A Controlled, 3-arm Parallel Group Study to Demonstrate Reduction in Exposure to Smoke Constituents in Healthy Smokers Switching to THS 2.2 or to Smoking Abstinence, Compared to Conventional Cigarettes for 5 Days in Confinement
Phase: NA
Conditions: Smoking
Sponsor: Philip Morris Products S.A.

 
 
Clinical Study Protocol 
ZRHR-REXC-04-JP 
 
Study title: 
A randomized, controlled, open-label, 3-arm parallel group, single-
center study to demonstrate reductions in exposure to selected 
smoke constituents in smoking, healthy subjects switching from 
conventional cigarettes to the Tobacco Heating System 2.2 (THS 
2.2) or smoking abstinence, compared to smokers continuing to use 
conventional cigarettes for 5 days in confinement   
Short study title: 
Reduced exposure study using THS 2.2 with 5 days in a 
confinement setting 
Registration number: Not assigned 
Product name: 
Tobacco Heating System 2.2 (THS 2.2)  
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Version number: 
Final 2.0 
Revision date: 
08 July 2013 
Authors: 
, PhD, Manager Clinical Science 
, MEng MSc, Biostatistician 
, MD, Medical Safety Officer 
, Medical Writer 
 
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. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 2 of 171 
 
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. 
 
SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
 
Name of Product: 
Tobacco Heating System 2.2 (THS 2.2) 
Study Title: 
A randomized, controlled, open-label, 3-arm parallel group, single-center study to 
demonstrate reductions in exposure to selected smoke constituents in smoking, healthy 
subjects switching from conventional cigarettes to the Tobacco Heating System 2.2 (THS 
2.2) or smoking abstinence, compared to smokers continuing to use conventional 
cigarettes for 5 days in confinement  
Short Study Title: 
Reduced exposure study using THS 2.2 with 5 days in a confinement setting 
Study Number: 
ZRHR-REXC-04-JP 
Primary Objective: 
The primary objective of this study is: 
• To demonstrate the reduction of primary biomarkers of exposure (BoExp) in smokers 
switching from conventional cigarettes (CC) to THS 2.2 as compared to smokers 
continuing to smoke CC. 
 
Secondary Objectives: 
The secondary objectives of this study are: 
• To determine the reduction of secondary BoExp on Day 5 in smokers switching from 
CC to THS 2.2 as compared to smokers continuing to smoke CC. 
• To describe the levels of primary and secondary BoExp over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers continuing to smoke 
CC. 
• To determine the levels of nicotine on Day 5 in smokers switching from CC to THS 
2.2 as compared to smokers continuing to smoke CC and to describe their levels over 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 3 of 171 
 
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 exposure period from Day 1 to Day 5. 
• To describe the levels of primary and secondary BoExp over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers switching from CC 
to smoking abstinence (SA). 
• To describe the pharmacokinetic (PK) profiles of the nicotine and cotinine in smokers 
switching from CC to THS 2.2 as compared to smokers continuing to smoke CC. 
• To describe the changes in Cytochrome P450 1A2 (CYP1A2) enzymatic activity on 
Day 5 in smokers switching from CC to THS 2.2, switching from CC to SA, and 
continuing to smoke CC. 
• To describe the daily THS Tobacco Stick/CC consumption over the exposure period 
in smokers switching from CC to THS 2.2 as compared to smokers continuing to 
smoke CC. 
• To monitor the safety profile during the study. 
 
Exploratory Objectives: 
The exploratory objectives of this study are: 
• To describe the following parameters in smokers switching from CC to THS 2.2 as 
compared to smokers continuing to smoke CC and smokers switching from CC to SA: 
• Excretion of mutagenic material in urine. 
• Subjective effects of smoking. 
• Cytochrome P450 2A6 (CYP2A6) activity, and 
• Selected risk markers. 
• To evaluate in smokers switching from CC to THS 2.2, smokers continuing smoking 
CC and smokers switching from CC to SA the relationship between: 
• Nicotine equivalents (NEQ) and primary and secondary BoExp. 
• Risk markers and primary, secondary BoExp, and NEQ. 
• To describe the following parameters over the course of the study in smokers 
switching from CC to THS 2.2 as compared to smokers continuing smoking CC: 
• Product evaluation. 
• Smoking pattern. 
• To describe the following parameter over the course of the study in smokers switching 
from CC to THS 2.2: 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 4 of 171 
 
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. 
 
• Potential combustion occurrences in tobacco plugs. 
 
Study Hypotheses: 
The hypothesis to be tested for each of the primary and secondary biomarkers of exposure 
is that the geometric mean level on Day 5 of the biomarker for THS 2.2 is lower relative 
to CC. 
 
Study Endpoints: 
The primary and secondary BoExp measured in this study are presented in Table S1. 
Table S1: 
 
Biomarkers of Exposure (BoExp) 
Harmful and potentially 
harmful constituents 
(HPHCs) 
Matrix 
Primary BoExp 
monohydroxybutenyl mercapturic acid 
(MHBMA) 
1,3-butadiene 
Urine 
3-hydroxypropylmercapturic acid 
(3-HPMA) 
acrolein 
Urine 
S-phenylmercapturic acid (S-PMA) 
benzene 
Urine 
carboxyhemoglobin (COHb)  
CO 
Blood 
Secondary BoExp 
carbon monoxide  
CO 
Exhaled 
breath 
total 1-hydroxypyrene (1-OHP) 
pyrene 
Urine 
total N-nitrosonornicotine (NNN) 
N-nitrosonornicotine 
Urine 
4-aminobiphenyl (4-ABP) 
4-aminobiphenyl  
Urine 
1-aminonaphthalene (1-NA) 
1-aminonaphthalene 
Urine 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 5 of 171 
 
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. 
 
2-aminonaphthalene (2-NA) 
2-aminonaphthalene 
Urine 
o-toluidine (o-tol) 
o-toluidine 
Urine 
2-cyanoethylmercapturic acid (CEMA) 
acrylonitrile 
Urine 
2-hydroxyethyl mercapturic acid 
(HEMA) 
ethylene oxide 
Urine 
3-hydroxy(a)benzopyrene 
benzo(a)pyrene 
Urine 
3-hydroxy-1-methylpropyl-mercapturic 
acid (HMPMA) 
crotonaldehyde 
Urine 
S-benzylmercapturic acid (S-BMA) 
toluene 
Urine 
total 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol (total NNAL) 
4 (methylnitrosamino)-
1-(3-pyridyl)-
1butanone (NNK) 
Urine 
BoExp to nicoitne 
nicotine equivalents (NEQ) 
free nicotine, nicotine-glucuronide, free 
cotinine, cotinine-glucuronide, free 
trans-3’-hydroxycotinine, trans-3’-
hydroxycotinine-glucuronide 
nicotine 
Urine 
nicotine 
nicotine 
Plasma 
cotinine 
nicotine 
Plasma 
 
Primary Endpoints: 
• To demonstrate the reduction of primary BoExp in smokers switching from CC to 
THS 2.2 as compared to those continuing to smoke CC. 
• MHBMA, 3-HPMA, S-PMA (concentration adjusted to creatinine) in 24-hour 
urine, and COHb in blood (expressed as % saturation of hemoglobin) as 
measured on Day 5. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 6 of 171 
 
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. 
 
Evaluation Criterion: The study will be considered successful if the study demonstrates 
a 50% reduction or more for all four primary BoExp in the THS 2.2 arm compared to 
the CC arm (as measured on Day 5). 
 
Secondary Endpoints: 
• To determine the reduction of secondary BoExp on Day 5 in smokers switching from 
CC to THS 2.2 as compared to smokers continuing to smoke CC. 
• BoExp listed as secondary (Table S1) for the comparison of levels between 
smokers switching from CC to THS 2.2 and smokers continuing to smoke CC as 
measured on Day 5 as follows: 
• CO (expressed as ppm) in exhaled breath.  
• Urinary BoExp (expressed as quantity excreted and concentration adjusted to 
creatinine) in 24-hour urine 
 
• To describe the levels of primary and secondary BoExp over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers continuing to 
smoke CC. 
• BoExp listed as primary and secondary (Table S1) for the comparison of levels 
between smokers switching from CC to THS 2.2 and smokers continuing to 
smoke CC as measured from Day 1 to Day 5. 
• CO (expressed as ppm) in exhaled breath.  
• COHb in blood  (expressed as % saturation of hemoglobin). 
• Urinary BoExp (expressed as quantity excreted and concentration adjusted to 
creatinine) in 24 hour urine. 
 
• To determine the levels of nicotine on Day 5 in smokers switching from CC to THS 
2.2 as compared to smokers continuing to smoke CC and to describe their levels 
over the exposure period from Day 1 to Day 5. 
• NEQ (expressed in quantity excreted and concentration adjusted to creatinine) 
(Table S1) in 24-hour urine on Day 5 and from Day 1 to Day 5. 
• Nicotine and cotinine in plasma on Day 5 and from Day 1 to Day 5. 
 
• To describe the levels of primary and secondary BoExp over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers switching from CC 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 7 of 171 
 
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. 
 
to SA. 
• BoExp listed as primary and secondary (Table S1) from Day 1 to Day 5 as 
follows: 
• CO (expressed as ppm) in exhaled breath  
• COHb in blood  (expressed as % saturation of hemoglobin) 
• Urinary BoExp (expressed as quantity excreted and concentration adjusted to 
creatinine) in 24 hour urine. 
 
• To describe the PK profiles of the nicotine and cotinine in smokers switching from 
CC to THS 2.2 as compared to smokers continuing to smoke CC.  
• Peak (highest concentration value along the day) on Day 5 in plasma. 
• Time to peak (actual time when the peak was observed compared to the time 
of the first cigarette) on Day 5. 
• Weighted average concentration over 24 hours on Day 5. 
 
• To describe the changes in CYP1A2 enzymatic activity on Day 5 in smokers 
switching from CC to THS 2.2, switching from CC to SA, and continuing to smoke 
CC.  
• Molar metabolic ratio of paraxanthine/caffeine in plasma on Day 5. 
 
• To describe the daily Tobacco Stick/CC consumption over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers continuing to 
smoke CC: 
• Number of Tobacco sticks and CC used each day for each subject from Day 1 
to Day 5. 
 
• To monitor the safety profile during the study: 
• Adverse events (AEs)/ serious adverse events (SAEs) and device events including 
THS 2.2 malfunction/misuse. 
• Respiratory symptoms: cough assessment by visual analogue scale (VAS), Likert 
scales, and one open question. 
• Vital signs. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 8 of 171 
 
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. 
 
• Spirometry. 
• Electrocardiogram. 
• Clinical chemistry, hematology, and urine analysis safety panel. 
• Physical examination. 
• Concomitant medications. 
 
Exploratory Endpoints: 
• To describe the following parameters in smokers switching from CC to THS 2.2 as 
compared to smokers continuing to smoke CC and to smokers switching from CC to 
SA: 
• Excretion of mutagenic material in urine: Ames Mutagenicity test 
(YG1024+S9) on Day 5 in 24-hour urine. 
• Subjective effects of smoking: Questionnaire of Smoking Urges (brief 
version); Minnesota Nicotine Withdrawal Scale, revised version on Day 5. 
• Cytochrome P450 2A6 (CYP2A6) enzymatic activity: in plasma on Day 6, 
using the molar metabolic ratio of trans-3’-hydroxycotinine/cotinine.  
• Selected risk markers: 8-epi-prostaglandine F2α (8-epi-PGF2α) and 
11-dehydro-thromboxane B2 (11-DTX-B2) measured in 24-hour urine on 
Day 5. 
 
• To evaluate in smokers switching from CC to THS 2.2, smokers continuing smoking 
CC, and smokers switching to  SA the relationship between: 
• NEQ and primary and secondary BoExp in 24-hour urine on Day 5. 
• Risk markers (8-epi-PGF2α and 11-DTX-B2) and primary, secondary BoExp, 
and NEQ with in 24-hour urine on Day 5. 
 
• To describe the following parameters over the course of the study in smokers 
switching from CC to THS 2.2 as compared to smokers continuing smoking CC: 
• Product evaluation: Modified Cigarette Evaluation Questionnaire. 
• Smoking pattern: human smoking topography (HST) parameters and HST 
questionnaire. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 9 of 171 
 
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. 
 
• To describe the following parameter over the course of the study in smokers switching 
from CC to THS 2.2: 
• Potential combustion occurrences in tobacco plugs: visual inspection of the 
tobacco plugs. 
 
Study Design: 
A randomized, controlled, open-label, 3-arm, parallel group, single-center study with a 
stratified randomization by sex and average daily cigarette consumption over the last 
4 weeks as reported during the Screening Visit (smokers smoking 10 to 19 CC and 
smokers smoking >19 CC per day). (Figure S1). 
This is an ad libitum smoking study. In general, smoking during confinement will be 
allowed between 06:30 AM and 11:00 PM.  
During the confinement period, compliance to product/regimen allocation (exclusive use 
of THS 2.2 and CC in THS 2.2 and CC arms respectively, and full abstinence from 
smoking in the SA arm) will be ensured by strict distribution of each Tobacco Stick/CC 
on demand of the subject. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 10 of 171 
 
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. 
 
Figure S1: Study Design
Day -1, Day 0
Day -2
Admission
Baseline
Day 6 to Day 13
9 days in confinement
CC 
ad libitum
Safety
follow-up
ad libitum use 
of tobacco products
Day 1 to Day 5
Screening
*Screening 
within 1-4 weeks 
prior to admission
THS 2.2
Discharge (Day 6)
Smoking abstinence
CC
THS 2.2: Tobacco Heating System 2.2; SA: smoking abstinence; CC: conventional cigarettes.
 
• Screening period over 4 weeks (Day -30 to Day -3) prior to admission to the clinic 
(Day -2): 
A demonstration of the THS 2.2 product will be done by the site collaborator during 
the Screening Visit. Subjects will be in a confinement setting for 9 days from Day -2 
onwards. 
• Run-in period (from admission on Day -2 until 06:29 AM of Day -1): 
Prior to enrolment on Day -2, as the last procedure of the eligibility assessments, 
subjects will have a product test of the THS 2.2 (use of up to 3 Tobacco Sticks). In 
female subjects, the THS 2.2 product test may only be done after pregnancy is 
excluded by a negative urine pregnancy test. Enrolment takes place after all inclusion 
and exclusion criteria have been satisfactorily met. Only subjects willing and able to 
use the product will be enrolled in the study. 
• Baseline period (from Day -1, 06:30 AM until Day 1, 06:29 AM): 
All subjects will continue smoking their single preferred brand of CC and baseline 
values will be recorded. On Day 0, subjects will be randomized to one of the 3 study 
arms in a 2:1:1 ratio using a stratified randomization: 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 11 of 171 
 
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. 
 
• THS 2.2 Arm: 80 subjects, ad libitum use of the product. 
• CC Arm: 40 subjects, ad libitum use of their preferred CC brand. 
• SA Arm: 40 subjects who will abstain from smoking. 
Subjects will be informed of their randomized study arm by the study site 
collaborator on Day 1 prior to 06:30 AM.  
• Exposure period (from Day 1, 06:30 AM until Day 5, 11:00 PM): 
The exposure period will consist of 5 days of ad libitum use of the assigned product 
between 06:30 AM and 11:00 PM in THS 2.2 and CC arms. Use of any 
tobacco/nicotine containing product other than the assigned product will not be 
allowed and may, at the discretion of the Investigator, result in the subject withdrawal 
from the study. 
Subjects in the SA arm will be asked to abstain from smoking any nicotine/tobacco 
containing product and will not be provided with medication to support SA. Subjects 
will be provided with psychological support during the period of smoking abstinence. 
The end of the 24-h urine collection period for Day 5 will end in the morning on Day 
6 prior to Discharge. 
• Day of Discharge (Day 6) (from Day 5, 11:01 PM to time of Discharge): 
Procedures of Discharge, including but not limited to laboratory parameters, will be 
conducted to discharge the subject from the clinic after 9 days in a confined setting. 
Use of CC will be allowed on Day 6, but only after spirometry has been performed.  
• Safety follow-up period (from the time of Discharge on Day 6 to Day 13): 
After time of Discharge, subject will enter a 7-day safety follow-up during which 
there will be recording of spontaneously reported new AEs/SAEs and the active 
follow-up of ongoing AEs/SAEs by the study site. In general, all AEs will be followed 
until resolved, stabilized (i.e., no worsening of the event), or a plausible explanation 
for the event has been found. The end of the study is defined as the time of Discharge 
on Day 6 plus 7-day follow-up period. 
During the study, any subjects who want to quit smoking will be encouraged to do so, and 
will be referred to medical services and will be withdrawn from the study. This is 
applicable for all subjects during screening to the baseline period and for subjects 
allocated to THS 2.2 or CC arms during the exposure period. 
 
Study Population and Main Criteria for Inclusion and Exclusion: 
160 female or male smoking, healthy Japanese adult subjects meeting the following main 
inclusion criteria: 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 12 of 171 
 
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. 
 
• Subject is aged from 23 to 65 years (inclusive). 
• Smoking, healthy subject as judged by the investigator is Japanese. 
• Subject smokes at least 10 commercially available non-menthol CCs per day (no 
brand restrictions) for the last 4 weeks, based on self-reporting.  
• Subject has smoked for at least the last 3 consecutive years.  
• Subject does not plan to quit smoking in the next 3 months. 
• The subject is ready to accept interruptions to smoking for up to 5 days. 
• The subject is ready to accept using the THS 2.2. 
Subjects who do not complete the study after randomization will not be replaced. 
Investigational Product; Dose; and Mode of Use: 
Test Product: Tobacco Heating System 2.2 (THS 2.2)  
Reference Product: The reference product to the THS 2.2 during the randomized 
exposure period is the subject’s own preferred commercially available single brand of CC 
Reference Point: Smoking abstinence 
Duration of Study: 
The entire study duration per subject will be 17 to 44 days, including a Screening period 
of up to 28 days prior to baseline (Day -30 to Day -3), an 9-day confinement period (from 
Day -2 to time of Discharge on Day 6), followed by a 7-day safety follow-up period (until 
Day 13). 
Expected Duration of the Entire Study: 
1st of July 2013 until 31st January 2014 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 13 of 171 
 
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. 
 
 
Statistical Methods: 
Statistical Analysis: 
Analysis of BoExp will be conducted on the natural log scale. The transformed data will 
be analyzed by means of a generalized linear model using randomized arm as covariate 
adjusting for the following baseline information: sex, average cigarette consumption over 
the previous 4 weeks, and baseline value of endpoint. Estimates of differences between 
groups will be back-transformed to provide relative effects. Assumptions of the ANOVA 
model will be tested. Markedly non-lognormally distributed BoExp data will be 
transformed or analyzed by appropriate non-parametric methods. 
Unless stated otherwise, all statistical tests will be two-sided and conducted at the 5% 
level, and all quoted confidence intervals will be two-sided 95% confidence intervals. 
Sample Size: 
A total of 160 subjects (80 in the THS 2.2 arm, 40 in the CC arm, and 40 in the SA arm) 
will be randomized. This sample size is needed to attain 80% power to show at least a 
50% reduction for any of the primary BoExp in THS 2.2 compared to the CC arm, 
one-sided test with 2.5% type I error probability. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 14 of 171 
 
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. 
 
 
TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................1 
TABLE OF CONTENTS .........................................................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................19 
1 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL ...........................................27 
1.1 
Institutional Review Board (IRB) Approval ..........................................................27 
1.2 
Ethical Conduct of the Study .................................................................................28 
1.3 
Subject Information and Consent...........................................................................28 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................30 
2 
INTRODUCTION ...........................................................................................................31 
2.1 
Background ............................................................................................................31 
2.2 
Purpose of the Study ..............................................................................................34 
2.3 
Anticipated Benefits and Risks ..............................................................................34 
3 
STUDY OBJECTIVES ....................................................................................................36 
3.1 
Primary Objective ..................................................................................................36 
3.2 
Secondary Objectives.............................................................................................36 
3.3 
Exploratory Objectives ..........................................................................................37 
3.4 
Study Endpoints .....................................................................................................38 
4 
INVESTIGATIONAL PLAN ..........................................................................................44 
4.1 
Overall Study Design and Plan ..............................................................................44 
4.2 
Rationale for Study Design and Control Groups ...................................................47 
4.3 
Appropriateness of Measurements .........................................................................49 
4.4 
Study Duration .......................................................................................................49 
5 
STUDY POPULATION ..................................................................................................51 
5.1 
Selection of Study Population ................................................................................51 
6 
INVESTIGATIONAL PRODUCTS ...............................................................................57 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 15 of 171 
 
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. 
 
6.1 
Description of Investigational Products .................................................................57 
6.2 
Use of Investigational Product ...............................................................................60 
6.3 
Method for Assigning Subjects to Study Arms .....................................................61 
6.4 
Blinding..................................................................................................................62 
6.5 
Investigational Product Accountability and Compliance ......................................62 
6.6 
Restrictions ............................................................................................................64 
6.7 
Concomitant Medications ......................................................................................65 
7 
STUDY PROCEDURES .................................................................................................69 
7.1 
Informed Consent/Subject Information Sheet .......................................................69 
7.2 
Advice on the Risk of Smoking and Debriefing ....................................................69 
7.3 
Support for the Smoking Abstinence Arm.............................................................70 
7.4 
Clinical Assessments .............................................................................................70 
7.5 
Biomarker Assessment...........................................................................................75 
7.6 
Laboratory Assessments ........................................................................................79 
7.7 
Sampling Handling and Storage ............................................................................81 
7.8 
Other Study Procedures .........................................................................................84 
8 
ADVERSE EVENTS .......................................................................................................91 
8.1 
Definitions..............................................................................................................91 
8.2 
Assessment of Adverse Events ..............................................................................92 
8.3 
Reporting of Serious Adverse Events ....................................................................95 
8.4 
Reporting of Other Events Critical to Safety Evaluations .....................................96 
8.5 
Reporting and Follow-Up of Pregnancies..............................................................98 
8.6 
Adverse Events Leading to Withdrawal ................................................................99 
8.7 
Investigational Device Misuse ...............................................................................99 
8.8 
Investigational Device Malfunction .......................................................................99 
9 
STUDY ACTIVITIES ...................................................................................................101 
9.1 
Screening Visit .....................................................................................................101 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 16 of 171 
 
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. 
 
9.2 
Confinement Period (Days -2 to 6) ......................................................................103 
9.3 
Safety Follow-up Period ......................................................................................119 
9.4 
Early Termination Procedures .............................................................................119 
10 CONTROL AND QUALITY ASSURANCE ...............................................................120 
10.1 
Monitoring ...........................................................................................................120 
10.2 
Training of Study Collaborator ............................................................................121 
10.3 
Audits and Inspections .........................................................................................121 
11 DATA MANAGEMENT ACTIVITIES........................................................................123 
11.1 
Data Capture ........................................................................................................123 
11.2 
Data Handling ......................................................................................................124 
12 PLANNED STATISTICAL METHODS ......................................................................126 
12.1 
General Considerations ........................................................................................126 
12.2 
Determination of Sample Size and Power Consideration ....................................127 
12.3 
Analysis Population .............................................................................................132 
12.4 
Primary Analysis ..................................................................................................132 
12.5 
Secondary Analysis ..............................................................................................134 
12.6 
Exploratory Analysis ...........................................................................................135 
12.7 
Demographics and Baseline Characteristics ........................................................136 
12.8 
Interim Analysis ...................................................................................................136 
13 ADMINISTRATIVE CONSIDERATIONS ..................................................................137 
13.1 
Investigators and Study Administrative Structure ...............................................137 
13.2 
Subject Confidentiality ........................................................................................139 
13.3 
Access to Source Documentation ........................................................................140 
13.4 
Record Retention .................................................................................................140 
13.5 
Clinical Study Report ...........................................................................................142 
13.6 
Financial Disclosure.............................................................................................143 
13.7 
Publication and Disclosure Policy .......................................................................143 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 17 of 171 
 
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. 
 
13.8 
Insurance ..............................................................................................................143 
14 REFERENCE LIST .......................................................................................................145 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 18 of 171 
 
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. 
 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1. 
Measured Aerosol Fractions for the THS Tobacco Sticks.........................58 
Table 2. 
Examples of Medications with Effects on CYP1A2 and CYP2A6 
Activity 
66 
Table 3. 
Clinical Laboratory Parameters for Safety Panel.......................................80 
Table 4. 
Human Smoking Topography – Per-Puff Parameters ...............................85 
Table 5. 
Human Smoking Topography – Per-Cigarette Parameters ........................85 
Table 6. 
Time Schedule – Screening Visit .............................................................101 
Table 7. 
Time Schedule – Day -2 ..........................................................................103 
Table 8. 
Time Schedule – Day -1 ..........................................................................105 
Table 9. 
Time Schedule – Day 0 ............................................................................106 
Table 10. 
Time Schedule – Day 1 ............................................................................108 
Table 11. 
Time Schedule – Day 2 ............................................................................110 
Table 12. 
Time Schedule – Day 3 ............................................................................112 
Table 13. 
Time Schedule – Day 4 ............................................................................114 
Table 14. 
Time Schedule – Day 5 ............................................................................115 
Table 15. 
Time Schedule – Day 6 ............................................................................118 
Table 16. 
Coefficients of Variation (YVD-CS01-EU study) ...................................129 
Table 17. 
Coefficients of Variation (ZRHX‐EX‐01 study) .....................................130 
Table 18. 
Expected Power (YVD-CS01-EU and ZRHX‐EX‐01 Studies 
Assumptions) .............................................................................................................131 
Figure 1. 
Study Design ..............................................................................................45 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events ...................................................................................155 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 19 of 171 
 
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. 
 
Appendix 2 
Participating Laboratories ........................................................................161 
Appendix 3 
Investigational Product and Instructions for Use .....................................162 
Appendix 4 
THS Package Label..................................................................................163 
Appendix 5 
SODIM® Device Description ...................................................................166 
Appendix 6 
Abnormal Laboratory Values ..................................................................167 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
1-NA 
1-aminonaphtalene 
1-OHP 
1-hydroxypyrene 
2-NA 
2-aminonaphthalene 
3-HPMA 
3-hydroxypropylmercapturic acid 
4-ABP 
4-aminobiphenyl 
8-epi-PGF2α 
8-epi-prostaglandine F2α 
11-DTX-B2 
11-dehydro-thromboxane B2 
ADL 
Activities of daily living 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic and Chemical (WHO drug classification index) 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 20 of 171 
 
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. 
 
ATS 
American Thoracic Society 
B 
Blood 
BMI 
Body mass index 
BoExp 
Biomarker(s) of exposure 
CAF 
Caffeine 
CC 
Conventional cigarette(s) 
CD 
Compact Disc 
CDISC 
Clinical data interchange standards consortium 
CEMA 
2-cyanoethylmercapturic acid 
CI 
Confidence interval 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
COPD 
Chronic obstructive pulmonary disease 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE  
Common Terminology Criteria for Adverse Event and Common Toxicity 
Criteria 
CTMS 
Clinical Trial Management System 
CV 
Coefficients of variation 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 21 of 171 
 
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. 
 
CVD 
Cardiovascular Disease 
CYP1A2 
Cytochrome P450 1A2 
CYP2A6 
Cytochrome P450 2A6 
DMP 
Data management plan 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EHCSS 
Electrically heated cigarette smoking system 
EOS 
End of Study Visit  
ERS 
European Respiratory Society 
FAS 
Full analysis set 
FDA 
Food and Drug Administration  
FEV1  
Forced expiratory volume in 1 second 
FSH 
Follicle stimulating hormone 
FTND 
Fagerström Test for Nicotine Dependence 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
Hb 
Hemoglobin 
HbA1c 
Hemoglobin A1c 
HbsAg 
Hepatitis B surface antigen 
Hct 
Hematocrit 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 22 of 171 
 
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. 
 
HCV 
Hepatitis C virus 
HDL 
High density lipoprotein 
HEMA 
2-hydroxyethyl mercapturic acid 
HIV 
Human immunodeficiency virus 
HMPMA 
3-hydroxy-1-methylpropylmercapturic acid 
HPHCs 
Harmful or potentially harmful constituents 
HST 
Human smoking topography 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IOM 
Institute of Medicine  
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IWRS 
Interactive Web and Voice Response System 
LDH 
Lactic dehydrogenase 
LDL 
Low density lipoprotein 
LLN 
Lower limit of the normal range 
LOCF 
Last observation carried forward 
MCEQ 
Modified Cigarette Evaluation Questionnaire  

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 23 of 171 
 
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. 
 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHBMA 
Monohydroxybutenyl mercapturic acid 
miRNA 
Micro-RNA 
MNWS 
Minnesota Nicotine Withdrawal Scale (revised version) 
MR 
Mean ratios 
mRNA 
Messenger-RNA 
MRTP 
Modified risk tobacco product 
NEQ 
Nicotine equivalents 
NNAL 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
NNAL-
glucuronides 
[4-(methylnitrosamino)-1-(3-pyridyl) but-1-yl]-β-N-D-glucosiduronic 
acid and [4-(methylnitrosamino)-1-(3-pyridyl) but-1-yl]-β-O-D-
glucosiduronic acid 
NNK 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 
NNN 
N-nitrosonornicotine 
NRT 
Nicotine Replacement Therapy 
NSAID 
Nonsteroidal Anti-inflammatory Drugs 
o-tol 
o-toluidine 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 24 of 171 
 
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. 
 
