An Observational Cohort Study in Japan to Assess the Patterns of Product Use and Changes in Health Outcomes Associated With the Use of HeatSticks With the IQOS Tobacco Heating System
Conditions: Smoking, Tobacco Product
Sponsor: Philip Morris Products S.A.



Philip Morris Products S.A. 
Observational Study Protocol 
Confidential 
P1-PMC-01-JP 
Final Version 6.0 
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without the written consent of Philip Morris Products S.A. 
SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchatel 
Switzerland 
Name of Product: 
IQOS 
Study Title: 
An observational cohort study in Japan to assess the patterns of product use and changes in 
health status associated with the use of HeatSticks with the IQOS tobacco heating system 
Study Number: 
P1-PMC-01-JP 
Study Short Title: 
Japanese Post-Market Cohort Study 
Objectives and Endpoints: 
The objectives and endpoints of this study will be analyzed in the study population of adults 
legally authorized to buy tobacco products. The Study will describe the patterns of use of 
tobacco and nicotine containing products and self-reported health outcomes and health 
related events in CC (Combustible Cigarette) smokers and IQOS users.  
Originally, the Study included a Clinical Sub-Study which would further assess the 
population level differences in levels of Biomarkers of Exposure (BoExp) to Harmful and 
Potentially Harmful Constituents (HPHC) contained in cigarette smoke, Clinical Risk 
Endpoints (CREs) and self-reported health outcomes and health related events between CC 
smokers, IQOS users and never-smokers. However, as recruitment into this part of the study 
had extremely low acceptance and there was little interest in participation from those 
enrolled in what was called the Main Study, it was decided to terminate the Clinical Sub-
Study earlier than planned. So far, out of the 570 participants to be enrolled in the Clinical 
Sub-Study during the first wave, only 5 had completed a Clinical Site Visit. 
Study Objectives: 
The objectives and endpoints of the Study are: 
1. To characterize and describe patterns of use of tobacco and nicotine containing products 
Endpoints: 

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 Mean number of cigarettes smoked (per day and/or per week) over time 
 Mean number of IQOS HeatSticks used (per day and/or per week) over time 
 Mean number of times e-cigarettes are used (per day and/or per week) over time 
 Product use patterns over time (individual and dual/poly use patterns) 
 Rate of increase or decrease in product use over time 
2. To identify intra-individual product use trajectories over time 
Endpoints: 
 Product switching 
 Uptake of new products 
 Rate of tobacco and nicotine product use transitions, within a given timeframe 
3. To describe the cessation rates of tobacco and nicotine containing products including CC 
over time 
Endpoints: 
 Rate of cessation of tobacco or nicotine containing products use, overall as well as by 
consumption within a given timeframe 
 Rate of cessation from CC use overall as well as by consumption within a given 
timeframe 
4. To identify and assess the motivations for quitting tobacco use and to characterize the 
quit attempts by product use over time 
Endpoints: 
 Rate and number of participants that want to quit 
 Reasons for wanting to quit 
 Rate and number of self-reported quit attempts 
 Characteristics of the quit attempts, including: 
- 
Length of quit attempt 
- 
Type of product used to help in quit attempts (if applicable) 
- 
Reasons for quit attempt 
- 
Outcome of quit attempt 
5. To characterize the users of tobacco and nicotine containing products over time 
Endpoints: 
 Demographics and socioeconomic characteristics of tobacco and nicotine containing 
products users 

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 Smoking history of tobacco and nicotine containing products users 
 Pre- IQOS tobacco and nicotine containing product usage and behaviors 
6. To assess subjective effects including urge to smoke, product reinforcement and self-
observed aesthetic improvements over time 
Endpoints: 
 Total score and factor scores from the Questionnaire on Smoking Urges-brief version 
(QSU-b) by product use 
 Subscales from the Modified Cigarette Evaluation Questionnaire (MCEQ) in IQOS 
users 
 Self-Reported Changes Questionnaire (SRCQ) in IQOS users. 
7. To assess the perception of risk associated with tobacco and nicotine containing products 
by product use over time 
Endpoints: 
 Perceived Risk Instrument (PRI-P) to measure perception of risk associated with 
using CC, IQOS and e-cigarettes based on exposure group at the time of assessment 
using the following domains: 
- 
Perceived Health Risk 
- 
Perceived Addiction Risk 
- 
Perceived Harm to Others 
8. To assess the strength of nicotine dependence by product use over time 
Endpoints: 
 Score from the Fagerström Test for Nicotine Dependence (FTND) questionnaire 
9. To describe the rates of self-reported signs, symptoms and diagnoses by product use over 
time 
Endpoints: 
 Signs and symptoms 
 Cardiovascular disease diagnoses: myocardial infarction, stroke, new diagnoses of 
hypertension, unstable angina, or other cardiovascular diseases 
 Respiratory diseases diagnoses: new diagnoses of chronic obstructive pulmonary 
disease (COPD), or other respiratory diseases, including asthma exacerbations 
 Malignancy diagnoses: all malignancies, including smoking-related malignancies 
(i.e., lung, larynx, and bladder) 
10. To summarize the number of health related events (hospitalizations) 

