 
therefore a 2:1 randomization ratio was chosen. 

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Table 22 
Expected Power 
Reduction 
Assumptions 
50% 
51% 
52% 
53% 
54% 
55% 
YVD-CS01-EU 
94% 
88% 
81% 
70% 
56% 
38% 
The test-wise powers to detect a reduction of 50% or more in the levels of MHBMA, 3-HPMA, 
S-PMA, and COHb on Day 5 and in total NNAL after 90 days in smokers switching from CC 
to the CHTP 1.2 as compared to smokers continuing to use CC, using a one-sided test with 
2.5% type I error probability using the assumptions from YVD-CS01-EU, and 120 randomized 
subjects in a 2:1 ratio (80 in CHTP 1.2 arm and 40 in CC arm) are described in Table 23. 
Table 23 
Test-Wise Power 
Parameter 
Test-Wise Power 
COHb 
96% 
3-HPMA 
>99% 
MHBMA 
>99% 
S-PMA 
>99% 
Total NNAL 
98% 
Given the above calculation, the sample size was considered sufficient to have more than 80% 
power to detect a reduction of 50% or more in the levels of MHBMA, 3-HPMA, S-PMA, and 
COHb in CHTP 1.2 arm compared to the CC arm after 5 days of exposure, and in the levels of 
total NNAL in the CHTP 1.2 arm compared to the CC arm after 90 days of exposure, using a 
one sided test with 2.5% type I error probability. 
12.3 Analysis Populations 
The study population characteristics will be described on the Safety Population and on the Per-
Protocol population. The per-protocol population will be the primary analysis set for 
biomarkers of exposure, clinical risk endpoints, FTND, MCEQ, Cough and QSU-brief. The 
Full Analysis Set will be the primary analysis set for exposure, compliance to randomization 
arm, Prochaska and SES. Exposure and questionnaires, as a secondary analysis, will be 
described by randomization arm and product used category (to be further described in the SAP) 
using the full analysis set. 
Safety will be analyzed using the safety population. 

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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 CHTP 1.2 or CC, and have at least one valid non-
safety assessment (CHTP 1.2, CC). 
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 CHTP 1.2, 
irrespective of whether or not the subject was exposed post-randomization. Subjects in the 
safety population will be analyzed according to actual exposure. 
12.4 Primary Endpoints 
12.4.1 
Primary Endpoints Analysis Variables 
The primary endpoints are: 
 
MHBMA (concentration adjusted for creatinine in 24-hour urine) on Day 5 
 
3-HPMA (concentration adjusted for creatinine in 24-hour urine) on Day 5 
 
S-PMA (concentration adjusted for creatinine in 24-hour urine) on Day 5 
 
COHb on Day 5 
 
Total NNAL level at Visit 4 
See section 3.1. 
Evaluation criterion: 
The study is designed to be able to detect a reduction of 50% or more in the levels of MHBMA, 
3-HPMA, S-PMA, and COHb after 5 days of exposure, and in total NNAL after 90 days in 
smokers switching from CC to the CHTP 1.2 as compared to smokers continuing to use CC, 
using a one-sided test with 2.5% type I error probability. 

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12.4.2 
Baseline Comparability 
Not applicable. 
12.4.3 
Descriptive Summary 
Primary endpoints will be summarized as described in sections 12.1.3 and 12.3. 
12.4.4 
Confirmatory Analyses 
The hypothesis to be tested for each of the BoExp of the primary and secondary objectives that 
the geometric mean level on Day 5 of the BoExp (MHBMA; 3-HPMA; S-PMA; COHb) and 
at Visit 4 of the BoExp total NNAL, respectively, for CHTP 1.2 is lower relative to CC. 
Analysis of BoExp will be conducted on the natural log scale. In order to test the following 
hypothesis: 
 
Null hypothesis (H0): m1 ≥ m2 
 
Alternative hypothesis (H1): m1 < m2 
Where m1 and m2 are the geometric means of the BoExp levels on Day 5 and at Visit 4, 
respectively, for CHTP 1.2 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: gender, average cigarette 
consumption over the previous 6 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. 
12.5 Secondary Safety Endpoint(s) 
12.5.1 
Secondary Endpoint Analysis Variables 
See section 3.2. 
More details on derivation rules will be given in the SAP. 
12.5.2 
Baseline Comparability 
Not applicable. 

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12.5.3 
Descriptive Analysis 
In general, secondary endpoints will be summarized as described in sections 12.1.3 and 12.3. 
12.5.4 
Safety Analysis 
In general, all safety data will be listed and tabulated by product arm, using the approach 
described sections 12.1.3 and 12.3. Safety variables collected during the exposure period 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. 
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 3.3. 
More details on derivation rules will be given in the SAP. 
12.6.2 
Baseline Comparability 
Not applicable. 
12.6.3 
Descriptive Analysis 
In general, exploratory endpoints will be summarized as described sections 12.1.3 and 12.3. 