PMI 
Philip Morris International 
PX 
Paraxanthine 
QSU-brief 
Questionnaire of Smoking Urges (brief version) 
RBC 
Red blood cell (count) 
RNA  
Ribonucleic acid 
SA 
Smoking abstinence 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SHM 
Sample handling manual 
SOP 
Standard Operating Procedure 
S-PMA 
S-phenylmercapturic acid 
THS 
Tobacco heating system 
U 
Urine 
 
 
ULN 
Upper limit of the normal range 
VAS 
Visual analogue scale 
WBC 
White blood cell (count) 
WHO 
World Health Organization 
WHO-DDE 
WHO Drug Dictionary Enhanced 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 25 of 171 
 
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. 
 
Definition of Terms 
The following special terms are used in this protocol: 
Baseline period 
06:30 AM at Day -1 until 06:29 AM of Day 1. 
Charger 
The function of the Charger (Model 4) is to recharge the Holder 
after use. It contains a battery with sufficient capacity to recharge 
the Holder approximately 20 times.  It is a convenient size to carry 
around, and can itself be recharged from a mains power source. 
CC 
The term ‘conventional cigarette’ refers to manufactured and 
commercially available cigarettes and excludes hand-rolled 
cigarettes, cigars, pipes, bidis, and other nicotine-containing 
products. 
CC incompatible with 
HST device 
All CCs that are incompatible with the HST device (e.g. slim CC). 
Day of Discharge 
Day 6.  
End of the study 
End of Study is defined as the last day of the 7 day safety follow-
up subsequent to discharge from the unit. 
Enrolment 
On Day -2 for eligible subjects after all applicable inclusion and 
exclusion criteria have been satisfactorily met and the subject is 
willing and ready to use THS 2.2 (the test of THS 2.2 is the last 
assessment prior to enrolment). 
Exposure period  
06:30 of Day 1 until 11:00 PM of Day 5. 
Investigator 
Principal Investigator or sub-Investigator 
Randomization  
Assignment of the subject randomization number in the Interactive 
Web and Voice Response System. This can be done any time on 
Day 0, however subjects are not to be informed of their 
randomization group and number prior Day 1. 
Run-in period 
Admission to site until 06:30 of Day -1. 
Safety follow-up 
After the time of discharge, a 7-day safety follow-up will be done 
for the recording of spontaneously reported new AEs/SAEs and the 
active follow-up of ongoing AEs/SAEs. In general, any AE will be 
followed-up until resolved, stabilized i.e., no worsening of the 
event, or a plausible explanation for the event has been found.  

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 26 of 171 
 
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. 
 
Screening failure 
Subjects who do not meet the entry criteria from ICF/ signature to 
the time of enrolment will be considered a screening failure and 
will be replaced by other subjects. 
Time of Discharge 
The time of day the subject is discharged on Day of Discharge. 
THS Tobacco Stick 
Holder (Holder) 
The function of the Holder (Model 4.2) is to heat the Tobacco 
Stick, delivering an aerosol to the user. The electrical heating is 
powered from an internal battery which delivers power for about 6 
minutes (allowing complete use of a single Tobacco Stick). 
Tobacco Heating 
Device  
The Device comprises everything in THS 2.2, except the Tobacco 
Stick 
Tobacco Heating 
System 2.2 (THS 2.2) 
THS 2.2 comprises the following components: Tobacco Stick, 
Holder, Charger, a Cleaning Tool, a mains power supply, and a 
USB cable. 
THS Tobacco Stick 
(Tobacco Stick) 
The THS Tobacco Stick (Tobacco Stick) (product code C3) 
contains tobacco which, when heated, generates an aerosol. It is 
custom-designed to be used with the Holder. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 27 of 171 
 
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. 
 
 
1 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL  
1.1 Institutional Review Board (IRB) Approval 
Prior to the start of the study, the clinical study protocol, together with its associated 
documents (informed consent form [ICF] including both subject information sheet and 
consent form, subject recruitment procedures [e.g. advertisements], written information to be 
provided to the subjects, Investigator’s Brochure [IB], available safety information, the 
Principal Investigator’s curriculum vitae and/or other evidence of qualifications, the list of 
sub-Investigators and any other documents requested by the Institutional Review Board 
[IRB]), will be submitted for review and approval to the relevant IRB. The IRB shall be 
appropriately constituted and perform its functions in accordance with the International 
Conference on Harmonization (ICH) Tripartite Guidance for Good Clinical Practice (GCP), 
and Ministerial Ordinance on Good Clinical Practice for Drugs and local requirements, as 
applicable. 
In accordance with GCP, a written confirmation of the IRB approval should be provided to 
the Sponsor. This should identify the study (Principal Investigator’s name, study number and 
title) and the documents that have been approved by the IRB, with dates and version 
numbers, as well as the date of approval. The composition of the IRB, including the name 
and occupation of the chairperson, should be supplied to the Sponsor together with a GCP 
compliance statement. 
The written approval from the IRB will be filed in the Investigator file, and another original 
copy will be filed in the Study Master File at the Sponsor or designated organization. The 
study must not start before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IRB. 
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the Principal Investigator. All amendments will be 
submitted to the IRB, and substantial amendments will only be implemented after approval 
by the IRB. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 28 of 171 
 
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. 
 
These requirements for approval should in no way prevent any action from being taken by 
the Principal Investigator or sub-Investigator (Investigator) or by the Sponsor in order to 
eliminate immediate hazards to the subjects. If such a change to the protocol is felt to be 
necessary by the Investigator, and is implemented for safety reasons, the Sponsor and the 
IRB should be informed immediately. 
Relevant safety information will be submitted to the IRB during the course of the study in 
accordance with national regulations and requirements. 
1.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki, 2008 and are consistent with ICH/GCP, Ethical Guidelines for 
Clinical Studies (Ministry of Health,  Labour and Welfare, 2003 [as last amended on July 31, 
2008), Ministerial Ordinance on Good Clinical Practice for Drugs (Ministry of Health 
Labour and Welfare, 1997 (as last amended by the Ordinance of Ministry of Health, Labour 
and Welfare No. 161 of December 28, 2012)) and applicable regulatory principles. 
The Principal Investigator agrees to conduct the clinical study in compliance with the 
protocol agreed upon with the Sponsor and approved by the IRB. The Principal Investigator 
and the Sponsor must sign the protocol (and protocol amendments, if applicable) to confirm 
this agreement. A copy of the Declaration of Helsinki, 2008 should be located in the 
Investigator’s Study File. 
1.3 
Subject Information and Consent 
1.3.1 
Study Consent/Subject Information Sheet for Participation to the Study 
Before or at the Screening Visit, the Investigator will ensure each subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and benefits 
of the study, and the Investigator will answer all questions the subject might have to his/her 
full satisfaction. The subject will have sufficient time for consideration of his/her 
participation in the study and will be notified that he/she is free to discontinue his/her 
participation at any time. Once the subject has received all necessary information, and if 
he/she agrees to participate, this will be documented in the ICF by the date and signature of 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 29 of 171 
 
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. 
 
both the subject and the person who conducted the inform consent discussion. No study-
specific procedures will be performed before the ICF has been signed. 
The original, dated and signed ICF(s) must be kept in the Investigator file at the site, and a 
copy must be given to the subject. 
The subject will be informed that additional data analyses not mentioned in the protocol or 
the statistical analysis plan might be performed with the collected data at a later time. If any 
additional analyses will be performed, they will fully be covered by data confidentiality, as 
for the main analyses described in this protocol.  
1.3.2 
Informed Consent Form/Subject Information Sheet for Long -term Bio-
Banking  
In addition to the ICF for the participation in the study, each subject will be asked for consent 
to the additional bio-banking for measurements of BoExp and risk markers in serum/plasma 
and urine and for consent to the additional bio-banking of blood for further transcriptomics 
(pharmacogenomics) analysis. 
1.3.2.1 
Bio-banking for Biomarkers of Exposure and Risk Markers 
Subjects will be provided with a separate subject information sheet and will be asked for 
their consent for samples (serum/plasma/urine) that will be stored in a bio-bank for 
subsequent analysis of biomarkers of exposure (BoExp) and/or risk markers following 
completion of this study. No genetic or transcriptomics testing will be done on these samples. 
1.3.2.2 
Bio-banking for Transcriptomics (Pharmacogenomics) 
Subjects will be provided with subject information sheet and will be asked for their consent 
to collect blood samples for bio-banking for transcriptomics (pharmacogenomics) in order to 
study the variation of the ribonucleic acid (mRNA and miRNA) in smokers using THS 2.2 as 
compared to smokers continuing to smoke CC or smokers switching to smoking abstinence. 
Comparison will be based on previously described biological networks. In-house data from 
an exploratory study to assess the reduction of exposure to HPHCs (clinical trial dot. gov 
identifier: NCT01780714) in smokers switching to THS 2.1 as compared to smokers 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 30 of 171 
 
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. 
 
continuing smoking CC shows that using THS 2.1, the earlier version of THS 2.2 results in 
significant variation of RNA characteristics as compared to smoking CC. 
1.3.2.3 
Information on Optional Consents to Bio-banking 
Each subject will be given full and adequate oral and written information about the nature, 
purpose, possible risks and benefits of bio-banking, and the Investigator will answer all 
questions the subject might have to his/her full satisfaction. The subject will be notified that 
he/she is free to discontinue his/her participation at any time. Once the subject has received 
all necessary information, and if he/she agrees to participate, this will be documented by the 
date and signature of both the subject and the Investigator /personnel who conducted the 
informed consent discussion. The subject’s consent to storage of any samples in a bio-bank is 
not a requirement for study participation and the subject’s participation in the study does not 
depend on their providing consent for sample bio-banking. 
1.3.3 
Amendment to the Informed Consent Forms 
If a protocol amendment is required, or if new information regarding the risk profile of the 
Investigational Product (IP) becomes available, an amendment may be required to the ICFs. 
If revision of the ICFs is necessary, the Principal Investigator will, with the support of the 
Sponsor, ensure that the documents have been reviewed and approved by a relevant IRB 
before subjects are required to re-sign the ICFs. 
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 Principal Investigator abide by the principles of the ICH guidelines on 
GCP. These guidelines apply specifically to pharmaceutical development, but nevertheless 
provide a robust and ethical framework for conducting clinical studies of tobacco products. 
In addition, the Investigator will carry out the clinical study in accordance with GCP and 
Ethical Guidelines for Clinical Studies. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 31 of 171 
 
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. 
 
 
2 INTRODUCTION 
2.1 Background 
2.1.1 Smoking-Related Diseases and Harm Reduction Strategy 
Cigarette smoking causes pulmonary and cardiovascular diseases and other serious diseases 
in smokers (U.S. Department of Health and Human Services, 2010). The effects of smoking 
and smoking cessation on mortality from cardiovascular disease among the Japanese 
population were investigated in cohort studies in Japan. These studies confirmed the 
association between smoking and mortality from cardiovascular disease and highlighted the 
importance of smoking cessation at any age to prevent cardiovascular disease in the Japanese 
population (Honjo et al., 2010a, Iso et al., 2005). In 2000 in Japan, the proportion of adult 
deaths due to smoking ranges from 20.0% to 24.9% in males and from 10.0% to 14.6% in 
females. In 2007, Japan became part of the top five conventional cigarette (CC)-consuming 
countries with a consumption of 234 billion annually in 2009 (World Lung Foundation, 
2012). There is no safe cigarette and the best way for smokers to reduce the adverse health 
consequences of smoking is to quit. Despite the risks which are attributable to smoking, some 
smokers cannot refrain from smoking or decide to continue smoking. To those smokers who 
are not able or not willing to quit, Philip Morris International (PMI) is developing alternative 
approaches by developing products with the potential to reduce the risks of tobacco-related 
diseases. These products are now referred by the US Food and Drug Administration (FDA) 
as modified risk tobacco products (MRTPs) (FDA, 2012a). 
The challenge in developing and commercializing MRTPs is two-fold, i.e. developing 
tobacco products that are shown to reduce risk and that are acceptable to smokers as 
substitutes for CCs. PMI is developing candidate MRTP that provide an inhalation 
experience without combustion. The novel approach to achieve this is by heating tobacco at 
significantly lower temperatures than required for CC. 
PMI’s approach to scientifically assessing the risk-reduction potential of its candidate 
MRTPs is described in the reference document (PMI White Paper Docket). Smoking 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 32 of 171 
 
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. 
 
cessation is the only intervention proven to reduce the risk of smoking-related diseases in 
smokers. Accordingly, PMI utilizes smoking cessation/smoking abstinence (SA) as the 
benchmark for assessing the risk reduction potential of its candidate MRTPs. The Institute of 
Medicine (IOM) observed that cessation is the “gold standard” for assessing risk reduction, 
and that “the closer risks and exposures from the MRTP are to cessation products, the more 
confident a regulator can be of achieving a net public health benefit” (Institute of Medicine, 
2012). PMI has already conducted studies and plans to conduct further clinical studies which 
observe measurable changes in blood chemistry, risk factors and health effects in smokers 
who switch to a candidate MRTP, comparing the changes with those observed in both 
smokers who continue smoking CC and smokers who stop using tobacco products. Longer-
term data from adults who continue to use the candidate MRTP can further substantiate 
reductions in individual risk in smokers and population harm. 
2.1.2 Description of the Product and Scientific Findings 
Thousands of chemicals - “smoke constituents” - are formed when tobacco is burned or 
combusted. More than 5,300 smoke constituents have been identified (Rodgman and Perfetti, 
2009), and more than 100 of them have been categorized as harmful and potentially harmful 
constituents (HPHCs) (FDA, 2011). There is no convincing evidence that selective reduction 
of smoke constituents can reduce tobacco related diseases (Hatsukami et al., 2007). Philip 
Morris International’s focus has been the development of products that do not combust 
tobacco but which replicate the “smoking experience” traditionally obtained with CC, as 
much as possible. Our approach limits pyrolysis and combustion, by heating tobacco at 
significantly lower temperatures than CC. Philip Morris International believes that such 
products present the best opportunity for reducing harm because they produce vastly lower 
levels of harmful smoke constituents and are more likely to be accepted by smokers as 
substitutes for cigarettes. Important to this effort has been providing nicotine in a way that 
closely parallels CC. 
The product developed by PMI, and to be assessed in this study, is the Tobacco Heating 
System 2.2 (THS 2.2). With this product, the heating of the tobacco is maintained below 
400°C, a temperature much lower than what is observed for CC, which can reach 900°C. The 
THS 2.2 is composed of the ‘THS Tobacco Stick Holder’, dedicated special Tobacco Sticks 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 33 of 171 
 
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. 
 
made of conventional tobacco, a charger, and different accessories. The energy of the THS 
Tobacco Stick Holder is sufficient to maintain approximately a 6 minute session. Unlike CC, 
the Tobacco Sticks do not burn down during their consumption and their lengths remain 
constant after use. 
The non-clinical assessment of THS 2.2 and its predecessors including THS 1.0 described in 
the Investigator’s Brochure (PMI, 2013) supports the initiation of the clinical studies. No 
new or increased toxicological hazard in the product’s aerosol was detected, compared with 
CC smoke. The aerosol was chemically analyzed confirming that none of the determined 
HPHCs in the THS 2.2 were increased compared to the CC. The biological activity was 
tested in a number of in vitro assays to assess the cytotoxicity and the genotoxicity of the 
aerosol fractions total particulate matter (TPM) and gas vapor phase (GVP). In vitro and in 
vivo results corroborated the concept that absence of combustion when consuming tobacco 
substantially lowers toxic effects seen in these biological models. Further details are given in 
the Investigator’s’ Brochure (PMI, 2013). 
Several clinical studies have been conducted on THS 1.0, an earlier development version of 
THS 2.2, in Europe, Asia, Africa and the United States. All studies showed reductions in 
exposure to the majority of measured HPHCs from both aerosol fractions, TPM and GVP, in 
subjects who used the THS 1.0 as compared to subjects continuing smoking CC, both, in 
controlled and ambulatory conditions.  
The previous version of THS 2.2, namely THS 2.1 was tested in two exploratory clinical 
studies to measure the nicotine plasma kinetic profile (PK) (clinical trial.gov identifier: 
NCT01780688) and to assess the reduction of exposure to HPHCs (clinical trial dot. gov 
identifier: NCT01780714) when switching from CC to THS 2.1. The observed nicotine 
plasma PK profile for THS 2.1 was similar to CC as well, there were significant reductions in 
the exposure to the majority of selected HPHCs. Clinical studies conducted so far revealed 
no safety concern for either of the previous version of THS 2.2 tested. Further details on the 
clinical data are provided in the Investigators’ Brochure (PMI, 2013). 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 34 of 171 
 
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. 
 
2.2 Purpose of the Study 
The overall goal of the study is to show that the ad libitum use of THS 2.2 for 5 days by adult 
healthy Japanese smokers results in a reduction in selected BoExp to HPHCs (except BoExp 
to nicotine) in a well-controlled environment and to obtain information about safety in 
subjects using the THS 2.2 product as compared to smokers continuing smoking their own 
preferred brand of CC to evaluate how similar is the reduced exposure in the THS 2.2 arm as 
compared to smoking abstinence. Smokers who are asked to abstain from using any 
nicotine/tobacco containing products will be used as a reference point. The subjects allocated 
to THS 2.2 and CC arms will be allowed to use their assigned product ad libitum. 
Additional parameters will be explored on selected variables (e.g., Cytochrome P450 2A6 
(CYP2A6)/Cytochrome P450 1A2 (CYP1A2) enzymatic activity, pharmacokinetic [PK] 
profile of nicotine and cotinine, product evaluation, product use and related subjective 
effects, human smoking topography, and selected risk markers). 
2.3 Anticipated Benefits and Risks 
2.3.1 Anticipated Benefits 
In Japan, research conducted by the Ministry of Health, Labour and Welfare has shown that 
35.9% of male and 43.6% of female respondents over 20 years of age expressed the wish to 
quit smoking (International Tobacco Online, 2012). In a large follow-up study of middle 
aged Japanese smokers, the predictors of smoking cessation were age, job, smoking habit, 
physical activity, health checkup participation, and health status (Honjo et al., 2010b). 
Advice on health risks associated with smoking and smoking cessation advice will be 
provided at Screening, at Admission, and at the Day of Discharge. The advice will follow the 
recommendations of the World Health Organization (WHO) (Raw et al., 2002) -“Evidence 
based Recommendations on the Treatment of Tobacco Dependence”. Subjects who are 
motivated to quit smoking during the study will be given the opportunity to continue their 
smoking cessation attempt and will be referred to appropriate stop smoking services for 
continuing support and counseling at a higher level. Subjects who participate in this study 
will also benefit from repeated, detailed health check-ups, which may help to uncover 
undiagnosed medical conditions. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 35 of 171 
 
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. 
 
2.3.2 Anticipated Foreseeable Risks due to Study Procedures 
• Risks related to blood sampling, e.g. excessive bleeding, fainting, hematoma, paresthesia, 
or infection. 
• Risks related to chest X-rays, e.g. a small increase of risk to develop cancer later in life. 
• Risks related to drug application as part of testing procedures (i.e. spirometry with 
short-acting bronchodilator at Screening) per study protocol and scientifically accepted 
standards. 
2.3.3 Anticipated Foreseeable Risks due to Investigational Product (THS 2.2/CC) 
• Change in smoking habits due to study requirements and related concomitant symptoms, 
(e.g., craving, withdrawal symptoms). 
All risks related to study procedures, IP, or support for smoking abstinence will be 
explained in detail to the subjects. Mitigation will include, but will not be limited to: 
• Close monitoring and medical evaluation of potential safety signals throughout 
the study and follow-up. 
• Using accepted research and scientific standards, (e.g., blood samples not to 
exceed local blood donation standards). 
• Management and follow-up of adverse events (AEs)/serious adverse events 
(SAEs). 
 
2.3.4 Unforeseeable Risks 
As with any new IP, there may be unforeseeable risks and hazards that could occur. The 
possibility of such will be explained at Screening and at Admission. Mitigation will include 
close monitoring and medical supervision to detect any unforeseeable risk or safety signals at 
the earliest possibility. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 36 of 171 
 
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. 
 
 
3 STUDY OBJECTIVES 
3.1 Primary Objective 
The primary objective of this study is: 
• 
To demonstrate the reduction of primary biomarkers of exposure (BoExp) in smokers 
switching from conventional cigarettes (CC) to THS 2.2 as compared to smokers 
continuing to smoke CC.  
 
3.2 Secondary Objectives 
The secondary objectives of this study are: 
• To determine the reduction of secondary BoExp on Day 5 in smokers switching from 
CC to THS 2.2 as compared to smokers continuing to smoke CC. 
• To describe the levels of primary and secondary BoExp over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers continuing to smoke 
CC. 
• To determine the levels of nicotine on Day 5 in smokers switching from CC to THS 2.2 
as compared to smokers continuing to smoke CC and to describe their levels over the 
exposure period from Day 1 to Day 5. 
• To describe the levels of primary and secondary BoExp over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers switching from CC to 
smoking abstinence (SA). 
• To describe the pharmacokinetic (PK) profiles of the nicotine and cotinine in smokers 
switching from CC to THS 2.2 as compared to smokers continuing to smoke CC. 
• To describe the changes in Cytochrome P450 1A2 (CYP1A2) enzymatic activity on 
Day 5 in smokers switching from CC to THS 2.2, switching from CC to SA, and 
continuing to smoke CC. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 37 of 171 
 
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. 
 
• To describe the daily THS Tobacco Stick/CC consumption over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers continuing to smoke 
CC. 
• To monitor the safety profile during the study. 
 
3.3 Exploratory Objectives 
The exploratory objectives of this study are:  
• To describe the following parameters in smokers switching from CC to THS 2.2 as 
compared to smokers continuing to smoke CC and smokers switching from CC to SA: 
• Excretion of mutagenic material in urine. 
• Subjective effects of smoking. 
• CYP2A6 activity, and 
• Selected risk markers. 
 
• 
To evaluate in smokers switching from CC to THS 2.2, smokers continuing smoking 
CC and smokers switching from CC to SA the relationship between: 
• Nicotine equivalents (NEQ) and primary and secondary BoExp. 
• Risk markers and primary, secondary BoExp, and NEQ. 
 
• 
To describe the following parameters over the course of the study in smokers 
switching from CC to THS 2.2 as compared to smokers continuing smoking CC: 
• Product evaluation. 
• Smoking pattern. 
• 
To describe the following parameter over the course of the study in smokers switching 
from CC to THS 2.2: 
• Potential combustion occurrences in tobacco plugs.  
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 38 of 171 
 
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. 
 
 
3.4 Study Endpoints 
The primary and secondary BoExp measured in this study are presented in Table S1. 
Table S1: 
 
Biomarkers of Exposure (BoExp) 
HPHCs 
Matrix 
Primary BoExp 
monohydroxybutenyl mercapturic acid 
(MHBMA) 
1,3-butadiene 
Urine 
3-hydroxypropylmercapturic acid (3-HPMA) 
acrolein 
Urine 
S-phenylmercapturic acid (S-PMA) 
benzene 
Urine 
carboxyhaemoglobin (COHb)  
CO 
Blood 
Secondary BoExp 
carbon monoxide  
CO 
Exhaled 
breath 
total 1-hydroxypyrene (1-OHP) 
pyrene 
Urine 
total N-nitrosonornicotine (NNN) 
N-nitrosonornicotine 
Urine 
4-aminobiphenyl (4-ABP) 
4-aminobiphenyl  
Urine 
1-aminonaphthalene (1-NA) 
1-aminonaphthalene 
Urine 
2-aminonaphthalene (2-NA) 
2-aminonaphthalene 
Urine 
o-toluidine (o-tol) 
o-toluidine 
Urine 
2-cyanoethylmercapturic acid (CEMA) 
acrylonitrile 
Urine 
2-hydroxyethyl mercapturic acid (HEMA) 
ethylene oxide 
Urine 
3-hydroxybenzo(a)pyrene 
benzo(a)pyrene 
Urine 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 39 of 171 
 
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. 
 
3-hydroxy-1-methylpropyl-mercapturic acid 
(HMPMA) 
crotonaldehyde 
Urine 
S-benzylmercapturic acid (S-BMA) 
toluene 
Urine 
total 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanol (total NNAL) 
4 
(methylnitrosamino)-
1-(3-pyridyl)-
1butanone (NNK) 
Urine 
BoExp to nicotine 
nicotine equivalents (NEQ) 
free nicotine, nicotine-glucuronide, free 
cotinine, cotinine-glucuronide, free trans-3’-
hydroxycotinine, trans-3’-hydroxycotinine-
glucuronide 
nicotine 
Urine 
nicotine 
nicotine 
Plasma 
cotinine 
nicotine 
Plasma 
 
3.4.1 Primary Endpoints 
• 
To demonstrate the reduction of primary BoExp in smokers switching from CC to THS 
2.2 as compared to those continuing to smoke CC. 
• MHBMA, 3-HPMA, S-PMA (concentration adjusted to creatinine) in 24-hour 
urine, and COHb in blood (expressed as % saturation of hemoglobin) as 
measured on Day 5. 
 
Evaluation Criterion: The study will be considered successful if the study demonstrates a 
50% reduction or more for all four primary BoExp in the THS 2.2 arm compared to the CC 
arm (as measured on Day 5). 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 40 of 171 
 
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. 
 
3.4.2 Secondary Endpoints 
• 
To determine the reduction of secondary BoExp on Day 5 in smokers switching from 
CC to THS 2.2 as compared to smokers continuing to smoke CC. 
• BoExp listed as secondary (Table S1) for the comparison of levels between smokers 
switching from CC to THS 2.2 and smokers continuing to smoke CC as measured 
on Day 5 as follows: 
• CO (expressed as ppm) in exhaled breath  
• Urinary BoExp (expressed as quantity excreted and concentration adjusted to 
creatinine) in 24-hour urine. 
 
• 
To describe the levels of primary and secondary BoExp over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers continuing to smoke 
CC. 
• 
BoExp  listed as primary and secondary (Table S1) for the comparison of levels 
between smokers switching from CC to THS 2.2 and smokers continuing to smoke CC 
as measured from Day 1 to Day 5. 
• CO (expressed as ppm) in exhaled breath  
• COHb in blood  (expressed as % saturation of hemoglobin) 
• Urinary BoExp (expressed as quantity excreted and concentration adjusted to 
creatinine) in 24-hour urine. 
 
• 
To determine the levels of nicotine on Day 5 in smokers switching from CC to THS 2.2 
as compared to smokers continuing to smoke CC and to describe their levels over the 
exposure period from Day 1 to Day 5. 
• NEQ (expressed in quantity excreted and concentration adjusted to creatinine) (Table 
S1) in 24-hour urine on Day 5 and from Day 1 to Day 5. 
• Nicotine and cotinine in plasma on Day 5 and from Day 1 to Day 5. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 41 of 171 
 
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. 
 
• 
To describe the levels of primary and secondary BoExp over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers switching from CC to 
SA. 
• BoExp listed as primary and secondary (Table S1) from Day 1 to Day 5 as follows: 
• CO (expressed as ppm) in exhaled breath.  
• COHb in blood (expressed as % saturation of hemoglobin). 
• Urinary BoExp (expressed as quantity excreted and concentration adjusted to 
creatinine) in 24-hour urine. 
 
• 
To describe the PK profiles of the nicotine and cotinine in smokers switching from CC 
to THS 2.2 as compared to smokers continuing to smoke CC.  
• 
Peak (highest concentration value along the day) on Day 5 in plasma. 
• 
Time to peak (actual time when the peak was observed compared to the time of 
the first cigarette) on Day 5. 
• 
Weighted average concentration over 24 hours on Day 5. 
 
• 
To describe the changes in CYP1A2 enzymatic activity on Day 5 in smokers switching 
from CC to THS 2.2, switching from CC to SA, and continuing to smoke CC.  
• Molar metabolic ratio of paraxanthine/caffeine in plasma on Day 5. 
 
• 
To describe the daily Tobacco Stick/CC consumption over the exposure period in 
smokers switching from CC to THS 2.2 as compared to smokers continuing to smoke CC: 
• 
Number of Tobacco Sticks and CC used each day for each subject from Day 1 to 
Day 5. 
 
• 
To monitor the safety profile during the study: 
• 
Adverse events (AEs)/ serious adverse events (SAEs) and device events 
including THS 2.2 malfunction/misuse. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 42 of 171 
 
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. 
 
