Assessment of Passive Environmental Aerosol Exposure Through IQOS (Tobacco Heating System [THS] With Marlboro Heatsticks) in a Restaurant Setting Where IQOS Use, But Not Cigarette Smoking, is Allowed.
Conditions: Environmental Exposure
Sponsor: Philip Morris Products S.A.



Philip Morris Products SA 
Assessment Study Protocol 
Confidential 
P1-PES-01-JP 
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PROTOCOL AUTHORISATION 
Assessment of passive environmental tobacco aerosol exposure through IQOS (Tobacco 
Heating System (THS) with Marlboro Heatsticks) in a restaurant setting where IQOS use, but 
not cigarette smoking, is allowed 
This study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the methods to be used, as well as with 
the moral, ethical, and scientific principles governing epidemiological research as set out in 
the current Declaration of Helsinki and the guidelines on Good Epidemiological Practice 
(GEP).  
 
 
 
 PhD, Lead Study Scientist (Print) 
 
 
 PhD, Lead Study Scientist (Signature) 
 
Date 
PhD, Study Scientist (Print) 
 
 
PhD, Study Scientist (Signature) 
 
Date 
PhD, Study Biostatistician (Print) 
 
 
PhD, Study Biostatistician (Signature) 
 
Date 
MD, Study Scientist (Print) 
 
 
MD, Study Scientist (Signature) 
 
Date 
PhD, Study Biostatistician (Print) 
 
 
PhD, Study Biostatistician (Signature) 
 
Date 

Philip Morris Products SA 
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without the written consent of Philip Morris Products S.A 
Dr.Takao Ohki, MD, PhD, Prinicpal Investigator (Print) 
 
 
Dr.Takao Ohki, MD, PhD, Prinicpal Investigator (Signature) 
 
Date 

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Assessment Study Protocol 
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SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Name of Product: 
IQOS (Tobacco Heating System [THS] with Marlboro Heatsticks) 
Study Title: 
Assessment of passive environmental aerosol exposure through IQOS (Tobacco Heating 
System (THS) with Marlboro Heatsticks) in a restaurant setting where IQOS use, but not 
cigarette smoking, is allowed 
Study Number: 
P1-PES-01-JP 
Short Title: 
Real Life Passive Exposure Assessment of IQOS 
Registration number: 
NA 
Study Location: 
This single-site, restaurant-based study, will be conducted in Japan. 

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commercial information, and the legal protections provided to such trade secrets and confidential information 
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Primary Objectives and Endpoints: 
1) To estimate the mean change in levels of urinary biomarker of exposure (BoExp) to 
selected tobacco specific harmful and potentially harmful constituents (HPHC)s 
representative of environmental tobacco smoke (ETS) after passive exposure to IQOS in 
a planned restaurant event (‘Exposure Event’) where IQOS use, but not cigarette 
smoking, is allowed. Mean change in BoExp will be estimated for the  Passive Exposure 
Group and stratified by product use status.  
Co-primary Endpoints (measured before the start and in the last sample collected prior to the 
individual participants’ end of the Events): 
• Nicotine 
o BoExp to Nicotine: Nicotine equivalents (NEQ): molar sum of free nicotine, 
nicotine-glucuronide, free cotinine, cotinine-glucuronide, free trans-3’-
hydroxycotinine, 
trans-3’-hydroxycotinine-glucuronide 
in 
spot 
urine 
(expressed as concentration adjusted to creatinine) 
• Tobacco 
Specific 
Nitrosamines 
(TSNAs): 
4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanone (NNK) and N-nitrosonornicotine (NNN) 
o BoExp 
to 
Tobacco 
Specific 
Nitrosamines 
(TSNAs): 
Total 
4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL) and Total N-
nitrosonornicotine (Total NNN) in spot urine (expressed as concentration 
adjusted to creatinine) 
Secondary Objectives and Endpoints: 
1. To evaluate Indoor Air Quality (IAQ) through the assessment of concentrations of select 
HPHCs representative of ETS in the air of the participating restaurant where both the 
Non-Exposure and Exposure Events will occur. 
Endpoints (measured before the start and during the Event): 
• ISO measurement standards for ETS (ISO Norm 18144:2003)1 
o 3-Ethenylpyridine (3-EP) [µg/m3] 
o Nicotine [µg/m3] 
                                                 
1 ISO Norms related to ETS (15593:2001, 18145:2003 and 11454:1997) are out of scope for indoor air 
collection as combustion does not occur in THS. 

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• Carbonyls 
o Acetaldehyde [µg/m3] 
o Acrolein [µg/m3] 
o Crotonaldehyde [µg/m3] 
o Formaldehyde [µg/m3] 
• Tobacco Specific Nitrosamines 
o NNN [µg/m3] 
o NNK [µg/m3] 
•  Real-time measurements of PM1-PM10 suspended particles in air. 
 
2. To evaluate the levels of exposure to additional selected HPHCs representative of ETS 
during both the Non-Exposure Events and Exposure Events in the study participants. 
Endpoints (measured before the start and in the last sample collected prior to the individual 
participants’ end of the Non-Exposure Events): 
• Nicotine 
o BoExp to Nicotine: NEQ: molar sum of free nicotine, nicotine-glucuronide, free 
cotinine, cotinine-glucuronide, free trans-3’-hydroxycotinine, trans-3’-
hydroxycotinine-glucuronide in spot urine (expressed as concentration adjusted to 
creatinine) 
• TSNAs: NNK and NNN 
o BoExp to TSNAs: Total NNAL and Total NNN in spot urine (expressed as 
concentration adjusted to creatinine 
Endpoints (measured before the start and in the last sample collected prior to the individual 
participants’ end of the Non-Exposure and Exposure Events): 
• Carbonyls 
o BoExp to crotonaldehyde: 3-hydroxy-1-methylpropylmercapturic acid (HMPMA) 
(concentration adjusted for creatinine) 
o BoExp to Acrolein: 3-hydroxypropylmercapturic acid (3-HPMA) in spot urine 
(concentration adjusted for creatinine)  
• Volatile Organic Compounds 
o BoExp to Benzene: S-phenylmercapturic acid (S-PMA) (concentration adjusted 
for creatinine)   

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• Ethylene Oxide 
o BoExp to ethylene oxide: 2-hydroxyethyl mercapturic acid (HEMA) 
(concentration adjusted for creatinine) 
Study Hypothesis: 
There are no formal statistical hypotheses to be tested in this study. The research objective is 
to assess the level of BoExp to selected HPHCs representative of ETS in study participants 
after passive exposure to IQOS use in a restaurant setting where IQOS use, but not cigarette 
smoking, is allowed. 
Study Design: 
This study is a non-interventional observational study designed to assess the impact of 
environmental tobacco aerosol exposure in Non-Smokers exposed to IQOS in a real-life 
restaurant setting. Three types of participant with the following characteristics will be 
enrolled in this study: 1) Non-Smokers; 2) Cigarette Smokers and 3) IQOS Users.  IQOS 
Users will be assigned to either the Passive Exposure or Active Exposure Group (see below). 
There are three steps in the core study design:  
• Identification and consent of participants;  
• Non-Exposure dinner events (‘Non-Exposure Event’) of 4h duration for the 
individual participant, where no use of any tobacco or nicotine containing  product is 
allowed, designed to establish background measurements in the absence of exposure 
to IQOS;  
• Exposure dinner Events (‘Exposure Event’) with 4h of exposure for the individual 
participants in the Passive Exposure Group, designed to measure BoExp to selected 
HPHCs representative of ETS in all participants.  
A sufficient number of Non-Exposure Events and Exposure Events will be conducted 
depending on the size of the selected location and to ensure the following minimum number 
of participants in the respective groups: 
Non-Exposure Event:  
• Non-Exposed Group (no product use): a minimum of 169 participants comprised of 
Non-Smokers, IQOS-users not using IQOS or any other tobacco or nicotine- 
containing product, and cigarette (CC) smokers not using cigarettes or any other 
tobacco or nicotine-containing product for the duration of the Non-Exposure event; 
Exposure Event: 
• Passive Exposure Group (no product use): a minimum of 169 participants passively 
exposed comprised of Non-Smokers, IQOS-users not using IQOS or any other 

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commercial information, and the legal protections provided to such trade secrets and confidential information 
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without the written consent of Philip Morris Products S.A 
Participants may attend a maximum of one Non-Exposure Event and one Exposure Event. 
Once participant confirms participation in the study, they are considered enrolled. No data 
will be recorded in the Study Database for the potential participants that do not consent to 
participate in the study. After consenting to participate in the study, participants can 
withdraw from the study at any time, but all data already provided by them, with the 
exception of their contact details, will be retained in the Study Database and analyzed as per 
the analysis plan. The contact details including personal information and personal identifiers 
will be kept separate from the study data. 
Study Population and Main Criteria for Inclusion/Exclusion: 
Main Criteria for Inclusion: 
A sufficient number of female or male Japanese adult IQOS Users, CC smokers or Non-
Smokers to ensure the required number of participants meeting the following main inclusion 
criteria will be enrolled in the study: 
• Participant is able to understand the information provided in the Subject Information 
Sheet (SIS) and informed consent form (ICF) (confirmed by signing the ICF) and has 
signed the ICF.. 
• Adults legally authorized to buy tobacco products in Japan (20 years of age). 
• Participant is Japanese as self-reported. 
•  
• Willing to participate in the study, comply to study procedures and has access to the 
Internet. 
• Participant is an active IQOS User, or CC smoker, or Non-Smoker as self-reported by 
the participants and as defined in this protocol. 
Criteria for Exclusion: 
• Participant with a medical history of severe cardiovascular or respiratory diseases 
(e.g., stroke, acute cardiovascular event, or pulmonary thrombosis) in the last 12 
months as self-reported. 
• Participant with currently active cancer or history of cancer within the last 5 years as 
self-reported. 
• Female participant who is pregnant or breast-feeding as self-reported. 
• Participant, or their first-degree relatives (parent or child), is a current or former 
employee of the tobacco industry. 

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commercial information, and the legal protections provided to such trade secrets and confidential information 
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• Participant, or their first-degree relatives (parent or child), is an employee of PMI, 
 vendors, the restaurant or the event location. 
Specific to participants who are Non-Smokers: 
• Participant lives in a household with users of tobacco or nicotine-containing products, 
or is exposed to the use of tobacco or nicotine-containing products at the workplace. 
Investigational Products, Dose, and Mode of Administration: 
The product tested in this study is the Tobacco Heating System (THS) with Marlboro 
Heatsticks, marketed in Japan under the brand name IQOS and referred to as IQOS in this 
protocol. All versions of IQOS and Marlboro Heatsticks that have been available for sale in 
Japan prior or at the time of study start or becoming available during the course of the study 
are allowed to be used in this study. 
Test product: IQOS. Participants in the Active Exposure Group (IQOS use) will be asked to 
bring their own IQOS device and HeatSticks for their own use during the entire study period 
as HeatSticks will not be provided by the Sponsor. Participants in the Active Exposure Group 
will use IQOS ad libitum with no HeatSticks variants restrictions.  
Duration of Study: 
The maximum duration of passive exposure in the Passive Exposure Group will be 
approximately 4h not exceeding 5h). The maximum duration of Active IQOS use by 
participants in the Active Exposure Group will be up to 8h (±15 min). Each participant can 
participate in a maximum of one Non-Exposure Event and a maximum of one Exposure 
Event. 
The overall duration of the study is currently planned for 6 weeks, but might be extended 
based on the number of events needed to secure the necessary number of participants.  
End of Study for a participant is defined as the end of the Non-Exposure Event or the last 
Exposure Event they participated in. The overall End of the Study is defined as the end of the 
last Exposure Event. 
Indoor Air Quality Measurements: 
For Non-Exposure Events, IAQ measurements will be performed at the Event location for up 
to 3h prior to the start of the Event and for 3h after the last participant has entered the Event 
for 1h. For Exposure Events, IAQ measurements will be performed at the Event location for 
up to 3h prior to start of the Exposure and for 3h after the last participant has been exposed 
for 1h to quantify and differentiate background exposure and to assess the impact of IQOS 
use on IAQ. Study samples will be collected at each Event (Non-Exposure and each 

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Exposure Event) at the Event location.  
To collect IAQ samples, three mobile sampling set-ups for indoor air pollutants will be used. 
The set-up consists of 3 aluminum sampling cases with 5 flow-controlled pumps. Each 
sampling case is equipped with: 
• 2 х AD-4 traps for Nicotine and 3-EP collection operated at a flow rate of 1.0 L/min 
for 3h; 
• 2 x 1 DNPH-silica traps for carbonyl collection (acetaldehyde, acrolein, 
crotonaldehyde and formaldehyde) operated at a flow rate of 1.2 L/min sequentially 
for 1h; 
• 2 glass fiber filters (Cambridge filters) spiked with ascorbic acid for TSNAs (NNN, 
NNK), operated at a flow rate of 1.0 L/min for 3 h. 
The position of the sampling cases will be inside the breathing zone as described by 
ASHRAE.2 
Additionally, two small instruments in front of the sampling cases will electronically record 
the ambient temperature and relative humidity. Furthermore, two portable instruments, used 
for on-line PM1-PM10 particle measurements will be used. The equipment are the property 
of PMI and will be used by a PMI trained scientist according to the ISO accredited method 
PMI-RRP-WKI-111642 “Dust Trax characterization for real time monitoring of aerosol mass 
concentration”. 
A total of 18 tubes per Event will be collected which will be analyzed using validated 
analytical methods at Analytisch-biologisches Forschungslabor [ABF] Munich.  
 
Statistical Methods:  
The Compliant Exposure Set will consist of all enrolled participants who have signed the 
ICF, have participated in either a Non-Exposure Event or an Exposure Event, have provided 
two urine samples (at minimum, one urine sample prior to the start of the event and one urine 
sample after a minimum of 2h of individual participation in the Non-Exposure or Exposure 
Event), and are compliant with the Event Groups (Non-Exposure vs. Passive Exposure vs. 
                                                 
2 ASHRAE, 2016. ANSI/ASHRAE Standard 62.1-2016. Ventilation for acceptable indoor air quality. Atlanta, 
GA: American Society of Heating, Refrigerating and Air-Conditioning Engineers. 
 