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Endpoints: 
 Rate of prevalence of emergency room visits and/or hospitalization reported by 
product use over time 
 Frequency 
of 
diagnoses 
associated 
with 
emergency 
room 
visits 
and/or 
hospitalizations reported over time 
11. To assess coughing by product use 
Endpoints: 
 Cough impact assessed by Visual Analog Scale (VAS), 
 Frequency and intensity of cough using the cough assessment 
  
Evaluation Criteria: 
The Study is observational in nature and therefore designed to identify product use patterns 
and assess the incidence of product use transitions and health outcomes in IQOS users and 
CC smokers. 
 
Study Design: 
This is a prospective, observational, open cohort study of adults, legally authorized to 
purchase tobacco products in Japan. The Study will describe the patterns of use of tobacco 
and nicotine containing products and self-reported health outcomes in CC smokers and IQOS 
users. Participants will be recruited into the cohort in annual waves over a period of about 
4 years. 
For IQOS users, the date of initiation of IQOS use is the trigger for all study assessments in 
the Study. However the process will be different for CC smokers for whom assessment 
timing will be based on the date of enrollment. IQOS users will be enrolled into the study at 
least 2 months after initiating use of IQOS (to ensure adoption of IQOS), but less than 12 
months after initiating use of IQOS (to ensure that each annual wave targets new users), the 
study assessments will start at the next appropriate study time point after enrollment.  
As this study is observational by design and is conducted in a post-market setting, adverse 
event (AE) reporting will follow the Sponsor’s established post-market Safety Surveillance 
Procedures for spontaneously reported events. IQOS users will be reminded of the product 
quality complaints (including AEs) hotline that is available for all IQOS consumers in Japan.  
IQOS users will be identified and invited for participation in the study until each annual 
wave of 500 participants is filled. Additionally, CC smokers will be recruited into the study, 
also in annual waves of 500, resulting in a total cohort size of 4000 participants (2000 per 

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exposure group) in the Study. Initially, there will be no quotas or restrictions on enrollment 
into the study; however, the study population will be monitored and quotas may be 
introduced to ensure representativeness within their target populations in the following 
annual waves. 
All participants enrolled in the Study will answer the computer assisted self-interviews 
(CASIs) which will include demographic information, the core questionnaire (which is a 
questionnaire including questions about smoking history, detailed product use and intention 
to stop tobacco and nicotine containing product use), lifestyle assessments, socio-economic 
status, the Questionnaire on Smoking Urges-brief version (QSU-b), the Perceived Risk 
Instrument (PRI-P), the Fagerström Test for Nicotine Dependence (FTND) questionnaire, 
self-reported health outcomes (symptoms and diagnoses) and health related events 
(hospitalizations), and the cough assessment, IQOS users will also be administered the 
Modified Cigarette Evaluation Questionnaire (MCEQ) and the self-reported changes 
questionnaire (SRCQ). The CASI provider for wave 1 is 
 and from wave 2 onwards it 
will be 
. 
 
Participant Identification and Enrollment: 
IQOS users will be identified via: 1) Philip Morris – Japan (PM-JP)’s consumer   database, 
and/or 2) through public advertisements, in which potential participants will be directed to 
log into the Study Database for screening and invited to participate in the Study. CC smokers 
will be identified in three ways: 1) through Philip Morris – Japan (PM-JP)’s consumer 
database, 2) market research and other available databases (e.g., 
s market research 
database), and 3) through public advertisements, in which potential participants will be 
directed to log into the Study Database for screening and invited to participate in the study. 
Potential participants for the Study will be sent an invitation for the study that will direct 
them to the Study Website where they will find more information about the Study. Interested 
participants, will click on a link that will re-direct them to the 
 portal for wave 1 
participants and once wave 2 is launched, to the 
 portal to register for the Study. 
Participants will confirm registration by logging into the system where they will then 
complete the informed consent, before being administered the “screening domain” of the 
CASI which is the set of questions and questionnaires to evaluate the participants’ eligibility 
for participation in the Study (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. Once a participant confirms participation 
in the Study, they are considered enrolled. Enrolled participants will be presented with the 
“baseline domain”, the set of questions and questionnaire to capture the detailed 
demographics, socio economic status and participant smoking status at their entry into the 
study. All IQOs participants will fill their baseline questionnaire at time of entry. After 
baseline CASI, the next CASI is dependent on the exposure time to IQOS.  IQOS 