• Respiratory symptoms: cough assessment by visual analogue scale (VAS), Likert 
scales, and one open question. 
• Vital signs. 
• Spirometry. 
• Electrocardiogram. 
• Clinical chemistry, hematology, and urine analysis safety panel. 
• Physical examination. 
• Concomitant medications. 
 
3.4.3 
Exploratory Endpoints 
• To describe the following parameters in smokers switching from CC to THS 2.2 as 
compared to smokers continuing to smoke CC and to smokers switching from CC to SA: 
• Excretion of mutagenic material in urine: Ames Mutagenicity test (YG1024+S9) 
on Day 5 in 24-hour urine. 
• Subjective effects of smoking: Questionnaire of Smoking Urges (brief version); 
Minnesota Nicotine Withdrawal Scale, revised version on Day 5. 
• Cytochrome P450 2A6 (CYP2A6) enzymatic activity: in plasma on Day 6, using 
the molar metabolic ratio of trans-3’-hydroxycotinine/cotinine.  
• Selected risk markers: 8-epi-prostaglandine F2α (8-epi-PGF2α) and 
11-dehydro-thromboxane B2 (11-DTX-B2) measured in 24-hour urine on Day 5. 
 
• To evaluate in smokers switching from CC to THS 2.2, smokers continuing smoking CC, 
and smokers switching to  SA the relationship between: 
• NEQ and primary and secondary BoExp in 24-hour urine on Day 5. 
• Risk markers (8-epi-PGF2α and 11-DTX-B2) and primary, secondary BoExp, and 
NEQ within 24-hour urine on Day 5. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 43 of 171 
 
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. 
 
• To describe the following parameters over the course of the study in smokers switching 
from CC to THS 2.2 as compared to smokers continuing smoking CC: 
• Product evaluation: Modified Cigarette Evaluation Questionnaire. 
• Smoking pattern: human smoking topography (HST) parameters and HST 
questionnaire. 
 
• To describe the following parameter over the course of the study in smokers switching 
from CC to THS 2.2: 
• Potential combustion occurrences in tobacco plugs: visual inspection of the 
tobacco plugs. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 44 of 171 
 
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. 
 
 
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
A randomized, controlled, open-label, 3-arm, parallel group, single-center study with a 
stratified randomization by sex and average daily cigarette consumption over the last 4 weeks 
as reported during the Screening Visit (smokers smoking 10 to 19 CC and smokers smoking 
>19 CC per day). (Figure 1. Study Design 
). 
This is an ad libitum smoking study. In general, smoking during confinement will be allowed 
between 06:30 AM and 11:00 PM.  
During the confinement period, compliance to product/regimen allocation (exclusive use of 
THS 2.2 and CC in THS 2.2 and CC arms respectively, and full abstinence from smoking in 
the SA arm) will be ensured by strict distribution of each Tobacco Stick/CC on demand of 
the subject. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 45 of 171 
 
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. 
 
Figure 1. 
Study Design 
Day -1, Day 0
Day -2
Admission
Baseline
Day 6 to Day 13
9 days in confinement
CC 
ad libitum
Safety
follow-up
ad libitum use 
of tobacco products
Day 1 to Day 5
Screening
*Screening 
within 1-4 weeks 
prior to admission
THS 2.2
Discharge (Day 6)
Smoking abstinence
CC
THS 2.2: Tobacco Heating System 2.2; SA: smoking abstinence; CC: conventional cigarettes.
 
• Screening period over 4 weeks (Day -30 to Day -3) prior to admission to the clinic (Day -
2): 
A demonstration of the THS 2.2 product will be done by the site collaborator during the 
Screening Visit. Subjects will be in a confinement setting for 9 days from Day -2 
onwards. 
• Run-in period (from admission on Day -2 until 06:29 AM of Day -1): 
Prior to enrolment on Day -2, as the last procedure of the eligibility assessments, subjects 
will have a product test of the THS 2.2 (use of up to 3 Tobacco Sticks). In female 
subjects, the THS 2.2 product test may only be done after pregnancy is excluded by a 
negative urine pregnancy test. Enrolment takes place after all inclusion and exclusion 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 46 of 171 
 
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. 
 
criteria have been satisfactorily met. Only subjects willing and able to use the product 
will be enrolled in the study. 
• Baseline period (from Day -1, 06:30 AM until Day 1, 06:29 AM): 
All subjects will continue smoking their single preferred brand of CC and baseline values 
will be recorded. On Day 0, subjects will be randomized to one of the 3 study arms in a 
2:1:1 ratio using a stratified randomization: 
• THS 2.2 Arm: 80 subjects, ad libitum use of the product. 
• CC Arm: 40 subjects, ad libitum use of their preferred CC brand. 
• SA Arm: 40 subjects who will abstain from smoking. 
Subjects will be informed of their randomized study arm by the study site 
collaborator on Day 1 prior to 06:30 AM.  
• Exposure period (from Day 1, 06:30 AM until Day 5, 11:00 PM): 
The exposure period will consist of 5 days of ad libitum use of the assigned product 
between 06:30 AM and 11:00 PM in THS 2.2 and CC arms. Use of any tobacco/nicotine 
containing product other than the assigned product will not be allowed and may, at the 
discretion of the Investigator, result in the subject withdrawal from the study. 
Subjects in the SA arm will be asked to abstain from smoking any nicotine/tobacco 
containing product and will not be provided with medication to support SA. 
The end of the 24-h urine collection period for Day 5 will end in the morning on Day 6 
prior to Discharge. 
• Day of Discharge (Day 6) (from Day 5, 11:01 PM to time of Discharge): 
Procedures of Discharge, including but not limited to laboratory parameters, will be 
conducted to discharge the subject from the clinic after 9 days in a confined setting. Use 
of CC will be allowed on Day 6, but only after spirometry has been performed.  
• Safety follow-up period (from the time of Discharge on Day 6 to Day 13): 
After time of Discharge, subject will enter a 7-day safety follow-up during which there 
will be recording of spontaneously reported new AEs/SAEs and the active follow-up of 
ongoing AEs/SAEs by the study site. In general, all AEs will be followed until resolved, 
stabilized (i.e., no worsening of the event), or a plausible explanation for the event has 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 47 of 171 
 
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. 
 
been found. The end of the study is defined as the time of Discharge on Day 6 plus 7-day 
follow-up period. 
 
During the study, any subjects who want to quit smoking will be encouraged to do so, and 
will be referred to medical services and will be withdrawn from the study. This is applicable 
for all subjects during screening to the baseline period and for subjects allocated to THS 2.2 
or CC arms during the exposure period. 
 
4.2 
Rationale for Study Design and Control Groups 
The minimum age of 23 years age in the inclusion criteria was selected based on: 
• The legal age of smoking in Japan is 20 years.  
• To account for the 3 years of smoking history. 
This clinical study aims to demonstrate reduction in exposure to selected HPHCs (except 
nicotine) in smokers switching to the THS 2.2, a candidate MRTP (see IB). 
The reference product in this study will be smokers who continue to smoke CC. Smokers 
who stop smoking (the SA arm) will be used as a reference point.  
The exposure period in confinement will provide information on exposure reductions in a 
well-controlled environment and will allow full control of daily cigarette consumption. The 
choice of HPHCs to be assessed in this study is derived from the WHO (Ashley et al., 2008 
and the draft guidance on Reporting Harmful and Potentially Harmful Constituents in 
Tobacco Products and Tobacco Smoke (FDA, 2011).  
In the WHO list, 9 HPHCs (acrolein, CO, 1-3 butadiene, benzene, N-nitrosonornicotine 
(NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), acetaldehyde, benzo[a]py-
rene, and formaldehyde) with evidence of carcinogenicity, respiratory, and cardiac toxicity 
were recommended to be measured as priority in the smoke chemistry for mandated lowering 
(Ashley et al., 2008). Exposure to four HPHCs (acrolein, CO, 1,3-butadiene, and benzene) 
among these 9 priority HPHCs will be assessed by measuring their respective BoExp as 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 48 of 171 
 
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. 
 
primary endpoints after 5 days of exclusive use of THS 2.2, CC, or SA. The following 
characteristics apply to these primary BoExps: 
• They are several-fold higher in smokers than in smokers abstinent from smoking 
(Lindner et al., 2011). 
• They exhibit, on average, an elimination half-life of ≤24-hours. Therefore, the 5 days of 
exposure are sufficient to reach the steady state with the THS 2.2 and SA arms (4 to 
5 times the half-life will lead to less than 5% of the original exposure levels of assessed 
biomarkers on Day 5). 
• They were decreased in smokers who switched to another tested candidate MRTP for 
5 days, similarly to that observed in smokers who stopped smoking (data on file from a 
previous study, PMI YVD-CS01-EU study). 
In addition to the 9 HPHCs recommended to be measured by WHO list, the FDA has 
required an additional 9 HPHCs for reporting to FDA (in total 18 HPHCs in cigarette smoke) 
(FDA, 2012b). From the WHO and FDA list, exposure to additional 9 HPHCs (acrylonitrile, 
4-aminobiphenyl [4-ABP], 1-aminonaphthalene [1-NA], 2-aminonaphthalene [2-NA], 
benzo[a]pyrene, crotonaldehyde, NNK, NNN, toluene) will be assessed by measuring the 
respective BoExp as secondary endpoints after 5 days of exclusive use of THS 2.2, CC, or 
SA.  
Cytochrome P450 1A2 activity, which is well known to be increased by smoking and to be 
decreased upon SA, will be measured in this study to evaluate the effect of THS 2.2 use on 
the activity of this enzyme (Faber and Fuhr, 2004) and to compare with the data on file from 
a previous study (PMI YVD-CS01-EU study). 
Additional risk markers will be assessed in this study as exploratory endpoints to understand 
if the reduced exposure results in biological changes. The risk markers have been selected 
based on their changes shown in smoking cessation studies as well as their believed 
association to health risks. The risk markers are: 
• Prostaglandin 8-epi-PGF2α is a well-established marker of oxidative stress, a pathway 
which is involved in atherosclerosis. F2-isoprostanes are bioactive prostaglandin-like 
compounds that are produced from arachidonic acid through a non-enzymatic process of 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 49 of 171 
 
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. 
 
lipid peroxidation catalyzed by oxygen free-radicals. On smoking cessation, the level of 
8-epi-PGF2α decreases rapidly within 1 to 2 weeks to the levels seen in non-smoker 
plasma, serum, and urine (Pilz et al., 2000). 
• 11-DTX-B2 (a major stable metabolite of thromboxane A2, which elicits mainly platelet 
aggregation). This risk marker was reported to decrease upon smoking cessation 
(Benowitz et al., 1993 and Morita et al., 2005). 
 
In addition, CYP2A6 activity, the enzyme involved in nicotine metabolism will be assessed 
in this study to evaluate if the use of THS 2.2 impacts the activity of this enzyme. 
Other parameters such as human smoking topography, product evaluation, and subjective 
effects including smoking urges and withdrawal symptoms will be evaluated.  
All subjects will be asked to provide their own CC according to their anticipated needs for 
the whole confinement period. This is to minimize any changes in their smoking behavior 
due to the participation in the study. 
4.3 
Appropriateness of Measurements 
The laboratory measures to be utilized in this study were selected based on the following 
criteria: 1) the availability of a validated analytical method, and 2) measure is known to be 
directly or indirectly affected by smoking; 3) measure is readily reversible after smoking 
cessation, 4) timeframe of reversibility of measure in the perspective of the study duration, 5) 
practicality/acceptability by subjects, and 6) robustness (rapid, simple, accurate). 
All used questionnaires, except the cough and HST questionnaires, are either available as a 
validated questionnaire in the local language or will be forward-translated and back-
translated with subsequent independent verification. 
 
4.4 
Study Duration 
The entire study duration per subject will be 17 to 44 days, including a Screening period of 
up to 28 days prior to baseline (Day -30 to Day -3), an 9-day confinement period (afternoon 
of Day -2 to time of Discharge at Day 6), followed by a 7-day safety follow-up period (until 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 50 of 171 
 
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. 
 
Day 13) for the recording of spontaneously reported new AEs/SAEs, and the active follow-
up of ongoing AEs/SAEs by the site. 
The 9-day confinement period consists of: 
• The run-in period: defined as from the admission to the ward until 06:29 AM of Day -1. 
• The baseline period: defined as 06:30 AM at Day -1 until 06:29 AM of Day 1. 
• The 5-day exposure period during confinement: defined as from 06:30 AM of Day 1 until 
11:00 PM of Day 5. 
• The Day of Discharge defined as from Day 5 (11:01 PM) until time of Discharge on 
Day 6. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 51 of 171 
 
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. 
 
 
5 
STUDY POPULATION 
5.1 
Selection of Study Population 
In total, 160 female or male smoking, healthy Japanese subjects who smoke per day at least 
10 non-menthol CC for the last 4 weeks with a maximum yield of 1 mg nicotine ISO per 
cigarette will be included in this study. The maximum number of CC is not limited. Subjects 
must have a smoking history of at least 3 years of consecutive smoking prior to the Screening 
Visit. There will be no brand restrictions. Subjects can smoke different non-menthol brands 
until Admission to the ward. From Admission to the ward onwards, however, they must 
restrict themselves to one preferred non-menthol CC brand. The smoking status will be 
verified with a urinary cotinine test (cotinine ≥200 ng/ml). Each sex and each of the smoking 
strata should have a quota applied to ensure they represent at least 40% of the population. 
5.1.1 
Inclusion Criteria 
At the Screening Visit/day of Admission, each subject must meet the following criteria: 
1. Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
1. Subject has signed the ICF and is able 
to understand the information 
provided in the Subject Information 
Sheet and ICF. 
Administrative X 
 
2. Subject is aged from 23 to 65 years 
(inclusive). 
Safety 
X 
 
3. Subject is Japanese. 
Effect 
X 
 
4. Smoking, healthy subject as judged by 
the Investigator based on all available 
assessments in the Screening 
period/day of Admission (e.g., safety 
laboratory, spirometry[forced 
Safety  
X 
X 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 52 of 171 
 
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. 
 
1. Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
expiratory volume in 1 second 
{FEV1}/forced vital capacity {FVC} 
>0.7 at post-bronchodilator basal 
spirometry, post-bronchodilator FEV1 
>80% predicted value, and 
post-bronchodilator FVC >0.8], vital 
signs, physical examination, ECG, 
chest X-ray, and medical history). 
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 labeled on the 
cigarette package, for the last 4 
weeks, based on self-reporting. 
Furthermore, the subject has been 
smoking for at least the last three 
consecutive years. The smoking status 
will be verified based on a urinary 
cotinine test (cotinine ≥200 ng/mL). 
Effect 
X 
X 
6. The subject does not plan to quit 
smoking in the next 3 months. 
Safety 
X 
 
7. The subject is ready to accept 
interruptions of smoking for up to 5 
days. 
Safety 
X 
X 
8. The subject is ready to accept using 
the THS 2.2. 
Effect  
 
X 
5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the 
study: 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 53 of 171 
 
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. 
 
Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
1. As per Investigator judgment, the 
subject cannot participate in the study 
for any reason (e.g. medical, 
psychiatric and/or social reason). 
Safety  
X 
X 
2. A subject who is legally incompetent, 
physically or mentally incapable of 
giving consent (e.g. emergency 
situation, under guardianship, 
prisoners or subjects who are 
involuntarily incarcerated). 
Administrative 
X 
 
3. The subject has medical condition 
requiring smoking cessation, or 
clinically relevant diseases (including 
but not limited to gastrointestinal, 
renal, hepatic, neurological, 
hematological, endocrine, 
oncological, urological, 
immunological, pulmonary and 
cardiovascular disease or any other 
medical condition [including but not 
limited to clinically relevant 
abnormal laboratory parameters]) in 
the judgment of the Investigator. 
Safety 
X 
X 
4. The subject has a body mass index 
(BMI) <18.5 or ≥32 kg/m2. 
Safety 
X 
 
5. As per Investigator judgment, the 
subject has medical conditions 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 
6. The subject has used 
nicotine-containing products other 
Effect 
X 
X 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 54 of 171 
 
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. 
 
Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
than commercially available CC 
(either tobacco-based products or 
NRT) as well as electronic cigarettes 
and similar devices, within 4 weeks 
prior to assessment. 
7. The subject has received medication 
(prescription or over-the-counter) 
within 14 days or within 5 half-lives 
of the drug (whichever is longer) 
prior to the Admission Day (Day -2), 
which has an impact on CYP1A2 or 
CYP2A6 activity. 
Effect 
 
X 
8. If a subject has received any 
medication (prescribed or over-the-
counter) within 14 days prior to 
Screening or prior to the Admission 
Day (Day -2), it will be decided at the 
discretion of the Investigator if these 
can potentially interfere with the 
study objectives or subject’s safety. 
Effect  
X 
X 
9. Concomitant use of non-steroidal 
anti-inflammatory drugs (NSAIDs) or 
acetylsalicylic acid. 
Effect 
X 
X 
10. The subject has a positive alcohol test 
and/or the subject has a history of 
alcohol abuse that could interfere 
with the subject’s participation in the 
study. 
Administrative 
X 
X 
11. The subject has a positive urine drug 
test. 
Administrative 
X 
X 
12. Positive serology test for HIV1/2, 
hepatitis B surface antigen (HbsAg), 
or hepatitis C virus (HCV). 
Safety 
X 
 
13. Donation or receipt of whole blood or 
blood products within 3 months prior 
Safety 
X 
X 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 55 of 171 
 
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. 
 
Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -2) 
to Admission. 
14. The subject is a current or former 
employee of the tobacco industry or 
of their first-degree relatives (parent, 
sibling, child). 
Administrative 
X 
 
15. The subject is an employee of the 
investigational site or any other 
parties involved in the study or of 
their first-degree relatives (parent, 
sibling, child). 
Administrative 
X 
 
16. The subject has participated in a 
clinical study within 3 months prior 
to the Screening Visit. 
Safety 
X 
 
17. The subject has previously 
participated in the same study at a 
different time (i.e. each subject can be 
included in the study population only 
once). 
Administrative 
X 
 
18. For women only: Subject is pregnant 
(does not have negative pregnancy 
tests at Screening and at Admission) 
or is breast feeding. 
Safety 
X 
X 
19. For women only: Subject does not 
agree to use an acceptable method of 
effective contraception* 
Safety 
X 
X 
* Intrauterine device, intrauterine system, established use of 
oral/injectable/implantable/transdermal hormonal methods, barrier methods of contraception 
(condoms, occlusive caps) with spermicidal foam/gel/film/suppository, vasectomized 
partner(s) or true abstinence (periodic abstinence and withdrawal are not effective methods) 
from Screening until the end of the safety follow-up period. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 56 of 171 
 
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. 
 
5.1.3 
Removal of Subjects from the Study 
Subjects will be informed that they are free to withdraw from the study at any time. Subjects 
should be questioned for the reason of premature withdrawal, although they are not obliged 
to disclose it. This needs to be fully documented in the Source Document and electronic Case 
Report Form (eCRF). 
When a subject withdraws or is removed from the study, the whole examination procedure 
planned on Day 6 must be performed as soon as possible after the time of withdrawal unless 
the subject has withdrawn their informed consent to do so. After the time of withdrawal, the 
subject will enter into the 7-day period of safety follow-up. Subjects withdrawn or removed 
from the study cannot re-enter the study. 
Subjects must be withdrawn from the study for any of the following reasons: 
• Withdrawal of informed consent. 
• Any AE or condition (including clinically relevant changes in a laboratory parameter), at 
the discretion of the Investigator. 
• Positive pregnancy testing (any invasive procedures, including the drawing of blood 
MUST NOT be performed after diagnosis of pregnancy, see Section 8.5). 
• The Sponsor or Principal Investigator terminates the study. If the Sponsor or the Principal 
Investigator decide to prematurely terminates the study, the head of the medical 
institution should be reported the fact and the reason in writing promptly. 
•  Withdrawal is considered to be in the best interest of the subject or the other subjects. 
• The subject wish to quit smoking (this is applicable for all subjects during screening to 
the baseline period and for subjects allocated to THS 2.2 or CC arms during the exposure 
period). 
Subjects may be discontinued from the study for any of the following reasons: 
• Lost to follow-up. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 57 of 171 
 
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. 
 
• Concomitant treatment with non-authorized medication as defined in the context of this 
study (in general, any concomitant medication should be discussed with the CRO 
Medical Monitor on an ongoing basis). 
• If a subject uses any CC or nicotine/tobacco-containing product other than the 
product/regimen he/she is assigned to, it will be at the discretion of the Investigator to 
decide whether or not to withdraw the subject from the study. 
• Non-compliance to the study procedures. 
 
Subjects withdrawn prematurely after randomization will not be replaced and will not be 
allowed to re-enter the study. All subject withdrawals have to be documented properly in the 
source documentation and the eCRF. 
5.1.4 
Violation of Selection Criteria 
Subjects who are eligible at Screening, but who do not meet the entry criteria at Admission 
Day (Day -2) will be considered a screening failure and will be replaced by other subjects. 
Subjects who violate the entry criteria prior to enrolment, but who were considered eligible, 
will be immediately withdrawn from the study when the violation is detected. If subjects are 
not yet randomized, they can be replaced. 
6 
INVESTIGATIONAL PRODUCTS 
6.1 
Description of Investigational Products 
6.1.1 
Test Product 
THS 2.2 comprises the following components:  Tobacco Stick, Holder, Charger, a Cleaning 
Tool, a mains power supply, and a USB cable: 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 58 of 171 
 
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. 
 
Charger:  
The function of the Charger (Model 4) is to recharge the Holder 
after use. It contains a battery with sufficient capacity to recharge 
the Holder approximately 20 times.  It is a convenient size to carry 
around, and can itself be recharged from a mains power source. 
 
Tobacco Stick  
Holder (Holder): 
The function of the Holder (Model 4.2) is to heat the Tobacco 
Stick, delivering an aerosol to the user. The electrical heating is 
powered from an internal battery which delivers power for about 6 
minutes (allowing complete use of a single Tobacco Stick). 
THS Tobacco Stick 
(Tobacco Stick): 
The Tobacco Stick (product code C3) contains tobacco which, 
when heated, generates an aerosol. It is custom-designed to be used 
with the Holder. 
The overall objective of the product design is to provide an acceptable experience in which 
the HPHCs levels in the aerosol are substantially reduced in comparison with CC. 
The THS 2.2 will be provided by the Sponsor. 
Per cigarette/Tobacco Stick tar, nicotine, and carbon monoxide yields are normally 
determined by standardized test methods. The most widely used test method is ISO 4387. 
PMI has developed a modified version of this method, which improves the determination of 
tar in products with high water content, which is typical for heated tobacco products (PMI, 
2012, PMI, 2013a, PMI, 2013c). Another method is the more intensive smoking method 
developed by Health Canada (Health Canada, 1999). 
Table 1 below lists the commonly reported measures (PMI, 2013). 
 
Table 1. 
Measured Aerosol Fractions for the THS Tobacco Sticks 
Constituent (mg/THS Tobacco Stick) 
ISO 1 
Health Canada  Intense 
regime 2 
Tar(NFDPM) 
4 
10.3 
Nicotine  
0.5 
1.32 
Carbon monoxide 
1 
0.6 
1 
International Organization for Standardization ISO machine-smoking regimen. The analytical method has 
been modified to avoid inaccuracies as a result of condensation from high water-content aerosols. 
2 
Health Canada Intense machine-smoking regimen (55 mL puff volume, 2-second puff duration, 30-second 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 59 of 171 
 
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. 
 
Constituent (mg/THS Tobacco Stick) 
ISO 1 
Health Canada  Intense 
regime 2 
inter-puff interval) (Health Canada, 1999) 
3 
NFDPM: Nicotine-free dry particulate matter 
 
6.1.2 
Reference Product / Baseline Period Products 
During the run-in period (Admission to clinic until 06:29 AM of Day -1) and the baseline 
period (from 06:30 AM of Day -1 until 06:29 AM of Day 1), all subjects will continue 
smoking their preferred commercially available single brand of non-menthol CC. Subjects 
are not allowed to roll their own CC.  
The reference product to the THS 2.2 during the randomized exposure period is the subject’s 
own preferred commercially available single brand of non-menthol CC. 
All eligible subjects will be asked to purchase their own preferred single brand CC prior to 
Admission and provide his/her anticipated amount of CC for a total of 9 days plus 4 extra 
packs on Day -2 (Admission Day) to the site study collaborator. The CCs will not be 
provided by the Sponsor. 
6.1.3 
Packaging and Labeling 
At Admission, all study subjects will provide the anticipated amount of CC in sealed packs to 
the study site collaborator. The CC packs provided by the subjects should not be opened and 
the cellophane wrapper should be intact. 
Each pack of CC provided by the subject will be labeled to identify which subject the 
cigarettes belong to (labels should be affixed by the study site collaborator to the cellophane 
wrapper of the lower part of the pack). Each pack of CCs will be labeled to identify 
necessary information to match the subject with its suppliers. 
For the Tobacco Sticks, the packs and cartons will be pre-labeled with the necessary 
information, including, product code. The labels will be translated into Japanese. See 
(Appendix 4). 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 60 of 171 
 
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. 
 
6.2 
Use of Investigational Product 
Subjects will never be requested or forced to smoke and will be free to stop smoking at any 
time during the study. The study is designed as an ad libitum use study. During the 
confinement period, smoking will generally be allowed between 06:30 AM to 11:00 PM. 
During the screening period, subjects will be allowed to smoke according to their smoking 
habits except during the procedures of the screening Visit at the discretion of the site. 
6.2.1 
Run-in Period 
Smoking ad libitum will be allowed prior to admission and throughout the day except during 
the procedures. All subjects will be allowed to continue smoking ad libitum their single 
preferred brand of usual CC. All subjects (except women with a positive pregnancy test at 
Screening or at Admission) will undergo a THS 2.2 product test prior to enrolment.  
Following the confirmation that the subject is able and willing to use the THS 2.2 product, 
subjects will be enrolled. 
6.2.2 
Baseline Period 
During the baseline period, all subjects will be allowed to continue smoking ad libitum their 
single preferred usual brand of non-menthol CC. 
6.2.3 
Exposure Period 
Subjects are not allowed to smoke any CC or use any nicotine/tobacco-containing products 
other than the product/regimen. 
6.2.3.1 
THS 2.2 Arm 
Subjects randomized to the THS 2.2 arm will use exclusively THS 2.2 from Day 1, 
06:30 AM onwards until Day 5, 11:00 PM.  

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 61 of 171 
 
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. 
 