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commercial information, and the legal protections provided to such trade secrets and confidential information 
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Active Exposure).  
The Active Exposure Set (PP) will consist of all enrolled participants who have signed the 
ICF, have participated in an Exposure Event, have provided two urine samples (at minimum, 
one urine sample prior to the start of the Event and one urine sample after a minimum of 2h 
after the start of the Active Exposure), and were in the Active Exposure Group. 
Descriptive statistics for continuous variables will include the number of participants, 
number and percent of participants with missing data, the mean and standard deviation, 
geometric means and coefficient of variation (CV) median, first and third quartiles, minimum 
and maximum, and 95% confidence interval (CI) for each product exposure, and summary 
across all participants. In addition, the results may be presented as a stratified summary as 
defined in the Statistical Analysis Plan (SAP). 
Analysis of the Primary Endpoint: 
The primary endpoints will be the pre-event urinary BoExp and latest post two hour urinary 
BoExp observation. A linear mixed effects model with event type, IAQ, duration of exposure 
(time between pre-event collection and last post exposure collection), product use status and 
product use status and event type interaction will be modelled as fixed effects with a random 
subject effect. Other covariates or interactions terms may be added as needed. Appropriate 
contrasts will be constructed to determine the effect of passive exposure to IQOS aerosol 
during the Exposure Event on the mean change in levels of urinary BoExp to selected 
tobacco specific HPHCs together with the 95% confidence intervals (CIs). Other contrasts 
can be constructed to determine the change in urinary BoExp for subjects with other smoking 
status after passive exposure to IQOS usage.  
Analysis of the Secondary Objectives:  
A similar statistical model as described in the analysis of the primary endpoint will be used to 
evaluate the levels of exposure to additional selected HPHCs representative of ETS during 
both the Non-Exposure Events and Exposure Events in the study population. The results will 
also be looked at stratified by incoming smoking status. 
Additional analysis may be defined in the SAP and performed and reported in the 
Assessment Study Report. 

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Analysis of the Active Exposure Group: 
The primary endpoints will look at the change between the pre-event urinary BoExp and 
latest post two-hour urinary BoExp observation. A linear mixed effects model with IAQ, 
duration of exposure (time between pre-event collection and last post exposure collection) 
and number of sticks used during the event, will be modelled as fixed effects with a random 
subject effect. Other covariates or interaction terms may be added as needed. Appropriate 
contrasts will be constructed to determine the effect of active exposure to IQOS usage during 
the Exposure Event on the mean change in levels of urinary BoExp to selected tobacco 
specific HPHCs together with the 95% confidence intervals (CIs). 
Data processing and analysis of IAQ samples: 
The IAQ data will be processed at ABF and the individual results per compound will be 
summarized and tabulated. 
An analysis of variance (ANOVA) design will be applied as the quantitative results of the 
IAQ sessions will be compared per compound. The mean, standard deviation, relative 
standard deviation, minimum and maximum will be computed per compound and the number 
of observations will be indicated. A significance level set at 0.05 will be used to determine 
equality between sessions.  
Sample Size: 
The sample size of approximately 169 participants in the Exposure and Non-Exposure Events 
each is based on the expected exposure of a Non-Smoker when exposed to cigarette smoke as 
documented in the literature. Variability of exposure levels and method variability were 
furthermore considered to estimate the sample size needed. 
Adverse Events and Participants Safety and Well-Being: 
As this study is observational by design and is conducted in a post-market setting, adverse 
event (AE) reporting will follow the Sponsor’s already established post-market Safety 
Surveillance Procedures for spontaneously-reported events. All study personnel and study 
participants will be reminded of the product quality complaints (including AEs) hotline that 
has been established for all users of IQOS in Japan.  
In the event that a medical event occurs in any of the study participants the study staff will be 
advised to call local emergency number to ensure appropriate medical treatment. The related 
cost for emergency treatment and transportation will be borne by the Sponsor.  
Security personnel will be on site at the event location to ensure secure and ordered conduct 
at the event. 
 

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without the written consent of Philip Morris Products S.A 
TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................4 
TABLE OF CONTENTS .........................................................................................................14 
1 
ETHICS AND REGULATIONS .....................................................................................21 
1.1 
Independent Ethics Committee (IEC) / Institutional Review Board (IRB) 
Approval ..............................................................................................................21 
1.2 
Ethical Conduct of the Study .................................................................................21 
1.3 
Subject Information and Consent...........................................................................22 
1.3.1 Informed Consent Form for Study Participation .........................................22 
1.3.2 Amendment to the Informed Consent Form ................................................22 
1.4 
Good Epidemiological Practice .............................................................................22 
1.5 
Risk Minimization .................................................................................................23 
2 
INTRODUCTION ...........................................................................................................23 
2.1 
Background ............................................................................................................23 
2.1.1 Smoking-Related Diseases and Harm Reduction Strategy ..........................23 
2.2 
Purpose of the Study ..............................................................................................25 
2.3 
Anticipated Benefits and Risks ..............................................................................25 
2.3.1 Anticipated Benefits .....................................................................................25 
2.3.2 Anticipated Foreseeable Risks due to Study Procedures .............................26 
2.3.3 Unforeseeable Risks.....................................................................................26 
3 
STUDY OBJECTIVES ....................................................................................................26 
3.1 
Primary Objective and Endpoints ..........................................................................26 
3.2 
Secondary Objectives and Endpoints .....................................................................27 
4 
INVESTIGATIONAL PLAN ..........................................................................................28 
4.1 
Overall Study Design and Plan ..............................................................................28 
4.1.1 Step 1: Identification of Participants and Informed Consent: Screening 
and Enrollment .......................................................................................32 
4.1.2 Step 2: Non-Exposure Events ......................................................................32 
4.1.3 Step 3: Exposure Events ..............................................................................33 
4.2 
Rationale for Study Design ....................................................................................34 
4.3 
Appropriateness of Measurements .........................................................................34 
4.4 
Study Duration .......................................................................................................35 
5 
STUDY POPULATION ..................................................................................................35 
5.1 
Selection of Study Population ................................................................................36 
5.1.1 Inclusion Criteria .........................................................................................36 
5.1.2 Exclusion Criteria ........................................................................................37 
5.2 
Discontinuation of Subjects from the Study ..........................................................38 
5.3 
Lost to Follow-up ...................................................................................................39 
5.4 
Violation of Selection Criteria ...............................................................................39 

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6 
INVESTIGATIONAL PRODUCTS ...............................................................................39 
6.1 
Description of Investigational Products .................................................................39 
6.2 
Use of Investigational Product(s) ...........................................................................40 
6.2.1 From Screening to Event Participation ........................................................41 
6.2.2 Non-Exposure Event ....................................................................................41 
6.2.3 Exposure Event ............................................................................................41 
6.2.4 In-between Event Participation ....................................................................41 
6.3 
Method for Assigning Subjects to Study Groups ..................................................41 
6.4 
Blinding..................................................................................................................41 
6.5 
Investigational Product Accountability and Compliance ......................................42 
6.5.1 Dispensing Investigational Product .............................................................42 
6.5.2 Adherence to allocated Exposure .................................................................42 
6.6 
Restrictions ............................................................................................................42 
6.6.1 General Restrictions .....................................................................................42 
6.6.2 Dietary Restrictions .....................................................................................42 
6.6.3 Product Use Restrictions ..............................................................................42 
7 
STUDY PROCEDURES .................................................................................................43 
7.1 
Informed Consent...................................................................................................43 
7.2 
Debriefing on IQOS ...............................................................................................43 
7.3 
Main Assessments ..................................................................................................43 
7.3.1 Questionnaires ..............................................................................................43 
7.3.2 Demographics ..............................................................................................43 
7.3.3 Self-reported tobacco and nicotine-containing product use .........................43 
7.3.4 Self-Reported Health Outcomes and Events Questionnaire ........................44 
7.3.5 Recording of IQOS Use ...............................................................................44 
7.3.6 Recording of Food and Alcohol Consumption ............................................44 
7.3.7 Biomarker of Exposure Assessment in Urine ..............................................44 
7.3.8 Assessment of Indoor Air Quality ...............................................................44 
7.4 
Sample Handling, Storage, and Shipment .............................................................46 
8 
ADVERSE EVENTS, PARTICIPANTS SAFETY AND WELL-BEING .....................47 
9 
STUDY ACTIVITIES .....................................................................................................47 
9.1 
Screening and Enrollment ......................................................................................47 
9.2 
Recruitment Period ................................................................................................48 
9.3 
Study Period ...........................................................................................................48 
10 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................52 
10.1 Monitoring .............................................................................................................52 
10.2 Training of Collaborators .......................................................................................52 
10.3 Audits and Inspections ...........................................................................................52 
11 DATA MANAGEMENT ACTIVITIES..........................................................................52 
11.1 Data Capture ..........................................................................................................53 
11.1.1 Data Capturing Tool, Case Report Forms and Study Records ....................53 

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are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
11.1.2 Protocol Deviations ......................................................................................53 
11.2 Data Handling ........................................................................................................54 
11.2.1 Data Verification ..........................................................................................54 
11.2.2 Database Lock ..............................................................................................54 
12 PLANNED STATISTICAL METHODS ........................................................................55 
12.1 General Considerations ..........................................................................................55 
12.1.1 Stratification Criteria ...................................................................................55 
12.1.2 Definitions for Statistical Data Analysis ......................................................55 
12.1.3 Descriptive Statistics ....................................................................................56 
12.1.4 Handling of Missing Values and of Values outside the Detection Limits ...56 
12.1.5 Significance Level for Inferential Analysis .................................................56 
12.2 Determination of Sample Size  ..............................................................................56 
12.3 Analysis Populations ..............................................................................................57 
12.3.1 Compliant Exposure Set ..............................................................................57 
12.3.2 Active Exposure Set .....................................................................................57 
12.4 Primary Analysis ....................................................................................................57 
12.5 Secondary Analysis ................................................................................................57 
12.5.1 Analysis of the Active Exposure Group ......................................................58 
13 ADMINISTRATIVE CONSIDERATIONS ....................................................................59 
13.1 Principal Investigator’s and Study Administrative Structure ................................59 
13.1.1 Principal Investigator ...................................................................................59 
13.1.2 Sponsor ........................................................................................................59 
13.1.3 Other Responsibilities ..................................................................................60 
13.2 Participant Confidentiality .....................................................................................60 
13.3 Access to Source Documentation ..........................................................................61 
13.4 Record Retention ...................................................................................................61 
13.5 Assessment Study Report ......................................................................................63 
13.6 Financial Disclosure ...............................................................................................63 
13.7 Publication and Disclosure Policy .........................................................................63 
13.8 Insurance ................................................................................................................63 
14 REFERENCES ................................................................................................................64 
 
 
 

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LIST OF IN-TEXT TABLES 
Table 1  
Relative Exposure/participants groups, measures and sample sizes, 
according to event type (Non-exposure vs Exposure) ...............................31 
Table 2  
Definition of an IQOS User, Cigarette User or Non-Smoker ....................37 
Table 3 
Test Product (IQOS) ..................................................................................40 
Table 4  
Constituents selected, technology and trap used for indoor air 
collection ....................................................................................................46 
Table 5 
List of samples generated for the main study. ...........................................46 
Table 6 
Schedule – Screening and Enrollment .......................................................48 
Table 7 
Schedule – Non – Exposure Event .............................................................49 
Table 8 
Schedule – Exposure Event .......................................................................50 
Table 9  
Definition of an IQOS User, Cigarette User or Non-Smoker ....................55 
 
LIST OF IN-TEXT FIGURES 
Figure 1 - Study Design .......................................................................................................8 
Figure 2 - Study Design .....................................................................................................30 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Events .....................................................................................68 
Appendix B 
List of Participating Laboratories ..............................................................70 
 
 

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ABBREVIATIONS AND DEFINITION OF TERMS 
 
3-HPMA 
3-hydroxypropylmercapturic acid 
AE 
Adverse Events  
ANOVA 
Analysis of Variance 
BKG 
Background 
BoExp 
Biomarker of Exposure 
CASI 
Computer Assisted Self Interview 
CC 
Cigarette  
CI 
Confidence Interval 
CRF 
Case Report Form 
CVD 
Cardiovascular Disease 
DMP 
Data Management Plan 
DNHP 
2,4-Dinitrophenylhydrazine 
EA 
Environmental Aerosol 
ETS 
Environmental Tobacco Smoke 
GC-MS 
Gas chromatography–mass spectrometry 
GEP 
Good Epidemiological Practice 
HEMA 
2-hydroxyethyl mercapturic acid 
HMPMA 
3-hydroxy-1-methylpropylmercapturic acid 
HPHC(s) 
Harmful and Potentially Harmful Constituent(s)  
IAQ 
Indoor Air Quality 
ICF 
Informed Consent Form  
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
LC-MS/MS  
Liquid chromatography-tandem mass spectrometry 
NEQ 
Nicotine Equivalents 

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NNK 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone  
NNN 
N-nitrosonornicotine 
PMI 
Philip Morris International 
PMP 
Philip Morris Products S.A. 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
S-PMA 
S-phenylmercapturic acid 
Total NNAL 
Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
Total NNN 
Total N-nitrosonornicotine 
THS 
Tobacco Heating System 
WHO 
World Health Organization 
 

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Explanation of Terms 
The following special terms are used in this protocol:  
Cigarette  
The term ‘cigarette’ refers to commercially available cigarettes 
(manufactured) and excludes IQOS with HeatSticks, cigars, cigarillos, e-
cigarettes, hand-rolled cigarettes, pipes, hookah, bidis, and other tobacco- 
or nicotine-containing products. 
End of study 
 
The end of the study for an individual participants will be defined as the 
end of the Non-Exposure Event or the last Exposure Event he/she 
participated in. The end of the entire study is defined as the end of the last 
participant’s individual end of the study/the end of the last Exposure 
Event. 
HeatSticks 
Marlboro HeatSticks are designed to be used with IQOS only. Each 
HeatStick is composed of: tobacco plug; hollow acetate tube; polymer-
film filter; mouth piece filter; outer and mouth-end papers. 
IQOS 
Unless otherwise specified, IQOS in this document refers to PMI’s 
Tobacco Heating System (THS) with Marlboro HeatSticks as available 
for purchase in the Japanese market. No other tobacco sticks should be 
used with the IQOS device. 
IQOS User 
(IQOS) 
 
• Used at least 100 HeatSticks 
• Uses IQOS daily > 1/day 
• Uses a cigarette less than daily 
• Uses less than 30 cigarettes/month 
• IQOS is > 95% of product use (all tobacco/nicotine product use) – 
excluding other products (e-cig/Ploom/etc.) 
Cigarette 
Smoker (CC) 
• Used at least 100 cigarettes 
• Uses cigarettes daily > 1/day 
• Uses IQOS less than daily 
• Uses less than 30 HeatSticks/month 
• Cigarette is > 95% of product use (all tobacco/nicotine product use) 
Non-Smoker 
(NS) 
• Abstinent for at least 12 months from the use of any nicotine and/or 
tobacco-containing product based on self-reporting. 
• Must not be exposed to cigarette smoke or IQOS use in any other 
substantial way (family, partner, other, or workplace). 