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12.7 Demographics and Baseline Characteristics 
Demographic and other Baseline characteristics will be summarized as described sections 
12.1.3 and 12.3. 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 Investigator’s and Study Administrative Structure 
13.1.1 
Investigator 
Investigator: 
 
BioVirtus Research Site Sp. z o.o. 
 
 
Poland 
Phone: +48 
 
Fax.: +48 
 
E-mail:
@biovirtus.eu 
Satellite site: 
BioVirtus Research Site Sp. z.o.o. 
 
 
Poland 
Phone: +48 
 
13.1.2 
Sponsor 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Tel: +41 (58) 242 2111 
Fax: +41 (58) 242 2811 
 
Lead Clinical Scientist 
Phone: +41 
 
Mobile: +41 
 
E-mail: 
@pmi.com 

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,
 
Clinical Scientist 
Phone: +41 
 
E-mail: 
@contracted.pmi.com 
 
 
Biostatistician 
Phone: +41 
 
Mobile: +41 
 
E-mail: 
@pmi.com 
  
Medical Safety Officer 
Phone: +41 
 
Mobile: +41 
 
E-mail:
@pmi.com  
 
Clinical Study Manager 
Phone: +41
 
Mobile: +41 
 
E-mail: 
@pmi.com 
  
Clinical Study Manager 
Phone: +41 
 
Mobile: +41
  
E-mail: 
@pmi.com 
13.1.3 
Reception and Handling of SAE and pregnancy reports 
Any reports of SAEs or pregnancies will be handled by: 
 
 
 
 
 
Fax: 
 
+41 
 
E-mail: 
 
Details of the laboratories conducting the clinical safety laboratory services and 
biopharmaceutical analyses are shown in Appendix B. 
13.2 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects' state of 
health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subject in writing and signed by the subject, in compliance with all local and 
national data protection and privacy legislation. 

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hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
The name of the subjects participating in this study will be kept confidential. Subjects will be 
identifiable by the Sponsor (or Sponsor’s authorized representative) on CRFs and other 
documents by their subject (or randomization) number/code, sex and age, but not by name, 
initial, or any other details relating to identifiable person (e.g., address, social security number, 
medical chart number, etc.). The assignment of a subject number/code for subject identification 
will be based on the appropriate data protection rules. 
The blood samples for transcriptomics,  lipidomics and DNA methylation sequencing analyses, 
and the data related to these samples will be anonymized. Anonymized data and samples are 
initially single or double coded where the link between the subjects’ identifiers and the unique 
code(s) is subsequently deleted. This is applicable for the blood bio-banking for 
transcriptomics, lipidomics and DNA methylation sequencing analyses only. 
Any documents that allow full identification of the subject (e.g., the subject’s signed ICF) must 
be maintained in confidence by the Investigator. If any document relating to this study shows 
a subject’s name or any other details relating to an identifiable person (e.g., address, social 
security number, medical chart number, etc.), the name or other identifiable details must be 
obscured before a copy of that document is supplied to the Sponsor or the Sponsor’s authorized 
representative. 
13.3 Access to Source Documentation 
Subjects will be informed that, during the course of the clinical study, the Sponsor, any 
authorized representatives of the Sponsor, IRB/IEC or regulatory authorities may inspect their 
medical records to verify the information collected and ensure that all personal information 
made available for inspection is handled in the strictest confidence and in accordance with 
national and local data protection and privacy legislation. 
The Investigator and all site collaborators involved with the study must permit direct access to 
source data/documents for study related monitoring, audits, IRB/IEC review and regulatory 
inspection(s). 
13.4 Record Retention 
All records of data, source data and source documents (original records or certified copies), in 
any form (including, but not limited to, written, electronic, magnetic, optical records and scans 
and ECGs) that describe or record the methods, conduct, and/or results of the study, the factors 
affecting the study and the actions taken will be maintained by the Investigator/study site for 
the study, as required by ICH/GCP and any other applicable local or national regulations. 

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without the written consent of Philip Morris Products S.A. 
Essential study documents/records, which individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced, are described in section 8 of the 
ICH Tripartite Guideline for Good Clinical Practice [1]. 
Essential documents must be retained by the Investigator for a minimum of: 
 
At least 15 years after completion or discontinuation of the study 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. 
Examples of essential records/documents include, but are not limited to: 
 
Signed informed consent documents for all subjects and master ICF 
 
Subject identification code list, Screening log and Enrolment log (if applicable) 
 
Record of all communications between the Investigator and the IRB/IEC, composition of 
the IRB/IEC 
 
Record of all communications/contact between the Investigator, the Sponsor, and its 
authorized representatives 
 
List of sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in the 
study, curricula vitae, and their signatures 
 
Investigator logs 
 
CRFs, study specific questionnaires (and associated data/scoring) 
 
AE reports and details of follow-up investigations, details of concomitant medication 
 
All other source documents (e.g., ECGs, consultation reports, physical examination, 
laboratory records) or any electronically captured study source data 
 
Clinical laboratory reports, laboratory normal ranges 
 
Original medical/hospital records, if applicable (the medical files of study subjects must be 
retained in accordance with local legislation and in accordance with the maximum period 
of time permitted by the hospital or study site) 
 
Record of any body fluids or tissue samples collected and retained 
 
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. 