6.2.3.2 
Conventional Cigarettes Arm 
Subjects randomized to the CC arm will continue smoking their CC from Day 1, 06:30 AM 
onwards until Day 5, 11:00 PM.  
6.2.3.3 
Smoking Abstinence Arm 
Subjects randomized to the SA study arm will be instructed to abstain from smoking from 
Day 1, 06:30 AM onwards until Day 5, 11:00 PM. They will not be provided with 
medication supportive for smoking abstinence.  
6.2.4 
Stopping Rules for Investigational Product 
For safety purposes, smoking should be temporarily stopped in the event of any signs 
suggesting nicotine overexposure, (e.g., gastrointestinal disturbance [nausea, vomiting, 
diarrhea, stomach or abdominal pain], cold sweats, headache, dizziness, and breathing 
problems) or any reasons at the discretion of the Investigator. 
6.2.5 
Safety Follow-up Period 
During the safety follow-up period (after the Time of Discharge at Day 6 until Day 13), all 
subjects are free to smoke their own CC ad libitum. Subjects in the SA arm, who wish to 
continue their SA, or any subject who wish to stop smoking will be referred for further 
treatment as per the standard of care in the country in which the study is conducted, if 
requested by the subject.  
6.3 
Method for Assigning Subjects to Study Arms 
When all the eligibility criteria have been met, randomization will be done through the 
Interactive Web and Voice Response System (IWRS) on Day 0 at any time during the day. 
Subjects will be informed of their randomized study arm in the morning of Day 1, prior to 
06:30 AM. 
Subjects will be randomized in one of the three study arms THS 2.2:CC:SA in a 2:1:1 ratio. 
Stratified randomization will be conducted by sex and by average daily cigarette 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 62 of 171 
 
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. 
 
consumption in the 4 weeks prior to the Screening Visit (those smoking 10 to 19 CC and 
those smoking >19 CC per day) reported by the subject. In each arm, each sex and each of 
the smoking strata should have a quota applied to ensure they represent at least 40% of the 
population. 
6.4 
Blinding 
This is an open-label study; therefore, the subjects and Investigators will be unblinded to the 
subject’s arm. However, there will be a limited degree of blinding in the data review and data 
analysis process. In particular, PMI and CRO personnel will be blinded to the randomized 
arm as summarized in the following table: 
Blinded Study Personnel 
End of Blinding Period 
PMI and CRO study 
statisticians 
After the statistical analysis plan (SAP) finalization or PMI 
blind database review(*), whichever comes last. 
PMI data manager 
After the finalization of PMI blind database review.(*) 
PMI safety and clinical 
scientists 
After the finalization of PMI blind database review(*). Can 
be actively un-blinded before that time point in case of the 
occurrence of any safety question, when appropriate. 
(*) As part of the PMI quality control (QC) activity, data listings will be reviewed by PMI before database lock, 
with no access to the randomization arm information. 
Any PMI and CRO personnel who are not listed in the above table will be unblinded by default.  
6.5 
Investigational Product Accountability and Compliance 
6.5.1 
Dispensing Investigational Product 
From Day-2 onwards, each CC will be dispensed to the subjects.  Subjects in the THS 2.2 
arm will be provided by the site personnel with Tobacco Sticks from Day 1 to Day 5.  One 
cigarette/tobacco stick will be allowed at a time, as per the study design, and documented in 
an appropriate Log. 
On each day of the confinement period, the time of dispense and the time of return for each 
product has to be documented from Day-1 for CC and from Day 1 for Tobacco Sticks 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 63 of 171 
 
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. 
 
onwards. The start of product use will correspond to the time of dispense of the first 
CC/Tobacco Stick. The subject must not take a puff of the tobacco stick during the 
pre-heating time. The product will not be promoted for commercial distribution or test 
market.  
6.5.2 
Storage and Accountability 
The study collaborator (the investigational product storage manager) designated by the head 
of the investigational site will be responsible for the storage and accountability of the 
investigational products. 
The THS 2.2 and CC will be stored in a secured storage site with access limited to authorized 
personnel only. Full accountability of the distributed products will be ensured by designated 
IP storage manager. Subjects will return each butt of CC and any used Tobacco Stick 
immediately after use. This will be documented in appropriate log. 
All tobacco plugs of all used Tobacco Sticks will be separated from the filters and the 
tobacco plugs will be collected from Day 1 to Day 5, using dedicated vials for accountability 
and subsequent analysis of potential combustion occurrences 7.8.2. 
6.5.3 
Investigational Product Retention 
The study site will destroy or return to the Sponsor any unused Tobacco Sticks and will 
return to the Sponsor the THS 2.2 product components upon study completion. Retention of 
THS 2.2 products will be documented. 
Irrespective of the study arm on the time of Discharge from the clinic, the site study 
collaborator will return to the subjects any remaining CCs given by them on the Day of 
Admission. 
6.5.4 
Compliance to Investigational Product(s) 
Compliance for all study arms will be ensured by strict distribution of the products (product 
by product) and collection of used Tobacco Sticks, the CC butts will be documented in 
appropriate log. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 64 of 171 
 
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. 
 
In addition, in the SA arm, compliance will be chemically verified using an exhaled CO 
breath test. The cut-off point for the CO breath test value to distinguish tobacco use vs no 
tobacco use will be 10 ppm (Benowitz et al., 2002). 
6.6 
Restrictions 
6.6.1 
Smoking Restrictions and Restrictions to the Smoking Abstinence Arm 
To avoid cross contamination between the 3 study arms, subjects must use THS 2.2 and CC 
must in separate rooms and subjects allocated to the SA arm should not have access to the 
smoking rooms. All precautions should be taken to remove any temptation to smoke for 
subjects who are randomized to the SA study arm. 
In the THS 2.2 and SA arms, subjects will not be allowed to smoke any CC or use any 
nicotine/tobacco containing products (including NRT) from Day 1 (06:30 AM) until Day 5 
(11:00 PM). In the CC arm, subjects will not be allowed to use the THS 2.2, any 
nicotine/tobacco containing products and other CC than collected to the site by the subject. 
During the confinement period, smoking will generally only be allowed during the 
designated smoking times, from 06:30 AM to 11:00 PM. Smokers will not have free access 
to their CC or THS 2.2; these will be dispensed by the study site collaborator individually as 
described in Section 6.5.1. 
Smoking will not be allowed during assessments on the Admission Day at the discretion of 
the site. Smoking is also not allowed from Day 5, 11:00 PM until the spirometry has been 
performed on Day 6.  
In general, the performance of scheduled procedures has priority over the wish of a subject to 
smoke. However, this is different at Day 5 due to the assessment of the nicotine profile. If the 
subject wants to smoke at Day 5 around the time of the blood draw, he/she should 
inhale/smoke first and the blood will be drawn after the tobacco stick/cigarette has been 
inhaled/smoked. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 65 of 171 
 
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. 
 
6.6.2 
Dietary Restrictions 
A standard diet will be designed by a dietician for the whole confinement period. For each 
meal, the caloric and fat content should be controlled in order to avoid “high-fat” diet. The 
FDA guidance on food-effect studies for bioequivalency testing identifies a “high-fat”diet as 
a diet which maintains approximately 50 percent of total caloric content of the meal and is 
high in calories (approximately 800 to 1000 calories) (FDA, 2002).  
In order to avoid any effect on assessment of BoExp, grilled or pan-fried meat, smoked pre-
cooked meats (e.g. tuna, ham, corned beef, and meats), smoked bacon and sausage will not 
be permitted (Tiffany et al. 1991). In addition, to avoid any effect on the measurement of 
CYP1A2 activity, alcohol, broccoli, brussels sprouts, cauliflower, grapefruit and 
xanthine-containing foods and beverages (coffee, tea, chocolate, cocoa, mate, guarana etc.) 
will be forbidden (Faber and Fuhr, 2004) (except for the uptake of caffeine tablet for 
CYP1A2 measurement). Consumption of quinine-containing drinks (e.g. tonic water) is not 
allowed. 
Subjects are not allowed to bring their own food or beverages to the investigational site. 
Meals will be served according to the schedules provided in Section 9. Additional light 
snack, fruits, and raw vegetables can be distributed to the subjects without restrictions at any 
time during confinement as long as they fulfill the above requirements described in this 
Section. Consumption of water is allowed as desired. The same menu and meal schedule will 
be administered uniformly for all subjects in all study arms. In addition, for the purpose of 
the Ames test planned on Day 0 and Day 5, the menus served on Day -1 and Day 4 will be 
identical. Fasting state has to be observed for at least 10 hours prior to blood draws for the 
safety laboratory at the Screening Visit, on Day 0, and Day 6, and for the serum/plasma bio-
banking samples for BoExp/risk markers on Day 0 and Day 6 and blood bio-banking samples 
for transcriptomics on Day 0 and Day 6. 
6.7 
Concomitant Medications 
No medication should be taken during the study from the Screening to the EOS (time of 
discharge plus 7-day safety follow-up period) without prior informing the Investigator. 
However, the Principal Investigator is responsible for the medical care of the subjects during 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 66 of 171 
 
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. 
 
their participation in this study. Any decisions regarding the prescribing of medication will 
be made in the best interests of the subject. 
Concomitant use of NSAIDs and acetylsalicyclic acid (including over-the counter products) 
is not allowed, as all of them could interfere with the levels of 11-DTX-B2 and possibly 
other risk factors. Paracetamol will be allowed at a daily total dose of up to 1500 mg. Any 
medication with an impact on the CYP1A2 and CYP2A6 metabolism (as prescription and 
over-the-counter products) as shown in Table 2 must be avoided. 
If the use of a concomitant medication cannot be avoided for the subject’s safety, it must be 
fully documented in the Source Document and transcribed into the eCRF (for details, see 
Section 7.4.5). Concomitant medications should be followed-up with the CRO Medical 
Monitor on an ongoing basis. 
The drugs and substances shown in Table 2 are a selection of drugs considered to have an 
impact on CYP1A2 and/or CYP2A6 activity (Chang and Kam, 1999, Ingelman-Sundberg et 
al., 1999, Lacy et al., 2007). Prior to database lock, concomitant medication will be assessed 
according to their potential impact on CYP1A2 and CYP2A6 activity and potential impact on 
the study results. 
Concomitant medication will first be assessed at Screening Visit. To be eligible for the study, 
any medication with impact on CYP1A2 and CYP2A6 metabolism must be discontinued at 
least 2 weeks prior to Admission to the clinic or for at least five half-lives (whichever is 
longer). They must not be used during the entire study until the time of Discharge. It is at the 
discretion of the Investigator to assess if the termination of such medication at Screening is 
medically justified and safe for the subject. 
Estrogens for contraception and for hormone replacement therapy, even though known to be 
CYP1A2 inhibitors, will be allowed in this study but must be documented on the eCRF. 
Table 2. 
Examples of Medications with Effects on CYP1A2 and CYP2A6 
Activity 
Drug name  
Substance Class 
Fluoroquinolones, including ciprofloxacin and 
ofloxacin, nafcillin, rifampicin 
Antibiotics 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 67 of 171 
 
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. 
 
Drug name  
Substance Class 
Fluvoxamine, fluoxetine, paroxetine, bupropion, 
duloxetine, amitriptyline, imipramine, sertraline, 
mirtazapine, citalopram, thioridazine 
Antidepressant 
Haloperidol, perphenazine, chlorpromazine, 
propoxyphene fluphenazine, clozapine, olanzapine 
Neuroleptic 
Phenobarbital, primidone, carbamazepine 
Antiepileptic 
Cholorquine, quinidine 
Antirheumatic 
Clotrimazole, terbinafine, fluconazole, ketoconazole, 
miconazole 
Antimycotic 
Erythromycin, ciprofloxacin, clarithromycin, 
norfloxacin 
Antibiotic 
Cimetidine, chlorpheniramine, diphenhydramine, 
ranitidine 
H2-receptor antagonist 
Amiodarone, verapamil, mibefradil, mexiletin, 
propafenone, propranolol, lidocaine 
Antiarrhythmic  
Losartan, amlodipine, nifedipine,  
Antihypertensive 
Drospirenone,, estrogens 
Hormonal contraception, hormonal 
replacement therapy (estrogens) 
Fluvastatin 
Cholesterol-lowering agent 
Theophylline 
Antispasmodic pulmonological 
agent/Bronchodilator agent 
Omeprazole, lansoprazole 
Proton pump inhibitor 
Interferon 
Antiviral/Immunomodulating agent 
Methoxsalen   
Anti-psoriatic 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 68 of 171 
 
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. 
 
Drug name  
Substance Class 
Modafinil, diclofenac, rofecoxib  
Analgesic 
Insulin 
Anti-diabetic 
Sildenafil  
Erectile dysfunction 
Quinine  
Leg cramps 
St. John’s Wort  
Over-the-counter (herbal remedy) 
antidepressant 
Psoralen 
Anti-psoriatic (substance class 
Furocoumarins) 
Pilocapine 
Cholinergic agonists (e.g., used for 
Glaucoma Therapy) 
Data source: Chang and Kam, 1999, Ingelman-Sundberg et al., 1999, Lacy et al., 2007.The 
list is not exhaustive. 
The list of drugs provided in Table 2 is intended to provide guidance for the Investigator; 
however, should not be considered exhaustive. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 69 of 171 
 
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. 
 
 
7 
STUDY PROCEDURES 
Personnel performing study measurements or recordings must have the appropriate training 
fully documented. Quality and control measures have to be in place. An overview of all study 
procedures is shown in the Schedule of Events (Appendix 1). In this Section, only the 
expected/planned time points for the various measurements are described. As not all subjects 
can undergo a procedure at the same time, adequate time windows are given for each study 
procedure and each time point (see Section 9). Site personnel will adhere to the site’s 
Standard Operating Procedures (SOPs) for all activities. Appropriate medical advice will be 
provided to the subject in case of any medial findings requiring health care. 
7.1 
Informed Consent/Subject Information Sheet 
Prior any study assessments is performed, the subject will be asked to provide his consent to 
participate to the study (ICF for study participation) Section 1.3. 
In addition to the ICF for study participation, the subject will be asked to provide his separate 
consent for two kinds of biobanking (Section 1.3).  
• ICF to the additional bio-banking of serum/plasma/urine samples for further 
measurements of BoExp and risk markers.  
• ICF to the additional bio-banking of blood sample for further transcriptomics 
(pharmacogenomics) analysis.  
The subject’s participation in the study does not depend on their consents for both bio-
banking (BoExp of exposure and risk markers and for pharmacogenomics analysis) will be 
separate to that for study participation. The three consents will be captured in the eCRF. 
7.2 
Advice on the Risk of Smoking and Debriefing 
Each subject will be given advice on the risks of smoking 3 times during the study: at the 
Screening Visit, at Admission (Day -2), and at Day 6. This will take the form of a brief 
interview according to WHO recommendations (Raw et al., 2002). Details of the interview 
will be recorded in the Source Document File. Information on the risk of smoking will be 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 70 of 171 
 
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. 
 
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 smoking cessation advice, a debriefing of subjects will be done at each 
smoking cessation advice session to address any intended or unintended beliefs participants 
have about the candidate MRTP. The goal of the debriefing would be to help ensure that 
subjects exit the study with an accurate understanding of product risks, including an 
understanding that the candidate MRTP has not been demonstrated to be less harmful. 
 
7.3 
Support for the Smoking Abstinence Arm 
All subjects in the SA arm will be closely monitored by the site study collaborator for 
possible signs and symptoms of nicotine withdrawal. This includes clinical monitoring, e.g. 
vital signs, physical examination and body weight. It will also involve close monitoring of 
the subject’s behavior, mood and any AEs. A psychologist may be contacted and will be 
available upon the subject’s request, or if considered necessary, upon the request of the 
Investigator or site study collaborator. 
7.4 
Clinical Assessments 
Any clinically relevant finding detected during the Screening Visit has to be documented as a 
concomitant disease. This also applies to clinically relevant findings in e.g. laboratory values, 
vital signs and ECGs, detected during the Screening Visit. Any untoward medical occurrence 
in a subject detected during the study which was not present at the Screening Visit must be 
documented as an AE. Worsening of a pre-existing condition from the Screening Visit 
onwards will also be documented as an AE. If a clinically relevant finding is detected during 
the Screening period, the Investigator needs to check if inclusion criterion no. 04 is still 
fulfilled. 
7.4.1 
Demographic Data 
Demographic data (sex, date of birth/age) will be recorded at the Screening Visit. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 71 of 171 
 
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. 
 
7.4.2 
Identification of the Current Cigarette Brand 
Identification of the current CC brand(s) smoked by the subject will be done at the Screening 
Visit and at Day -2. At the Screening Visit, smokers will be asked to bring a pack of their 
current CC brand(s) to the site. On Day -2, subjects will hand their CC supply for the entire 
confinement period to the site study collaborator. The site study collaborator will document 
the brand name and yields. A photograph of the front and the side of the cigarette pack 
supplied by the subject (bearing the tar and nicotine yields) will be taken by the study site 
collaborator in addition to recording the brand name and yields. These photographs will be 
considered as Source Documentation. A copy of the photographs will be provided to the 
Sponsor electronically (as Digital Video Disk or Compact Disc [CD]). 
7.4.3 
Smoking History and Willingness to Quit Smoking 
Subjects will be asked about their smoking history. At Screening and on the Day of 
Admission (Day -2) this will include questions to evaluate whether the subject has smoked 
for at least the last 3 consecutive years, to determine the number of CC smoked during the 
previous 4 weeks, and to evaluate if the CCs smoked during the previous 4 weeks were non-
menthol CCs. At the Screening Visit only, the subject will also be asked if he/she plans to 
quit smoking within the next 3 months. In addition, the subject will be asked if he/she has 
used nicotine-containing products other than commercially available CC (either tobacco-
based products or NRT), electronic cigarettes, or similar devices, within 4 weeks prior to 
assessment. 
At Screening and on the Day of Admission (Day -2), subjects will also be asked if they are 
ready to abstain from smoking for at least 5 days (as required in the study protocol inclusion 
criteria). Only subjects who are prepared and able to comply with this requirement will be 
considered for participation in the study. 
7.4.4 
Demonstration and Trial of the THS 2.2 
All subjects will have a demonstration of the THS 2.2 product at the Screening Visit. On 
Day -2, as the last procedure of the eligibility assessments on that day, subjects will have a 
trial of the THS 2.2 product (use of up to three THS Tobacco Sticks).  

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 72 of 171 
 
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. 
 
In female subjects, the THS 2.2 product trial must only be done after pregnancy is excluded 
by a urine pregnancy test. Enrolment takes place after all requested inclusion and exclusion 
criteria have been satisfactorily met at Day -2. Only those subjects who are willing and able 
to use the product can participate in the study. The product test will be the last assessment 
prior to enrolment. 
7.4.5 
Medical History, Concomitant Diseases, Previous and Ongoing Medications 
Relevant medical history will be documented at the Screening Visit. Any concomitant 
disease will be documented at the Screening Visit. Medical history is defined as any 
condition that started prior to and ended prior to Screening. A concomitant disease is defined 
as any condition that started prior to the Screening Visit and is still ongoing at the Screening 
Visit. 
Prior medication taken 4 weeks prior to Screening Visit and any concomitant medication 
needs to be documented. Any medication which was started prior to the Screening Visit and 
is still being taken by the subject will be considered a concomitant medication. Medication 
initiated after Screening is also referred to as concomitant medication. This applies to both 
prescription and over-the-counter products. 
Records of any medication taken must include the drug name (preferably both generic and 
trade name), route of administration (e.g. oral, intravenous), total daily dose/unit (e.g. 
expressed in mg, ml, or IU), indication, the start and (if applicable), the stop date (day, month 
and year). Any therapy changes (including changes of regimen) during the study are to be 
documented. Any concomitant medication that is still being taken by the subject at the end of 
the study will be recorded on the eCRF. 
 
7.4.6 
Physical Examination 
A physical examination will be conducted at the Screening Visit, at Admission (Day -2), and 
at Day 6.  
Appropriate medical advice will be provided to the subject in case of any medical findings 
requiring health care. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 73 of 171 
 
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. 
 
7.4.7 
Body Height and Weight 
Body weight will be recorded at all time-points at the Screening Visit, at Admission (Day -
2), and at Discharge on Day 6. Body height will be measured only at the Screening Visit.  
Body mass index will be calculated from the body weight and height using the following 
formula: 
BMI =  
weight in kilograms 
————————     ( kg/m² ) 
height in meters² 
 
7.4.8 
Vital signs 
Systolic and diastolic blood pressure, pulse rate and respiratory rate will be measured at the 
Screening Visit, at Admission (Day -2), and in the morning of every day of the confinement 
period (i.e. Days -1 to 6). All measurements will be made after the subject has rested for at 
least 5 minutes in a supine position. 
For every measurement, it will be documented if the subject has smoked within 15 minutes 
prior to the measurement. 
7.4.9 
Other Clinical Assessments 
7.4.9.1 
Spirometry 
Spirometry with and without a short-acting bronchodilator will be done at the Screening Visit 
to evaluate inclusion/exclusion criteria (the post-bronchodilator results). At screening, 
spirometry without bronchodilator will be done first, and then, spirometry with 
bronchodilator. Furthermore, spirometry without bronchodilator will be performed at Day 0 
(baseline values), and at Day 6 (for comparison with the baseline values). Spirometry has to 
be done prior to smoking the first cigarette of the day. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 74 of 171 
 
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. 
 
Spirometry will follow the 2005 testing and quality recommendations by the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) Joint Task Force on the 
standardization of spirometry along with the electronic data submission and documentation 
processes. Spirometry predicted values will be standardized to the NHANES III predicted set. 
All personnel performing lung function testing should have the appropriate training and 
quality control (QC) measures should be put into place and be properly documented and filed 
at the pulmonary function laboratory (including the records of the calibration, if applicable). 
The forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) will be 
recorded. 
The subject will be submitted to a spirometry with maximum voluntary ventilation 
measurement. 
For spirometry, assessed parameters will include: 
• FEV1. 
• FVC. 
• FEV1/FVC. 
 
7.4.9.2 
Electrocardiogram 
An ECG will be recorded at Screening, and at Day 6. Electrocardiogram testing will be 
performed as per the site’s local practice. A standard 12-lead ECG will be recorded after the 
subject has rested for at least 10 minutes in a supine position. 
The following parameters will be documented: heart rate, PR interval, QRS interval, QT 
interval and QT interval corrected by the ECG machine according to Bazett’s formula. Every 
ECG has to be assessed as normal, abnormal – clinically not relevant, or abnormal – 
clinically relevant. A diagnosis has to be provided on the eCRF for all ECGs assessed as 
abnormal – clinically relevant. All ECG print-outs will be interpreted by a qualified 
physician. Any print-outs of ECGs on thermo-sensitive paper must be photocopied and 
stapled together for inclusion in the Source Documents. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 75 of 171 
 
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. 
 
7.4.9.3 
Chest X ray 
A chest X-ray (anterior-posterior and left lateral views) will be assessed during the Screening 
period to exclude subjects with relevant pulmonary diseases. Subjects will be referred to a 
radiology facility for this procedure. No new examination is required if the subject can 
present a chest X-ray with anterior-posterior and left lateral views at the Screening Visit 
which is not older than 6 months. 
7.5 
Biomarker Assessment 
All bioanalytical assays and laboratory assessments will be carried out using validated 
methods (see Sections 7.6 and 7.7). The bioanalytical methods used will be documented in 
the Bioanalytical Plans/Reports. A list of laboratories is provided in Appendix 2. 
Precautions should be taken during blood sampling and processing to prevent the 
contamination of samples with environmental nicotine or CO. 
7.5.1 
Biomarker of Exposure  
7.5.1.1 
Exhaled CO and Carboxyhemoglobin 
Carboxyhemoglobin measured in blood and exhaled CO will be investigated as a measure of 
CO in all three study arms. The CO breath test should be conducted in timely conjunction 
with the blood sampling for COHb, where applicable. In the SA arm, the CO breath test will 
serve as a verification of compliance (Section 6.5.4). 
CO Breath Test 
Carbon monoxide in exhaled breath will be measured using the Smokerlyzer® such as Micro 
4 Smokerlyzer® device or similar.  
On Days -1 to Day 5, the CO breath test will be conducted four times per day. The first test 
should be conducted within 15 minutes prior to the first product use. The other three tests 
should be conducted as described in section 9. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 76 of 171 
 
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. 
 
For subjects in the SA arm, the first CO breath test will be done between 08:00 AM-09:30 
AM.  The other three tests should be conducted as described in section 9. 
On Day -2, Day 6, the CO breath tests will be conducted once irrespective of time of product 
use. 
Carboxyhemoglobin 
Assessment for COHb measurement will be performed at the local laboratory. 
Carboxyhemoglobin in blood will be assessed on a daily basis, starting from Day -1 until 
Day 5.  
On Day -1 to Day 4: one blood sample will be collected between 08:00 PM-09:30 PM. 
On Day 5: one blood sample will be collected within 15 minutes prior to the first product use. 
The three other blood samples will be collected as described in section 9. 
For subjects in the SA arm, the first COHb will be done between 08:00 AM-09:30 AM. The 
three other blood samples will be collected as described in section 9. 
7.5.1.2 
Plasma Nicotine and Cotinine 
Nicotine and cotinine concentrations will be measured in plasma to evaluate the exposure to 
nicotine. For subjects in the SA arm, blood samples will be collected on Days 0 to 4, at 
comparable time points. No nicotine PK profile will be done for subjects in the SA arm on 
Day 5 and Day 6. 
• On Day 0 to Day 4 (all study arms): 
One blood sample for nicotine and cotinine will be drawn each day between 08:00 PM-09:30 
PM. 
• Nicotine/cotinine PK Profile on Day 5 and Day 6 (THS 2.2 and CC arms only): 
In total, 9 blood samples will be drawn on Day 5. The first blood sample on Day 5 will be 
drawn within 15 minutes prior to the first product use (=T0). On Day 5, T0 will serve as a 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 77 of 171 
 
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. 
 
reference for the time to peak concentration. An additional 8 blood samples will be drawn in 
2-hour intervals after T0. The last blood sample should be drawn no later than 11:00 PM, 
corresponding to the end of the product use period. At all time-points, if the subject wants to 
smoke around the time of the blood draw, he/she should smoke first and the blood will be 
drawn after the product has been used. Depending on the time of the first product use, it may 
be that fewer than 8 blood samples will be collected from a subject after T0. 
On Day 6, two blood samples will be drawn. The first one will be 20 hours after T0 and the 
second blood sample will be 24 hours after T0 (with T0 being the time of the first product use 
on Day 5). 
• On Day 5 and Day 6 (SA arm only): 
On Day 5, one blood sample will be drawn between 08:00 PM-09:30 PM. 
On Day 6, one blood sample will be drawn between 08:00 AM-09:30 AM. 
7.5.1.3 
Other Biomarkers of Exposure 
The following BoExp will be measured in 24-hour urine collection samples as per the 
Schedule of Events (see also Appendix 1): 
• Primary BoExp: MHBMA, 3-HPMA, S-PMA.  
• Secondary BoExp: total NNAL, 1-NA, total 1-OHP, total NNN, 3-
hydroxy(a)benzopyrene, 4-ABP, 2-NA, o-tol, NEQ, CEMA, HEMA, S-BMA, and 
HMPMA. 
For normalization of BoExp, creatinine will also be measured in the 24-hour urine samples. 
7.5.2 
Other assessments 
7.5.2.1 
Risk markers 
The following risk markers will be recorded/measured at the following time points: 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 78 of 171 
 
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. 
 
• 8-epi-PGF2α to be measured in 24-hour urine on Day 0 and Day 5. 
• 11-DTX-B2 to be measured in 24-hour urine on Day 0 and Day 5. 
 
7.5.2.2 
CYP1A2 activity test 
CYP1A2 activity will be measured at Day 0, and at Day 5. Measurement of enzyme activity 
will be assessed through paraxanthine (PX) and caffeine (CAF) plasma molar concentrations 
approximately 6 hours (±15 minutes) after the intake of one Tomerumin® (LionCorp.) 
caffeine tablet (around 170 mg caffeine) with 150 ml ±10 ml water (Faber and Fuhr, 2004).  
The exact time of intake of the caffeine tablet in the morning and of the blood sampling 
(blood sample will be taken 6 hours [±15 minutes] after the intake of the caffeine tablet) must 
be recorded. Cytochrome P450 1A2 activity will be assessed by the measurement of the 
molar PX/CAF metabolic ratio (Faber and Fuhr, 2004). 
7.5.2.3 
CYP2A6 activity 
CYP2A6 activity will be measured in plasma on Day 0, and at Day 6, using the metabolic 
molar ratio of trans-3’-hydroxycotinine/cotinine (Jacob et al., 2011). Blood sampling for 
CYP2A6 activity will be done prior to product use. 
CYP2A6 activity drives the hepatic metabolism of nicotine to cotinine and subsequent 
metabolites. 
7.5.2.4 
Ames Mutagenicity Test 
Urine mutagenicity, a biomarker for measuring mutagen load, will be measured on Day 0 and 
on Day 5 in 24-hour urine.  
The urinary determination of each sample will be done in one bacterial strain 
(S. typhimurium strain YG1024), using S9 metabolic activation and 4 doses for each of the 
urine extracts.  

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 79 of 171 
 
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. 
 
7.6 
Laboratory Assessments 
7.6.1 
Clinical Chemistry, Hematology, and Urine Analysis for Safety Panel  
Hematology, clinical chemistry and urine analysis for the safety panel will be measured at 
Screening, Day 0, and at Day 6. Blood samples will be taken after at least 10 hours of fasting 
(see Section 6.6.2). The urine test will be performed semi-quantitatively as a urine dip-stick 
test. Parameters to be measured are listed in Table 3. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 80 of 171 
 
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. 
 
Table 3. 
Clinical Laboratory Parameters for Safety Panel 
Hematology 
Clinical Chemistry 
Urine analysis 
- Hematocrit 
- Hemoglobin 
- Mean corpuscular hemoglobin 
(MCH) 
- Mean corpuscular hemoglobin 
concentration (MCHC) 
- Mean corpuscular volume 
(MCV) 
- Platelet count 
- Red blood cell (RBC) count  
- White blood cell (WBC) count 
- Differential WBC count:  
• 
Neutrophils 
• 
Basophils  
• 
Eosinophils  
• 
Lymphocytes 
• 
Monocytes 
 
 
- Albumin 
- Total protein 
- Alkaline phosphatase (AP) 
- Alanine aminotransferase 
(ALT) 
- Aspartate aminotransferase 
(AST) 
- Blood urea nitrogen (BUN) 
- Creatinine 
- Gamma-glutamyl 
transferase (GGT) 
- Fasting Glucose 
- Lactate dehydrogenase 
(LDH) 
- Potassium  
- Sodium 
- Total bilirubin 
- Direct bilirubin 
- Total cholesterol 
- Triglycerides 
 
- pH 
- Bilirubin 
- Glucose 
- Nitrite 
- Red blood cell traces 
- Protein 
- Specific gravity 
 
7.6.2 
Serology 
A test for HbsAg, HCV, and anti-HIV1/2 and p24 antigen will be done at Screening. In case 
of positive results, the subject will be referred to appropriate medical care. 
7.6.3 
Urine Drug Screen 
A urine drug screen will be performed at the study site at the Screening Visit and on the day 
of Admission (Day -2). The urine will be screened for amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, and opiates. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 81 of 171 
 
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. 
 