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1 
ETHICS AND REGULATIONS 
1.1 
Independent Ethics Committee (IEC) / Institutional Review Board 
(IRB) Approval 
Prior to the start of the study, the study protocol, together with its associated documents 
(informed consent forms [ICF] which include the participant information sheet and informed 
consent, participant recruitment procedures, written information to be provided to the 
participants, and any other documents requested by the Independent Ethics Board 
[IEC]/Institutional Review Board [IRB]), will be submitted for review and approval to the 
relevant IEC/IRB. The IEC/IRB shall be appropriately constituted in accordance with the 
International Epidemiological Association (IEA) Guidance for Good Epidemiological 
Practice (GEP)  [1] and the Ethical Guidelines for Medical and Health Research Involving 
Human Subjects [2]. 
A written confirmation of the IEC/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 IEC/IRB, with dates and version numbers, as well 
as the date of approval. The composition of the IEC/IRB, including the name and occupation 
of the chairperson, should be supplied to the Sponsor. 
The written approval from the IEC/IRB 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 IEC/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 IEC/IRB, and substantial amendments will only be implemented after 
approval by the IEC/IRB. 
These requirements for approval should in no way prevent any action from being taken by 
the Sponsor in order to eliminate immediate hazards to the participants. If such a change to 
the protocol is felt to be necessary by the Principal Investigator, and is implemented for 
safety reasons, the Sponsor and the IRB should be informed immediately. 
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 2013 [3] and are consistent with GEP [1], and the Ethical Guidelines 
for Medical and Health Research Involving Human Subjects [2]. The Principal Investigator 
agrees to conduct the study in compliance with the protocol agreed upon with the Sponsor 
and approved by the IEC/IRB. The Principal Investigator and the Sponsor must sign the 

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protocol (and protocol amendments, if applicable) to confirm this agreement. A copy of the 
declaration of Helsinki should be located in the Principal Investigator study file. 
1.3 
Subject Information and Consent 
1.3.1 Informed Consent Form for Study Participation 
Before the “screening domain” is administered, the participant will be informed about the 
nature and purpose of the study via the Study Website. Participants interested in participating 
in the study initiate the informed consent process by clicking on the link from the Study 
Website that will re-direct them to a Computer-Assisted Self-Interview (CASI) to assess 
eligibility, register for the study, and give informed consent. The ICF will be administered 
electronically for participants and will be recorded in the Study Database. Participants will be 
informed that they are free to discontinue their participation at any time. 
No data will be recorded in the Study Database for the potential participants that do not 
consent to participate in the study. Participants will be informed that after consenting for 
participation in the study, they can withdraw from the study at any time, but that all data 
already provided by the participant with the exception of their contact details, and all samples 
collected from the participant until the time of withdrawal will be retained in the database 
and/or analyzed as per the analysis plan. The contact details including personal information 
and personal identifiers will be kept separate from the study data. They will also be informed 
and will be asked to provide their consent for any additional data analyses not mentioned in 
the protocol or the Statistical Analysis Plan (SAP) that may be performed with the collected 
data at a later time. Any additional analysis performed will be covered by data 
confidentiality, as for the main analysis described in this protocol. 
1.3.2 Amendment to the Informed Consent Form 
If a protocol amendment is required, an amendment may be required to one or more of the 
ICFs. If revision of the ICF is necessary, the Principal Investigator will, with the support of 
the Sponsor, ensure that the documents have been reviewed and approved by a relevant 
IEC/IRB before participants are required to re-sign the ICF. 
1.4 
Good Epidemiological Practice 
The procedures set out in this observational study protocol pertaining to the conduct, 
evaluation, and documentation of this study are designed to ensure that the Sponsor, its 
authorized representative, and the Principal Investigator abides by the principles of the 
guidelines on GEP [1]. These guidelines apply specifically to epidemiological studies and 
therefore provide a robust and ethical framework for conducting observational studies. In 

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addition, the Principal Investigator will carry out the study in accordance with the Ethical 
Guidelines for Medical and Health Research Involving Human Subjects [2][. 
1.5 
Risk Minimization 
There are no anticipated specific risks from participating in this observational study as the 
study is conducted to reflect a real-life setting utilizing an existing IQOS-only restaurant in 
Japan. Study participation is by invitation only. 
2 
INTRODUCTION 
2.1 
Background 
2.1.1 Smoking-Related Diseases and Harm Reduction Strategy 
Public health authorities, including the World Health Organization (WHO), have concluded 
that exposure to Environmental Tobacco Smoke (ETS), also named secondhand smoke, 
which is a mixture of sidestream smoke (tobacco smoke which is emitted from the lit end of 
a cigarette or cigar) and exhaled smoke, causes heart disease, cancer, as well as respiratory 
disease and other conditions. The U.S. Environmental Protection Agency, the U.S. National 
Toxicology Program, the U.S. Surgeon General, and the International Agency for Research 
on Cancer have all classified ETS as carcinogenic [4-8].  
For cardiovascular disease (CVD), it is estimated that ETS increases the risk of heart disease 
by ~30%, accounting for at least 35,000 deaths annually in the United States [9]. Six meta-
analyses have been published summarizing data reported over the last 30 years [10-15] 
yielding relative risks of heart disease from ETS exposure ranging between 1.2 and 1.3. In 
2004, Whincup et al published a 20-year prospective study of ETS exposure and coronary 
heart disease that estimated that the risk associated with ETS exposure was between 1.45 
(95% CI, 1.10 to 2.08) and 1.57 (95% CI, 1.08 to 2.28), depending on the level of ETS 
exposure [16]. 
A literature review and meta-analysis to systematically evaluate the association between ETS 
and lung cancer in Japan identified four cohort studies and five case-control studies on which 
a quantitative synthesis was conducted only for ETS exposure in the home during adulthood. 
The pooled relative risk of lung cancer associated with secondhand smoke exposure was 1.28 
(95% confidence interval: 1.10-1.48). The authors concluded that ETS exposure in the home 
during adulthood results in a statistically significant increase in the risk of lung cancer [17]. 
These results are in line with the estimate of the U.S. Surgeon General who estimates that 
ETS increases a nonsmoker’s chances of developing lung cancer by 20 to 30 percent [11] . 
Philip Morris International (PMI) develops, assesses and commercializes a portfolio of 
innovative products that have the potential to reduce the risk of smoking-related diseases in 

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comparison to smoking cigarettes. The objective is to develop products that (1) significantly 
reduce the risk of smoking-related disease compared to continued smoking of cigarettes and 
(2) are accepted by smokers as substitutes for cigarettes.  
One of these novel products is the Tobacco Heating System (THS) which is commercialized 
in Japan since November 2014 under the brand name IQOS and uses tobacco sticks called 
HeatSticks (sold in Japan as Marlboro Heatsticks). IQOS heats the tobacco instead of 
burning it and the temperature is maintained below 350°C, a temperature much lower than 
what is observed for cigarettes, which can reach 900°C.  More than 6000 smoke constituents 
have been identified when the tobacco is burned or combusted [18], and more than 100 of 
them have been categorized as harmful and potentially harmful constituents (HPHCs) [19]. 
By heating the tobacco instead of burning it, an aerosol is produced that is not the product of 
combustion and therefore many of the chemical reactions associated with combustion do not 
take place. As a result IQOS produces an aerosol with significantly lower levels of HPHCs 
than cigarette smoke, which is the key to THS’s potential to reduce the risk of smoking-
related disease as HPHCs are formed primarily through combustion and pyrolysis in 
cigarettes.  
IQOS is composed of the Tobacco Stick Holder and a Charger which recharges the Holder 
after each use. IQOS was designed to be used with dedicated Tobacco Sticks, the HeatSticks.  
Various pre-clinical and clinical studies have been conducted and in summary, the scientific 
evidence available to date has shown that: 
1. The aerosol of IQOS contains on average 90 to 95% lower levels of HPHCs 
compared to the smoke from a standard reference cigarette [20]. 
2. The aerosol of IQOS is on average 90% less toxic compared to the smoke of a 
standard reference cigarette (cytotoxicity, bacterial, and mammalian mutagenicity) 
[21]. 
3. In animal models, continuous inhalation and exposure to IQOS aerosol, even at a 
multiple of the aerosol concentration, resulted in a dramatically lower systemic 
toxicity, extensively reduced lung inflammation and histopathological changes in the 
nasal epithelium as well as lung tissue [22]. Furthermore, in an Apoe-/- mouse model, 
exposure to IQOS aerosol does not enhance cardiovascular disease or emphysema, 
when compared to cigarette smoke, and switching from cigarette smoke to IQOS 
aerosol exposure results in a reversal of the aortic plaque growth in a similar manner 
as Smoking Cessation (SC) [22]. 
4. PK studies demonstrated comparable nicotine exposure in subjects using IQOS as in 
subjects using cigarettes [23-26] 
5. The exposure reduction to selected HPHCs in current adult smokers switching to 
IQOS is scientifically substantiated compared to cigarette smoking and is close to 

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what is observed in adult smokers who stop smoking for the duration of our clinical 
studies [27-31]. 
6. Improvements of cardiovascular and other clinical risk endpoints have been observed 
in healthy adult smokers who switched to IQOS, similarly to what has been observed 
in smoking abstinence over a period of up to 3 months [29-31].  
7. No safety signals have been detected indicating any new or increased risks of health 
issues in smokers switching from smoking cigarettes to IQOS. 
8. As indicated in markets where IQOS is now available, IQOS has been accepted by 
smokers (with over 3 million adult users to-date) and appears to be an acceptable 
substitute for current adult smokers with various smoking habits and patterns. 
An IAQ study conducted showed that, out of 23 analytes assessed, only 2 HPHCs, namely 
nicotine and acetaldehyde, as well as glycerin were detectable in air following the use of 
IOQS but at levels that were much lower than the thresholds defined in existing air quality 
guidelines. These results indicated that IQOS is not a source of ETS.  The study therefore 
showed that, based on existing indoor air quality guidelines, there is no impact on the overall 
Indoor Air Quality (IAQ) when using IQOS in an indoor environment [32, 33]. 
2.2 
Purpose of the Study 
The purpose of the study is to show that Non-Smokers exposed to IQOS in a restaurant 
setting (i.e., through planned dinner “Events”) do not have higher urinary levels of 
Biomarkers of Exposure (BoExp) to selected HPHCs representative of ETS compared to the 
urinary levels of BoExp to selected HPHCs representative of ETS caused by background 
exposure in Non-Smokers before IQOS exposure. Furthermore the impact of passive IQOS 
exposure on IQOS Users and Cigarette Smokers not using any nicotine or tobacco containing 
nicotine product will be investigated. The addition of IQOS Users who don’t use IQOS, and 
Cigarette Smokers who don’t use any nicotine or tobacco products, allows for of the 
assessment of individuals with varying levels of exposure to HPHCs in their personal lives, 
in order to assess whether there is any measurable additive exposure from IQOS. Relatedly, 
the study will also evaluate IAQ through the assessment of concentrations of selected HPHCs 
representative of tobacco-specific and IAQ markers in the air during the Event. 
2.3 
Anticipated Benefits and Risks 
2.3.1 Anticipated Benefits 
There are no major benefits from participating in this study for the overall study population 
other than to collaborate in the understanding of how the use of IQOS affects by-standers in a 
real-life setting. 

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2.3.2  Anticipated Foreseeable Risks due to Study Procedures 
There are no anticipated risks from participating in this study. The study is conducted in a 
real-life setting in an IQOS-only restaurant in Japan where participation of study participants 
is by invitation-only. 
2.3.3 Unforeseeable Risks 
It is unlikely that any unforeseeable risks will occur from participating in this observational 
study. However, the possibility of unforeseeable events/risks will be explained when 
information about the study is provided. Non-expected malfunction of IQOS may lead to 
unforeseeable risks. Participants will be informed that IQOS is not demonstrated yet to be less 
harmful than cigarettes. Mitigation will include close monitoring to detect any unforeseeable 
risks at the earliest time possible. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective and Endpoints 
The primary objective of this study is: 
1) To estimate the mean change in levels of urinary biomarker of exposure (BoExp) to 
selected tobacco specific harmful and potentially harmful constituents (HPHC)s 
representative of environmental tobacco smoke (ETS) after passive exposure to IQOS in 
a planned restaurant event (‘Exposure Event’) where IQOS use, but not cigarette 
smoking, is allowed. Mean change in BoExp will be estimated for the Passive Exposure 
Group and stratified by product use status.  
 