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without the written consent of Philip Morris Products S.A. 
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 for 15 years after the CSR has been finalized. 
13.5 Clinical Study Report 
The Sponsor must ensure that a CSR for this study is prepared regardless of whether the study 
is completed or prematurely terminated. 
The CSR will be written based on standards of the ICH Guideline for the “Structure and 
Content of Clinical Study Reports”. In certain circumstances, an abbreviated CSR may be 
acceptable. Submission of the CSR to the IRB/IEC will complied with as requested by local 
requirements. 
13.6 Financial Disclosure 
Investigators and designees are required to provide financial disclosure information to the 
Sponsor. In addition, the Investigators and designees must provide the Sponsor with a 
commitment to promptly update this information if any relevant changes occur during the 
course of the investigation and for one year following the completion of the study. 
13.7 Publication and Disclosure Policy 
This document contains information that is confidential and proprietary to the Sponsor. This 
information is being provided solely for the purpose of evaluation and/or conducting this 
clinical study for the Sponsor. Disclosure of the content of this document is allowed only to 
study personnel, IRB/IEC, or duly authorized representatives of regulatory agencies for this 
purpose under the condition that confidentiality is maintained. The contents of this document 
may not be used in any other clinical study, disclosed to any other person or entity without the 
prior written permission of the Sponsor. The foregoing shall not apply to disclosure required 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
by any regulations; however, prompt notice will be given to the Sponsor prior to any such 
disclosure. 
The Sponsor plans to disclose details of the study protocol on a web-based, publicly available, 
clinical trial register database (e.g., ClinicalTrials.gov). 
13.8 Insurance 
The Sponsor is responsible for AEs and health damage of the subjects that are associated with 
the CHTP 1.2 product or with study procedures which are used during the study, except for 
AEs and health damage of the subjects caused by a negligent or an intentional misconduct 
and/or significant deviation to the protocol of the Investigator or the clinical study site or the 
subjects. The Sponsor has taken out insurance to cover any bodily injury and property damage 
caused by the operations carried out by the insured. 

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14 REFERENCE LIST 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
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disclosed without the written consent of Philip Morris Products S.A. 
Appendix A 
Schedule of Events 
Table A1 
Study Assessments (Separate Table [Table A2] Shown for 24-hour Urine Collections) 
 
Screening 
Confinement Period 
 
Ambulatory Period 
Safety 
Follow-up r 
Visit (Time Window) 
Screening 
Visit 
Visit 1 
 
 
Visit 2 
(Day 30 ± 5 
days) 
Visit 3 
(Day 60 ± 5 
days) 
Visit 4 
(Day 90 ± 5 
days) 
 
Study Day 
-45 to -4 
-3 
-2 
-1 
1 2 3 4 5 
6 p 
30 q 
31 q 
60 q 
61 q 
90 q 
91 q 
91 to 119 
Informed consent for study 
participation and three 
informed consents for bio-
banking 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission/Discharge 
 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
Information on the risk of 
smoking/smoking cessation 
advice and debriefing 
● 
● 
 
 
 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
Inclusion/exclusion criteria 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization procedures 
 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Allocation to study arms 
 
 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical 
history 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant diseases 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-Economic 
Questionnaire 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
 
 
 

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Screening 
Confinement Period 
 
Ambulatory Period 
Safety 
Follow-up r 
Visit (Time Window) 
Screening 
Visit 
Visit 1 
 
 
Visit 2 
(Day 30 ± 5 
days) 
Visit 3 
(Day 60 ± 5 
days) 
Visit 4 
(Day 90 ± 5 
days) 
 
Study Day 
-45 to -4 
-3 
-2 
-1 
1 2 3 4 5 
6 p 
30 q 
31 q 
60 q 
61 q 
90 q 
91 q 
91 to 119 
Vital signs a 
● 
● 
● 
● 
● ● ● ● ● 
● 
● 
 
● 
 
 
● 
 
Physical examination 
● 
● 
 
 
 
 
 
 
 
● 
● 
 
● 
 
 
● 
 
Body height and weight b 
● 
● 
 
 
 
 
 
 
 
● 
● 
 
● 
 
 
● 
 
Waist circumference 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
Spirometry c 
● 
 
 
 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
Prior/concomitant medication 
● 
● 
● 
● 
● ● ● ● ● 
● 
● 
● 
● 
● 
● 
● 
● 
B/U: Hematology, clinical 
chemistry, safety urine 
analysis 
● 
 