7.6.4 
Urine Cotinine Screening 
A urine cotinine test will be performed at Screening and at Admission to the clinic (Day -2) 
in order to confirm the subject’s smoking status. The test must detect cotinine with a cotinine 
threshold of ≥200 ng/mL. 
7.6.5 
Alcohol Breath Test 
Subjects will have a breath alcohol test at the Screening Visit and at Admission to the clinic 
(Day -2) using an alcometer device. 
7.6.6 
Urine Pregnancy Testing 
All female subjects will undergo pregnancy testing at the Screening Visit, at Admission (Day 
-2), at Day 6. Female subjects with a positive pregnancy test at the Screening Visit or at Day 
-2 cannot be enrolled and will be considered a screening failure. The product test at 
Admission must be done only in female subjects with a negative pregnancy test. In any case 
of a positive pregnancy test, the Investigator will inform the subject about the risks 
associated with smoking during pregnancy. In the event of an unclear urine pregnancy test, 
absence of pregnancy should be confirmed by a serum follicle stimulating hormone (FSH) 
level >20 IU/l. 
All pregnancies detected during the study must be reported and handled as described in 
Section 8.5. 
7.7 
Sampling Handling and Storage 
All blood samples are to be tested at a central laboratory with the exception of COHb blood 
sample and the safety laboratory panel which will be tested at a local laboratory (see 
Appendix 2). The urine cotinine test, urine pregnancy tests and urine drug screen will be 
done by personnel at the study sites. 
Detailed procedures for sample collection and handling of samples are described in a 
separate Sample Handling Manual (SHM). Safety laboratory samples will be destroyed as 
per the laboratory’s standard procedures. All other samples (except bio-banking samples) 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 82 of 171 
 
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. 
 
will be destroyed after the CSR has been finalized. The facility(ies) at which the samples are 
stored will be informed in writing by the Sponsor when destruction of the samples will be 
allowed. 
The bioanalytical lab(s) are listed in Appendix 2. 
7.7.1 
Blood samples 
Blood samples will be collected by qualified and trained site personnel. Subjects should be in 
a seated position during blood collection. The maximal total volume of blood drawn for each 
subject will be around 170 ml, which includes 30 ml for safety and repeated analysis, 20 ml 
of blood for long-term storage of the bio-banking samples for further analysis of BoExp and 
risk markers and 10 ml for long-term storage bio-banking samples for transcriptomics (only 
if additional consents are given (see Section 7.7.3)). 
The blood sampling for transcriptomics and the data related to these samples will be 
anonymized. Anonymized data and samples are initially single or double coded where the 
link between the subjects’ identifiers and the unique code(s) is subsequently deleted. This is 
applicable for the blood bio-banking for transcriptomics only. 
 
7.7.2 
Urine samples 
Spot urine samples will be used for the urine drug screen, urine cotinine screen, urine 
pregnancy tests, and safety urinalysis.  
For the 24-hour urine collection, subjects will empty their bladders shortly before 06:30 AM 
on the study day indicated in the Schedule of Events (Appendix 1, Table A2). The collection 
period starts at 06:30 AM and ends on the following day at 06:29 AM. Shortly before 
06:29 AM, after nearly 24-hours of urine collection, subjects will empty their bladder again 
and this urine will be used as the final portion of the 24-hour urine sample. During the 
sampling period, all urine passed must be collected and put into the sampling bottle, with the 
exception of about 10 ml for the spot urine tests (described above). No urine must be passed 
into the toilet. The start and the end time of the 24-hour urine collection will be recorded by 
the study site collaborator. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 83 of 171 
 
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. 
 
For assessment of urine BoExp, creatinine for normalization of urine BoExp, sample 
bio-banking and urine mutagenicity, aliquots from the 24-hour urine collection will be taken. 
In the Schedule of Events for the 24-hour urine collection (see Appendix 1, Table A2), the 
dot corresponds to the day on which the 24-hour urine collection period starts. For example, 
for NEQ measured at Day 5 in the 24-hour urine collection that starts on Day 5 and ends later 
on Day 6. 
At time of Discharge on Day 6, subjects will empty their bladder shortly before 06:29 AM. 
This will be the last urine portion for the 24-hour urine for the Day 5 dot mark in the 
Schedule of Events. 
7.7.3 
Bio-banking Long Term Storage of Blood and Urine 
If a subject gives consent for sample bio-banking for BoExp/risk markers, additional samples 
of urine (from the 24 hour urine collection) and serum/plasma (20 ml of blood total) will be 
collected. 
• Samples from the 24-hour urine will be collected from the urine collections that started 
on Day 0, and on Day 5 respectively (10 tubes of 10 ml each per timepoint). 
• Serum/plasma will be collected on Day 0, and plasma on Day 6 (2 tubes of 5 ml of blood 
drawn per timepoint. From one tube 2 x 1 ml plasma and from second 2 x 1 ml of serum 
will be collected and stored). 
These samples are intended for possible later analysis of additional BoExp/risk markers. No 
genetic testing or pharmacogenomics testing will be performed on these samples. 
If a subject gives consent for sample bio-banking of whole blood for transcriptomics, a total 
of 10 ml of blood will be collected to that purpose at Day 0 and Day 6 (1 tube of 5 ml per 
timepoint. The 5 ml will be further split into 2 tubes with 2.5 ml of whole blood each and 
stored). 
The samples intended for sample bio-banking will be kept frozen according to the SHM, 
separate from the other samples collected, and will be shipped to a central storage facility. 
After the final CSR is signed, samples of plasma/serum will be stored for a maximum of 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 84 of 171 
 
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. 
 
5 years and samples of urine will be stored for a maximum of 2 years. The blood bio-banking 
for transcriptomics will be stored for a maximum of 5 years. 
The facility at which the samples are stored will follow their procedures for destruction of 
banked samples if a subject withdraws their consent for sample bio-banking. 
7.8 
Other Study Procedures 
7.8.1 
Human Smoking Topography Assessment 
Human smoking topography (HST) involves the measurement of each smoker’s unique way 
of smoking CCs or using THS Tobacco Sticks using the HST SODIM® device. The HST 
SODIM® device, model SPA/M (SODIM® Instrumentation, Fleury les Aubrais, France) is a 
device which is used to measure smoking topography (see Appendix 5). It consists of a 
special cigarette holder (containing a constriction in the middle) which is placed between the 
smoker’s mouth and the filter of the CC or the THS Tobacco Stick being smoked/used. The 
holder is connected by two narrow tubes to a portable data logger/recording system (see 
Appendix 5 for a description of the device). Any malfunction of the HST SODIM® device 
will be documented in appropriate log. 
At Day 0, the HST SODIM® device has to be used for all CC smoked for all subjects. On 
Day 1 and Day 4 of the confinement period, the HST SODIM® device has to be used for 
every product use for all subjects in the CC and THS 2.2 arms. 
Smoking topography with the HST SODIM® device will not be recorded for subjects 
smoking CC that are incompatible with the HST SODIM® device (e.g. slim CC). 
For each subject, one HST SODIM® device will be assigned at Day -1, which will be used by 
that subject on all HST assessment days (in the case of malfunction, the device will be 
exchanged). SODIM® devices will be assigned to all subjects smoking non-slim CCs at each 
cohort bur only the 40 first subjects will have an assigned HST SODIM®.  
From Day 1, for subjects in the SA arm, no HST assessments will be performed. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 85 of 171 
 
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 Sponsor or designee will provide training on the use of the HST SODIM® device to the 
study site collaborator. The study site collaborator will, in turn, provide training to the 
subjects. All SODIM® devices will be returned to the Sponsor after completion of the study. 
7.8.1.1 
Human Smoking Topography Parameters: 
The HST SODIM® device measures and records the flow and other per-puff parameters 
listed in Table 4 below. From the per-puff parameters (Table 4), the per cigarette parameters 
shown in Table 5 will be derived (representing average values or totals per cigarette). 
Prior to calculation of the per-cigarette parameters, the Sponsor HST group will validate the 
data and discard any invalid data. Only valid data for the per-cigarette parameters will be part 
of the study database and will be analyzed. 
Table 4. 
Human Smoking Topography – Per-Puff Parameters 
Description 
Variable 
Unit 
Puff number  
Ni 
 
Puff volume 
Vi 
ml 
Puff duration 
Di 
s 
Average flow [Vi/Di] 
Qmi 
ml/s 
Peak flow 
Qci 
ml/s 
Inter puff interval 
Ii 
s 
Sum of Ii and Di 
DFi 
s 
Work [INT Pmi*FinalFlow*dt] 
Wi 
mJ 
Average pressure drop 
Pmi 
mmWG 
Peak pressure drop 
Pci 
mmWG 
Average resistance [Pmi/Qmi] 
Rmi 
mmWG/ml/s 
Peak resistance [Pci/Qci] 
Rci 
mmWG/ml/s 
 
Table 5. 
Human Smoking Topography – Per-Cigarette Parameters 
Description 
Variable 
Formula 
Unit 
Total number of puffs 
NPC 
∑ Ni 
  

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 86 of 171 
 
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. 
 
Description 
Variable 
Formula 
Unit 
Total puff volume 
TVOL 
∑ Vi 
ml 
Average puff volume  
AvgVi 
∑ Vi / NPC, i=1 ... NPC 
ml 
Average puff duration 
AvgDi 
∑ Di / NPC, i=1 ... NPC 
s 
Total puff duration 
TDi 
∑ Di 
s 
Average flow 
AvgQmi 
∑ Qmi / NPC, i=1 … NPC 
ml/s 
Peak flow  
AvgQci 
∑ Qci / NPC, i=1 … NPC 
ml/s 
Total inter puff interval  
TIi 
∑ Ii 
s 
Average inter puff interval 
AvgIi 
∑ Qci / NPC, i=1 … NPC 
s 
Total smoking duration 
TDFi 
∑ DFi  
s 
Total Work 
TWi 
∑Wi 
mJ 
Average Work 
AvgWi 
∑Wi / NPC, i=1 … NPC 
mJ 
Average pressure drop 
AvgPmi 
∑Pmi / NPC, i=1 … NPC 
mmWg 
Average Peak pressure drop 
AvgPci 
∑Pci / NPC, i=1 … NPC 
mmWg 
Smoking Intensity 
SMINT 
TVOL/TDFi 
ml/s 
Puffing Time Index 
PTI 
(100*TDi)/TDFi 
% 
Puff Frequency 
PFeq 
NPC/(TDFi/60) 
 
 
 
7.8.2 
Visual Inspection of Tobacco Plugs 
All tobacco plugs collected during the study will be sent to the Sponsor for subsequent visual 
inspection to determine whether combustion occurred during product use.  
7.8.3 
Questionnaires 
The subject questionnaires and the VAS will be entered by the subject directly in the 
electronic patient reported outcomes device, or on paper copy. The questionnaires and the 
VAS will be reviewed for completeness by the study site study collaborator and subjects will 
be requested to complete any missing information. 
Symptoms or worsening of symptoms documented on any of the questionnaires or the VAS 
do not need to be documented as additional AEs because the questionnaire and the VAS will 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 87 of 171 
 
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. 
 
be analyzed as part of the final report. However, it is at the discretion of the Investigator to 
decide whether to document such symptoms as additional AEs. The main source for AE 
collection will be the face-to-face interview between the subject and study site trial 
collaborator, using open, non-directive questions (see Section 8). 
7.8.3.1 
Fagerström Test for Nicotine Dependence (revised version) 
Potential nicotine dependence will be assessed via a questionnaire at Screening using the 
Fagerström Test for Nicotine Dependence (FTND) (Fagerström et al., 2012). 
The questionnaire consists of 6 questions which will be answered by the subject 
himself/herself. The scores obtained on the test permit the classification of nicotine 
dependence into 3 levels: Mild (0-3 points), moderate (4-6 points), and severe (7-10 points) 
(Fagerström et al., 2012). 
7.8.3.2 
Assessment of Cough 
Subjects will be asked to assess the respiratory symptom ‘cough’ on a VAS, on 3 Likert 
scales, and with an open question on a daily basis during the confinement period from Day 0 
to Day 6. On each day, cough assessment has to be done prior to product use but no later 
than10: 00 AM. 
Subjects will be asked if they have experienced a regular need to cough, (e.g., whether they 
have coughed several times in the previous 24-hours prior to assessment). If the answer is 
‘yes’, subjects will be asked to complete a VAS, 3 Likert scales, and to answer the open 
question. 
On the VAS, subjects will assess how bothersome their cough was during the previous 
24-hours. The VAS ranges from ‘not bothering me at all’ to ‘extremely bothersome’. 
Furthermore, subjects will assess the intensity and frequency of cough and the amount of 
sputum production during the previous 24-hours on Likert scales. 
The intensity of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = very mild -   2 = mild - 3 = moderate  - 4 = severe - 5 = very severe. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 88 of 171 
 
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 frequency of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = rarely - 2 = sometimes - 3 = fairly often - 4 = often  - 5 = almost always. 
The amount of sputum production will be assessed on a 4-point Likert scale ranging from 
0 to 3, with 0 = no sputum - 1 = a moderate amount of sputum - 2 = a larger amount of 
sputum - 3 = a very large amount of sputum. 
Finally, subjects will be asked with an open question if they want to share any other 
important observations with the study collaborator about their coughing. 
7.8.3.3 
Modified Cigarette Evaluation Questionnaire  
Product evaluation will be assessed using the Modified Cigarette Evaluation Questionnaire 
(MCEQ; Cappelleri et al., 2007). The MCEQ assesses the degree to which subjects 
experience the reinforcing effects of smoking, by measuring: 
• Smoking satisfaction (satisfying, tastes good, enjoys smoking). 
• Psychological rewards (calms down, more awake, less irritable, helps concentrate, 
reduces hunger). 
• Aversion (dizziness, nauseous). 
• Enjoyment of respiratory tract sensations (single-item assessment). 
• Craving reduction (single-item assessment). 
The MCEQ will be completed by subjects during the confinement period from Day -1 to 
Day 5. On Day -1 and Day 0, all subjects will complete the questionnaire. From, Day 1, only 
subjects who are randomized to the THS 2.2 and CC arms will complete this questionnaire. 
The subjects will complete the questionnaire by themselves. 
7.8.3.4 
Questionnaire of Smoking Urges (QSU-brief) 
To assess the urge-to-smoke, all subjects will be asked to fill-in a 10-item brief version of the 
Questionnaire of Smoking Urges (QSU-brief; Cox et al., 2001). The QSU-brief is a self-

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 89 of 171 
 
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. 
 
reported questionnaire with 10 items to be rated on a 7-point scale, ranging from 1 (strongly 
disagree) to 7 (strongly agree). Higher scores in this questionnaire indicate a higher urge to 
smoke. 
The QSU-brief will be completed by the subject himself/herself on a daily basis from Day -1 
to Day 5.  
 
7.8.3.5 
Minnesota Nicotine Withdrawal Scale (revised version) 
The MNWS is a valid and reliable scale that has been used previously to examine signs and 
symptoms of withdrawal from cigarette smoking (Hughes and Hatsukami, 1986; Hughes and 
Hatsukami, 2008). It consists of two scales: a ‘self-report scale’ and an ‘observer scale’. 
For the purpose of this study, only the self-reporting scale will be used and filled-in by the 
subject. Furthermore, the subject’s weight will not be recorded for the purpose of the 
MNWS. At the end of the assessment of the questionnaire, the subject’s pulse rate will be 
recorded. 
Subjects will be asked to rate the items for the previous 24-hours on a scale ranging from 0 to 
4 (where 0 = none, 1 = slight, 2 = mild, 3 = moderate, 4 = severe). 
The MNWS (revised version) will be completed on a daily basis from Day 0 to Day 6. On 
each day, MNWS has to be asked prior to product use but no later than 10:00 AM. 
7.8.3.6 
Human Smoking Topography Questionnaire 
A specific questionnaire, used for exploratory purposes, has been developed by PMI to 
evaluate the impact of the utilization of the HST SODIM® device on smoker’s 
smoking/inhalation experience in terms of ritual disruption. 
This is a questionnaire with 5 items to be rated on a 5-point scale and open questions. 
Subjects will be asked by the Investigator to complete the HST questionnaire at: 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 90 of 171 
 
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 end of the baseline period on Day 0 for all subjects smoking CC compatible with the 
HST device (i.e., non-slim CC). 
• On Day 4 for all subjects in the THS 2.2 and CC arms smoking CC compatible with the 
HST device (i.e., non-slim CC). 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 91 of 171 
 
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. 
 
 
8 
ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
The FDA MRTP guidelines specify the following definition for adverse events for tobacco 
products: an AE is any health-related event associated with the use of tobacco product in 
humans, which is adverse or unfavorable, whether or not it is considered related to the 
tobacco product, as defined by the MRTP guidelines.  
An AE is defined as any untoward medical occurrence in a subject, or clinical investigation 
subject administered an IP, which does not necessarily have a causal relationship with the IP. 
An AE can therefore be any unfavorable and unintended sign (including a clinically relevant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
IP, whether or not to it is considered related to the IP.  
 
8.1.2 
Serious Adverse Events 
An SAE is defined as, but not limited to, any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, 
they may jeopardize the subject or the subject may require medical or surgical intervention to 
prevent one of the outcomes listed in the above definitions. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 92 of 171 
 
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. 
 
Any pre-planned hospitalizations that are known at the time of signing the ICF will not be 
recorded as SAEs (they will be recorded only as AEs). However, any AE that occurs during 
this pre-planned hospitalization will be considered according to the above definitions. 
8.2 
Assessment of Adverse Events 
The Investigator is responsible for obtaining, assessing and documenting all AEs during the 
study. 
8.2.1 
Collection of Information 
Adverse event information will be collected from the time of signature of the ICF onwards 
until End of Study (EOS) either by the Investigator via spontaneous reporting or by the use of 
consistent, open, non-directive questions from study site study collaborator (e.g. “Have you 
had any health problems since the previous visit/How are you feeling since you were last 
asked?”). At the discretion of the Investigator, the collection of AE information may also be 
triggered from his/her review of the subject questionnaires and the VAS. However, the main 
source for AE collection will be the face-to-face interview with the subject. 
Information recorded will include: verbatim description of the AE, start and stop dates and 
times, seriousness, severity (intensity), action taken (e.g. whether or not the AE led to the 
subject’s withdrawal from the study), and outcome (e.g. resolved, withdrawal due to AE).  
For each AE the intensity will be graded on a 3-point intensity scale (mild, moderate, severe) 
using the definitions provided in Section 8.2.3. 
Any exacerbation/worsening or increased frequency of an AE or pre-existing condition shall 
be evaluated and recorded. 
Correct medical terminology/concepts are preferred when recording AE terms, and 
abbreviations must be avoided. Wherever possible, a diagnosis is to be used to describe an 
AE rather than individual signs and symptoms (e.g. record ‘pneumonia’ rather than ‘fever’, 
‘cough’, ‘pulmonary infiltrate’ or ‘septicemia’ rather than ‘fever’ and ‘hypotension’ 
following blood sample). 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 93 of 171 
 
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. 
 
Any AE that meets the serious criteria must be recorded both on the AE report form of the 
case report form (eCRF) and on a separate SAE report form (see Section 8.3). 
8.2.2 
Period of Collection 
From the signature of the ICF onwards until EOS, all AEs (includes SAEs) will be collected 
by the Investigators and study collaborator as described below.  
8.2.3 
Screening Period  
All existing health conditions identified during the Screening period will be recorded as 
concomitant disease and the subject’s eligibility for admission to the study will be reviewed. 
Any AEs which occur during the screening period will be captured by the study site staff and 
assessed by the Investigator in order to establish relationship or relatedness in respect to 
study procedures. Only the study procedures-related AEs will be reported in the clinical 
study report and in accordance with respective regulatory guidelines.  
 
8.2.4 
Admission Day until the End of Study 
From Admission onwards until Day of Discharge, all AEs will be actively collected by the 
study site staff.  
Any new, clinically relevant, abnormal finding or worsening of a pre-existing 
condition/concomitant disease detected during the study will be documented as an AE and/or 
SAE as described in the safety management plan.  
During the safety follow-up period new AEs and/or SAEs will be recorded after spontaneous 
reporting by the subject. SAEs will be reported by the Investigator as described in this 
document and the Safety Management Plan. Any ongoing AEs/SAEs during the safety 
follow-up period will be actively followed up by the Investigator until they have been 
resolved, stabilized (i.e., no worsening of condition), or an acceptable explanation has been 
found. 
At the end of the safety follow-up period all ongoing AEs/SAEs will be followed up by the 
Investigator on behalf of the sponsor (see Section 8.3) until they have resolved, stabilized 
(i.e., no worsening of condition), or an acceptable explanation has been found. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 94 of 171 
 
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. 
 
 
8.2.5 
Intensity of Adverse Event 
For each AE, the intensity will be graded by the Investigator on a 3-point intensity scale 
(mild, moderate, severe) using the following definitions: 
Mild:   
The AE is easily tolerated and does not interfere with activities of daily living 
(ADL). 
Moderate: The AE interferes with ADL, but the subject is still able to function. 
Severe:  
The AE is incapacitating and requires medical intervention. 
 
8.2.6 
Relationship to Investigational Product and Relationship to Study 
Procedures 
According to the Council for International Organizations of Medical Sciences VI Working 
Group, there are no definitive methods for distinguishing most adverse drug reactions (i.e., 
events that are causally attributed to the IP) from clinical AEs that occur as background 
findings in the population and have only temporal association with the IP.  
In general, all AEs and/or SAEs will be assessed by the Investigator as either ‘related’ or ‘not 
related’ to IP as described below. In addition to the assessment of the relationship of the 
clinical event to the IP, the Investigator shall document a potential relationship of the clinical 
event to any particular study procedure. 
Not related: The temporal relationship of the clinical event to IP administration or a study 
procedure makes a causal relationship unlikely, or, concomitant medication, 
therapeutic interventions, or underlying conditions provide a sufficient 
explanation for the observed event. 
Related: 
The temporal relationship of the clinical event to study IP administration or a 
certain study procedure makes a causal relationship possible, and concomitant 
medication, therapeutic interventions, or underlying conditions do not provide 
a sufficient explanation for the observed event. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 95 of 171 
 
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. 
 
8.2.7 
Expectedness 
An AE will be regarded as ‘unexpected’ if its nature or severity is not consistent with 
information already known about the IP, and/or has not been previously observed and is not 
listed in the current IB. The IB provides further detail on signs or symptoms that might be 
expected with the use of the IP, including information relating to device malfunction or 
misuse. 
 
8.3 
Reporting of Serious Adverse Events 
Any SAEs reported or observed during the study after signature of the ICF until the end of 
the safety follow-up period (i.e. up to 7 days after study Discharge), whether or not 
attributable to the IP, to any other medication or to any study procedures, must be reported by 
the Principal Investigator within 24 hours after first awareness by any party to 
 
 and to the Sponsor, and the head of the Investigational site. 
An SAE report form must be faxed or e-mailed as attachment to: 
: 
Phone number: 
 
E-mail: 
 
 
Address: 
 
 
 
 
Sponsor: 
Contact: 
  
Phone number: +41
 
E-mail: 
@pmi.com 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube 
5 Quai Jeanrenaud 
2000 Neuchâtel 
Switzerland 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 96 of 171 
 
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 Principal Investigator/the head of the investigational site is responsible for local 
reporting (e.g. to the IRB) of SAEs that occur during the study, according to local 
regulations. 
Any follow-up information will be detailed in a subsequent SAE report form and sent to 
 and the Sponsor. 
The follow-up SAE report form must include the minimum information required for form 
completion and only changed/new information needs to be specified. Information provided in 
the follow-up SAE report form supersedes any information that is initially reported. 
All SAEs will be followed-up by the Investigator until resolution or until the Investigator 
considers the event to be stabilized (i.e. no worsening of condition), or an acceptable 
explanation has been found (e.g. chronic condition). 
The SAE report form to be used in this study is provided as a separate document. All SAEs 
will be recorded on the relevant eCRF page, in addition to the SAE report form. 
8.4 
Reporting of Other Events Critical to Safety Evaluations 
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator and assessed for clinical relevance. If the Investigator considers 
the abnormal result to be of clinical relevance, then it must be recorded as a concomitant 
disease at Screening, or if not present at Screening, as an AE during the study. 
The grading scheme shown in (reference to the Common Terminology Criteria for Adverse 
Events and Common Toxicity Criteria [CTCAE] version 4.03) will be used by the 
Investigator to assess abnormal laboratory AEs as follows: 
• All Grade 1 abnormal laboratory values will be evaluated by the Investigator with respect 
to baseline value and clinical relevance. If considered to be clinically relevant, the 
Investigator must report it as an AE. All Grade 2 and higher abnormal laboratory values 
must be reported as or linked to an AE/concomitant disease. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 97 of 171 
 
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. 
 
• If a subject has Grade 2 and higher abnormal laboratory values at Screening, it is at the 
discretion of the Investigator to enroll the subject or not. This decision must be 
documented in the source documentation and captured in the eCRF. 
• If there is any worsening in grade from Grade 2 and above during the study, the 
Investigator must report this worsening as an AE. 
• Where there is no grading available, the abnormal laboratory value will be evaluated by 
the Investigator, and assessed for clinical relevance. If considered to be clinically 
relevant, the Investigator will report it as an AE. 
• Any other abnormal clinical laboratory result (including those that are not part of the core 
safety assessments) can, at the discretion of the Investigator, be reviewed and assessed. 
Even if they do not meet the criteria of the CTCAE grading scheme (please see above), 
the Investigator may consider them to be of clinical relevance and, if they are, must 
report them as AEs. 
• In general, laboratory values will be recorded as ‘increased <lab parameter>’ or 
‘decreased <lab parameter>’ to ensure consistency of recording/coding. 
All other information (e.g., relationship to IP, intensity, seriousness, outcome) will be 
assessed as for other AEs. 
 
8.4.2 
Abnormal Results of Other Tests or Investigations 
An ongoing medical condition or clinically relevant finding detected during the Screening 
Visit (including elevated laboratory parameters), will be considered a concomitant disease 
and the subject’s eligibility for admission to the study will be reviewed. 
Any new, clinically relevant, abnormal finding or worsening of a pre-existing condition 
detected during the study after Screening until the end of the study will be documented as an 
AE. 
Any new onset of symptoms or worsening of pre-existing symptoms identified through the 
study questionnaires may be documented as AEs at the discretion of the Investigator. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 98 of 171 
 
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. 
 
8.5 
Reporting and Follow-Up of Pregnancies 
For pregnancies detected during the Screening period and prior to first THS 2.2 use, the 
subject will be considered as a screening failure and removed from the study. No Pregnancy 
Form will be filled; however, the diagnosed pregnancy must be captured in the Screen 
Failure eCRF.  
All pregnancies occurring after signature of the ICF and diagnosed after first exposure to the 
IP until completion of the study must be reported by the Investigator.  
Any pregnancy potentially associated to exposure to the IP, including pregnancies 
spontaneously reported to the Investigator after the EOS must be reported by the Investigator 
and followed-up. Potential association with exposure to the IP is defined as the conception 
date being calculated before the last exposure to the IP.   
The Investigator will complete a Pregnancy Form (provided as a separate document) for all 
pregnancies diagnosed (including positive urine pregnancy tests). 
The procedure to report a pregnancy and provide any additional/follow-up information to 
 and the Sponsor must be followed in the same manner and within the same 
timelines as described for an SAE (see Section 8.3). In addition, each pregnancy has to be 
reported as a non-serious AE. No invasive procedures, including drawing of blood, must be 
done in such subjects after the discovery of pregnancy.  
 will follow-up pregnancies only if they were detected 
after first product use (i.e., after THS 2.2 test on Admission Day). If pregnancies are to be 
followed-up, they will be followed-up until an outcome is reached (e.g., normal delivery, 
spontaneous abortion, or voluntary termination). Any pregnancy complications, adverse 
pregnancy outcomes, or maternal complications will be recorded. 
The Principal Investigator/head of the investigational site is responsible for informing the 
IRB of any pregnancy that occurs during the study and its outcome, according to local 
regulations. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 99 of 171 
 
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. 
 
8.6 
Adverse Events Leading to Withdrawal 
Subjects who are withdrawn from the study because of an AE will undergo the procedures, as 
described for the Day of Discharge, as soon as possible and will enter the period of safety 
follow-up. The Investigator will follow-up these AEs until they have resolved, stabilized 
(i.e., no worsening of condition), or an acceptable explanation has been found. 
 