Co-primary Endpoints (measured before the start and in the last sample collected prior to 
the individual participants’ end of the Events): 
• Nicotine 
o BoExp to Nicotine: Nicotine equivalents (NEQ): molar sum of free nicotine, 
nicotine-glucuronide, free cotinine, cotinine-glucuronide, free trans-3’-
hydroxycotinine, 
trans-3’-hydroxycotinine-glucuronide 
in 
spot 
urine 
(expressed as concentration adjusted to creatinine) 
• Tobacco Specific Nitrosamines (TSNAs): 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanone (NNK) and N-nitrosonornicotine (NNN) 
o BoExp 
to 
Tobacco 
Specific 
Nitrosamines 
(TSNAs): 
Total 
4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL) and Total N-

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nitrosonornicotine (Total NNN) in spot urine (expressed as concentration 
adjusted to creatinine) 
3.2 
Secondary Objectives and Endpoints 
Secondary objectives of this study are:  
1. To evaluate IAQ through the assessment of concentrations of select HPHCs 
representative of ETS in the air of the participating restaurant where both the Non-
exposure and Exposure Events will occur. 
Endpoints (measured before the start and during the Event): 
• International Organization for Standardization (ISO) measurement standards for ETS 
(ISO Norm 18144:2003)3 
o 3-Ethenylpyridine (3-EP) [µg/m3] 
o Nicotine [µg/m3] 
• Carbonyls 
o Acetaldehyde [µg/m3] 
o Acrolein [µg/m3] 
o Crotonaldehyde [µg/m3] 
o Formaldehyde [µg/m3] 
• Tobacco Specific Nitrosamines 
o N-nitrosonornicotine (NNN) [µg/m3] 
o 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) [µg/m3] 
•  Real-time measurements of PM1-PM10 suspended particles in air. 
 
2. To evaluate the levels of exposure to additional selected HPHCs representative of ETS 
during both the Non-Exposure Events and Exposure Events in the study participants. 
Endpoints (measured before the start and in the last sample collected prior to the individual 
participants’ end of the Non-Exposure Events): 
• Nicotine 
                                                 
3 ISO Norms related to ETS (15593:2001, 18145:2003 and 11454:1997) are out of scope for indoor air 
collection as combustion does not occur in THS. 

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o BoExp to Nicotine: NEQ: molar sum of free nicotine, nicotine-glucuronide, free 
cotinine, 
cotinine-glucuronide, 
free 
trans-3’-hydroxycotinine, 
trans-3’-
hydroxycotinine-glucuronide in spot urine (expressed as concentration adjusted to 
creatinine) 
• TSNAs: NNK and NNN 
o BoExp to TSNAs: Total NNAL and Total NNN in spot urine (expressed as 
concentration adjusted to creatinine 
Endpoints (measured before the start and in the last sample collected prior to the individual 
participants’ end of the Non-Exposure and Exposure Events): 
• Carbonyls 
o BoExp to crotonaldehyde: 3-hydroxy-1-methylpropylmercapturic acid (HMPMA) 
(concentration adjusted for creatinine) 
o BoExp to Acrolein: 3-hydroxypropylmercapturic acid (3-HPMA) in spot urine 
(concentration adjusted for creatinine)  
• Volatile Organic Compounds 
o BoExp to Benzene: S-phenylmercapturic acid (S-PMA) (concentration adjusted 
for creatinine)   
• Ethylene Oxide 
o BoExp to 
ethylene oxide: 
2-hydroxyethyl 
mercapturic acid 
(HEMA) 
(concentration adjusted for creatinine) 
 
  
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This study is a non-interventional observational study designed to assess the impact of 
environmental tobacco aerosol exposure in Non-Smokers exposed to IQOS in a real-life 
restaurant setting (henceforth referred to as the ‘Event’). Three types of participant with the 
following characteristics will be enrolled in this study: 1) Non-Smokers; 2) Cigarette 
Smokers and 3) IQOS Users. IQOS Users will be assigned to either the Passive Exposure 
Group (not using IQOS during the Exposure Events) or Active Exposure Group (using IQOS 
during the Exposure Events - see below). 
 There are three steps in the core study design:  

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1. 
Identification and consent of participants;  
2. 
Non-Exposure dinner events (‘Non-Exposure Event’) of 4h duration for the 
individual participant where no use of any tobacco or nicotine-containing product 
is allowed, designed to establish background measurements in the absence of 
exposure to IQOS;  
3. 
Exposure dinner Events (‘Exposure Event’) with 4h of exposure for the individual 
participants in the Passive Exposure Group, designed to measure BoExp to 
selected HPHCs representative of ETS in all participant groups.   
A sufficient number of Non-Exposure Events and Exposure Events will be conducted 
depending on the size of the selected location and to ensure the following minimum number 
of participants in the respective groups:  
Non-Exposure Event: 
• Non-Exposed Group (no product use): a minimum of 169 participants comprised of 
Non-Smokers, IQOS-users not using IQOS or any other tobacco or nicotine-
containing product and CC smokers not using the cigarettes or any other tobacco or 
nicotine-containing product for the duration of the Non-Exposure Event; 
Exposure Event: 
• Passive Exposure Group (no product use): a minimum of 169 participants passively 
exposed comprised of Non-Smokers, IQOS-users not using IQOS or any other 
tobacco or nicotine-containing product and CC smokers not using the cigarettes or 
any other tobacco or nicotine-containing product for the duration of the Exposure 
Event; 
• Active Exposure Group (IQOS Use): 20% ± 5% of the available seats at the Event 
location of current IQOS Users using IQOS for the duration of the Exposure Event. 
If necessary, additional Non-Exposure and Exposure Events might be conducted to achieve 
the necessary number of participants.  
 

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Table 1  
Relative Exposure/participants groups, measures and sample 
sizes, according to event type (Non-exposure vs Exposure) 
Variable 
Non-Exposure Event 
 
Exposure Event 
 
Participants (group sizes can vary by ± 5%) 
 
 
Sample Size required for Non-Exposure 
and Passive Exposure Group 
N = 169 
N = 169 
• Group 1: Non-Smokers 
50% 
50% 
• Group 2: Cigarette Smokers  
25%
1
 
25%
1
 
• Group 3a: IQOS Users (not using IQOS) 
25%
1
 
25%
1
 
Total 
100% participants in Non-
Exposure Events 
100% participant passively 
exposed  in Exposure 
Events 
• Group 3b: IQOS Users (using IQOS) 
n/a 
20% of the total number of 
available seats in the event 
location
2
 
 
 
 
Measures 
 
 
• Urine (void) 
Before Start of the Event,     
as of ≥2h after start of the 
Event until the end of the 
Event (last void analyzed 
only). 
Before Start of the Event,     
as of ≥2h after start of the 
Exposure until the end of the 
Event (last void analyzed 
only). 
• Indoor Air Quality measures 
For up to 3h prior to start of 
the Event; for 3h after the 
last participant has entered 
the Event for 1h.  
For up to 3h prior to start of 
the Exposure; for 3h after the 
last participant has entered 
and has been exposed for 1h. 
1 Participants refrain from using any tobacco or nicotine products, including IQOS and/or cigarettes.  
2 Participants create the exposure to environmental tobacco aerosol through IQOS use. 
 
 

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4.1.1 
Step 1: Identification of Participants and Informed Consent: Screening 
and Enrollment 
This step involves the identification of participants, and obtaining informed consent prior to 
the study (Non-Exposure or Exposure Events). Current adult IQOS Users and Cigarette 
Smokers will be identified and invited to participate through PMI’s product database. A 
vendor will identify and recruit Non-Smokers from a panel of existing participants used for 
other research and survey purposes. Additionally, public advertisements might be used.  
Potential candidates for participation in the study will be sent a link to a study website to 
provide information on study details and to complete a Computer-Assisted Self-Interview 
(CASI) system to assess eligibility and obtain informed consent. After completion of 
informed consent, the web system proceeds to a “screening domain” of the CASI which is 
the set of questions and questionnaires to evaluate the participants’ eligibility for 
participation (i.e., inclusion and exclusion criteria, eligible participants).  
At the end of the “screening domain” eligible participants will be directed to the “enrollment 
domain” to confirm their participation in the study. Eligible participants will be presented 
with the available dates for the Non-Exposure and Exposure Events and asked to confirm his 
/ her preferred dates for participation in maximum one Non-Exposure Event and maximum 
one Exposure Event. Once a participant confirms participation in the study, they are 
considered enrolled in the study.  
No data will be recorded in the Study Database for the potential participants that do not 
consent to participate in the study. After consenting for participation in the study, participants 
can withdraw from the study at any time.. The contact details of the participants, including 
personal information and personal identifiers will be kept separate from the study data. 
Subjects will only be compensated for the Non-Exposure or Exposure events they 
participated in. 
4.1.2 
Step 2: Non-Exposure Events  
The Non-Exposure Events are planned dinner events of 4-hour duration for the individual 
participant in a restaurant setting with a sufficient number of events ensuring a minimum 169 
participants with the following smoking phenotypes: 50% (±5%) of participants are Non-
Smokers, 25% (±5%) of participants are IQOS Users (not using IQOS), 25% (±5%) of 
participants are  Cigarette Smokers (not smoking) who are invited to attend a dinner party 
and enrolled into the study at no cost to them (see Table 1). The Non-Exposure Events are 
both nicotine- and tobacco-free (i.e., no nicotine or tobacco products are allowed to be used), 
and participants must agree to this study requirement. This step allows for non-exposure 
measurements to be obtained in order to estimate levels of primary endpoints in the absence 
of IQOS exposure.  

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IAQ measurements will be sampled for up to 3h prior to the start of the Event and for 3h 
after the last participant has entered the Event for 1h. Urine specimens per person will be 
collected for analysis as follows:  
The first urine sample will be collected prior to the start of the Event. For the second urine 
sample, collection will start with the first void after 2 hours of participation in the event to 
allow sufficient exposure to the event environment to have occurred and therefore detection 
of BoExp in the urine characterizing the background exposure. From the 2h time point 
onwards every subsequent void will be collected and the previous urine sample discarded 
with the last void collected ideally at the end of the 4h exposure period. Only the first and the 
last urine sample taken (ideally after 4h of participation in the Event) will be analyzed. The 
time of urine collection will be recorded to ensure that only urine samples taken after 2 hours 
of participation in the Non-Exposure Event are analyzed.  
Urine specimens will also be used to confirm self-reported non-smoking status of the invited 
participants. Participants who misstate their non-smoking status will not be included in the 
final analysis.  
A fixed menu of food and non-alcoholic and alcoholic beverages typically served in Japanese 
restaurants will ensure homogeneity of types of potential confounders of both IAQ endpoints 
and BoExp in the unexposed participant group. The overall amount of food consumed per 
food type and beverages consumed by type will be recorded. 
4.1.3 
Step 3: Exposure Events 
This step comprises the Exposure Events which will occur in the same restaurant setting as 
the Non-Exposure Events in order to control for restaurant-related exposures that could 
confound study results. The first of the Exposure Events will occur within 4 weeks of the 
Non-Exposure Events and will replicate both the meal, beverages and restaurant dynamics 
(i.e. same location, air ventilation and table setting) of the Non-Exposure Event.  
Exposure Event participants may or may not have attended a Non-Exposure Event, as this is 
not a study requirement. Participants attend the dinner event at no cost to themselves. These 
participants represent the same product use phenotypes as in the Non-Exposure Events, 
except that IQOS Users will be assigned for the Exposure Events to either a) IQOS Users 
who will use IQOS during the dinner event, or b) IQOS Users who agree not to use IQOS (or 
any nicotine or tobacco product) during the dinner event (see Table 1).   
The Exposure Events will include a minimum of 169 passively exposure participants with the 
following product use phenotypes: 50% (±5%) Non-Smokers, 25% (±5%) IQOS Users who 
refrain from using any nicotine or tobacco product, and 25% (±5%) Cigarette Smokers who 
refrain from using any nicotine or tobacco products.  

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In addition, a total of 20% ± 5% of the available seats at the Event location of actively 
exposed IQOS Users (who use IQOS during the event) will participate in each of the 
Exposure Events. 
Participants actively using IQOS will enter the event location first and start using IQOS ad-
libitum for 1h prior to the other participants (passive Exposure Group) entering the event 
location.  
IAQ measurements will be sampled for up to 3h prior to the start of the Event and for 3h 
after the last participant was exposed for 1h. Urine specimens per person will be collected for 
analysis as follows:  
The first urine sample will be collected prior to the start of the event. For the second urine 
sample, collection will only start with the first void after 2 hours of IQOS exposure to allow 
sufficient exposure to have occurred and therefore detection of BoExp in the urine. From the 
2h time point onwards every subsequent void will be collected and the previous urine sample 
discarded with the last void collected ideally at the end of the 4h exposure period. Only the 
first and the last urine sample taken (ideally after 4h of exposure) will be analyzed. The time 
of urine collection will be recorded to ensure that only urine samples taken after 2 hours 
exposure to IQOS are analyzed.   
A fixed menu of food and non-alcoholic and alcoholic beverages typically served in Japanese 
restaurants will ensure homogeneity of types of potential confounders of both IAQ endpoints 
and BoExp in the unexposed and passively-exposed participant groups. The overall amount 
of food consumed per food type and beverages consumed by type will be recorded. 
4.2 
Rationale for Study Design  
IQOS is currently used by over 2 million users in Japan. Various restaurants and bars exist 
where IQOS use is allowed but not CC smoking. This observational study will determine the 
impact of IQOS use on IAQ and the impact of exposure to environmental tobacco aerosol 
through measurement of BoExp in urine representative of ETS in a restaurant setting where 
IQOS use, but not smoking, is allowed.  
4.3 
Appropriateness of Measurements 
Nicotine is one of the markers for ETS, however ETS covers several other markers. In this 
study, ISO Norms related to ETS (15593:2001, 18145:2003 and 11454:1997) are out of 
scope for indoor air collection as combustion does not occur in THS. Indoor Air Quality 
Markers selected for assessment in this study are based on: 

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1. ISO measurement standards for ETS (ISO Norm 18144:2003)4 
2. Their relevance for air quality 
3. Their relative abundance in THS2.2 aerosol (i.e. the most abundant) 
4. Gas-phase tobacco non-specific markers 
The BoExp endpoints to assess passive exposure in humans are accepted biomarkers of 
exposure to ETS, and were furthermore selected based on the following criteria:  
1. Availability of a validated analytical method 
2. Measure is known to be directly or indirectly affected by the use of tobacco product 
3. Timeframe of metabolic decay in the perspective of the study duration 
4. Robustness of the method (rapid, simple, accurate) 
5. Limited exposure through other sources than tobacco 
4.4 
Study Duration 
The maximum duration of participants in the Passive Exposure Group will be approximately 
4h (not exceeding 5h). The maximum duration of active IQOS use by participants in the 
Active Exposure Group will be up to 8h (±15 min). Each participant can participate in 
maximum one Non-Exposure Event and maximum one Exposure Event. 
The overall duration of the study is currently planned for 6 weeks, but might be extended 
based on the number of events needed to secure the necessary number of participants..  
End of Study for a participant is defined as the end of the Non-Exposure Event or the last 
Exposure Event he/she participated in. The overall End of the Study is defined as the end of 
the last Exposure Event. 
5 
STUDY POPULATION 
A sufficient number of female or male Japanese adult IQOS Users, CC smokers, or Non-
Smokers to achieve 169 participants in each of the Non-Exposed and Passive Exposure 
Groups, who meet the Inclusion criteria below, will be enrolled in the study. In addition a 
sufficient number of IQOS Users, actively using the product during Exposure Events, will be 
enrolled to ensure that 20% ± 5% of the available seats of the event location are occupied by 
                                                 
4 ISO Norms related to ETS (15593:2001, 18145:2003 and 11454:1997) are out of scope for indoor air 
collection as combustion does not occur in THS. 