 
● 
 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
Electrocardiogram 
● 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
Chest X-ray d 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B: HIV, hepatitis B and C 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine cotinine screening test 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U: Urine drug screening 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B: Serum: Pregnancy test 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U: Pregnancy test 
 
● 
 
 
 
 
 
 
 
● 
● 
 
● 
 
 
● 
 
Alcohol urine or breath test 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FTND 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 

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Screening 
Confinement Period 
 
Ambulatory Period 
Safety 
Follow-up r 
Visit (Time Window) 
Screening 
Visit 
Visit 1 
 
 
Visit 2 
(Day 30 ± 5 
days) 
Visit 3 
(Day 60 ± 5 
days) 
Visit 4 
(Day 90 ± 5 
days) 
 
Study Day 
-45 to -4 
-3 
-2 
-1 
1 2 3 4 5 
6 p 
30 q 
31 q 
60 q 
61 q 
90 q 
91 q 
91 to 119 
Questions about smoking 
habits 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intention to quit smoking in 
the next 6 months using 
Prochaska’s Questionnaire 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
Identification of the current 
CC brand 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CHTP 1.2 demonstration 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CHTP 1.2 product test e 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Question on product 
Preference 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of CC butts for 
accountability 
 
● 
● 
● 
● ● ● ● ● 
● 
 
 
 
 
 
 
 
Collection of used CHTP 1.2 
sticks for accountability 
 
● 
 
 
● ● ● ● ● 
● 
 
 
 
 
 
 
 
Collection of empty/partially 
used CHTP 1.2 packs for 
accountability 
 
 
 
 
 
 
 
 
 
 
● 
 
● 
 
● 
 
 
CO breath test f 
 
● 
● 
● 
● ● ● ● ● 
 
● 
 
● 
 
● 
 
 
B: BoExp in blood: COHb g 
 
 
● 
● 
● ● ● ● ●  
 
● 
 
● 
 
● 
 
 

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Screening 
Confinement Period 
 
Ambulatory Period 
Safety 
Follow-up r 
Visit (Time Window) 
Screening 
Visit 
Visit 1 
 
 
Visit 2 
(Day 30 ± 5 
days) 
Visit 3 
(Day 60 ± 5 
days) 
Visit 4 
(Day 90 ± 5 
days) 
 
Study Day 
-45 to -4 
-3 
-2 
-1 
1 2 3 4 5 
6 p 
30 q 
31 q 
60 q 
61 q 
90 q 
91 q 
91 to 119 
B: BoExp to nicotine in 
plasma: nicotine, cotinine h 
 
 
 
● 
● ● ● ● ● 
● 
● 
 
● 
 
● 
 
 
U: All urinary BoExp in 24-
hour urine (defined as 
primary and secondary 
endpoints, and BoExp to 
nicotine) (see Table A2) 
 
 
● 
● 
● ● ● ● ● 
 
● 
 
● 
 
● 
 
 
B: Serum: Clinical risk 
endpoints: hs-CRP, MPO, 
blood glucose, LDL, HDL,  
 
 
 
● 
 
 
 
 
 
 
 
● 
 
● 
 
● 
 
B: Plasma: Clinical risk 
endpoints: fibrinogen, 
homocysteine 
 
 
 
● 
 
 
 
 
 
 
 
● 
 
● 
 
● 
 
B: Serum: Clinical risk 
endpoint: sICAM-1 
 
 
 
● 
 
 
 
 
 
● 
 
● 
 
● 
 
● 
 
B: Clinical risk endpoint: 
HbA1C 
 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
 
B: Serum: Clinical risk 
endpoints: Apo A1, and 
Apo B 
 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
 
B: Serum: Biomarkers of 
oxidative stress: 4-HNE, 
TAC 
 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
● 
 

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Screening 
Confinement Period 
 
Ambulatory Period 
Safety 
Follow-up r 
Visit (Time Window) 
Screening 
Visit 
Visit 1 
 
 
Visit 2 
(Day 30 ± 5 
days) 
Visit 3 
(Day 60 ± 5 
days) 
Visit 4 
(Day 90 ± 5 
days) 
 
Study Day 
-45 to -4 
-3 
-2 
-1 
1 2 3 4 5 
6 p 
30 q 
31 q 
60 q 
61 q 
90 q 
91 q 
91 to 119 
B: Plasma: Clinical risk 
endpoints/Biomarkers of 
oxidative stress: 8-epi-
PGF2α, PGF2α i 
 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
● 
 
U: Clinical risk 
endpoints/Biomarkers of 
oxidative stress in 24-hour 
urine: 11-DTX-B2, 8-epi-
PGF2α, 8-OHdG (see Table 
A2) 
 
 
 
● 
●  
 
 
 
● 
 
● 
 
● 
 
● 
 
Intake of a cup of coffee 
 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
● 
 
 
B: CYP1A2 activity 
 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
● 
 
 
B: CYP2A6 activity 
 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
Product use diary j 
 
 
 