8.7 
Investigational Device Misuse 
Any occurrences of the THS Tobacco Stick Holder or THS Charger misuse (use not in 
accordance with its label and instruction) by a subject, will be documented by the 
Investigator or his/her designated study collaborator using a Device Issue Log.  
Investigational device misuse may result in use-related hazards. 
Use-related hazards are derived from the US Food and Drug Administration Medical Device 
Use-Safety Guidance (FDA, 2012c): 
• 
Hazards caused specifically by how a device is used 
• 
Unanticipated use scenarios (e.g., modification of Charger, applying any chemicals, 
using conventional cigarettes, mechanical damage of the device, etc.) that result in 
hazards must be documented and reported by the Investigator. 
According to FDA Medical Device Regulation, data should be collected regarding the 
use-related hazards that have occurred with the device and when information pertaining to 
device use safety is extensive, it is helpful to provide it in summary form that highlights the 
most important issues, considerations, resolutions, and conclusions. The level of detail of 
device use documentation submitted should be consistent with the level of concern of use-
related hazards for the device.  
  
8.8 
Investigational Device Malfunction  
Any occurrences of malfunction of the Tobacco Stick Holder or Charger will be documented 
by the Investigator or his/her designated study collaborator using a Device Issue Log. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 100 of 171 
 
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. 
 
Furthermore, any malfunctions of the Tobacco Stick Holder or Charger that lead to an 
AE/SAE will follow the same processes as described above. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 101 of 171 
 
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. 
 
 
9 
STUDY ACTIVITIES 
A detailed schedule of assessment can be found in Appendix 1. The time points shown are to 
be considered the time of assessment for the first subject. As not all subjects can be treated at 
the same time, a short time window will be implemented for subsequent subjects. 
Measurements not conducted at the exact time point, but conducted within the given time 
window (if applicable) do not constitute a protocol deviation but an accepted variability for 
the given time point. 
In general, if no start time for the procedures is provided, then the procedure can be 
performed at any time during the day. 
9.1 
Screening Visit 
The screening Visit will be performed within 4 weeks (Day -30 to Day -3) prior to admission 
(Day -2). Subjects will attend the investigational site in at least 10-hour fasting state for 
clinical laboratory to be assessed. Table 6 shows the assessments that will be performed at 
the Screening Visit. First, the ICF should be given to the subject. When/if the ICF is signed, 
the other screening procedures can be performed in the order deemed most practical. While it 
is recommended to complete as much screening procedures as possible in one day, it is 
permissible to complete those over more than one day. Smoking is allowed during screening. 
 
Table 6. 
Time Schedule – Screening Visit 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Screening 
 
 
 
ICF for study participation and ICFs for both 
bio-bankings  
 
 
 
Advice on the risk of smoking and 
debriefing 
 
 
 
Demographic data collected 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 102 of 171 
 
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 
 
Screening 
 
 
 
Identification of current CC brand 
 
 
 
Medical history/concomitant disease 
 
 
 
Prior medication (4 weeks prior to Screening 
Visit) and concomitant medication 
 
 
 
Smoking history 
 
 
 
Willingness to quit smoking within the next 
3 months and readiness to abstain from 
smoking for at least 5 days 
 
 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to measurement 
 
√ 
Clinical laboratory parameters (hematology, 
urine analysis, clinical chemistry) 
To be done at least 10 hours after 
fasting 
 
√ 
HIV, hepatitis B and C 
 
 
 
Physical examination and  height, weight, 
calculation of BMI 
 
 
 
THS 2.2 product demonstration 
 
 
 
Chest X-ray (if not performed 6 months prior 
to Screening Visit) 
 
 
 
Urine drug screen 
 
 
 
Urine cotinine screening test 
 
 
 
Alcohol breath test screen 
 
 
 
Urine pregnancy test (all females only) 
 
 
 
Fagerström Test for Nicotine Dependence 
(FTND) 
 
 
 
Spirometry first without short-acting 
bronchodilator then with. 
To be done at least 1 hour after 
smoking 
 
 
ECG 
At least 10 minutes in supine 
position prior to recording 
 
 
AE/SAE recording 
If the Screening Visit is 
performed on two separate days 
the AE/SAE questions will be 
asked again 
 
 
Inclusion/exclusion criteria 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 103 of 171 
 
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 
 
Screening 
 
Abbreviations: AE = adverse event; BMI = body mass index; CC = conventional cigarette(s); ECG = electrocardiogram; 
HIV = human immunodeficiency virus; SAE = serious adverse event; THS = tobacco heating system. 
9.2 
Confinement Period (Days -2 to 6) 
9.2.1 
Admission (Day -2) 
The procedures of Day -2 can be performed in order deemed most practical except product 
test which will be the last assessment prior to enrolment after all eligibility criteria have been 
met. Table 7 shows the assessments that will be performed at Admission (Day -2): 
Table 7. 
Time Schedule – Day -2 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Admission 
 
 
 
AE/SAE recording; concomitant medication  
All day 
 
 
Urine pregnancy test (all females only) 
 
 
 
Advice on the risk of smoking and 
debriefing 
 
 
 
Smoking history  
 
 
 
Readiness to abstain from smoking for at 
least 5 days 
 
 
 
Urine drug screen  
 
 
 
Urine cotinine screening test 
 
 
 
Alcohol breath test screen 
 
 
 
CO breath test   
 
 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to measurement 
 
 
Physical examination, weight, BMI 
 
 
 
Inclusion/exclusion criteria 
 
 
 
Identification of current CC brand 
 
 
 
Trial of THS 2.2 product  
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 104 of 171 
 
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. 
 
Evening until 
09:00 PM 
 
Dinner 
 
 
 
Enrolment 
Only after all eligibility criteria 
have been met 
Until 11:PM 
 
Smoking period 
 
11:00 PM 
 
End of study day 
 
Abbreviations: AE = adverse event; BMI = body mass index; CC = conventional cigarette(s); CO = carbon 
monoxide; SAE: serious adverse event; THS = tobacco heating system. 
9.2.2 
Baseline Period (Day-1 to Day 0) 
Table 8 and Table 9 show the assessments that will be performed at baseline (Day -1 and 
Day 0, respectively): 
The timings given are for the first subject. All subsequent subjects should complete 
procedures within the time window given in the tables. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 105 of 171 
 
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. 
 
Table 8. 
Time Schedule – Day -1 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Baseline Day -1 
 
 
 
AE/SAE recording; concomitant medication 
All day 
06:30 AM+/-
20min 
 
Start collection to Day -1 sampling bottle 
 
 
 
CO breath test 
Within 15 minutes before first 
product use 
06:30 AM 
 
Beginning of smoking period 
 
Before10:00 
AM 
 
Breakfast 
 
Before11:30 
AM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to measurement 
12:00 PM-
01:30 PM 
 
CO breath test 
 
Before 02:30 
PM 
 
Lunch 
 
04:00 PM-
05:30 PM 
 
CO breath test 
 
Afternoon 
 
Snacks 
 
Evening until-
09:00 PM 
 
Dinner 
 
08:00 PM-
09:30 PM 
 
CO breath test 
 
08:00 PM-
09:30 PM 
√ 
COHb in blood 
 
08:00 PM-
11:00 PM 
 
MCEQ questionnaire,  
QSU-brief questionnaire 
 
11:00 PM 
 
End of smoking period 
 
06:30 AM-
11:15 PM 
 
Collection of all smoked CC butts  
For accountability 
Abbreviations: AE = adverse event; BoExp = biomarkers of exposure; CC = conventional cigarette(s); CO = 
carbon monoxide; COHb = carboxyhemoglobin; MCEQ = Modified Cigarette Evaluation Questionnaire; 
QSU-brief = Questionnaire of Smoking Urges (brief version).SAE: serious adverse events; THS = tobacco 
heating system. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 106 of 171 
 
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. 
 
Table 9. 
Time Schedule – Day 0 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Baseline Day 0 
 
 
 
AE/SAE recording; concomitant 
medication 
All day 
 
 
Randomization 
At any time during the day after 
eligibility criteria have been met. 
Subjects are not to be informed of 
their assigned arm until Day 1. 
06:29 AM+/-
20min 
 
Analysis sample to be taken after final 
portion of urine has been added to 
Day -1 sampling bottle. 
BoExp and creatinine in 24-hour 
urine 
06:30 AM+/-
20min 
 
Start collection to Day 0 sampling 
bottle  
 
 
√ 
CYP2A6 activity in plasma 
To be done prior to smoking. 
 
 
Assessment of cough (VAS) 
To be done prior to smoking but 
not later than 10:00 AM. 
 
 
MNWS questionnaire 
To be done prior to smoking but 
not later than 10:00 AM . 
 
 
Spirometry without short-acting 
bronchodilator 
To be done prior to smoking 
 
 
CO breath test 
To be done within 15 minutes 
prior to smoking 
 
 
HST 
HST SODIM® device has to be 
used for all product uses if 
compatible CCs are smoked 
06:30 AM 
 
Beginning of smoking period 
 
 
√ 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
In at least 10 hours of fasted 
condition 
 
√ 
Bio-banking for transcriptomics (if 
consent is obtained) 
In at least 10 hours of fasted 
condition . 
 
√ 
Bio-banking for BoExp/ risk markers 
in serum/plasma (if consent is 
obtained) 
In at least 10 hours of fasted 
condition 
 
 
Urine safety analysis  
 
Before 10:00 
AM 
 
Breakfast 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 107 of 171 
 
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 
 
Baseline Day 0 
 
10:00 AM-
11:30 AM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to measurement 
10:00 AM-
11:30 AM 
 
A caffeine tablet containing around 
170 mg of CAF with 150±10mL 
water 
 
12:00 PM-01:30 
PM 
 
CO breath test 
 
Before 02:30 
PM 
 
Lunch 
 
04:00 PM-05:30 
PM 
√ 
CYP1A2 activity in plasma 
6 hours +/-15minutes after intake 
of caffeine tablet 
04:00 PM-05:30 
PM 
 
CO breath test 
 
Afternoon 
 
Snacks 
 
 In the evening 
until 09:00 PM 
 
Dinner 
 
08:00 PM-09:30 
PM 
 
CO breath test 
 
08:00 PM-09:30 
PM 
√ 
COHb in blood 
 
08:00 PM-09:30 
PM 
√ 
Nicotine, cotinine in plasma 
 
08:00 PM-09:30 
PM 
 
HST questionnaire 
 
08:00 PM- 
11:00 PM 
 
MCEQ questionnaire,  
QSU-brief questionnaire 
 
11:00 PM 
 
End of smoking period 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 108 of 171 
 
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 
 
Baseline Day 0 
 
6:30 AM-11:15 
PM 
 
Collection of all CC butts  
For accountability 
Abbreviations: AE = adverse event; BoExp = biomarkers of exposure; CAF = caffeine; CC = conventional 
cigarette(s); CO = carbon monoxide; COHb = carboxyhemoglobin; CYP1A2 = Cytochrome P450 1A2; 
CYP2A6 = Cytochrome P450 2A6 HST = human smoking topography; MCEQ = Modified Cigarette 
Evaluation Questionnaire; MNWS = Minnesota Nicotine Withdrawal Scale (revised version); QSU-
brief = Questionnaire of Smoking Urges (brief version); SAE = serious adverse event; THS = tobacco heating 
system; VAS = Visual analogue scale 
9.2.3 
Exposure Period (Days 1 to 5) 
The tables in this Section show the assessments that will be performed during the 
confinement period (Day 1 to Day 5). Table 10 shows the assessments that will be performed 
on Day 1: 
Table 10. 
Time Schedule – Day 1 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 1 
 
 
 
AE/SAE  recording; 
concomitant medication 
All day 
 
 
Support during smoking 
abstinence (SA arm only) if 
needed 
All day 
Before 06:30 AM 
 
Subjects are informed of their 
assigned study arm. 
 
6:29 AM+/-20min 
 
Analysis sample to be taken 
after final portion of urine has 
been added to Day 0 sampling 
bottle. Must be prior to first 
product use of Day 1 
 
BoExp, creatinine, and Ames 
mutagenicity in 24-hour urine 
Risk markers: 8-epi-PGF2α and 11-
DTX-B2 
Bio-banking for BoExp/ risk markers 
in 24-hour urine (if additional consent 
is obtained) 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 109 of 171 
 
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 
 
6:30 AM+/-20min 
 
Start collection to Day 1 
sampling bottle  
 
 
 
Assessment of cough (VAS) 
To be done prior to product use but 
not later than 10:00 AM 
 
 
MNWS questionnaire 
To be done prior to product use but 
not later than 10:00 AM 
 
 
CO breath test 
Within 15 minutes before first product 
use (for THS 2.2 and CC arms) or 
between 08:00 AM-09:30 AM (SA 
arm) 
06:30 AM-11:00 
PM 
 
HST 
In THS 2.2 and CC arms, HST 
SODIM® device has to be used for all 
product uses if compatible CCs are 
smoked 
6:30 AM 
 
Beginning of product use 
 
Before 10:00 AM 
 
Breakfast 
 
10:00 AM-11:30 
AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine position 
prior to measurement  
12:00 PM-01:30 
PM 
 
CO breath test  
 
Before 02:30 PM 
 
Lunch  
 
04:00 PM-05:30 
PM 
 
CO breath test 
 
Afternoon 
 
Snacks 
 
In the evening until 
09:00 PM 
 
Dinner  
 
08:00 PM-09:30 
PM 
 
CO breath test 
 
08:00 PM-09:30 
PM 
√ 
COHb in blood  
 
08:00 PM-09:30 
PM 
√ 
Nicotine, cotinine in plasma 
 
08:00 PM - 11:00 
PM 
 
MCEQ questionnaire (THS 2.2 
and CC arms only),  
QSU-brief questionnaire 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 110 of 171 
 
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 
 
11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
Collection of all smoked CC 
butts, and all used Tobacco 
Sticks (tobacco plugs will be 
collected into dedicated vials) 
For accountability and further 
analysis 
Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-
thromboxane B2; AE = adverse event; BoExp = biomarkers of exposure; CC = conventional 
cigarette(s); CO = carbon monoxide; COHb = carboxyhemoglobin; HST = human smoking 
topography; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = Minnesota 
Nicotine Withdrawal Scale (revised version); QSU-brief= Questionnaire of Smoking Urges 
(brief version); SAE = serious adverse event; THS = tobacco heating system; VAS = Visual 
analogue scale. 
Table 11 shows the assessments that will be performed on Day 2 of the confinement period: 
Table 11. 
Time Schedule – Day 2 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 2 
 
 
 
AE/SAE recording; 
concomitant medication 
All day 
 
 
Support during smoking 
abstinence (SA arm only) if 
needed 
All day 
6:29 AM+/-20min 
 
Analysis sample to be taken 
after final portion of urine has 
been added to Day 1 sampling 
bottle. Must be prior to first 
product use of Day 2 
BoExp and creatinine in 24-hour 
urine 
6:30 AM+/-20min 
 
Start collection to Day 2 
sampling bottle  
 
 
 
MNWS questionnaire 
To be done prior product use but not 
later than 10:00 AM 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 111 of 171 
 
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 
 
 
 
Assessment of cough (VAS) 
To be done prior product use but not 
later than 10:00 AM 
 
 
CO breath test 
Within 15 minutes before first 
product use (for THS 2.2 and CC 
arms) or between 08:00 AM-09:30 
AM(SA arm) 
6:30 AM 
 
Beginning of product use 
 
Before 10:00 AM 
 
Breakfast 
 
10:00 AM-11:30 
AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine position 
prior to measurement  
12:00 PM-01:30 
PM 
 
CO breath test 
 
Before 02:30 PM 
 
Lunch  
 
04:00 PM-05:30 
PM 
 
CO breath test 
 
Afternoon 
 
Snacks 
 
In the evening until 
09:00 PM 
 
Dinner  
 
08:00 PM-09:30 
PM 
 
CO breath test 
 
08:00 PM-09:30 
PM 
√ 
COHb in blood  
 
08:00 PM-09:30 
PM 
√ 
Nicotine, cotinine in plasma 
 
08:00 PM-11:00 
PM 
 
MCEQ questionnaire (THS 2.2 
and CC arms only),  
QSU-brief questionnaire 
 
11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
Collection of all smoked CC 
butts, and all used Tobacco 
Sticks (tobacco plugs will be 
collected into dedicated vials) 
For accountability for further 
analysis 
 
 
Abbreviations: AE = adverse event; BoExp = biomarkers of exposure; CC = conventional cigarette(s); CO = carbon 
monoxide; COHb = carboxyhemoglobin; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = Minnesota 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 112 of 171 
 
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. 
 
Nicotine Withdrawal Scale (revised version); QSU-brief = Questionnaire of Smoking Urges (brief version); SAE = serious 
adverse event; THS = tobacco heating system; VAS = Visual Analog Scale. 
 
Table 12 shows the assessments that will be performed on Day 3 of the confinement period: 
Table 12. 
Time Schedule – Day 3 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 3 
 
 
 
AE/SAE recording; 
concomitant medication 
All day 
 
 
Support during smoking 
abstinence (SA arm only) if 
needed 
All day 
6:29 AM+/-20min 
 
Analysis sample to be taken 
after final portion of urine has 
been added to Day 2 sampling 
bottle. Must be prior to first 
product use of Day 3 
BoExp and creatinine in 24-hour urine 
6:30 AM+/-20min 
 
Start collection to Day 3 
sampling bottle  
  
 
 
MNWS questionnaire  
To be done prior product use but not 
later than 10:00 AM 
 
 
Assessment of cough (VAS) 
To be done prior product use but not 
later than 10:00 AM 
 
 
CO breath test 
Within 15 minutes before first product 
use for THS 2.2 and CC arms) or 
between 08:00 AM-09:30 AM (SA 
arm) 
6:30 AM 
 
Beginning of product use 
 
Before 10:00 AM 
 
Breakfast 
 
10:00 AM-11:30 
AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine position 
prior to measurement  
12:00 PM-01:30 
PM 
 
CO breath test  
 
Before 02:30 PM 
 
Lunch  
 
04:00 PM-05:30 
PM 
 
CO breath test 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 113 of 171 
 
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 3 
 
Afternoon 
 
Snacks 
 
In the evening 
before 09:00 PM 
 
Dinner  
 
08:00 PM-09:30 
PM 
 
CO breath test 
 
08:00 PM-09:30 
PM 
√ 
COHb in blood 
 
08:00 PM-09:30 
PM 
√ 
Nicotine, cotinine in plasma 
 
08:00 PM - 11:00 
PM 
 
MCEQ questionnaire (THS 
2.2 and CC arms only),  
QSU-brief questionnaire 
 
11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
Collection of all smoked CC 
butts, and all used Tobacco 
Sticks (tobacco plugs will be 
collected into dedicated vials) 
For accountability and further analysis 
 
 
 
Abbreviations: AE = adverse event; BoExp = biomarkers of exposure; CC = conventional cigarette(s); CO = carbon 
monoxide; COHb = carboxyhemoglobin; MCEQ = Modified Cigarette Evaluation Questionnaire; MNWS = Minnesota 
Nicotine Withdrawal Scale (revised version); QSU-brief = Questionnaire of Smoking Urges (brief version); SAE = serious 
adverse event; THS = tobacco heating system; VAS = Visual Analog Scale 
 
Table 13 shows the assessments that will be performed on Day 4 of the confinement period: 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 114 of 171 
 
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. 
 
Table 13. 
Time Schedule – Day 4 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
Day 4 
 
 
 
AE/SAE recording; 
concomitant medication 
All day 
 
 
Support during smoking 
abstinence (SA arm only) if 
needed 
All day 
6:29 AM+/-20min 
 
Analysis sample to be taken 
after final portion of urine has 
been added to Day 3 sampling 
bottle. Must be prior to first 
product use of Day 4 
BoExp and creatinine in 24-hour urine  
 
6:30 AM+/-20min 
 
Start collection to Day 4 
sampling bottle  
 
 
 
Assessment of cough (VAS) 
To be done prior to product use but 
not later than 10:00 AM 
 
 
MNWS questionnaire 
To be done prior to product use but 
not later than 10:00 AM 
 
 
CO breath test 
Within 15 minutes before first product 
use for THS 2.2 and CC arms) or 
between 08:00 AM-09:30 AM (SA 
arm) 
 
 
HST  
In THS 2.2 and CC arms, HST 
SODIM® device has to be used for all 
product uses if compatible CCs are 
smoked 
6:30 AM 
 
Beginning of product use 
 
Before 10:00 AM 
 
Breakfast 
 
10:00 AM-11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine position 
prior to measurement  
12:00 PM-01:30 PM  
 
CO breath test  
 
Before 02:30 PM 
 
Lunch  
 
04:00 PM-05:30 PM 
 
CO breath test 
 
Afternoon 
 
Snacks 
 
In the evening before 
09:00 PM 
 
Dinner  
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 115 of 171 
 
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 4 
 
08:00 PM:09:30 PM 
 
CO breath test 
 
08:00 PM:09:30 PM 
√ 
COHb in blood  
 
08:00 PM:09:30 PM 
√ 
Nicotine, cotinine in plasma 
 
08:00 PM-08:30 PM 
 
HST questionnaire  
In THS 2.2 and CC arms only 
08:00 PM-11:00 PM 
 
MCEQ questionnaire (THS 
2.2 and CC arms only),  
QSU-brief questionnaire 
 
11:00 PM 
 
End of product use 
 
6:30 AM-11:15 PM 
 
Collection of all smoked CC 
butts, and all used Tobacco 
Sticks (tobacco plugs will be 
collected into dedicated vials) 
For accountability and further analysis 
 
 
Abbreviations: AE = adverse event;; BoExp = biomarkers of exposure; CC = conventional cigarette(s); CO = carbon 
monoxide; COHb = carboxyhemoglobin; HST = human smoking topography; MCEQ = Modified Cigarette Evaluation 
Questionnaire; MNWS = Minnesota Nicotine Withdrawal Scale (revised version); QSU-brief = Questionnaire of Smoking 
Urges (brief version); SAE = serious adverse event; THS = tobacco heating system; VAS = Visual Analog Scale 
 
Table 14 shows the assessments that will be performed on Day 5 of the confinement period: 
Table 14. 
Time Schedule – Day 5 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Day 5 
 
 
 
AE/SAE recording; concomitant 
medication 
All day 
 
 
Support during smoking abstinence (SA 
arm only) if needed 
All day 
6:29 AM+/-
20min 
 
Analysis sample to be taken after final 
portion of urine has been added to Day 4 
sampling bottle. Must be prior to first 
product use of Day 5 
BoExp and creatinine in 24-hour urine 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 116 of 171 
 
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 5 
 
6:30 AM+/-
20min 
 
Start collection to Day 5 sampling bottle  
 
 
 
Assessment of cough (VAS) 
To be done prior product use but not 
later than 10:00 AM 
 
 
MNWS questionnaire 
To be done prior product use but not 
later than 10:00 AM 
 
 
CO breath test 
Within 15 minutes before first product 
use for THS 2.2 and CC arms) or 
between 08:00 AM-09:30 AM (SA arm) 
 
√ 
COHb in blood 
Within 15 minutes before first product 
use for THS 2.2 and CC arms) or 
between 08:00 AM-09:30 AM (SA arm) 
6:30 AM 
 
Beginning of product use 
 
 
√ 
Nicotine, cotinine in plasma 
For THS 2.2 and CC arms: within 
15 minutes before first product use (T0): 
then additional blood samples at 2 hour 
intervals from T0 until 11:00 PM. Each 
sample has a time window of +5 minutes 
For SA arm: between 08:00 PM-09:30 
PM. 
Before 10:00 
AM 
 
Breakfast 
 
10:00 AM-
11:30 PM 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine position 
prior to measurement 
10:00 AM-
11:30 PM 
 
A caffeine tablet containing around 170 
mg of CAF with 150±10mL water 
 
12:00 PM-
01:30 PM 
 
CO breath test 
 
12:00 PM-
01:30 PM 
√ 
COHb in blood 
 
01:00 PM-
02:30 PM 
 
Lunch 
 
04:00 PM-
05:30 PM 
 
CO breath test 
 
04:00 PM-
05:30 PM 
√ 
COHb in blood 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 117 of 171 
 
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 5 
 
04:00 PM-
05:30 PM 
√ 
CYP1A2 activity in plasma 
6 hours +/-15minutes after intake of 
caffeine tablet 
Afternoon 
 
Snacks 
 
In the 
evening 
before 09:00 
PM 
 
Dinner 
 
08:00 PM-
09:30 PM 
 
CO breath test 
 
08:00 PM-
09:30 PM 
√ 
COHb in blood 
 
08:00 PM-
11:00 PM 
 
MCEQ questionnaire (THS 2.2 and CC 
arms only),  
QSU-brief questionnaire 
 
11:00 PM 
 
End of product use 
 
6:30 AM-
11:15 PM 
 
Collection of all smoked CC butts, and 
all used Tobacco Sticks (tobacco plugs 
will be collected into dedicated vials) 
For accountability and further analysis 
 
Abbreviations: AE = adverse event; BoExp = biomarkers of exposure; CAF = caffeine; CC = conventional cigarette(s); CO 
= carbon monoxide; COHb = carboxyhemoglobin; CYP1A2 = cytochrome P450 1A2 HST = human smoking topography; 
MCEQ = Modified 
Cigarette 
Evaluation 
Questionnaire; 
MNWS = 
Minnesota 
Nicotine 
Withdrawal 
Scale; 
QSU = Questionnaire of Smoking Urges; SA = smoking abstinence; SAE = serious adverse event; VAS = Visual Analog 
Scale. 
 
9.2.4 
Day of Discharge (Day 6) 
Table 15 shows the assessments that will be performed on Day 6, prior to Discharge from the 
study unit: 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 118 of 171 
 
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. 
 
Table 15. 
Time Schedule – Day 6 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of 
procedure 
 
Day of Discharge procedures 
 
 
 
AE/SAE recording; concomitant medication 
All day until time of discharge 
 
√ 
Nicotine, cotinine in plasma  
For THS 2.2 and CC arms: 20 
hours and 24-hours blood 
sampling after T0 of Day 5. Each 
sample has a time window of 
+5 minutes 
For SA arm: between 08:00 AM-
09:30 AM. 
06:29 AM+/-
20min 
 
Analysis sample to be taken after final 
portion of urine has been added to Day 5 
sampling bottle  
BoExp, creatinine, and Ames 
mutagenicity in 24-hour urine 
Risk markers: 8-epi-PGF2α and 
11-DTX-B2 
Bio-banking for BoExp/ risk 
markers in 24-hour urine (if 
additional consent is obtained) 
 
√ 
CYP2A6 activity in plasma 
To be done prior to smoking  
 
 
Assessment of cough (VAS) 
To be done prior to smoking but 
not later than 10:00 AM 
 
 
MNWS questionnaire 
To be done prior to smoking but 
not later than 10:00 AM 
 
 
Spirometry without short-acting 
bronchodilator 
To be done prior to smoking  
 
√ 
Clinical laboratory parameters (hematology, 
clinical chemistry) 
To be done after at least 10 hours 
of fasting 
 
√ 
Bio-banking for transcriptomics (if 
consent is obtained) 
To be done after at least 10 hours 
of fasting.  
 
√ 
Bio-banking for BoExp/ risk markers in 
serum/plasma (if consent is obtained) 
To be done after at least 10 hours 
of fasting 
Before 
discharge 
 
Urine safety analysis 
 
Before 
discharge 
 
Urine pregnancy test (females only) 
 
Before 10:00 
AM 
 
Breakfast 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 119 of 171 
 
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. 
 
Before 
discharge 
 
CO breath test 
 
Before 
discharge 
 
Physical examination, and weight and 
calculated BMI 
 
Before 
discharge 
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 minutes in supine 
position prior to measurement 
Before 
discharge 
 
ECG 
At least 10 minutes in supine 
position prior to recording 
 
 
Advice on risk of smoking and debriefing 
 
 
 
Discharge 
 
Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = adverse 
event; BMI = body mass index; BoExp = biomarkers of exposure; CO = carbon monoxide; CYP2A6 = cytochrome P450 
2A6 ECG = electrocardiogram; MNWS = Minnesota Nicotine Withdrawal Scale (revised version); SAE = serious adverse 
event; VAS = visual analog scale. 
 
9.3 
Safety Follow-up Period 
All subjects participating in the product trial on Day -2 and are not enrolled into the study 
will enter a 7-day safety follow-up period.  
After subjects have completed the assessments at Day 6 (or if they are prematurely 
withdrawn from the study), they will enter a 7-day safety follow-up period after the time of 
Discharge. 
During the 7-day safety follow-up period, there will be spontaneous reporting by the subject 
of new AEs and new SAEs. Any ongoing AEs/SAEs will be actively followed-up by the site.  
Any AEs or SAEs that are ongoing at the end of the 7-day safety follow-up period will be 
handled as described in Section 8. 
9.4 
Early Termination Procedures 
The assessments of the Day of Discharge will be performed as early termination procedures 
(see Section 9.2.4). 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 120 of 171 
 
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. 
 