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IQOS Users actively using IQOS during the Exposure Event. Distribution of adult IQOS 
Users, CC smokers or Non-Smokers to these groups are outlined in Table 1.  
5.1 
Selection of Study Population 
5.1.1 Inclusion Criteria 
Participants who meet the following primary inclusion criteria will be enrolled: 
• Participant is able to understand the information provided in the Subject Information 
Sheet (SIS) and informed consent form (ICF) (confirmed by signing the ICF) and has 
signed the ICF.  
• Adults legally authorized to buy tobacco products in Japan (20 years of age). 
• Participant is Japanese as self-reported. 
• Willing to participate in the study, comply to study procedures and has access to the 
Internet.  
• Participant is an active IQOS User, CC smoker or Non-Smoker as self-reported and 
as defined in Table 2. 

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Table 2  
Definition of an IQOS User, Cigarette User or Non-Smoker 
Category label 
General description 
IQOS User (IQOS) 
 
• Used at least 100 HeatSticks 
• Uses IQOS daily > 1/day 
• Smokes a cigarette less than daily 
• Smokes less than 30 cigarettes/month 
• IQOS is > 95% of tobacco/nicotine product (all product use) – 
excluding other products (e-cig/Ploom/etc.) 
Cigarette Smoker (CC) 
• Used at least 100 cigarettes 
• Smokes cigarettes daily > 1/day 
• Uses IQOS less than daily 
• Uses less than 30 HeatSticks/month 
• Cigarette is > 95% of tobacco/nicotine product (all product use) 
Non-Smoker (NS) 
• Abstinent for at least 12 month from the use of any nicotine 
and/or tobacco-containing product based on self-reporting. 
• Must not be exposed to tobacco or nicotine-containing 
products use in any other substantial way (family, partner, 
workplace, etc.). 
Note: Details of the product use categories will be reported in the SAP. 
5.1.2 Exclusion Criteria 
Participants who meet any of the following Exclusion Criteria may not be enrolled in the 
study: 
• Participant with a medical history of severe cardiovascular or respiratory diseases (e.g., 
stroke, acute cardiovascular event, pulmonary thrombosis) in the last 12 months as 
self-reported. 
• Participant with currently active cancer or history of cancer within the last 5 years as 
self-reported. 
• Female participant who is pregnant or breast-feeding as self-reported. 
• Participant is a current or former employee of the tobacco industry or their first-degree 
relatives (parent and child). 

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• Participant is an employee of PMI, 
 vendors, restaurant/event 
location employee or their first-degree relatives (parent and child). 
Specific to participants who are Non-Smokers: 
• Participant lives in a household with users of tobacco or nicotine-containing products, 
or is exposed to the use of tobacco or nicotine-containing products at the workplace. 
 
5.2 
Discontinuation of Subjects from the Study 
Discontinued participants will include both, participants who withdraw from the study 
(participants’ decision) and participants who are discontinued from the study by the decision 
of the Principal Investigator. Participants can only be discontinued from the study after 
enrollment. Participants will be informed that they are free to withdraw from the study at any 
time. Participants should be questioned for the reason of withdrawal from the study, although 
they are not obliged to disclose it. 
If the patient withdraws from the study during an Event, he/she will be asked whether he/she 
would agree to still check out procedures (section 9.3), but with no obligation. 
Discontinuation from the study  
 
Participants must be discontinued from the study for any of the following reasons:  
1. Withdrawal of informed consent.  
2. The Sponsor terminates the study. If the Sponsor or the Principal Investigator decides to 
prematurely terminate the study, the participants will be promptly informed. The Sponsor 
should report the fact and the reason in writing to the IEC/IRB.  
3. Participant becomes an employee of any other parties involved in the study.  
4. Use of any tobacco or nicotine-containing product (if not allowed). 
 
Participant may be discontinued from the study for the following reasons:  
1. Non-compliance to the study procedures based on the judgment of the Principal 
Investigator. 
2. The number of participants has exceeded the number of necessary participants in the 
Non-Exposure or Exposure Groups.  

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5.3 
Lost to Follow-up 
If a participant has been enrolled in the study via the Study Website but does not show up at 
the scheduled events, no attempt to follow-up with the participant will be made and the 
participant will be marked as “no show”. 
5.4 
Violation of Selection Criteria 
Any participant who is in violation of selection criteria as checked at Screening or prior to 
each Event shall be discontinued from the study. 
6 
INVESTIGATIONAL PRODUCTS 
6.1 
Description of Investigational Products 
The product tested in this study is the Tobacco Heating System (THS) with Marlboro 
Heatsticks, marketed in Japan under the brand name IQOS and generally referred to as IQOS 
in this protocol. All versions of IQOS and Marlboro Heatsticks available for sale in Japan at 
the time or prior to the Study start or becoming available during the course of the Study are 
allowed to be used in the context of this study. IQOS is composed of the following 
components: a tobacco HeatStick, a Holder and a Charger (Table 3), as well as a cleaning tool, a 
power supply, and a USB cable.  

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Table 3 
Test Product (IQOS) 
Component 
Description 
HeatStick 
The HeatStick is designed to function with the Holder. The HeatStick is 
made up of: tobacco plug, hollow acetate tube, polymer-film filter, mouth 
piece filter, outer and mouth-end papers. 
All materials have been evaluated with regards to their toxicological 
potential and have been approved for use. 
The tobacco plug is made from tobacco, glycerin, water, guar gum, 
cellulose, propylene glycol, natural and artificial flavorings. 
The average amount of nicotine in the tobacco plug is 4.3-5.4 mg/stick per 
HeatStick. 
Holder 
The Holder is a slim electrical heating unit that heats the HeatStick in a 
controlled manner by using a heater blade. 
The Holder stores enough energy for a single experience, delivering 
consecutive puffs over a period of about 6 minutes or 14 puffs (whichever 
comes first). A Light Emitting Diode indicates the end of the experience. 
Once this cycle is complete, the Holder must be recharged before a new 
HeatStick can be used. 
Charger 
The power supply for the Holder is the Charger. 
The Charger holds enough energy for approximately 20 uses of the Holder 
and can be recharged from household power. 
The Charger stores the Holder when not in use, and provides a secure 
environment for the cleaning process of the heater blade.  
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 the smoke of a 
cigarette [20, 34]. A summary of description of the product, pre-clinical and clinical data 
available on IQOS is provided in the SPI [35]. 
6.2 
Use of Investigational Product(s) 
Participants in the Active Exposure Group (IQOS use) will be asked to bring their own IQOS 
device and HeatSticks for their own use during the entire study period as HeatSticks will not 
be provided by the Sponsor. Participants in the Active Exposure Group will use IQOS ad 
libitum with no Heatsticks variant restrictions.  
Urine samples collected during the study will also be used to verify self-reported smoking 
status as well as compliance with protocol restrictions on IQOS and cigarette use during the 
events. 

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6.2.1 From Screening to Event Participation 
There are no restrictions on use of IQOS or cigarettes or any other tobacco or nicotine-
containing products during screening until participation in any of the events. 
6.2.2 Non-Exposure Event  
Participants will not be permitted to use IQOS, cigarettes or any other tobacco or nicotine-
containing products during the 4-hour Non-Exposure Event.  
6.2.3 Exposure Event  
IQOS Users assigned to the Active Exposure Group will be permitted to use exclusively 
IQOS during the 4-hour Exposure Event. All other participants will not be allowed to use any 
tobacco or nicotine-containing products for the duration of their participation in the event. 
6.2.4  In-between Event Participation 
There are no restrictions on use of IQOS, cigarettes, or any other tobacco or nicotine-
containing products, during the periods between participation in Events. 
6.3 
Method for Assigning Subjects to Study Groups 
In the Non-Exposure Events, participants will be assigned to the IQOS User Group, Cigarette 
Smoker Group, or Non-Smoker Group based on self-reported smoking status.  
The same applies to the Exposure Events with the exception that IQOS Users will be 
assigned during the enrollment process to be either an IQOS User who is allowed to use 
IQOS during the Event (Active Exposure Group), or an IQOS User who is not allowed to use 
any tobacco or nicotine-containing products for the duration of their participation in the 
event. The assignment to either of the two groups will be automatically done by the system 
with the Active Exposure Group to be filled first to ensure that the necessary sample size for 
the Active Exposure Group can be assured for each of the events.  
6.4 
Blinding 
There is no blinding in this study. 

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6.5 
Investigational Product Accountability and Compliance 
6.5.1 Dispensing Investigational Product 
Participants in the Active Exposure Group will be asked to bring their own HeatSticks for 
their own use during the entire study period as HeatSticks will not be provided by the 
Sponsor. Participants in the Active Exposure Group will use IQOS ad libitum with no flavor 
restrictions. 
6.5.2 
Adherence to allocated Exposure 
Adherence to allocated Exposure, no use of any tobacco or nicotine-containing product 
during the Non-Exposure Events and no use of any tobacco or nicotine-containing product 
during the Exposure Events, with the exception of the Active Exposure Group, will be 
monitored by the staff at the Event location. Any product use by any participant in the 
Passive Exposure Group and any product use other than IQOS in the Active Exposure Group 
will lead to the discontinuation of the participant from the study. 
6.6 
Restrictions 
6.6.1 
General Restrictions 
As the study objective is to represent a real life setting, no restrictions apply to any of the 
participants other than stated in the Inclusion/Exclusion criteria (i.e., with regards to smoking 
prior to the events, wearing perfume, dress code, etc.)  
6.6.2 
Dietary Restrictions 
For the duration of an Event, participants will only be allowed to consume food and drinks 
provided at the Event location. Participants will not be allowed to bring in their own food or 
beverages. The food and beverages served during the event represent a typical and often 
requested choice in Japanese restaurants, however it can only represent a sub-selection of 
choices available in the variety of restaurant settings. 
6.6.3 
Product Use Restrictions 
Participants in the Active Exposure Group will only be allowed to use IQOS. IQOS use in 
the Active Exposure Group is not limited in terms of HeatStick variants or number of 
HeatSticks used. . All other participants will not be allowed to use any tobacco or nicotine 
containing product for the duration of the event. Any product use other than allocated will be 
recorded by the study staff and checked by the Principal Investigator or designee. 
 
 

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7 
STUDY PROCEDURES 
An overview of all study procedures is shown in the schedule of events (see Appendix A). In this 
section, only the expected/planned time points for the various measurements are described. 
7.1 
Informed Consent 
Prior to participating in any Event, the participant will be asked to provide their consent to 
participate to the study (ICF) (section 1.3.1). 
7.2 
Debriefing on IQOS 
A debriefing of participants will be done at each Event to address any intended or unintended 
beliefs participants may have about IQOS, and to inform participants on the current status of 
knowledge about IQOS. The goal of the debriefing is to ensure that participants have an 
accurate understanding of product risks including an understanding that IQOS has not been 
demonstrated to be less harmful than cigarettes. 
7.3 
Main Assessments 
7.3.1 Questionnaires  
The participant questionnaires used in this study will be entered by the participant directly in 
the CASI survey. All questionnaires, as well as instructions will be provided in Japanese (the 
local language).  
See Appendix A for the time points of assessment.  
7.3.2 Demographics  
Demographic data corresponding to inclusion/exclusion criteria (i.e., sex, age, and ethnicity) will 
be recorded in the screening domain.  
See Appendix A for the time points of assessment.  
7.3.3 Self-reported tobacco and nicotine-containing product use 
The self-reported tobacco and nicotine-containing product use questionnaire will be 
administered at enrollment within the CASI and during the check-in procedures of each event 
to confirm self-reported product use status.  
See Appendix A for the time points of assessment.  