 
 
 
 
 
 
● 
● 
● 
● 
● 
● 
 
 
Intent to Use Questionnaire 
(ITUQ) 
 
 
● 
 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
QSU-brief Questionnaire k 
 
 
● 
● 
● ● ● ● ● 
 
● 
 
● 
 
● 
 
 
MCEQ (modified version) l 
 
 
● 
● 
● ● ● ● ● 
 
● 
 
● 
 
● 
 
 
Assessment of cough m 
 
 
● 
● 
● ● ● ● ● 
● 
 
● 
 
● 
 
● 
 
AE/SAE recording 
● 
● 
● 
● 
● ● ● ● ● 
● 
● 
● 
● 
● 
● 
● 
●  

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Screening 
Confinement Period 
 
Ambulatory Period 
Safety 
Follow-up r 
Visit (Time Window) 
Screening 
Visit 
Visit 1 
 
 
Visit 2 
(Day 30 ± 5 
days) 
Visit 3 
(Day 60 ± 5 
days) 
Visit 4 
(Day 90 ± 5 
days) 
 
Study Day 
-45 to -4 
-3 
-2 
-1 
1 2 3 4 5 
6 p 
30 q 
31 q 
60 q 
61 q 
90 q 
91 q 
91 to 119 
B: Bio-banking for BoExp, 
clinical risk endpoints and 
other circulating proteins n, o 
 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
U: Bio-banking for BoExp 
and clinical risk endpoints n 
 
 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
● 
 
B: Bio-banking for 
transcriptomics,  lipidomics 
and DNA methylation 
sequencing n, o 
 
 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
● 
 
Abbreviations: 4-HNE = 4-Hydroxy-2-nonenal; 8-epi-PGF2α = 8-epi-prostaglandine F2α; 8-OHdG = 8-Hydroxy-2’-deoxyguanosine; 11-DTX-B2 = 11-dehydro-thromboxane B2; 
AE = Adverse event; Apo: Apolipoprotein; B = Blood sample required; BMI = Body mass index; BoExp = Biomarker(s) of exposure; CC = Combustible cigarette(s); CHTP 1.2 = 
Carbon Heated Tobacco Product 1.2; CO = Carbon monoxide; COHb = Carboxyhemoglobin; CYP1A2 = Cytochrome P450 1A2; CYP2A6 = Cytochrome P450 2A6; DNA = 
Deoxyribonucleic acid; FTND = Fagerström Test for Nicotine Dependence; HbA1c = Hemoglobin A1c; HDL = High density lipoprotein; HIV = Human immunodeficiency virus; 
hs-CRP = High-sensitive C-reactive protein; LDL = Low density lipoprotein; MCEQ = Modified Cigarette Evaluation Questionnaire; MPO = Myeloperoxidase; PGF2α = 
prostaglandine F2α; QSU-brief = Questionnaire of Smoking Urges (brief version); SA = Smoking abstinence; SAE = Serious adverse event; sICAM-1 = Soluble inter-cellular 
adhesion molecule; TAC = Total anti-oxidant capacity; U = Urine sample required; WBC = White blood cell count; TC = Total cholesterol, TG = Triglycerides. 
a 
Systolic and diastolic blood pressure, pulse rate, and respiratory rate (systolic and diastolic blood pressure will also be analyzed as risk markers on Day -1, Day 6, Visit 2, Visit 
3, and Visit 4 (first day of the respective visits). 
b 
Including height (only at the Screening Visit). 
c 
Spirometry without bronchodilator will be performed at the Screening Visit (Visit 1) at least 1 hour after having stopped smoking and must be done prior to spirometry with 
bronchodilator. 
Spirometry post-bronchodilator will be done at Visit 1, on Day 6 and at Visit 4. On Day 6 and Visit 4, spirometry post-bronchodilator will be performed prior to product use 
(CC or CHTP 1.2). 
d 
Pre-study chest X-ray (with anterior-posterior and left lateral views) may be used if performed within 6 months prior to Screening. 