 
10 CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
The Clinical Research Associate (“Monitor”) will be responsible for the monitoring of the 
study. Monitoring will be performed according to CRO’s Standard Operating Procedure 
(SOPs) and as per the agreed monitoring plan with the Sponsor. 
The Principal Investigator/head of the investigational site shall permit the Monitor to review 
study data as frequently as considered necessary to ensure that data are being recorded in an 
adequate manner and that protocol adherence is satisfactory. 
The Investigator shall access medical records for the Monitor in order that entries in the 
eCRFs may be verified. The Investigator, as part of their responsibilities, is expected to 
ensure that the study adheres to GCP requirements. 
An Investigator’s meeting will be held prior to the site initiation visit. During this meeting, 
the general training of the study procedures and specific training on selected procedures will 
be done and documented. 
Subsequent to the Investigator’s meeting, and before the first subject is screened into the 
study, site initiation visit will be conducted by the Monitor and, if necessary, with Sponsor or 
its authorized representative. The purpose of the site initiation visit will be detailed in the 
monitoring plan. 
Communication by telephone, mail, and e-mail may be used as needed to supplement site 
visits. The Investigator and study personnel will cooperate with the Monitor, provide all 
appropriate documentation, and will be available to discuss the study. 
The Monitor and the Sponsor’s personnel will be available between visits, should the 
Investigator or other study collaborator at the sites need information and advice. 
Site visits will be made at regular intervals during the study. The frequency of the monitoring 
visits will be defined in the monitoring plan agreed with the Sponsor. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 121 of 171 
 
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 Investigator, or a designated member of the Investigator’s study collaborator, must be 
available during the monitoring visit to review the data and resolve any queries, and to allow 
direct access to the subject’s records for source data verification. 
10.2 Training of Study Collaborator 
A formal meeting (Investigator’s meeting) will be conducted prior to site initiation. During 
this meeting, the Sponsor or its authorized representative will discuss the requirements of the 
clinical study protocol and related documents and will also provide training in the relevant 
systems and other study-specific procedures. The activities of the Investigator’s meeting will 
be described in the monitoring plan.  
In addition to the Investigator meeting, the Investigator will ensure that appropriate training 
relevant to the study is provided to all study collaborator involved in the study, and that any 
new information relevant to the performance of this study is forwarded to the study 
collaborator involved in a timely manner. The record of all individuals involved in the study 
will be maintained in the Site Investigator File. 
10.3 Audits and Inspections 
Good Clinical Practice regulations require that there are independent inspections of clinical 
program activities. Such inspections may be performed at any time before, during and/or 
after the study. 
Authorized representatives of the Sponsor, regulatory agencies and/or an IRB may perform 
audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, ICH/GCP guidelines, and any 
applicable regulatory requirements. The Principal Investigator/head of investigational site 
will contact the Sponsor or the authorized representative immediately, if contacted by a 
regulatory agency about an inspection at their site. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 122 of 171 
 
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 Investigator and study collaborator are responsible for maintaining a comprehensive and 
accurate filing system of all study-related documentation that will be suitable for inspection 
at any time by the Sponsor, its authorized representative, and/or regulatory agencies. In 
signing this protocol, the Investigator understands and agrees to provide access to the 
necessary documentation and files. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 123 of 171 
 
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. 
 
 
11 DATA MANAGEMENT ACTIVITIES 
All Data Management Activities will be described in detail in the Data Management Plan and 
documents specified therein. 
11.1 Data Capture 
11.1.1 
Case Report Forms and Study Records 
With the exception of the subject reported outcome data, all results from the clinical 
assessments will be recorded in the Source Documents by the Investigator or authorized 
designee and then captured in the eCRFs at the study site. The subject questionnaires and the 
VAS will be entered by the subject directly in the electronic patient reported outcomes device 
or on paper copy. Trained study personnel will be responsible for capturing the data from the 
observations, tests, and assessments specified in the protocol in the source documents and 
then transferring the data into the eCRF according to the eCRF Completion Guidelines. 
The Principal Investigator has ultimate responsibility for the collection and reporting of all 
data related to the clinical study and ensuring that the data are accurate, authentic/original,  
legible, timely (contemporaneous), enduring, and available when required. The eCRF must 
be signed by the Investigator to attest that the data contained in the eCRF are true and 
accurate. Any corrections made to Source Documents must be clearly recorded, without 
obscuring the original values and be accompanied by the date of change, reason for change, 
and identification of the person making the change. The eCRF for each subject will be 
checked against the Source Documents at the study site by the CRA. Instances of missing or 
unclear data will be discussed with the Investigator for resolution. An eCRF will be 
generated for all subjects that sign the ICF. 
11.1.2 
Protocol Deviations 
All protocol deviations will be entered into the Clinical Trial Management System (CTMS) 
or other approved format. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 124 of 171 
 
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. 
 
Information from the Source Documents will represent the primary source of protocol 
deviations. Information following site monitoring and other manual reviews will be 
documented in the site visit reports, follow-up letters, audit documentation, or other manual 
review and will be recorded and tracked in the CTMS or other approved format. 
Telecommunications and other verbal communications regarding deviations will be 
considered and handled as important communication, documented and tracked as protocol 
deviations, as necessary. 
Individual entries for protocol deviations that are recorded in the CTMS, or other approved 
format, following site monitoring and other manual reviews will be reviewed against the 
individual data points in the eCRF database but will not be formally reconciled with the 
eCRF database (e.g., their description or occurrence date). The overall procedure for 
managing protocol deviations are described in the SOPs of the CRO Data Management 
Team. All deviations will be reviewed periodically, as determined at study start, to identify 
trends to improve monitoring and/or potential impact on the statistical analysis. 
11.2 Data Handling 
All study data will be managed by the Data Management Team at the CRO. The overall 
procedures for quality assurance of clinical study data are described in the SOPs of the CRO 
Data Management Team. The Data Management Team at CRO will prepare a DMP, to be 
reviewed and approved by the Sponsor, prior to the start of the study. This document will 
describe, in detail, the Data Management related procedures and processes. 
All data of all subjects enrolled and screening failures who experience an AE during the 
study (from time of informed consent to end of the safety follow-up period) will be captured 
and stored in the study database. 
All data collected during the study is property of the Sponsor irrespective of the location of 
the database and the Data Management CRO. 
11.2.1 
Data Validation 
The data will be validated as defined in the DMP and Data Validation Specifications. 
Discrepancies will be reported as defined in DMP and Data Validation Plan. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 125 of 171 
 
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. 
 
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: 
Medical history: 
Medical Dictionary for Regulatory Activities (MedDRA®) 
Adverse events: 
MedDRA® 
Medications: 
WHO Drug Dictionary Enhanced and Anatomical Therapeutic 
and Chemical classification system 
THS 2.2 device  
issues and/or 
malfunctions: 
C54451/Medical_Device_Problem_Codes_FDA_CDRH 
 
11.2.3 
Database Lock 
When all outstanding Data Management issues have been resolved and all validation, quality 
review, and cleaning activities are complete, the database or selected data is/are declared soft 
locked. Access to change data in the soft-locked database or to change selected data at this 
time is limited. 
After the data is reviewed by the Sponsor, resolution of all raised queries and QC of the 
changed data, database, or selected data upon Sponsor approval as applicable, is declared 
locked. 
Any changes to the database after that time can only be made by written agreement between 
the Sponsor and the Data Management and Statistical Team at the CRO. Any of those 
changes must be documented in the database log file. 
After study completion, the study database will be transferred to the Sponsor in the format 
specified in the DMP in Clinical Data Interchange Standards Consortium’s Study Data 
Tabulation Model (SDTM) Data Structure Specifications. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 126 of 171 
 
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. 
 
 
12 PLANNED STATISTICAL METHODS   
12.1 General Considerations 
Full details of the statistical analysis will be given in a SAP. Any changes to the planned 
statistical methods will be documented in the CSR. The statistical evaluation will be 
performed using SAS®, version 9.2 or later. 
 
12.1.1 
Stratification Criteria 
For the primary analysis of the BoExp, the following stratification criteria will be used:  
1. Sex (male; female). 
2. Average daily CC consumption over the last 4 weeks as reported during Screening. 
 
12.1.2 
Definitions for Statistical Data Analysis 
In general, baseline is the last available time-point prior to Day 1, 06:30 AM. 
 
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by product arm and subject, unless otherwise 
specified. 
Descriptive statistics for continuous variables (number of subjects [n], number and percent of 
subjects with data, mean, standard deviation [SD], median, first and third quartiles, minimum 
and maximum for continuous data, and the n and absolute and relative [%] frequency for 
categorical data) will be presented by product arm and overall at each time point, where 
applicable. 
For BoExp, the geometric mean and coefficient of variation (CV) will be presented in 
addition to the mean and SD. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 127 of 171 
 
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. 
 
12.1.4 
Handling of Missing Values and of Values outside the Detection Limits 
Missing values for the BoExp will be imputed using the last observation carried forward 
approach. 
For questionnaire data, total scores and domain or subscale scores may use a certain degree 
of imputation by averaging across individual item scores. 
Values below the lower limit of quantification (LLOQ) will be imputed using 0.5 x LLOQ. 
For values above the upper limit of quantification (ULOQ), the ULOQ will be used for 
calculation and reporting in summary tables. The number of values below LLOQ or above 
ULOQ will be presented in each summary table. 
Further details will be provided in the SAP. 
 
12.1.5 
Significance Level for Inferential Analysis 
Unless stated otherwise, all statistical tests will be two-sided and conducted at the 5% level, 
and all quoted confidence intervals (CIs) will be two-sided 95% CIs. 
The primary endpoints will be tested using a multiple testing procedure to preserve the 
overall alpha level by simultaneously testing the endpoints using a closed procedure with 
each test performed at an alpha level of 5%. This implies that statistical significance is 
required for all primary endpoints in order to be able to make confirmatory claims about any 
of the endpoints. 
Full details of this approach will be provided in the SAP.  
 
12.2  Determination of Sample Size and Power Consideration 
The following discussion addresses the ability to demonstrate on Day 5 a reduction of at least 
50% on 4 selected primary BoExps in smokers switching from CC to THS 2.2 as compared 
to smokers continuing to smoke CC. 
Table 16 describes the expected coefficients of variation (CV) and mean ratios (MR) 
between THS 2.2 and the two control arms based on data from a controlled, randomized, 
open-label, 3-arm parallel single-center confinement study that investigated exposure to 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 128 of 171 
 
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. 
 
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. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 129 of 171 
 
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. 
 
Table 16. 
Coefficients of Variation (YVD-CS01-EU study) 
 
THS 2.2 /CC 
MR (CV) 
THS 2.2 /SA 
MR (CV) 
COHb 
0.40 (0.32) 
2.10 (0.20) 
3-HPMA 
0.30 (0.50) 
1.70 (0.33) 
MHBMA 
0.15 (0.70) 
1.00 (0.35) 
S-PMA 
0.20 (0.70) 
1.15 (0.42) 
Abbreviations: 3-HPMA = 3-hydroxypropylmercapturic acid; CC = conventional cigarettes; 
COHb = carboxyhemoglobin; CV = coefficients of variation; MHBMA = 
monohydroxybutenyl mercapyuric acid; MR = mean ratios; S-PMA = S-phenylmercapturic 
acid; SA = smoking abstinence; THS 2.2 = Tobacco Heating System 2.2. 
 
Table 17 describes the expected coefficients of variation (CV) and mean ratios (MR) 
between THS 2.2 and the CC control arm based on data from a single-center, open-label, 
randomized, controlled, 2-arm parallel group study to evaluate the exposure to selected 
smoke constituents in smoking, but otherwise healthy subjects switching from conventional 
cigarettes to THS 2.1 compared to subjects continuing to smoke CC for 5 days, the ZRHX-
EX-01 study (ClinicalTrials.gov: ID: NCT01780714) sponsored by PMI. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 130 of 171 
 
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. 
 
Table 17. 
Coefficients of Variation (ZRHX‐EX‐01 study) 
 
THS 2.2 /CC 
MR (CV) 
COHb 
0.44 (0.14) 
3-HPMA 
0.28 (0.20) 
MHBMA 
0.11 (0.47) 
S-PMA 
0.07 (0.50) 
Abbreviations: 3-HPMA = 3-hydroxypropylmercapturic acid; CC = conventional cigarettes; COHb = carboxyhemoglobin; 
CV = coefficients of variation; MHBMA = monohydroxybutenyl mercapyuric acid; MR = mean ratios; S-PMA = S-
phenylmercapturic acid; THS 2.2 = Tobacco Heating System 2.2. 
 
Based on these two sets of assumptions, the power to demonstrate a reduction was computed. 
Table 18 describes the expected power to demonstrate a reduction on 4 primary BoExps in 
smokers switching from CC to THS 2.2 as compared to those continuing to smoke CC, using 
one-sided test with 2.5% type I error probability using the assumptions from YVD-CS01-EU 
and ZRHX‐EX‐01 and 160 smokers (80 in THS 2.2, 40 in CC, and 40 in the SA arm). 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 131 of 171 
 
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. 
 
Table 18. 
Expected Power (YVD-CS01-EU and ZRHX‐EX‐01 Studies 
Assumptions) 
Reduction 
Assumptions 
50% 
51% 
52% 
53% 
54% 
55% 
YVD-CS01-EU  
96% 
91% 
85% 
75% 
63% 
48% 
ZRHX‐EX‐01  
>99% 
>99% 
96% 
81% 
48% 
16% 
 
A total of 160 smokers (80 in THS 2.2, 40 in CC, and 40 in the SA arm) will be randomized 
to demonstrate a reduction of at least 50% on 4 primary BoExps in smokers switching from 
CC to THS 2.2 as compared to those continuing to smoke CC, using one-sided test with 2.5% 
type I error probability. 
Power considerations related to secondary endpoints of biological changes: 
The sample size is sufficient to obtain 95% CIs for the ratio between (geometrical) mean 
levels of primary BoExps in THS 2.2 and SA see Section 12.2 with upper and lower limits 
deviating  not more than 18% from the point estimates, with an 80% overall probability of 
achieving the desired precision of estimating the true mean. 
This study has 80% power using a one-sided test with 2.5% type I error probability: 
• To detect a 0.631 [ml/min/kg] (29%) difference between THS 2.2 and CC in CYP1A2 
activity, as measured by the CAF clearance, assuming a standard deviation of 0.564. 
Effect size and variability are derived from data obtained in the YVD-CS01-EU study 
sponsored by PMI. 
• To detect a 24.71 [ng/g creatinine] (20%) difference between THS 2.2 and CC in 
11-DTX-B2, assuming a standard deviation of 43.78, as reported by Saareks et al., 2001. 
The anticipated effect size of THS 2.2 is assumed to be about 90% of the effect of 
smoking cessation reported in the paper by Saareks et al., 2001. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 132 of 171 
 
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. 
 
12.3 Analysis Population 
The main population for non-safety analysis will be the full analysis set (FAS) population. 
The per-protocol (PP) population will be used only for the analysis of the primary endpoint 
to examine the robustness of the primary analyses. 
Safety will be analyzed using the safety population. 
 
12.3.1 
Full Analysis Set 
The FAS consists of all the randomized subjects who had at least one post-randomization 
product use experience, if randomized to THS 2.2 or CC, and have at least one valid non-
safety assessment (THS 2.2, CC, SA arms). 
 
12.3.2 
Per Protocol Population 
The PP population is a subset of FAS and includes all randomized subjects who fulfill key 
compliance criteria of the protocol, and have no major protocol deviation (to be further 
described in the SAP). 
 
12.3.3 
Safety Population 
The safety population consists of all the subjects who had at least one exposure to THS 2.2 
(product test at Admission Day). Subjects in the safety population will be analyzed according 
to actual exposure. 
 
12.4 Primary Analysis 
12.4.1 
Primary Endpoint Analysis Variables 
The primary endpoints are: 
• COHb on Day 5. 
• MHBMA on Day 5. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 133 of 171 
 
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. 
 
• 3-HPMA on Day 5. 
• S-PMA on Day 5. 
See section 3.4.1. 
Evaluation Criterion: The study will be considered successful if the study demonstrates a 
50% reduction or more for all four primary BoExp in the THS 2.2 arm compared to the CC 
arm (as measured on Day 5), using a one-sided test with 2.5% type I error probability. 
 
12.4.2 
Baseline Comparability 
Not applicable. 
 
12.4.3 
Descriptive Analysis 
Primary endpoints will be summarized as described in Section 12.1.3 on the FAS. 
Should more than 20% of the subjects be excluded from the FAS population, the above 
descriptive analysis will be repeated on the PP population. 
 
12.4.4 
Confirmatory Analysis 
The hypothesis to be tested for each of the primary and secondary biomarkers of exposure is 
that the geometric mean level on Day 5 of the biomarker for THS 2.2 is lower relative to CC. 
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 biomarker levels on Day 5 for THS 2.2 
and CC respectively. 
The transformed data will be analyzed by means of a generalized linear model using product 
arm as covariate adjusting for the following baseline information: sex, average cigarette 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 134 of 171 
 
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. 
 
consumption over the previous 4 weeks, and baseline value of endpoint. Estimates of 
differences between groups will be back-transformed to provide relative effects.  
Assumptions of the analysis of variance model will be tested. Markedly non-lognormally 
distributed BoExp data will be transformed or analyzed by appropriate non-parametric 
methods. 
Should more than 20% of the subjects be excluded from the FAS, would the above 
confirmatory analysis will be repeated on the PP population. 
 
12.5 Secondary Analysis 
12.5.1 
Secondary Endpoint Analysis Variables 
See section 3.4.2 
More details on derivation rules will be given in the SAP. 
 
12.5.2 
Baseline Comparability 
Not applicable. 
 
12.5.3 
Descriptive Analysis 
In general, secondary endpoints will be summarized as described in Section 12.1.3 on the 
FAS. 
 
12.5.4 
Safety Analysis  
In general, all safety data will be listed and tabulated on the safety population by product 
arm, using the approach described in Section 12.1.3. Safety variables collected during 
exposure periods will also be reported by product exposure. 
Adverse event data will serve as the primary assessment of safety. Other safety variables 
monitored in this study include: respiratory symptoms (cough assessment VAS and Likert 
scales); vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate); 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 135 of 171 
 
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. 
 
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 3.4.3. 
 
12.6.2 
Baseline Comparability 
Not applicable. 
 
12.6.3 
Descriptive Analysis 
In general, exploratory endpoints will be summarized as described in Section 12.1.3 on the 
FAS. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 136 of 171 
 
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. 
 
12.7 Demographics and Baseline Characteristics 
Demographic and other baseline characteristics will be reported for safety population. 
Summary statistics will be provided by exposure group and stratified by sex and by cigarette 
consumption. Formal statistical analysis will not be performed on baseline demographic data. 
 
12.8 Interim Analysis 
There are no planned interim analyses. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 137 of 171 
 
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. 
 
 
13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Principal Investigators and Study Administrative Structure 
13.1.1 
Principal Investigator 
Principal Investigator: 
Takuya Kunito, MD 
Daito Bldg., 1-11-3, Okubo, Shinjuku-ku, Tokyo 169-
0072 Japan 
Higashi Shinjuku Clinic 
TEL:
 
E-mail:
 
13.1.2 
Sponsor 
Sponsor: 
Philip Morris Products S.A, 
Quai Jeanrenaud 5, 
2000 Neuchâtel, 
Switzerland. 
Tel: + 41 (58) 242 2111 
Fax: + 41 (58) 242 2811 
, PhD 
Manager Clinical Science 
Phone: +41 
 
Mobile: +41
 
E-mail: 
@pmi.com 
, MEng, 
MSc 
Staff Scientist (Expert Statistician) 
Phone: +41
 
Mobile: +41
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 138 of 171 
 
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. 
 
E-Mail: 
  
, MD 
Medical Safety Officer 
 
Phone: +41 
 
Mobile: +41 
 
Email:
@pmi.com 
 
Medical Writer 
Phone: +41
 
Mobile: +41
 
E-mail: 
@pmi.com 
, MSc  
Clinical Study Manager 
Phone: +41 
 
Mobile: +41
 
E-Mail: 
@pmi.com 
13.1.3 
Other Responsibilities 
 
 is the local Contract Research Organization designated by PMI to manage and 
monitor the study: all duties and responsibilities transferred to 
 by PMI will be defined 
in the agreement signed between the two parties.  
 
 
 
 
 
 
 
 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 139 of 171 
 
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. 
 
 
 
Any SAEs or pregnancies will be handled by: 
 
 
 
 
 
 
 
 
 
Details of the laboratories conducting the clinical safety laboratory services, 
biopharmaceutical analyses and the analyses of BoExp are shown in Appendix 2. 
13.2 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects' state of 
health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subject in writing and signed by the subject, in compliance with all local 
and national data protection and privacy legislation. 
The anonymity of subjects participating in this study will be maintained. Subjects will be 
identifiable by the Sponsor (or Sponsor’s authorized representative) on eCRFs and other 
documents by their subject (or randomization) number/code, sex and date of birth, but not by 
name, initial, or any other details relating to identifiable person (e.g. address, health 
insurance ID card, medical chart number, etc.). The assignment of a subject number/code for 
subject identification will be based on the appropriate data protection rules. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 140 of 171 
 
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. 
 
Any documents that allow full identification of the subject (e.g. the subject’s signed study 
ICF) must be maintained in confidence by the Investigator. If any document relating to this 
study shows a subject’s name or any other details relating to an identifiable person (e.g. 
address, health insurance ID card, medical chart number, etc.), the name or other identifiable 
details must be obscured before a copy of that document is supplied to the Sponsor or the 
Sponsor’s authorized representative. 
13.3 Access to Source Documentation 
Subjects will be informed that, during the course of the clinical study, the Sponsor, any 
authorized representatives of the Sponsor, IRB, or regulatory authorities may inspect their 
medical records to verify the information collected, and ensure that all personal information 
made available for inspection is handled in the strictest confidence and in accordance with 
national and local data protection and privacy legislation. 
The Investigator/head of the investigational site and all study site trial collaborator involved 
with the study must permit direct access to source data/documents for study related 
monitoring, audits, IRB review, and regulatory inspection(s). 
13.4 Record Retention 
All records of data, source data and source documents (original records or certified copies), 
in any form (including, but not limited to, written, electronic, magnetic, optical records and 
scans, X-rays, and ECGs) that describe or record the methods, conduct, and/or results of the 
study, the factors affecting the study, and the actions taken will be maintained by the 
Principal Investigator/head of investigational site for the study, as required by ICH GCP and 
any other applicable local or national regulations. For X-rays at least the radiologist’s 
assessment is required as source documentation. If the actual image is available it can be 
stored on CD as well. 
Essential study documents/records, which individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced, are described in Article 41 of 
Ministerial Ordinance on GCP (Ordinance of the Ministry of Health and Welfare No. 28 of 
March 27, 1997 (as last amended by the Ordinance of Ministry of Health, Labour and 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 141 of 171 
 
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. 
 
Welfare No. 161 of December 28, 2012). Essential documents must be retained by the 
Principal Investigator/head of investigational site for a minimum of: 
• At least 15 years after completion or discontinuation of the study, or 
• At least 2 years depending on, for example, the circumstances, or 
• After formal discontinuation of clinical development of the IP. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. 
Examples of essential records/documents include, but are not limited to: 
• Signed informed consent documents for all subjects and Master ICF. 
• Subject identification code list, Screening Log and Enrolment Log (if applicable). 
• Record of all communications between the Principal Investigator  and the IRB, 
composition of the IRB. 
• Record of all communications/contact between the Investigator, Sponsor, and its 
authorized representatives. 
• List of sub-Investigators and other appropriately qualified persons to whom the head of 
the investigational site has delegated significant study-related duties, together with their 
roles in the study. 
• Investigator Logs. 
• eCRFs, study specific questionnaires (and associated data/scoring), subject diaries. 
• Adverse event reports and details of follow-up investigations, details of concomitant 
medication. 
• All other source documents (e.g. chest X-rays, ECGs, consultation reports, physical 
examination, laboratory records) or any electronically captured study source data. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 142 of 171 
 
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. 
 
• Clinical laboratory reports, laboratory normal ranges. 
• Original medical/hospital records, if applicable (the medical files of study subjects must 
be retained in accordance with local legislation and in accordance with the maximum 
period of time permitted by the hospital or study site). 
• Record of any body fluids or tissue samples collected and retained. 
• Device Issue Log, IP Accountability Logs, dispensing records. 
• Information regarding subjects’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the Principal Investigator/head of 
investigational site as to when these documents no longer need to be retained. 
The Principal Investigator/head of investigational site must take measures to prevent 
accidental or premature destruction of these documents. 
If the head of the investigational site wishes to assign the study records to another party or 
move them to another location, the Sponsor must be notified in advance. 
The head of the investigational site must obtain written approval from the Sponsor before 
destruction of any records. Normally, these records will be held in the Investigator’s 
archives. If the head of the investigational site is unable to meet this obligation, they must ask 
the Sponsor for permission to make alternative arrangements. Details of these arrangements 
must be documented. 
The Sponsor or Sponsor’s authorized representative will maintain documentation relating to 
the study as long as the IP is on the market, and/or for 15 years after the CSR has been 
finalized. 
13.5 Clinical Study Report 
The Sponsor must ensure that a CSR for this study is prepared regardless of whether the 
study is completed or prematurely terminated. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 143 of 171 
 
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 CSR will be written based on standards of the ICH Guideline for the Structure and 
Content of Clinical Study Reports. In certain circumstances, an abbreviated CSR may be 
acceptable. Submission of the CSR to the IRB will be complied with as requested by local 
requirements. 
The results of the additional variables for analysis will be presented in reports separate from 
the study CSR. 
13.6 Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor. In 
addition, the Investigators must provide to the Sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year following the completion of the study. 
13.7 Publication and Disclosure Policy 
This document contains data, information and trades secretes that are confidential and 
proprietary to the Sponsor. This document is being provided solely for the purpose of 
evaluation and/or conducting this clinical study for the Sponsor. Disclosure of the content of 
this document is allowed only to study personnel, IRB, or duly authorized representatives of 
regulatory agencies for this purpose under the condition that confidentiality is maintained. 
The contents of this document may not be used in any other clinical study, disclosed to any 
other person or entity without the prior written permission of the Sponsor. The foregoing 
shall not apply to disclosure required by any regulations; however, prompt notice will be 
given to the Sponsor prior to any such disclosure. 
The Sponsor plans to disclose details of the study protocol on a web-based, publicly 
available, clinical trial register database (e.g., ClinicalTrials.gov). 
13.8 Insurance 
The Sponsor is responsible for AEs and health damage of the subjects that are associated 
with the THS 2.2 product or 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 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 144 of 171 
 
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. 
 
and/or significant deviation to the Protocol of the Investigator or the clinical trial site or the 
subjects. The Sponsor have taken out insurance to cover any bodily injury and property 
damage caused by the operations cried out by the insured.. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 145 of 171 
 
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. 
 
 
14 REFERENCE LIST 
Ashley et al., 2008 
Ashley DL, Burns D, Djordjevic M, Dybing E, Gray N, Hammond SK, et al. WHO Study 
Group on Tobacco Product Regulation. The scientific basis of tobacco product regulation. 
World Health Organ Tech Rep Ser. 2008; (951): 1-277, 1 p following 277. 
  
Benowitz et al., 1993 
Benowitz NL, Fitzgerald GA, Wilson M, Zhang Q. Nicotine effects on eicosanoid formation 
and hemostatic function: comparison of transdermal nicotine and cigarette smoking. J Am 
Coll. Cardiol. 1993 Oct; 22 (4): 1159-67. 
 
Benowitz et al., 2002 
SNRT subcommittee on biochemical verification. Biochemical verification of tobacco use 
and cessation. Nicotine Tob Res. 2002; 4 (2): 149-159. 
 
Cappelleri et al., 2007 
Cappelleri JC, Bushmakin AG, Baker CL, Merikle E, Olufade AO, Gilbert DG. 
Confirmatory factor analyses and reliability of the modified cigarette evaluation 
questionnaire. Addict Behav. 2007 May; 32 (5): 912-23. 
 
Chang and Kam, 1999 
Chang GW, Kam PC. The physiological and pharmacological roles of cytochrome P450 
isoenzymes. Anaesthesia. 1999 Jan; 54 (1): 42-50. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 146 of 171 
 
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. 
 
 
Connolly et al., 2011 
Connolly GN, Behm I, Osaki Y, Wayne GF. The impact of menthol cigarettes on smoking 
initiation among non-smoking young females in Japan. Int J Environ Res Public Health. 
2011; 8 (1): 1-14. 
 
Cox et al., 2001 
Cox LS, Tiffany ST, Christen AG. Evaluation of the brief questionnaire of smoking urges 
(QSU-brief) in laboratory and clinical settings. Nicotine Tob Res. 2001; 3 (1): 7-16. 
 
Declaration of Helsinki, 2008 
Declaration 
of 
Helsinki. 
World 
Medical 
Association. 
Available 
from: 
http://www.wma.net/en/30publications/10policies/b3/index.html (accessed on 21 March 
2012). 
 
Faber and Fuhr, 2004 
Faber MS, Fuhr U. Time response of cytochrome P450 1A2 activity on cessation of heavy 
smoking. Clin Pharmacol Ther. 2004 Aug; 76 (2): 178-84. 
 