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7.3.4 Self-Reported Health Outcomes and Events Questionnaire 
A self-reported health outcomes questionnaire will be administered at enrollment within the 
CASI and during the check-in procedures of each event to confirm self-reported health status. 
The self-reported health outcomes and events questionnaire will focus on diagnoses of 
smoking-related disease and if the participant is pregnant or breastfeeding.  
7.3.5 Recording of IQOS Use 
IQOS product use will be periodically counted and recorded at each Exposure Event by the 
study personnel to evaluate the total number of HeatSticks used during the Exposure Event 
overall. 
7.3.6 Recording of Food and Alcohol Consumption 
Overall use of alcohol will be recorded at each Event using alcohol drink tickets.   The 
overall food consumption per food type will be recorded at each event.   
7.3.7 Biomarker of Exposure Assessment in Urine 
All bioanalytical assays will be carried out using validated methods. The bioanalytical 
methods used will be documented in the Bioanalytical Plans/Reports. A list of laboratories is 
provided in Appendix B. 
Spot urine will be collected at each Non-Exposure Event before the start of the Event and as 
of  ≥2h after start of the Event until the end of the Event (last void analyzed only). For 
Exposure Events, urinary samples will be collected before the start of the Event and as of  
≥2h after start of the Exposure until the end of the Event (last void analyzed only) for 
analysis of: 
Creatinine, NEQ, a set of BoExp to nicotine; total NNAL, a biomarker for NNK; total NNN, 
a BoExp for NNN; 3-HPMA, a BoExp to acrolein; 3-HMPMA, a BoExp to crotonaldehyde; 
HEMA, a BoExp to Ethylene Oxide. Creatinine will be measured for normalization of urinary 
BoExp.  
7.3.8 Assessment of Indoor Air Quality 
For Non-Exposure Events, IAQ measurements will be performed at the Event location for up 
to 3h prior to the start of the Event and for 3h after the last participant has entered the Event 
for 1h. For Exposure Events IAQ measurements will be performed at the Event location for 
up to 3h prior to start of the Exposure and for 3h after the last participant has been exposed 
for 1h to quantify and differentiate background exposure and to assess the impact of IQOS 

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use on IAQ. The sample collection starts one hour after the entry of the participants in order 
to sample a homogeneous atmosphere during the collection time (i.e., 3 hours). 
Study samples will be collected at each Event (Non-Exposure and each Exposure Event) at 
the Event location.  
To collect IAQ samples, three mobile sampling set-ups, for indoor air pollutants will be used. 
The set-up consists of 3 aluminum sampling cases with 5 flow-controlled pumps. Each 
sampling case are equipped with: 
• 2 x AD-4 traps for Nicotine and 3-EP collection operated at a flow rate of 1.0 L/min 
for 3h; 
• 2 x 1 DNPH-silica traps for carbonyl collection (acetaldehyde, acrolein, 
crotonaldehyde and formaldehyde) operated at a flow rate of 1.2 L/min sequentially 
for 1h 
• 2 glass fiber filters (Cambridge filters) spiked with ascorbic acid for TSNAs (NNN; 
NNK), operated at a flow rate of 1.0 L/min for 3h. 
The position of the sampling cases will be inside the breathing zone as described by 
ASHRAE.5 
Moreover, two small instruments in front of the sampling cases are electronically recording 
the ambient temperature and relative humidity. In addition, two portable instruments, used 
for on-line PM1-PM10 particle measurements will be used. The equipment are the property 
of PMI and will be used by a PMI-trained scientist according to the ISO accredited method 
PMI-RRP-WKI-111642 “Dust Trax characterization for real time monitoring of aerosol mass 
concentration”. 
The analytical methods to be applied at the analyzing laboratory (see Appendix B.) for the air 
samples are listed in Table 4. 
                                                 
5 ASHRAE, 2016. ANSI/ASHRAE Standard 62.1-2016. Ventilation for acceptable indoor air quality. Atlanta, 
GA: American Society of Heating, Refrigerating and Air-Conditioning Engineers. 
 

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Table 4  
Constituents selected, technology and trap used for indoor air 
collection 
Chemical class 
(constituents) 
Analytical method / 
Technology 
Trap to collect the air 
Carbonyls (formaldehyde, 
acetaldehyde, acrolein, 
crotonaldehyde) 
LC-MS/MS 
DNPH-coated silica cartridge 
Tobacco-specific markers 
(Nicotine, 3-ethenylpyridine) 
GC-MS 
XAD-4 
Tobacco-specific nitrosamines 
(NNN; NNK) 
LC-MS/MS 
Ascorbic acid-spiked glass fiber 
filters 
Notes: LC-MS/MS = Liquid chromatography-tandem mass spectrometry; GC-MS = Gas chromatography–mass spectrometry; DNHP = 2,4-
Dinitrophenylhydrazine; NNK = 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; NNN = N-nitrosonornicotine 
 
A total of 18 tubes per Event will be collected. Table 5 shows the repartition of samples. 
Table 5 
List of samples generated for the main study. 
Purpose 
Non-Exposure Event 
Exposure Event 
 
Event 1 
Event 2 
Event 3 
Event 4 
Event 5 
Nature of 
sample 
(duration) 
BKG (3h) then 
EA (3h) 
BKG (3h) then 
EA (3h) 
BKG (3h) then 
EA (3h) 
BKG (3h) then 
EA (3h) 
BKG (3h) then 
EA (3h) 
Sample ID 
BKG1/ EA1 
BKG2/EA2 
BKG3/EA3 
BKG4/EA4 
BKG5/EA5 
Notes: BKG = Background; EA= Environmental Aerosol 
7.4 
Sample Handling, Storage, and Shipment 
Participating laboratories for the analyses of urinary samples are listed in Appendix B. 
Detailed procedures for handling of samples are described in a separate Laboratory 
Instruction Manual. All samples will be destroyed post database lock or post finalization of 
the bioanalytical reports depending on which one is coming the latest. 
For urinary samples, the collected samples will be stored at 4°C up to 24h after the collection 
period. Longer storage periods will be at ≤ -20°C. Samples will be shipped on dry ice to 
Celerion, USA, within a few days after completion of the study. Several shipments might be 
considered to respect the stability of the samples.  

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For IAQ assessment, the collected samples will be stored at 4°C up to 12h after the collection 
period. Longer storage periods will be at ≤-20°C. Samples will be shipped on dry ice to ABF 
Munich, Germany, within a few days after completion of the event. Extraction will be done 
by ABF. Weekly shipments will be considered to respect the stability of the samples, 
especially for DNPH cartridges.6 
8 
ADVERSE EVENTS, PARTICIPANTS SAFETY AND WELL-BEING 
As this study is observational by design and is conducted in a post-market setting, adverse 
event (AE) reporting will follow the Sponsor’s already established post-market Safety 
Surveillance Procedures for spontaneously-reported events. All study personnel and study 
participants will be reminded of the product quality complaints (including AEs) hotline that 
has been established for all users of IQOS in Japan.  
In the event that a medical event occurs in any of the study participant the study staff will be 
advised to call local emergency number to ensure appropriate medical treatment. The related 
cost for emergency treatment and transportation will be carried by the Sponsor.  
Security personnel will be on site at the event location to ensure secure and ordered conduct 
at the event. 
9 
STUDY ACTIVITIES 
If no start time for the procedures is provided, then the procedure can be performed at any 
time during the visit. Assessments will be conducted only by qualified and trained site 
personnel.  
A detailed schedule of assessments can be found in Appendix A. 
9.1 
Screening and Enrollment  
Screening will be done entirely online as detailed in Section 4.1.1. 
Table 6 shows the assessments that will be performed at the screening and enrollment: 
                                                 
6 Stability Carbonyl samples on DNPH cartridges: up to 2 weeks in the freezer after collection. Stability of 
eluate of Carbonyls samples collected on DNPH cartridges: up to 3 months when stored at – 20 °C. Stability 
nicotine samples on XAD-4 tubes: up to 8 weeks in the freezer after collection, stability of eluate of nicotine 
samples collected on XAD-4 tubes: up to 2months when stored at – 20 °C. 
 

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Table 6 
Schedule – Screening and Enrollment 
Time 
Sample 
collection 
Procedures 
Additional 
information 
Start of procedure 
 
Screening, Enrollment and Baseline 
Online Information 
and Questionnaire 
 
ICF signature 
 
 
 
Demographics data 
Sex, date of birth, 
ethnicity 
 
 
Tobacco or nicotine-containing product 
use self-reporting 
Participants will be 
questioned on their 
product use history. 
 
 
Self-Reported Health Outcomes and 
Events Questionnaire 
 
 
 
Readiness to comply to study procedures 
 
 
 
Verification of eligibility 
All eligibility criteria must 
be checked and met to 
continue to enrollment. 
 
 
Selection of participation dates for Non-
Exposure and  Exposure Events 
 
 
 
Enrollment 
If all eligibility criteria are 
met. 
Assignment of IQOS 
Users 
 
Assignment of IQOS Users into the Active 
Exposure of Passive Exposure Group 
Participants who are self-
reported IQOS Users  
 
 
Confirmation email to subject 
Needs to be presented 
during check-in procedure 
at the event. 
End of Screening 
and Enrollment 
 
 
 
Abbreviations: ICF = Informed Consent 
9.2 
Recruitment Period 
Recruiting for this study will be open for the entire study period as outlined in Figure 2. 
9.3 
Study Period 
Procedures to be conducted during the Non-Exposure Event are detailed in section 4.1.2 and 
Table 7. Procedures for the Exposure Event are detailed in section 4.1.3 and Table 8. 

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Table 7 
Schedule – Non – Exposure Event 
Time 
Sample 
collection 
Procedures 
Additional 
information 
Start of procedure 
 
Non-Exposure Event 
IAQ Assessment 
IAQ 
See section 7.3.8 
For 3h prior to the first 
participant entering the 
Event location 
Arrival and Check-In 
 
Participant Identification, check if ICF 
has been signed 
 
 
 
Confirmation of demographics data 
Sex, date of birth, ethnicity 
 
 
Tobacco or nicotine-containing product 
use self-reporting 
Participant to fill 
questionnaire 
 
 
Readiness to comply to study 
procedures 
 
 
 
Self-Reported Health Outcomes and 
Events Questionnaire 
 
Prior to entering the 
Event 
U 
Spot urine collection for NEQ, total 
NNAL, total NNN, 3-HPMA, HMPMA, 
HEMA and creatinine samples. 
Process samples BoExp 
analysis according to 
laboratory manual/SHM. 
During the Event 
 
Dinner and Drinks 
Food typically served in 
Japanese restaurants, soft-
drinks, tea, alcoholic 
beverages as typically 
served in Japanese 
restaurants 
IAQ Assessment 
IAQ 
See section 7.3.8 
For 3h starting 1h after the 
last participant entered the 
Event. 
During the Event as of 
2h after entering the 
event 
U 
Spot urine collection for NEQ, total 
NNAL, total NNN, 3-HPMA, HMPMA, 
HEMA and creatinine samples. 
Only last void to be kept for 
analysis (ideally the one 
prior to check-out). Prior 
voids to be discarded. 
Process samples BoExp 
analysis according to 
laboratory manual/SHM. 
Check-Out prior to 
leaving the Event 
U 
Spot urine collection for NEQ, total 
NNAL, total NNN, 3-HPMA, HMPMA, 
HEMA and creatinine samples 
 
 
 
Check if study questionnaires have 
been completed. 
 
Pick-Up of samples 
 
Collection of samples for shipping to 
analyzing laboratories 
 

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Confirmation that no 
other product than 
allowed as per 
protocol was used 
 
 
PI or designee 
End of the visit 
 
 
 
Abbreviations: IAQ = Indoor Air Quality; ICF = Informed Consent; SHM = Sample Handling Manual; BoExp 
= Biomarker of Exposure; NEQ = Nicotine Equivalents; total NNAL = Total 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol; Total NNN = Total N-nitrosonornicotine; 3-HPMA = 3-hydroxypropylmercapturic acid; 
HMPMA = 3-hydroxy-1-methylpropylmercapturic acid; HEMA = 2-hydroxyethyl mercapturic acid; U = urine 
 
Table 8 
Schedule – Exposure Event 
Time 
Sample 
collection 
Procedures 
Additional 
information 
Start of procedure 
 
Exposure Event 
IAQ Assessment 
IAQ 
See section 7.3.8 
For 3h prior to the first 
participant entering the 
Event location 
Arrival and Check-
In 
 
Participant Identification, check if ICF 
has been signed 
 
 
 
Confirmation of demographics data 
Sex, date of birth, 
ethnicity 
 
 
Tobacco or nicotine-containing product 
use self-reporting 
Participant to fill 
questionnaire 
 
 
Readiness to comply to study 
procedures 
 
 
 
Self-Reported Health Outcomes and 
Events Questionnaire 
 
Check assignment 
of IQOS Users 
 
Check assignment of IQOS Users into 
the Active Exposure of Passive 
Exposure Group 
Participants who are self-
reported IQOS Users 
and have brought their 
device and HeatSticks 
Prior to entering the 
Event 
U 
Spot urine collection for NEQ, total 
NNAL, total NNN, 3-HPMA, HMPMA, 
HEMA and creatinine samples. 
Process samples BoExp 
analysis according to 
laboratory manual/SHM. 
“Priming” of Event 
location 
 
The Active Exposure Group will enter 
the event location approximately 1h 
before the Passive Exposure Group to 
start using IQOS. 
 
During the Event 
 
Dinner and Drinks 
Food typically served in 
Japanese restaurants, 
soft-drinks, tea, alcoholic 

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beverages as typically 
served in Japanese 
restaurants 
In regular intervals, 
depending on 
product use 
(approximately 
every hour) 
 
Regular count of used IQOS HeatSticks 
PI or designee 
IAQ Assessment 
IAQ 
See section 7.3.8 
For 3h starting 1h after 
the last participant 
entered the Event. 
During the Event as 
of 2h after entering 
the event and prior 
to leaving the Event 
U 
Spot urine collection for NEQ, total 
NNAL, total NNN, 3-HPMA, HMPMA, 
HEMA and creatinine samples. 
Only last void to be kept 
for analysis (ideally the 
one prior to check-out). . 
Prior voids to be 
discarded. Process 
samples BoExp analysis 
according to laboratory 
manual/SHM. 
 
 
Check if study questionnaires have been 
completed. 
 