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e 
On Day -3 (Admission), after all inclusion/exclusion criteria (see section 5) are checked, eligible subjects will be enrolled and then perform a product test using up to 5 CHTP 1.2. 
After the product test, subjects not willing and ready to use the CHTP 1.2 will be discontinued. 
f 
CO breath test: During the confinement period on Days -2 to Day 5, the CO breath test will be conducted once per day, preferably in the evening around 08:00 PM ± 1.5 hour 
in conjunction (i.e., within 30 minutes) with COHb tests, where applicable. On Day -3 and during the ambulatory period at Visit 2, Visit 3. and Visit 4 (first day of the respective 
visits), the CO breath tests will be conducted once per day, irrespective of time of product use. 
g 
COHb: Assessments should be done in conjunction (i.e., within 30 minutes) with CO breath tests, where applicable. COHb will be assessed on a daily basis from Day -2 to Day 
5. From Day -2 to Day 5, one blood sample for the COHb assessment will be collected in the evening around 08:00 PM ± 1.5 hour. At Visit 2, Visit 3, and Visit 4 (first day of 
the respective visits), one blood sample for the COHb assessment will be collected during the visit, irrespective of the time of product use. 
h 
Nicotine/cotinine: From Day -1 to Day 5 (both study arms): one blood sample between 08:00 PM ± 1.5 hour. On Day 6 (both study arms): one blood sampling between 06:29 
AM ± 1.5 h . At Visit 2, Visit 3, and Visit 4 (first day of  the respective visits) in both study arms: one blood sample to be drawn during the visit, irrespective of the time of 
product use. 
i 
As of 01 June 2016, samples for this endpoint will no longer be collected 
j 
Daily during ambulatory period only (from Discharge on Day 6 to Discharge at Visit 4 . Use of any tobacco/nicotine containing products will be captured in the e-diary. 
k 
QSU-brief: Daily, from Day -2 to Day 5 and at every visit during the ambulatory period, i.e., Visit 2, Visit 3 and Visit 4 (first day of the respective visits). 
l 
MCEQ: Day -2 to Day 5 on a daily basis, and on Visit 2, Visit 3 and Visit 4 (first day of the respective visits) for all subjects. 
m 
Cough Questionnaire to be done daily from Day -2 to Day 6 prior product use but no later than 11: 30 AM. At Visit 2 Visit 3, and Visit 4 (second day of the respective visits) 
no later than 11:30 AM, irrespective of product use. 
n 
Samples will only be taken if additional consent for bio-banking is given by the subject. 
o 
Has to be done in at least 10 hours of fasting condition. 
p 
All examinations listed at the Day of Discharge (Day 6) will be conducted in subjects discontinuing the study. 
q 
The first and second day of each respective visit during the exposure period in the ambulatory setting.  
r 
Spontaneous reporting of new AEs/SAEs by the subject and active follow-up of ongoing AEs/SAEs by the site. 

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Table A2 
Schedule for 24-hour Urine Collection Assessments 
 
Baseline Period 24-hour 
Urine 
Confinement Exposure Period 
24-hour Urine 
Ambulatory Exposure Period 
24-hour-Urine 
Study Day 
Day -2 
(Day -2 to 
Day -1) 
Day -1 
(Day -1 to 
Day 1) 
Day 1 
(Day 1 to 
Day 2) 
Day 2 
(Day 2 to 
Day 3) 
Day 3 
(Day 3 to 
Day 4) 
Day 4 
(Day 4 to 
Day 5) 
Day 5 
(Day 5 to 
Day 6) 
Visit 2 
(First day 
to Second 
Day) 
Visit 3 
(First Day 
to Second 
Day) 
Visit 4 
(First Day 
to Second 
Day) 
BoExp in urine a 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Creatinine 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
11-DTX-B2, 
8-epi-PGF2 8-
OHdG 
● 
● 
 
 
 
 
● 
● 
● 
● 
Ames 
mutagenicity 
test 
 
● 
 
 
 
 
● 
 
 
● 
Bio-banking b 
 
● 
 
 
 
 
● 
 
 
● 
Abbreviations: 1-NA = 1-aminonaphthalene; 2-NA = 2-aminonaphthalene; Total 1-OHP = Total 1-hydroxypyrene; 3-HPMA = 3-hydroxypropylmercapturic acid; 4-ABP = 4-
aminobiphenyl; 8-epi-PGF2α = 8-epi-prostaglandine F2α; 8-OHdG = 8-hydroxy-2'-deoxyguanosine; 11-DTX-B2 = 11-dehydro-thromboxane B2; BoExp = Biomarker(s) of 
exposure; CEMA = 2-cyanoethylmercapturic acid; HEMA = 2-hydroxyethyl mercapturic acid; HMPMA = 3-hydroxy-1-methylpropyl-mercapturic acid; NEQ = Nicotine equivalents; 
Total NNAL = 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; Total NNN = N-nitrosonornicotine; MHBMA = Monohydroxybutenyl mercapturic acid; S-PMA = S-
phenylmercapturic acid. 
a 
MHBMA, 3-HPMA, S-PMA, total NNAL, total 1-OHP, total NNN, 4-ABP, 1-NA, 2-NA, o-tol, CEMA, HEMA, 3-hydroxybenzo(a)pyrene, HMPMA, NEQ. 
b 
Samples (5 tubes of 10 mL urine for each time point) will only be taken if additional consent for the relevant sample bio-banking is given by the subject. 
 