Fagerström et al., 2012 
Fagerström K, Russ C, Yu C, Yunis C, Foulds J. The Fagerström Test for Nicotine 
Dependence as a Predictor of Smoking Abstinence: A Pooled Analysis of Varenicline 
Clinical Trial. Nicotine & Tobacco Research. 2012; first published online March 30, 2012. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 147 of 171 
 
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. 
 
FDA, 2002 
Guidance for Industry, Food-Effect Bioavailability and Fed Bioequivalence Studies, 2002. 
Available 
at 
http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126833.pdf 
(accessed 
27 Sep 2012). 
 
FDA, 2011 
United States Food and Drug Administration, Harmful and Potentially Harmful Constituents 
in Tobacco Products and Tobacco Smoke; Request for Comments (76 FR 50226, Aug. 12, 
2011). 
 
FDA, 2012a 
United States Food and Drug Administration, Center for Tobacco Products. Modified Risk 
Tobacco Product Applications: Draft Guidance for Industry, March 2012. Available from 
http://www.fda.gov/TobaccoProducts/GuidanceComplianceRegulatoryInformation/default.ht
m.  
FDA, 2012b 
United States Food and Drug Administration, U.S. Department of Health and Human 
Services, Center for Tobacco Products (CTP), Reporting Harmful and Potentially Harmful 
Constituents in Tobacco Products and Tobacco Smoke Under Section 904(a)(3) of the 
Federal Food, Drug, and Cosmetic Act, March 2012. 
 
FDA, 2012c 
United States Food and Drug Administration. Implementation Specifications, reporting 
medical device problems, C54451/Medical Device  Problem Codes, FDA, CDRH. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 148 of 171 
 
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. 
 
Available 
from 
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/EventProblemCodes/ucm13574
1.htm#  (accessed on 04 October 2012). 
 
Health Canada, 1999 
Health Canada. Determination of “Tar”, Nicotine and Carbon, Monoxide in Mainstream 
Tobacco Smoke. Available at www.hc-sc.gc.ca. 
 
Hatsukami et al., 2007 
Hatsukami DK, Joseph AM, Lesage M, Jensen J, Murphy SE, Pentel PR, et al. Developing 
the science base for reducing tobacco harm. 9(4) Nicotine & Tobacco research S537 (Dec. 
2007). 
 
Honjo et al., 2010a 
Honjo K, Iso H, Tsugane S, Tamakoshi A, Satoh H, Tajima K et al. The effects of smoking 
and smoking cessation on mortality from cardiovascular disease among Japanese: pooled 
analysis of three large-scale cohort studies in Japan. Tob Control. 2010; 19 (1): 50-57. 
 
Honjo et al., 2010b 
Honjo K, Iso H, Inoue M, Tsugane S; JPHC Study Group. Smoking cessation: predictive 
factors among middle-aged Japanese. Nicotine Tob Res. 2010; 12 (10): 1050-1054. 
 
Hughes and Hatsukami, 1986 
Hughes JR, Hatsukami D. Signs and symptoms of tobacco withdrawal. Arch Gen Psychiatry. 
1986 Mar; 43 (3): 289-94. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 149 of 171 
 
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. 
 
 
Hughes and Hatsukami, 2008 
Hughes JR, Hatsukami D. Background on the Minnesota Withdrawal Scale-Revised 
(MNWS-R). 2008 May; (www.uvm.edu/~hbpl). 
 
ICH GCP, 1996 
ICH Guideline for Good Clinical Practice E6 (R1). July 1996. CPMP/ICH/135/95/Step 5. 
 
Ingelman-Sundberg et al., 1999 
Ingelman-Sundberg M, Oscarson M, McLellan RA. Polymorphic human cytochrome P450 
enzymes: an opportunity for individualized drug treatment. Trends Pharmacol Sci. 1999 Aug; 
20 (8): 342-9. 
 
Institute of Medicine, 2012 
Institute of Medicine Consensus Report. Scientific Standards for Studies on Modified Risk 
Tobacco Products. Released: December 14, 2011. Board on Population Health and Public 
Health 
Practice. 
(http://www.iom.edu/Reports/2011/Scientific-Standards-for-Studies-on-
Modified-Risk-Tobacco-Products.aspx). 
 
International Tobacco Online, 2012 
http://www.internationaltobaccoonline.com/japanese-survey-said-the-percentage-of-smokers-
in-japan-is-lower-than-20-p-927.html (accessed 19 June 2012). 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 150 of 171 
 
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. 
 
Iso et al., 2005 
Iso H, Date C, Yamamoto A, Toyoshima H, Watanabe Y, Kikuchi S et al.; JACC Study 
Group. Smoking cessation and mortality from cardiovascular disease among Japanese men 
and women: the JACC Study. Am J Epidemiol. 2005; 161 (2): 170-179. 
 
Jacob et al., 2011 
Jacob P 3rd, Yu L, Duan M, Ramos L, Yturralde O, Benowitz NL. Determination of the 
Nicotine Metabolites Cotinine and Trans-3'-Hydroxycotinine in Biologic fluids of Smokers 
and Non-smokers using Liquid Chromatography - Tandem Mass Spectrometry: Biomarkers 
for Tobacco Smoke Exposure and for Phenotyping Cytochrome P450 2A6 Activity. J 
Chromatogr B Analyt Technol Biomed Life Sci. 2011 Feb 1; 879 (3-4): 267-76. 
 
Lacy et al., 2007 
Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15th ed. 
Hudson, OH; LexiComp Inc. 2007: 1899-1912. 
 
Lindner et al., 2011 
Lindner D, Smith S, Leroy CM, Tricker AR. Comparison of Exposure to Selected Cigarette 
Smoke Constituents in Adult Smokers and Nonsmokers in a European, Multicenter, 
Observational Study. Cancer Epidemiol Biomarkers Prev. 2011;20:1524-36. Published 
OnlineFirst May 25, 2011. 
 
LionCorp. 
http://www.lion.co.jp/en/products/html/pro_d036.htm (in English)  Contains 500 mg of 
caffeine anhydrous per 3 tablets. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 151 of 171 
 
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. 
 
  
Ministry of Health Labour and Welfare, 1997 
Ministerial Ordinance on Good Clinical Practice for Drugs, Ordinance of the Ministry of Health 
and Welfare No. 28 of March 27, 1997, as last amended by the Ordinance of Ministry of 
Health, Labour and Welfare No. 161 of December 28, 2012. 
 
Morita et al., 2005 
Morita H, Ikeda H, Haramaki N, Eguchi H, Imaizumi T. Only two-week smoking cessation 
improves platelet aggregability and intraplatelet redox imbalance of long-term smokers. 
J Am Coll Cardiol. 2005 Feb 15; 45 (4):589-94. 
 
Pilz et al., 2000 
Pilz H, Oguogho A, Chehne F, Lupattelli G, Palumbo B, Sinzinger H. Quitting Cigarette 
Smoking Results in a Fast Improvement of in vivo Oxidation Injury (Determined via Plasma, 
Serum and Urinary Isoprostane. Thrombosis Research. 99 (2000) 209-21. 
 
PMI, 2012 
Philip Morris International, 2012. In French. Work Instruction PMI_RD_WKI_000527: 
Guide d’utilisation de l’extracteur in situ, nettoyage des seringues, des pistons, des aiguilles 
et des pieges (R2540.M109). Version 3.0. 
 
PMI, 2013a 
Philip Morris International. 2013. Internally-modified method based on International 
Organization for standardization’s ISO 4387:2000. In French.  PMI_RD_WKI_000530: 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 152 of 171 
 
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. 
 
Détermination du TMP et CO et trappage de l’eau, nicotine, acide pyruvique et des smoke 
constituents:BaP, phénols, TSNA et amines aromatiques. 
 
PMI, 2013b 
Philip Morris International, Neuchatel, Switzerland, 2013. Investigator’s Brochure for 
Tobacco Heating System 2.2. 
 
PMI, 2013c 
Philip Morris International. 2013. David Ghosh. Experimental report: Identifying the 
appropriate technique to collect and extract water, nicotine and glycerin from the TPM to 
further characterize the tar of the ZURICH product. Version 1.0. 
 
PMI YVD-CS01-EU study 
Philip Morris International. YVD-CS01-EU study. Available at www.ClinicalTrials.gov, ID: 
NCT00812279. 
 
PMI White Paper Docket 
Food and Drug Administration (FDA), Division of Dockets Management. Philip Morris’s 
International comments on the scientific evaluation of the modified risk tobacco product 
applications. Docket no. FDA-2011-N-0443. 
 
Raw et al., 2002 
Raw M, Anderson P, Batra A, Dubois G, Harrington P, Hirsch A et al. World Health 
Organization European Partnership Project to Reduce Tobacco Dependence. WHO Europe 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 153 of 171 
 
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. 
 
evidence based recommendations on the treatment of tobacco dependence. Tob Control. 
2002; 11 (1): 44-46. 
 
Rodgman and Perfetti, 2009 
Rodgman A, Perfetti TA. The chemical components of tobacco and tobacco smoke (Taylor 
& Francis Group 2009). 
 
Saareks et al., 2001 
Saareks V, Ylitalo P, Alanko J, Mucha I, Riutta A. Effects of smoking cessation and nicotine 
substitution on systemic eicosanoid production in man. Naunyn Schmiedebergs Arch 
Pharmacol. 2001 May; 363 (5): 556-61. 
 
Tiffany et al. 1991 
Tiffany ST, Drobes DJ. The development and initial validation of a questionnaire on 
smoking urges. British Journal of Addiction. 1991; 86: 1467-1476. 
 
U.S. Department of Health and Human Services, 2010 
U.S. Department of Health and Human Services. How Tobacco Smoke Causes Disease: The 
Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon 
General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease 
Control and Prevention, National Center for Chronic Disease Prevention and Health 
Promotion, Office on Smoking and Health, 2010. 
(http://www.surgeongeneral.gov/library/tobaccosmoke/report/executivesummary.pdf). 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 154 of 171 
 
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. 
 
World Lung Foundation, 2012 
Tobacco 
Atlas 
– 
Fourth 
Edition. 
ISBN-13: 
978-1-60443-093-6. 
Available 
at 
www.tobaccoatlas.org. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 155 of 171 
 
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. 
 
 
Appendix 1 
Schedule of Events 
Table A1. 
Study Assessments (separate table [Table A2] shown for 24-hour 
urine collections) 
 
Screening 
Confinement Period  
  
Safety 
Follow-
Upp 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7-14 
Informed consent for 
study participation 
and two informed 
consents for bio-
banking  
● 
 
 
 
 
 
 
 
 
 
 
Admission/Discharge 
 
● 
 
 
 
 
 
 
 
● 
 
Advice on the risk of 
smoking and 
debriefing 
● 
● 
 
 
 
 
 
 
 
● 
 
Support for SA arm 
 
 
 
 
● 
● 
● 
● 
● 
 
 
Inclusion/exclusion 
criteria 
● 
● 
 
 
 
 
 
 
 
 
 
Enrolment 
 
● 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
● 
 
 
 
 
 
 
 
Demographics, 
medical history, 
concomitant diseases 
● 
 
 
 
 
 
 
 
 
 
 
Vital signs a 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Physical examination 
b 
● 
● 
 
 
 
 
 
 
 
● 
 
Spirometry c 
● 
 
 
● 
 
 
 
 
 
● 
 
Prior/concomitant 
medication 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
B/U: Hematology, 
clinical chemistry, 
urine analysis  
● 
 
 
● 
 
 
 
 
 
● 
 
Electrocardiogram 
● 
 
 
 
 
 
 
 
 
● 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 156 of 171 
 
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. 
 
 
Screening 
Confinement Period  
  
Safety 
Follow-
Upp 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7-14 
Chest X-ray d 
● 
 
 
 
 
 
 
 
 
 
 
B: HIV, hepatitis B 
and C 
● 
 
 
 
 
 
 
 
 
 
 
U: Urine drug screen, 
urine cotinine 
screening test 
● 
● 
 
 
 
 
 
 
 
 
 
U: Pregnancy test 
● 
● 
 
 
 
 
 
 
 
● 
 
Alcohol breath test 
● 
● 
 
 
 
 
 
 
 
 
 
FTND 
● 
 
 
 
 
 
 
 
 
 
 
Smoking history 
● 
● 
 
 
 
 
 
 
 
 
 
Willingness to quit 
smoking e 
● 
● 
 
 
 
 
 
 
 
 
 
Identification of 
cigarette brand 
● 
● 
 
 
 
 
 
 
 
 
 
THS 2.2 
demonstration 
● 
 
 
 
 
 
 
 
 
 
 
THS 2.2 product test f 
 
● 
 
 
 
 
 
 
 
 
 
CO breath test g 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
B: BoExp in blood: 
COHb h 
 
 
● 
● 
● 
● 
● 
● 
● 
(x4) 
 
 
B: Biomarker of 
exposure in plasma: 
nicotine, cotinine i 
 
 
 
● 
● 
● 
● 
● 
● 
● 
 
B: CYP1A2 activity 
 
 
 
● 
 
 
 
 
● 
 
 
B: CYP2A6 activity 
 
 
 
● 
 
 
 
 
 
● 
 
QSU-brief 
questionnaire j 
 
 
● 
● 
● 
● 
● 
● 
● 
 
 
MNWS (revised 
version) k 
 
 
 
● 
● 
● 
● 
● 
● 
● 
 
MCEQ (modified 
version; THS 2.2 and 
CC arms) l 
 
 
● 
● 
● 
● 
● 
● 
● 
 
 
HST (THS 2.2 and 
 
 
 
● 
● 
 
 
● 
 
 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 157 of 171 
 
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. 
 
 
Screening 
Confinement Period  
  
Safety 
Follow-
Upp 
Study Day 
-30 to -3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7-14 
CC arms) m 
HST questionnaire 
(THS 2.2 and CC 
arms) 
 
 
 
● 
 
 
 
● 
 
 
 
Assessment of cough 
 
 
 
● 
● 
● 
● 
● 
● 
● 
 
AE/SAE recording 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Collection tobacco 
plugs of used 
Tobacco Sticks for 
combustion analysis 
and accountability 
 
 
 
 
● 
● 
● 
● 
● 
 
 
Collection of used CC 
butts for 
accountability 
 
 
● 
● 
● 
● 
● 
● 
● 
 
 
B: Bio-banking for 
BoExp and risk 
markers n 
 
 
 
● 
 
 
 
 
 
● 
 
U: Bio-banking for 
BoExp and risk 
markers n 
 
 
 
● 
 
 
 
 
● 
 
 
B: Bio-banking for 
transcriptomicso 
 
 
 
● 
 
 
 
 
 
● 
 
 
Abbreviations: AE = adverse event; B = blood sample required; CC = conventional 
cigarette(s); CO = carbon monoxide; CoHb = carboxyhemoglobin; CYP = cytochrome P450 
enzyme; FTND = Fagerström Test for Nicotine Dependence; HIV = human 
immunodeficiency virus; HST = human smoking topography; MCEQ = Modified Cigarette 
Evaluation 
Questionnaire; 
MNWS 
= 
Minnesota 
Nicotine 
Withdrawal 
Scale; 
QSU = Questionnaire of Smoking Urges; SA = smoking abstinence; SAE = serious adverse 
event; THS = tobacco heating system; U = urine sample required. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 158 of 171 
 
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. 
 
a: Systolic and diastolic blood pressure, pulse rate, and respiratory rate 
b: Including height (only at Screening), body weight and calculated BMI. 
c: Spirometry does not need to be done prior to smoking at screening. At screening, 
spirometry without brochondilator will be done first and then with. On Day 0 and Day 6, 
spirometry has to be done prior to smoking.  
d: Pre-study chest X-ray (with anterior-posterior and left lateral views) may be used, if 
performed within 6 months prior to Screening. 
e: Subjects will be asked if they plan to quit smoking within the next 3 months (at Screening 
only) and, in order to satisfy the protocol inclusion criteria, if they are ready to abstain from 
smoking for at least 5 days (at Screening and Day -2). 
f: THS 2.2 product test to be conducted as the last procedure of eligibility check at Day -2 
(and after urine pregnancy test has been done in female subjects to exclude pregnancy). 
g: CO breath test; Days -1 to Day 5: the test will be conducted four times per day. The first 
test should be conducted within 15 minutes prior to the first product use (for subjects in the 
THS 2.2 and CC arms) and between 08:00 AM and 09:30 AM for subjects in the SA arm. 
The other three tests should be conducted between 12:00 PM and 01:30 PM, 04:00 PM and 
05:30 PM, and 08:00 PM and 9:30 PM. Day -2 and Day 6: once during the visit, irrespective 
of the time of product use. 
h: COHb; Assessments should be done in conjunction with CO breath tests, where 
applicable. Day -1 to Day 4: one blood sample in the evening between 08:00 PM and 09:30 
PM. 
Day 5: one blood sample within 15 minutes prior to the first product use (for subjects in the 
THS 2.2 and CC arms) and between 08:00 AM and 9:30 AM for subjects in the SA arm, and 
one blood sample between 12:00 PM and 01:30 PM, 04:00 PM and 05:30 PM, and 08:00 PM 
and 9:30 PM. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 159 of 171 
 
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. 
 
i: Nicotine/cotinine; Day 0 to Day 4 (all study arms): one blood sample in the evening 
between 08:00 PM and 09:30 PM. 
Day 5 and Day 6 (THS 2.2 and CC arms): one sample within 15 minutes prior to the first 
product use (T0); eight blood samples afterT0 each at 2 hour intervals. On Day 6, two blood 
samples will be drawn. The first sample will be 20 hours after T0 and the second blood 
sample will be 24 hours after T0 (with T0 being the time of the first product use on Day 5). 
Day 5 and Day 6 (SA arm): on Day 5, one blood sample in the evening between 08:00 PM 
and 09:30 PM. On Day 6, one blood sample to be drawn in the morning between 08:00 AM 
and 9:30 AM. 
j: QSU-brief: Daily, from Day -1 to Day 5. 
k: MNWS: daily from Day 0 to Day 6. 
l: MCEQ: Day -1 to Day 5 on a daily basis. On Day -1 and Day 0, all subjects will complete 
the questionnaire. From, Day 1, only subjects who are randomized to the THS 2.2 and CC 
arms will complete this questionnaire. 
m: On Day 0, HST and HST questionnaire will be done in all subjects smoking CC 
compatible with the HST SODIM® device. On Day 1 and Day 4, HST and HST 
questionnaire will be done in all subjects in the THS 2.2 and CC arms. Smoking topography 
with the HST device will not be done in subjects smoking CC that are incompatible with the 
HST SODIM® device (e.g. slim CC). No HST assessments will be done in subjects in the SA 
arm. 
n: Samples will only be taken if additional consent for BoExp and risk markers bio-banking 
is given by the subject. 
o: Samples will only be taken if additional consent for transcriptomics bio-banking is given 
by the subject.  
p: all safety examinations listed on the Day of Discharge (Day 6) will be conducted in 
subjects whose participation in the study is prematurely terminated. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 160 of 171 
 
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. 
 
Table A2  
 
Schedule for 24 hour Urine Collection Assessments 
 
Baseline period 
Confinement Exposure Period 
24 hour urine samples 
Day -1 
to  
Day 0 
 Day 0 
to  
Day 1 
Day 1 
to  
Day 2 
Day 2 
to  
Day 3 
Day 3 
to  
Day 4 
Day 4 
to  
Day 5 
Day 5 
to  
Day 6 
BoExp in urine a 
● 
● 
● 
● 
● 
● 
● 
Creatinine  
● 
● 
● 
● 
● 
● 
● 
Ames mutagenicity test, 11-DTX-
B2 and 8-epi-PGF2α 
 
● 
 
 
 
 
● 
Bio-banking for BoExp and risk 
markers b 
 
● 
 
 
 
 
● 
Abbreviations: 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-
thromboxane B2 
a: BoExp in urine: Primary (MHBMA, 3-HPMA, S-PMA); Secondary (total NNAL, 1-NA, 
1-OHP, total NNN, 3-hydroxy(a)benzopyrene, 4-ABP, 2-NA, o-tol, Neq, CEMA, HEMA, S-
BMA  and HMPMA). In the above table, the dot corresponds to the day on which the 
24-hour urine collection period starts. The end of the 24-hour urine collection period will be 
the following day. 
b: Samples will only be taken if additional consent for BoExp and risk marker bio-banking is 
given by the subject. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 161 of 171 
 
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. 
 
 
Appendix 2 
Participating Laboratories 
The following Laboratories will be used in the study: 
 
 
 
 
 
 
  
  
 
 
 
 
More details will be found in the study laboratory manuals.  
 
For samples biobanking: 
 
 
 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 162 of 171 
 
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. 
 
 
Appendix 3 
Investigational Product and Instructions for Use 
The product user guide will be provided as a separate document. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 163 of 171 
 
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. 
 
 
Appendix 4 
THS Package Label 
The package label for the THS Tobacco Sticks (example): 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 164 of 171 
 
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. 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 165 of 171 
 
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 package label for the THS Tobacco Sticks carton (example): 
 
 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 167 of 171 
 
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. 
 
 
Appendix 6 
Abnormal Laboratory Values 
CTCAE ABNORMAL LABORATORY VALUES RATING: SERUM CHEMISTRY 
PARAMETERS 
Serum Chemistry* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Sodium - Hyponatremia (mmol/l) ** (1) 
<LLN - 130 
- 
<130 - 120 
Sodium - Hypernatremia (mmol/l) ** (1) 
>ULN - 150 
>150 - 155 
>155 - 160; 
hospitalization 
indicated 
Potassium - Hyperkalemia (mmol/l)**(1) 
>ULN - 5.5 
>5.5 - 6.0 
>6.0 -7.0; 
hospitalization 
indicated 
Potassium - Hypokalemia (mmol/l) ** (1) 
<LLN - 3.0 
<LLN - 3.0; 
symptomatic; intervention 
indicated 
<3.0 - 2.5; 
hospitalization 
indicated 
Glucose - Hypoglycemia ** (1)    (mg/dl) 
                                                   (mmol/l)  
<LLN - 55; 
<LLN - 3.0 
<55 - 40; 
<3.0 - 2.2 
<40 - 30; 
<2.2 - 1.7 
Glucose – Hyperglycemia: ** (1) 
 
 
 
 
 
     Fasting (mg/dl) 
(mmol/l) 
 
 
 
 
    Non-fasting (mg/dl) 
(mmol/l) 
 
 
>ULN-160; 
>ULN-8.9 
- 
- 
 
 
>160-250; 
>8.9-13.9 
- 
- 
 
 
- 
- 
>250-500; 
>13.9-27.8; 
hospitalization 
indicated 
Blood Urea Nitrogen (BUN) (mg/dl) (2) 
23 - 26 
27 - 31 
> 31 
Creatinine increased** (1) 
>1 - 1.5 x baseline; 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x baseline; 
>1.5 - 3.0 x ULN 
>3.0 x baseline; 
>3.0 - 6.0 x ULN 
Albumin - Hypoalbuminemia** (1) (g/dl) 
                                                          (g/l) 
<LLN - 3; 
<LLN - 30 
<3 - 2; 
<30 - 20 
<2; 
<20 
Total Protein - Hypoproteinemia (2) 
(g/dl) 
 
5.5 - 6.0 
 
5.0 - 5.4 
 
< 5.0 
Alkaline phosphatase increased** (1) 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
ALT / AST increased** (1) 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 168 of 171 
 
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. 
 
Gamma-glutamyl transferase (GGT) 
increased (1) 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
Blood bilirubin increased ** (1) 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 ULN 
Cholesterol high** (1)                      
 
 
 
 
 
 
 
(mg/dl) 
(mmol/l) 
 
>ULN - 300; 
>ULN - 7.75 
 
>300-400; 
>7.75-10.34 
 
>400-500; 
>10.34-12.92 
Triglycerides - Hypertriglyceridemia (1) 
(mg/dl) 
(mmol/l) 
 
150 - 300; 
1.71 - 3.42 
 
>300 - 500; 
>3.42 - 5.70 
 
>500 - 1000; 
>5.70 - 11.40 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; LLN = 
lower limit of the normal range; ULN = upper limit of the normal range. 
Data Sources: 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials, U.S. Department of Health and Human Services, FDA, Center for Biologics 
Evaluation and Research - Guidance for Industry. 
(2) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, FDA, 
Center for Biologics Evaluation and Research - Guidance for Industry. 
* Those parameters that are not listed do not have grading categories in either the CTCAE or 
the FDA guidance documents and will therefore be reviewed by the Investigator and only 
reported as an AE if considered to be clinically relevant. 
**  Where parameters in this table are listed in both the CTCAE and the FDA guidance 
documents, and each document has different values within each grading category, the 
grading in CTCAE guidance document predominates. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 169 of 171 
 
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. 
 
CTCAE ABNORMAL LABORATORY VALUES RATING: HEMATOLOGY 
PARAMETERS 
Hematology* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Hemoglobin (Female) – (g/dl) (1) 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
change from baseline value – (g/dl) (1) 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
Hemoglobin (Male) – (g/dl) (1) 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
change from baseline value – (g/dl) (1) 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
Hemoglobin increase – (g/dl) (2) 
Increase in >0 – 2 
above ULN or above 
baseline if baseline is 
above ULN 
Increase in >2 – 4 
above ULN or above 
baseline if baseline is 
above ULN 
Increase in >4 above 
ULN or above baseline 
if baseline is above 
ULN 
WBC Increase  – (cell/mm3) (1) 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25,000 
WBC Decrease - (cell/mm3) (2)** 
<LLN – 3000; 
<LLN – 3.0 x 10-9/l 
<3000 - 2000; 
<3.0 – 2.0 x 10-9/l 
<2000 - 1000; 
<2.0 – 1.0 x 10-9/l 
Lymphocytes Increase - (cell/mm3) (2) 
- 
>4,000 – 20,000 
>20,000 
Lymphocytes Decrease  - (cell/mm3) (2)** 
<LLN – 800; 
<LLN – 0.8 x 10-9/l 
<800 - 500; 
<0.8 – 0.5 x 10-9/l 
<500 - 200; 
<0.5 – 0.2 x 10-9/l 
Neutrophils Decrease  - (cell/mm3) (2)** 
<LLN – 1500; 
<LLN – 1.5 x 10-9/l 
<1500 - 1000; 
<1.5 – 1.0 x 10-9/l 
<1000 - 500; 
<1.0 – 0.5 x 10-9/l 
Eosinophils - (cell/mm3) (1) 
650 – 1500 
1501 - 5000 
>5000 
Platelets Decrease - (cell/mm3) (2)** 
<LLN – 75,000; 
<LLN – 75.0 x 10-9/l 
<75,000 – 50,000; 
<75.0 – 50.0 x 10-9/l 
<50,000 – 25,000; 
<50.0 – 25.0 x 10-9/l 
Abbreviations: LLN = lower limit of the normal range; ULN = upper limit of the normal 
range; WBC = white blood cell. 
Data Source: (1) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human 
Services, FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
    (2) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 170 of 171 
 
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. 
 
*  Those parameters that are not listed do not have grading categories in either the CTCAE or 
the FDA guidance documents and will therefore be reviewed by the Investigator and only 
reported as an AE if considered to be clinically relevant. 
**  Where parameters in this table are listed in both the CTCAE and the FDA guidance 
documents, and each document has different values within each grading category, the 
grading in CTCAE guidance document predominates. 

 
 
 
 
 
ZRHR-REXC-04-JP 
Clinical Study Protocol 
Confidential 
 
Final 2.0/08 July 2013 
Page 171 of 171 
 
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. 
 
CTCAE ABNORMAL LABORATORY VALUES RATING: URINALYSIS 
PARAMETERS 
Urine* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Protein** (1) 
1+ proteinuria; 
urinary protein 
<1.0 g/24 hours 
2+ proteinuria; 
urinary protein 
1.0-3.4 g/24 hours 
Urinary protein 
≥3.5 g/24 hours 
Glucose (2) 
Trace 
1+ 
2+ 
Blood – Hematuria ** (1) 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Symptomatic; 
urinary catheter or 
bladder irrigation 
indicated; limiting 
instrumental ADL 
Gross hematuria; 
transfusion, IV 
medications or 
hospitalization 
indicated; elective 
endoscopic, 
radiologic or 
operative 
intervention 
indicated; limiting 
self-care ADL 
Abbreviations: ADL = activities of daily living; IV = intravenous. 
Data Source: (1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
 (2) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, FDA, 
Center for Biologics Evaluation and Research - Guidance for Industry. 
*  Those parameters that are not listed do not have grading categories in either the CTCAE or 
the FDA guidance documents and will therefore be reviewed by the Investigator and only 
reported as an AE if considered to be clinically relevant. 
**  Where parameters in this table are listed in both the CTCAE and the FDA guidance 
documents, and each document has different values within each grading category, the 
grading in CTCAE guidance document predominates.