Pick-Up of samples 
 
Collection of samples for shipping to 
analyzing laboratories 
 
Confirmation that no 
other product than 
allowed as per 
protocol was used 
 
 
PI or designee 
End of the visit 
 
 
 
Abbreviations: IAQ = Indoor Air Quality; ICF = Informed Consent; SHM = Sample Handling Manual; BoExp 
= Biomarker of Exposure; NEQ = Nicotine Equivalents; total NNAL = Total 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol; Total NNN = Total N-nitrosonornicotine; 3-HPMA = 3-hydroxypropylmercapturic acid; 
HMPMA = 3-hydroxy-1-methylpropylmercapturic acid; HEMA = 2-hydroxyethyl mercapturic acid; U = urine 
 
 

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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
N/A 
10.2 Training of Collaborators 
A formal meeting will be conducted prior to the start of the study. During this meeting, the 
Sponsor or its authorized representative will discuss the requirements of the study protocol 
and related documents and will also provide training to the relevant systems and other study-
specific procedures. The activities of this meeting will be described in the Event 
Coordination Plan. 
10.3 Audits and Inspections 
Good Epidemiological Practice guidelines do not specify independent inspections of study 
program activities, however, in order to guarantee adequate site performance, such 
inspections may be performed at any time before, during and/or after the study.  
Authorized representatives of the Sponsor, regulatory agencies and/or an IRB/IEC may 
perform audits or inspections. 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, GEP guidelines [1], the Ethical Guidelines for Medical and Health 
Research Involving Human Subjects [2] and any applicable regulatory requirements. The 
Principal Investigator or designee will contact the Sponsor or the authorized representative 
immediately if contacted by a regulatory agency about an inspection at their site.  
The Principal Investigator or designee are responsible for maintaining a comprehensive and 
accurate filing system of all study-related documentation that will be suitable for inspection 
at any time by the Sponsor, its authorized representative and/or regulatory agencies. By 
signing this protocol, the Principal Investigator or designee understands and agrees to 
provide access to the necessary documentation and files. 
11 DATA MANAGEMENT ACTIVITIES 
All data management activities will be documented in the Data Management Plan (DMP) and 
documents specified therein. The electronic CASI system used to collect participant data will 
be FDA 21 CFR Part 11 compliant. 

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11.1 Data Capture 
11.1.1 
Data Capturing Tool, Case Report Forms and Study Records 
All data collected during the screening and enrollment process will be collected through the 
CASI questionnaire. As the CASI questionnaire is administered directly to the subject it will 
be administered in Japanese. Any data that are reported in open-ended questions will be 
recorded in Japanese and translated to English. 
Trained study personnel (Principal Investigator or his authorized designee(s)) at the event site 
will be responsible for performing the assessment specified in the protocol and documenting 
the results in the Source Data. These results will also be captured in the data capture tool.  
The Principal Investigator has the ultimate responsibility for the collection and reporting of 
the data related to the assessments in the study and ensures that the data are accurate, 
authentic/original, legible, timely (contemporaneous), enduring and available when required. 
The data capture tool for the study will be signed by the Principal Investigator to attest that 
the data contained in are true and accurate. Any corrections made to Source Data and/or data 
capturing tool must be recorded, without obscuring the original values, and must be 
accompanied by the date of change, reason for change and identification of the person 
making the change. Instances of missing or unclear data will be discussed with the Principal 
Investigator for resolution. 
IAQ data will be recorded with the instrumentation listed above and analyzed and reported in 
a separate report. The results and discussion however will be integrated in the Assessment 
Study Report. 
 
11.1.2 
Protocol Deviations 
All protocol deviations will be entered into the Clinical Trial Management System (CTMS) 
or other approved format. 
Information from the source documents will represent the primary source of protocol 
deviations. Information following site monitoring and other manual reviews will be 
documented in the site visit reports, follow-up letters, audit documentation, or other manual 
review and will be recorded and tracked in the CTMS or other approved format. 
Telecommunications and other verbal communications regarding deviations will be 
considered and handled as important communication, and documented and tracked as 
protocol deviations, as necessary. 
Individual entries for protocol deviations that are recorded in the CTMS, or other approved 
format, following site monitoring and other manual reviews will be reviewed against the 
individual data points in the CRF database but will not be formally reconciled with the CRF 
database (e.g., their description or occurrence date). The overall procedures for managing 
protocol deviations are described in the SOPs of the CRO Data Management Team. All 

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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, with the exception 
of the IAQ data (see above). The processed results of the IAQ data will be integrated on a 
dataset level after analysis. The overall procedures for quality assurance of study data are 
described in the SOPs of the CRO data management team. The data management team at the 
CRO will prepare a DMP, to be reviewed and approved by the Sponsor, prior to the go live 
of systems used to capture study data. This document will describe, in details, the data 
management-related procedures and processes.  
All data collected during the study are declared property of the Sponsor, irrespective of the 
location of the database and the data management CRO.  
Additional details are covered in the DMP. 
11.2.1 Data Verification 
The data will be validated as defined in the DMP. Discrepancies will be reported as defined 
in DMP and Data Validation Plan.  
11.2.2 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 and QC of the changed data, database, or selected 
data upon Sponsor approval, as applicable, the database is declared locked.  
Any changes to the database after that time can only be made by written agreement between 
the Sponsor and the Data Management and Statistical Team at the CRO. Any of those 
changes must be documented in the database log file.  
After study completion, the study database will be transferred to the Sponsor in the format 
specified in the DMP in Clinical Data Interchange Standards Consortium’s Study Data 
Tabulation Model Data Structure Specifications, with the exception of the IAQ data, for 
which the raw data will be kept at ABF according to the vendor’s data management process. 
The processed data will be provided to the Sponsor as defined in the DMP.  

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12 PLANNED STATISTICAL METHODS 
12.1 General Considerations 
Full details of the statistical analysis will be given in the Statistical Analysis Plan (SAP). Any 
changes to the planned statistical methods will be documented in the study report. The 
statistical evaluation will be performed using SAS®, version 9.2 or later. 
12.1.1 
Stratification Criteria 
 For the primary analysis, the following stratification criteria will be used:  
1. Product use Status. 
2. Event type. 
3. Sex. 
12.1.2 
Definitions for Statistical Data Analysis 
The following definitions of an IQOS User, Cigarette User or Non-Smoker will be used for 
this study and analysis of results. 
Table 9  
Definition of an IQOS User, Cigarette User or Non-Smoker 
Category label 
General description 
IQOS User (IQOS) 
 
• 
Used at least 100 HeatSticks 
• 
Uses IQOS daily > 1/day 
• 
Uses a cigarette less than daily 
• 
Uses less than 30 cigarettes/month 
• 
IQOS is > 95% of tobacco/nicotine product use (all product use) – 
excluding other products (e-cig/Ploom/etc.) 
Cigarette Smoker (CC) 
• 
Used at least 100 cigarettes 
• 
Uses cigarettes daily > 1/day 
• 
Uses IQOS less than daily 
• 
Uses less than 30 HeatSticks/month 
• 
Cigarette is > 95% of tobacco/nicotine product use (all product use) 
Non-Smoker (NS) 
• 
Abstinent for at least 12 month from the use of any nicotine and/or 
tobacco-containing product based on self-reporting. 
• 
Must not be exposed to tobacco or nicotine-containing products use 

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in any other substantial way (family, partner, other workplace). 
Note: Details of the product use categories will be reported in the SAP. 
12.1.3 
Descriptive Statistics 
Descriptive statistics for continuous variables will include the number of participants, 
number and percent of participants with missing data, the mean and standard deviation, 
geometric means and coefficient of variation (CV), median, first and third quartiles, 
minimum and maximum, and 95% confidence interval (CI) for each product exposure, and 
summary across all participants. In addition, the results may be presented as a stratified 
summary as defined in the Statistical Analysis Plan (SAP). 
12.1.4 
Handling of Missing Values and of Values outside the Detection Limits 
For BoExp parameters: 
• Values below the lower limit of quantification (LLOQ) will be imputed using 
LLOQ/2. For values above the upper limit of quantification (ULOQ), the ULOQ will 
be imputed. 
• The number of values below LLOQ or above ULOQ will be presented in each 
summary table. If more than 50% of the data are below LLOQ, only the number and 
percentage of values below LLOQ will be reported in the summary together with the 
minimum and maximum values. 
For CASI data: 
Subject missing the complete CASI will not be considered for analysis. Those with 
incomplete CASI’s will be analyzed based on the available data. 
Further details will be provided in the SAP. 
 
12.1.5 
Significance Level for Inferential Analysis 
Not applicable as there are no formal statistical hypotheses to be tested in this study.  
12.2 Determination of Sample Size  
The sample size of a minimum of 169 participants in the Exposure and Non-Exposure Events 
Each is based on the expected exposure of a Non-Smoker when exposed to cigarette smoke 
as documented in the literature. Variability of exposure levels and method variability were 
furthermore considered to estimate the sample size needed. 

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Confidentiality Statement 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
12.3 Analysis Populations 
The main population for analysis will be the Compliant Exposure Set.  
12.3.1 
Compliant Exposure Set  
The Compliant Exposure Set will consist of all enrolled participants who have signed the ICF 
and who have participated in either a Non-exposure Event or an Exposure Event, have 
provided two urine samples (at minimum, one urine sample prior to the start of the event and 
one urine sample after a minimum 2h of individual participation in the event) and are 
compliant with the Event Exposure Groups (Non-Exposure vs. Passive Exposure).  
12.3.2 
 Active Exposure Set  
The Active Exposure Set (PP) will consist of all enrolled participants who have signed the 
ICF and who have participated in an Exposure Event, have provided two urine samples (at 
minimum, one urine sample prior to the start of the event and one urine sample after a 
minimum of 2h after start of the Active Exposure) and were in the Active Exposure Group. 
12.4 Primary Analysis 
The primary endpoints will be the pre-event urinary BoExp and latest post two hour urinary 
BoExp observation. A linear mixed effects model with event type, IAQ, duration of exposure 
(time between pre-event collection and last post exposure collection), product use status and 
product use status and event type interaction will be modelled as fixed effects with a random 
subject effect. Other covariates or interactions terms may be added as needed. Appropriate 
contrasts will be constructed to determine the effect of passive exposure to IQOS aerosol 
during the Exposure Event on the mean change in levels of urinary BoExp to selected 
tobacco specific HPHCs together with the 95% confidence intervals (CIs). Other contrasts 
can be constructed to determine the change in urinary BoExp for subjects with other smoking 
status after passive exposure to IQOS usage 
12.5 Secondary Analysis 
The same statistical model described in the analysis of the primary endpoint will be used to 
analyze to evaluate the levels of exposure to additional selected HPHCs representative of 
ETS during both the Non-Exposure Events and Exposure Events in the study population. The 
results will also be looked at stratified by incoming smoking status. Additional analysis may 
be defined in the SAP and performed and reported in the Assessment Study Report. 
The IAQ data will be processed at the assessing laboratory (see Appendix B) and the 
individual results per compound will be summarized and tabulated. An Analysis of variance 
(ANOVA) design will be applied as the quantitative results of the IAQ sessions will be 
compared per compound. The mean, standard deviation, relative standard deviation, 

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without the written consent of Philip Morris Products S.A 
minimum and maximum will be computed per compound and the number of observation will 
be indicated. A significance level set at 0.05 will be used to determine equality between 
sessions.  
12.5.1 Analysis of the Active Exposure Group 
 
The primary endpoints will look at the change between the pre-event urinary BoExp and 
latest post two-hour urinary BoExp observation. A linear mixed effects model with IAQ, 
duration of exposure (time between pre-event collection and last post exposure collection) 
and number of sticks used during the event, will be modelled as fixed effects with a random 
subject effect. Other covariates or interaction terms may be added as needed. Appropriate 
contrasts will be constructed to determine the effect of active exposure to IQOS usage during 
the Exposure Event on the mean change in levels of urinary BoExp to selected tobacco 
specific HPHCs together with the 95% confidence intervals (CIs). 
 

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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Principal Investigator’s and Study Administrative Structure 
13.1.1 Principal Investigator 
Principal Investigator: 
Dr. Takao Ohki, MD, PhD 
Tokyo Jikei University School of Medicine 
 
 
 
 
 
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 
 
Study Coordinator 
Phone: +41 
 
Mobile: +41 
 
E-mail: 
 
 
Study Scientist 
Phone: +41 
 
Mobile: +41
 
E-mail: 
 
 
Study Biostatistician 
Phone: +41 
 
Mobile: +41
 
E-mail: 
 

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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
13.1.3 Other Responsibilities 
 is the 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. 
CRO: 
 
 
 
 
 
 
 
Lead Study Scientist 
Phone: +1
 
E-mail: 
 
 
Study Scientist  
 
 
 
 
 
 
 
Project Lead 
Phone: +34 
 
E-mail: 
 
13.2 Participant Confidentiality 
All information obtained during the conduct of the study with respect to the participants' state 
of health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the participant. An agreement to disclose any such information will 
be obtained from the participant in writing and signed electronically by the participant, in 
compliance with all local and national data protection and privacy legislation. 
The anonymity of participants participating in this study will be maintained. Participants will 
be identifiable by the Sponsor (or Sponsor’s authorized representative) on CRFs and other 
documents by their participant number/code, sex and date of birth, but not by name, initial, or 

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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
any other details relating to identifiable person (e.g., address). The assignment of a 
participant number/code for participant identification will be based on the appropriate data 
protection rules. 
Any documents that allow full identification of the participant (e.g., the participant’s signed 
ICF) must be maintained in confidence by the Principal Investigator. If any document 
relating to this study shows a participant’s name or any other details relating to an 
identifiable person (e.g., address), the name or other identifiable details must be obscured 
before a copy of that document is supplied to the Sponsor. PRX staff will have access to 
email, geographical data and phone number as well as other personal data (i.e. passport 
check).  
In the exceptional case where a participant a) is recruited into the study through PMP’s Product 
Registration Database, and b) communicates in any way their intention to quit smoking or 
stop using IQOS, their email address will be shared with PMP so that this participant no 
longer receives any commercial communication from the Sponsor moving forward. No other 
identifiers will be shared with the Sponsor so that no study data will be linked to that email 
address. 
13.3 Access to Source Documentation 
Participants enrolled in the study will be informed that, during the course of the study, the 
Sponsor, any authorized representatives of the Sponsor, IRB, or regulatory authorities may 
inspect 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 Principal Investigator and all study site collaborators 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 
test results) 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 for the study. After the finalization of the study the Principal Investigator can 
request that all study related files (Essential study documents/records, which individually and 
collectively permit evaluation of the conduct of a study and the quality of the data produced) 
are transferred to the Sponsor. The Sponsor will perform a quality control check for 
completeness of the data prior to accepting the request. Ones the request is accepted and the 
transfer is complete, essential study documents/records, which individually and collectively 

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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
permit evaluation of the conduct of a study and the quality of the data produced must be 
retained by the Sponsor 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 participants and master ICF  
• Participant identification code list, enrollment 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 Principal Investigator, Sponsor, 
and its authorized representatives  
• Study specific questionnaires (and associated data/scoring), CASI data  
• All other source documents (e.g., laboratory records) or any electronically captured 
study source data  
• Record of any body fluids or tissue samples collected and retained 
• Information regarding participants’ discontinuation. 
The Principal Investigator (until transfer to the Sponsor is complete) and the Sponsor (after 
completion of the transfer) must take measures to prevent accidental or premature destruction 
of these documents. 
If the Principal Investigator wishes to assign the study records to another party or move them 
to another location during or after the study, the Sponsor must be notified in advance.  
The Principal Investigator must obtain written approval from the Sponsor before destruction 
of any records. Normally, these records will be held in the Principal Investigator’s archives. 
If the Principal Investigator is unable to meet this obligation, they must ask the Sponsor for 
permission to make alternative arrangements. Details of these arrangements must be 
documented. In case the Principal Investigator has agreed with the Sponsor to transfer the 
files to the Sponsor it is the obligation of the Sponsor to document the destruction of the 
records according to local law and regulations. 
The Sponsor or Sponsor’s authorized representative will maintain documentation relating to 
the study for 15 years after the Study Report has been finalized. 