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without the written consent of Philip Morris Products S.A. 
Appendix B 
Participating Laboratories 
 
 
 
 
USA  
 
Phone: +1 
 
 
  
 
 
Switzerland 
Phone: +41 
 
 
   
 
 
Poland 
Phone: +48 
 
 
  
  
  
Canada 
 
Biobanking of samples: 
 
 
  
Germany 

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Appendix C 
Prochaska “Stage of Change” Questionnaire 
The Prochaska questionnaire is structured as follows: 
 
Currently smoking
Yes
No
Quit in last 6 months
(Action)
Quit more than 6 months
(Maintenance)
Seriously considering quitting 
next 6 months
Yes
No
(Precontemplation)
Planning to quit next 30 days
Yes
No
(Contemplation)
24 hour quit attempt past year
Yes
(Preparation)
No
(Contemplation)

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

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Appendix D 
Summary of Biomarkers of Exposure to HPHC 
HPHC [smoke phase] 
HPHC List 
Biomarker 
Matrix 
t1/2 
 
1,3-Butadiene [gas] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
Monohydroxybutenylme
rcapturic acid (MHBMA) 
Urine 
4 to 16 h 
 
1-Aminonaphthalene 
[particulate]  
FDA-18, 
FDA-93, HC 
PMI-58 
1-Aminonaphthalene (1-
NA) 
Urine 
Not 
described 
 
2-Aminonaphthalene 
[particulate] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
2-Aminonaphthalene (2-
NA) 
Urine 
9 h 
 
4-Aminobiphenyl 
[particulate] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
4-Aminobiphenyl  
(4-ABP) 
Urine 
26 h 
 
4-(methylnitrosamino)-
1-(3-pyridyl)-1-
butanone (NNK) 
[particulate] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
Total 4-
(methylnitrosamino)-1-
(3-pyridyl)-1-butanol 
(total NNAL) 
Urine 
10 to 18 
days 
 
 
 
 
 
 
 
Acrolein [gas] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
3-Hydroxypropyl-
mercapturic acid  
(3-HPMA) 
Urine 
10 h 
 
Acrylonitrile [gas] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
2-
Cyanoethylmercapturic 
acid (CEMA) 
Urine 
17 h 
 
Benzene [gas] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
S-Phenylmercapturic 
acid (S-PMA) 
Urine 
9 to 15 h 
 
Benzo[a]pyrene 
[particulate] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
3-
Hydroxybenzo[a]pyrene 
B[a]P 
Urine 
3 to 4 h 
 

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HPHC [smoke phase] 
HPHC List 
Biomarker 
Matrix 
t1/2 
 
Carbon monoxide 
[gas] 
FDA-18 
FDA-93 HC 
PMI-58 
WHO-18  
CO 
Breath 
/ 
 
Pyrene 
FDA-18 
FDA-93 HC 
PMI-58 
WHO-18 
Total 1-hydroxypyene  
( Total 1-OHP)  
Urine 
6 to 35 h 
 
Crotonaldehyde [gas] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
3-Hydroxy-1-
methylpropyl-
mercapturic acid (3-
HMPMA) 
Urine 
2 days 
 
Ethylene oxide [gas] 
FDA-93, 
PMI-58 
2-Hydroxyethyl-
mercapturic acid 
(HEMA) 
Urine 
5 h 
 
NNN [particulate] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
Total N-
nitrosonornicotine (total 
NNN) 
Urine 
15 h 
 
o-Toluidine [gas] 
FDA-93, 
PMI-58 
o-Toluidine (o-TOL) 
Urine 
10 to 16 h 
 
Nicotine [particulate] 
FDA-18, 
FDA-93, HC 
PMI-58 
Nicotine (NIC-P) 
Plasma 
1 to 2 h 
 
 
 
Cotinine (COT-P) 
3-OH Cotinine 
(3-OHCOTP) 
Plasma  
16 to 18 h 
- 
 
 
 
Nicotine equivalents 
(Neq) 
Urine 
16 h 
(estimated) 
 
 
 

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Appendix E 
Abnormal Laboratory Values 
ABNORMAL LABORATORY VALUES RATING: SERUM CHEMISTRY PARAMETERS 
Serum Chemistry * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-Threatening 
(Grade 4) 
Sodium – 
Hyponatremia [49] 
(mmol/L) 
< LLN - 130 
- 
< 130 - 120 
< 120 
Sodium – 
Hypernatremia [49] 
(mmol/L) 
> ULN - 150 
> 150 - 155 
> 155 – 160 
hospitalization 
indicated 
> 160 
Potassium – 
Hyperkalemia [49] 
(mmol/L) 
> ULN - 5.5 
> 5.5 - 6.0 
> 6.0 - 7.0 
hospitalization 
indicated 
> 7.0 
Potassium – 
Hypokalemia [49] 
(mmol/L) 
< LLN - 3.0 
< LLN - 3.0; 
symptomatic; 
intervention 
indicated 
< 3.0 - 2.5 
hospitalization 
indicated 
< 2.5 
Glucose – 
Hypoglycemia [49] 
(mg/dL) 
(mmol/L)  
< LLN – 55 
< LLN – 3.0 
< 55 – 40 
< 3.0 – 2.2 
< 40 – 30 
< 2.2 – 1.7 
< 30; 
< 1.7 
Glucose – 
Hyperglycemia [49] 
Fasting (mg/dL) 
(mmol/L) 
> ULN - 160 
> ULN - 8.9 
> 160 - 250 
> 8.9 - 13.9 
> 250 - 500 
> 13.9 - 27.8 
hospitalization 
indicated 
> 500 
> 27.8 
Creatinine increased [49] 
> 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 
> 6.0 x ULN 
Albumin - 
Hypoalbuminemia [49] 
(g/dL) 
(g/L) 
< LLN – 3 
< LLN - 30 
< 3 – 2 
< 30 - 20 
< 2 
< 20 
- 
Alkaline phosphatase 
increased [49] 
> ULN – 2.5 x 
ULN 
> 2.5 – 5.0 x ULN 
> 5.0 – 20.0 x 
ULN 
> 20.0 x ULN 
ALT/AST increased [49] 
> ULN – 3.0 x 
ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x 
ULN 
> 20.0 x ULN 

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Serum Chemistry * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-Threatening 
(Grade 4) 
Gamma-glutamyl 
transferase (GGT) 
increased [49] 
> ULN – 2.5 x 
ULN 
> 2.5 – 5.0 x ULN 
> 5.0 – 20.0 x 
ULN 
> 20.0 x ULN 
Blood bilirubin 
increased [49] 
(total and direct) 
> ULN – 1.5 x 
ULN 
> 1.5 – 3.0 x ULN 
> 3.0 – 10.0 x 
ULN 
> 10.0 x ULN 
Cholesterol high [49] 
(mg/dL) 
(mmol/L) 
> ULN - 300 
> ULN - 7.75 
> 300 - 400 
> 7.75-10.34 
> 400 - 500 
> 10.34-12.92 
> 500 
> 12.92 
Triglycerides – 
Hypertriglyceridemia [49] 
(mg/dL) 
(mmol/L) 
150 – 300 
1.71 – 3.42 
> 300 – 500 
> 3.42 – 5.70 
> 500 – 1000 
> 5.70 – 11.40 
> 1000 
> 11.4  
Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; BUN = Blood urea nitrogen; GGT = 
Gamma-glutamyl transferase; LLN = Lower limit of the normal range; ULN = Upper limit of the normal range. 
* Those parameters that are not listed do not have grading categories in the CTCAE will be reviewed by the Principal 
Investigator and only reported as an AE if considered to be clinically significant. 

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ABNORMAL LABORATORY VALUES RATING: HEMATOLOGY PARAMETERS 
Hematology* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
(Grade 4) 
Anemia (hemoglobin) 
(g/dL) 
(mmol) 
g/L 
< LLN-10.0 
< LLN-6.2 
< 100 
< 10-8.0 
< 6.2-4.9 
< 100-80 
< 8.0 
< 4.9 
< 80 Transfusion 
indicated 
Life threateming 
consequences; 
urgent 
intervention 
indicated 
Hemoglobin increase [49] 
(g/dL) 
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 decrease [49] 
(cell/mm3) 
10-9/l 
< LLN – 3000 
< LLN – 3.0 
< 3000 – 2000 
< 3.0 – 2.0  
< 2000 - 1000 
< 2.0 – 1.0  
< 1000 
< 1.0  
Lymphocytes increase [49] 
(cell/mm3) 
- 
> 4,000 – 20,000 
> 20,000 
- 
Lymphocytes decrease [49] 
(cell/mm3) 
10-9/l 
< LLN – 800 
< LLN – 0.8 
< 800 - 500 
< 0.8 – 0.5 
< 500 - 200 
< 0.5 – 0.2 
< 200 
< 0.2 
Neutrophils decrease [49] 
(cell/mm3) 
10-9/l 
< LLN – 1500 
< LLN – 1.5 
< 1500 - 1000 
< 1.5 – 1.0 
< 1000 - 500 
< 1.0 – 0.5 
< 500 
< 0.5 
Platelets decrease [49] 
(cell/mm3) 
10-9/l 
< LLN – 75,000 
< LLN – 75.0 
< 75,000 – 50,000 
< 75.0 – 50.0 
< 50,000 – 25,000 
< 50.0 – 25.0 
< 25,000 
< 25.0 
Abbreviations: LLN = Lower limit of the normal range; ULN = Upper limit of the normal range; WBC = White blood cell. 
* Those parameters that are not listed do not have grading categories in the CTCAE will be reviewed by the Principal 
Investigator and only reported as an AE if considered to be clinically significant. 

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ABNORMAL LABORATORY VALUES RATING: URINALYSIS PARAMETERS 
Urine * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-Threatening 
(Grade 4) 
Protein [49] 
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 
- 
Abbreviations: ADL = Activities of daily living; IV = Intravenous. 
* Those parameters that are not listed do not have grading categories in the CTCAE will be reviewed by the Principal 
Investigator and only reported as an AE if considered to be clinically significant.