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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
13.5 Assessment Study Report 
The Sponsor must ensure that an assessment study report for this study is prepared regardless 
of whether the study is completed or prematurely terminated. In certain circumstances, an 
abbreviated assessment study report may be acceptable. Submission of the assessment study 
report 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 assessment study report. 
13.6 Financial Disclosure 
Principal Investigator is required to provide financial disclosure information to the Sponsor. 
In addition, the Principal Investigator 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 one year following the completion of the study. 
13.7 Publication and Disclosure Policy 
This document contains data, information and trade secrets that are confidential and 
proprietary to the Sponsor. This document is being provided solely for the purpose of 
evaluation and/or conducting this 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 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 to the participants that are associated 
with the IQOS use or with study procedures which are used during this study, except for AEs 
and health damage to the participants caused by a negligent or an intentional misconduct 
and/or significant deviation to the protocol of the Principal Investigator or the Event Site or 
the participants. The Sponsor has taken out insurance to cover any bodily injury and property 
damage caused by the operations carried out by the insured.  
 

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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 REFERENCES 
1. International Epidemiological Association. Good Epidemiological Practice (GEP). IEA 
Guidelines for Proper Conduct in Epidemiological Research. 2007.  2015. 
2. Ministry of Health, Labour, and Welfare. Ethical Guidelines for Medical and Health 
Research Involving Human Subjects. Japan 2015. 
3. World Medical Association (WMA). Declaration of Helsinki - Ethical principles for 
medical 
research 
involving 
human 
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4. WHO (World Health Organization). Protection from exposure to second-hand tobacco 
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5. National Toxicology Program. NTP 11th Report on Carcinogens. Report on 
carcinogens: carcinogen profiles 2004; 11: 1. 
6. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 
Organization WH, Cancer IAfRo. Tobacco smoke and involuntary smoking: Iarc 2004. 
7. U.S. Department of Health and Human Services. How tobacco smoke causes disease: the 
biology and behavioral basis for smoking-attributable disease: a report of the Surgeon 
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Health Promotion, Office on Smoking and Health 2010. 
8. U.S. EPA. Respiratory Health Effects of Passive Smoking (also known as exposure to 
secondhand smoke or environmental tobacco smoke - ETS). In: U.S. Environmental 
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Environmental Assessment, ed. Washington, DC: U.S. Environmental Protection 
Agency 1992:525. 
9. Barnoya J, Glantz SA. Cardiovascular effects of secondhand smoke. Circulation 2005; 
111: 2684-98. 
10. Glantz SA, Parmley WW. Passive smoking and heart disease. Epidemiology, 
physiology, and biochemistry. Circulation 1991; 83: 1-12. 
11. Glantz SA, Parmley WW. Passive smoking and heart disease: mechanisms and risk. 
Jama 1995; 273: 1047-53. 

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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
12. Law MR, Morris J, Wald NJ. Environmental tobacco smoke exposure and ischaemic 
heart disease: an evaluation of the evidence. Bmj 1997; 315: 973-80. 
13. He J, Vupputuri S, Allen K et al. Passive smoking and the risk of coronary heart 
disease—a meta-analysis of epidemiologic studies. New England Journal of Medicine 
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14. Thun M, Henley J, Apicella L. Epidemiologic studies of fatal and nonfatal 
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15. Wells AJ. Passive smoking as a cause of heart disease. Journal of the American College 
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16. Whincup PH, Gilg JA, Emberson JR et al. Passive smoking and risk of coronary heart 
disease and stroke: prospective study with cotinine measurement. BMJ 2004; 329: 200-5. 
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17. Hori M, Tanaka H, Wakai K et al. Secondhand smoke exposure and risk of lung cancer 
in Japan: a systematic review and meta-analysis of epidemiologic studies. Japanese 
journal of clinical oncology 2016; 46: 942-51. 
18. Rodgman A, Perfetti TA. The chemical components of tobacco and tobacco smoke. 2nd 
ed: CRC Press, Taylor & Francis Inc (United States) 2013. 
19. U.S. Department of Health and Human Services, FDA (Food and Drug Administration). 
[Docket No. FDA-2012-N-0143]: harmful and potentially harmful constituents in 
tobacco products and tobacco smoke; established list. Fed Regist 2012; 77: 20034-7. 
20. Schaller J-P, Keller D, Poget L et al. Evaluation of the Tobacco Heating System 2.2. Part 
2: Chemical composition, genotoxicity, cytotoxicity, and physical properties of the 
aerosol. 
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21. Hoeng J, Deehan R, Pratt D et al. A network-based approach to quantifying the impact 
of biologically active substances. Drug Discov Today 2012; 17: 413-8. 
22. Phillips B, Veljkovic E, Boue S et al. An 8-month systems toxicology 
inhalation/cessation study in Apoe-/- mice to investigate cardiovascular and respiratory 
exposure effects of a candidate modified risk tobacco product, THS 2.2, compared with 
conventional cigarettes. Toxicol Sci 2016; 149: 411-32. 

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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
23. Philip Morris Products S.A. Nicotine pharmacokinetic profile and safety of the Tobacco 
Heating System 2.2 (THS 2.2)[ZRHR-PK-01-EU]. In: ClinicalTrials.gov [Internet]. 
Bethesda (MD): National Library of Medicine (US). 2013-2014 [cited 2015 Jun 16]. 
Available 
from: 
http://clinicaltrials.gov/show/NCT01967732 
NLM 
Identifier: 
NCT01967732. 
24. Philip Morris Products S.A. A single-center, open-label, randomized, controlled, 
crossover study to investigate the nicotine pharmacokinetic profile and safety of THS 2.2 
following single use in smoking, healthy subjects compared to conventional cigarettes 
and nicotine gum [ZRHR-PK-02-JP]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): 
National Library of Medicine (US). 2013-2014 [cited 2015 Aug 26]. Available from: 
http://clinicaltrials.gov/show/NCT01959607 NLM Identifier: NCT01959607. 
25. Philip Morris Products S.A. A single-center, randomized, controlled, crossover study to 
investigate the nicotine pharmacokinetic profile and safety of THS 2.2 Menthol 
following single use in smokers compared to menthol conventional cigarettes and 
nicotine gum [ZRHM-PK-05-JP]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): 
National Library of Medicine (US). 2013-2014 [cited 2016 Jan 03]. Available from: 
http://clinicaltrials.gov/show/NCT01967706 NLM Identifier: NCT01967706. 
26. Philip Morris Products S.A. A single-center, randomized, controlled, crossover study to 
investigate the nicotine pharmacokinetic profile and safety of THS 2.2 Menthol 
following single use in smokers compared to menthol conventional cigarettes and 
nicotine nasal spray [ZRHM-PK-06-US]. In: ClinicalTrials.gov [Internet]. Bethesda 
(MD): National Library of Medicine (US). 2013-2014 [cited 2015 Jun 16]. Available 
from: http://clinicaltrials.gov/show/NCT01967719 NLM Identifier: NCT01967719. 
27. Haziza C, de La Bourdonnaye G, Skiada D et al. Evaluation of the Tobacco Heating 
System 2.2. Part 8: 5-day randomized reduced exposure clinical study in Poland. Regul 
Toxicol 
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May 2017): S139-50. 
28. Haziza C, de La Bourdonnaye G, Merlet S et al. Assessment of the reduction in levels of 
exposure to harmful and potentially harmful constituents in Japanese subjects using a 
novel tobacco heating system compared with conventional cigarettes and smoking 
abstinence: a randomized controlled study in confinement. Regul Toxicol Pharmacol 
2016; 81: 489-99. 
29. Philip Morris Products S.A. Reduced exposure study using the Tobacco Heating System 
2.2 (THS 2.2) Menthol for 91 days in confinement and ambulatory [ZRHM-REXA-08-
US]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine 

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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
(US). 
2013-2015 
[cited 
2015 
Jun 
16]. 
Available 
from: 
http://clinicaltrials.gov/show/NCT01989156 NLM Identifier: NCT01989156. 
30. Ludicke F, Picavet P, Baker G et al. Effects of switching to the Tobacco Heating System 
2.2 menthol, smoking abstinence, or continued cigarette smoking on biomarkers of 
exposure: a randomized, controlled, open-Label, multicenter study in sequential 
confinement and ambulatory settings (part 1). Nicotine Tob Res 2017. 
31. Ludicke F, Picavet P, Baker G et al. Effects of switching to the menthol Tobacco 
Heating System 2.2, smoking abstinence, or continued cigarette smoking on clinically 
relevant risk markers: a randomized, controlled, open-label, multicenter study in 
sequential confinement and ambulatory settings (part 2). Nicotine Tob Res 2017. 
32. Mottier N, Tharin M, Cluse C et al. Validation of selected analytical methods using 
accuracy profiles to assess the impact of a Tobacco Heating System on indoor air 
quality. Talanta 2016; 158: 165-78. 
33. Mitova MI, Campelos PB, Goujon-Ginglinger CG et al. Comparison of the impact of the 
Tobacco Heating System 2.2 and a cigarette on indoor air quality. Regul Toxicol 
Pharmacol 2016; 80: 91-101. 
34. Schaller JP, Pijnenburg JP, Ajithkumar A, Tricker AR. Evaluation of the Tobacco 
Heating System 2.2. Part 3: influence of the tobacco blend on the formation of harmful 
and potentially harmful constituents of the Tobacco Heating System 2.2 aerosol. Regul 
Toxicol 
Pharmacol 
2016; 
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2. 
Available 
from: 
http://www.sciencedirect.com/science/article/pii/S0273230016303051 (Accessed on 03 
May 2017): S48-58. 
35. Philip Morris Products S.A. Unpublished on file data: Summary of product information 
(SPI) - iQOS with HeatSticks. Version 2.0. 2017. 
 

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without the written consent of Philip Morris Products S.A 
APPENDIX A 
SCHEDULE OF EVENTS 
 
Variable 
Screening and 
Enrollment 
Non-Exposure 
Events 
Exposure 
Events 
CASI Questionnaire  
 
 
 
Informed Consent 
● 
 
 
Inclusion and Exclusion Criteria 
● 
●g 
● g 
Selection of Event Dates 
● 
 
 
Enrollment in the Study 
● 
 
 
Demographics 
● 
 
 
Self-reported tobacco and nicotine-
containing product use 
● 
 
 
Self-Reported Health Outcomes and 
Events Questionnaire a 
● 
 
 
Exposure and Non-Exposure 
Events 
 
 
 
Registration and Check In b 
 
● 
● 
Self-Reported Health Outcomes and 
Events Questionnaire a 
 
● 
● 
Recording of Product Use during 
Event c 
 
● 
● 
Indoor Air Quality Assessment d 
 
● 
● 
Dinner and Drink 
 
● 
● 
Self-reported tobacco and nicotine-
containing product use 
 
● 
● 
Spot Urine for Biomarker of 
Exposure Assessment e 
 
● 
● 
Check Out f 
 
● 
● 
a: Questionnaire to assess if the participants had a medical history of severe cardiovascular or respiratory 
diseases (e.g., stroke, acute cardiovascular event, pulmonary thrombosis) as self-reported in the last 12 
months, has a currently active cancer or history of cancer within the last 5 years or is pregnant or breast-
feeding. 
b:  see Table 7 and Table 8 
c: Collection of used IQOS HeatSticks for product use counting purposes and recording by PI. 
d: Assessment of IAQ parameters as defined in section 7.3.8. 
e:  Spot urine will be collected before and during the 4-hour Event. A minimum of two spot urine must be 
collected (one prior to the Event and one after post 2-hour Event. The latest spot urine should be kept from 
the post-2 hour spot urine collection 
f: Check out procedures, i.e. time of departure, confirm that all required urine samples have been provided and 
collected and registered. 

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g: Re-check of Self-reported Health Outcomes and Events questionnaire and Self-reported Tobacco and 
Nicotine-containing product use questionnaire 

Philip Morris Products SA 
Assessment Study Protocol 
Confidential 
P1-PES-01-JP 
Final 1.0 / 10th OCT 2017  
Page 70 of 70 
Related to PMI_RD_WKI_000759 
 
 
 
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 B 
LIST OF PARTICIPATING LABORATORIES 
The following laboratories will be used in the study: 
Laboratory for analysis of urine samples 
for BoExp assessment: 
Celerion Lincoln 
 
 
and/or 
Celerion Zurich 
 
 
 
 
Laboratory for analysis of IAQ 
assessment: 
ABF GmbH