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participants will not complete a CASI if their baseline CASI is within the timeframe (± 4 
weeks of the next required CASI). This aims to limit the time necessary for the study 
participant to complete the questionnaires. 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 it at any time, but all data 
already provided by them, 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. 
After Enrollment Through Month 18: 
During the first 18 months of the Main Study the CASI ‘follow-up domains’ will be 
administered on a quarterly basis (every 3 months ± 4 weeks), for up to 6 times at Months 3, 
6, 9, 12, 15 and 18 respectively. 
 
After Month 18 Through Year 3: 
During the second 18 months of the Main Study the CASI ‘follow-up domains’ will be 
administered on a bi-annual basis (every 6 months ± 4 weeks) in total 3 times, at Months 24, 
30, and 36. 
After Year 3 through Year 5: 
During the last 2 years of the Main Study the CASI “follow-up domains” will be 
administered on an annual basis (every 12 months ± 4 weeks), up to 2 times, at Months 48, 
and 60 respectively. 
Study Population and Main Criteria for Inclusion: 
Female or male adult participants meeting the following main criteria: 
Inclusion Criteria: 
 Adults legally authorized to buy tobacco products in Japan (20 years of age) 
 The participant is Japanese 
 Participant is able to understand the information provided in the  Informed Consent form 
(ICF). 
 Signed informed consent form 
 Willing to participate in the study and has access to the internet 
 For IQOS users: 
- 
Is currently using IQOS HeatSticks 

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- 
Has used at least 100 IQOS HeatSticks in their lifetime, and 
- 
Has used IQOS HeatSticks for 2 months or more 
Note: The use of IQOS HeatSticks defines the user as an IQOS user, regardless of other 
tobacco or nicotine product use. 
 For CC smokers: 
- 
Is currently using CC 
- 
Is not currently using IQOS HeatSticks, and 
- 
Has used at least 100 CC in their lifetime 
Exclusion Criteria: 
 Tobacco industry employees 
 Employed by the Sponsor, CRO or Clinical Site 
 For IQOS users: 
- 
More than 12 months of IQOS use 
 For Former Smokers: 
- 
Is not currently using CC 
- 
Is not currently using IQOS HeatSticks, and 
- 
Has used at least 100 CC and/or IQOS HeatSticks in their lifetime 
 
- 
 
Investigational Product; Dose; and Mode of Administration: 
Not Applicable 
Duration of Study: 
The study will have a follow up of a maximum of 5 years, the recruitment will be open for 
the first 4 years of the study. The minimum planned follow-up for any given participant will 
be 1 year. 
Statistical Methods: 
All data will be presented in listings, ordered by product use group at study entry, unless 
otherwise specified. 
Descriptive statistics will be provided by usage groups for endpoint parameters at each 
collection time point. 
Descriptive statistics for continuous variables (number of participants [n], number and 

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percent of participants with data, mean, standard deviation [SD], median, first and third 
quartiles, minimum and maximum for continuous data, and the n and absolute and relative 
[%] frequency for categorical data) will be presented by arm at each time point. Summary 
statistics of the endpoints will include changes over time when applicable. 
Sample Size: 
A total of 4000 participants will be enrolled in the Main Study. Enrollment will happen in 
four annual waves. 
Considering an annual drop-out rate of 5% and a maximum of 20% of participants changing 
from CC smoker or IQOS user to another group annually, the person-year pool in each group 
will be for each annual analysis as described in the below table: 
Table 11 
Summary of Person-Years - Pooled for Annual Analyses 
Wave 
Year 1 
Report 
Year 2 
Report 
Year 3 
Report 
Year 4 
Report 
Year 5 
Report 
Person-Years 
per Wave 
1 
375 
281 
210 
157 
117 
1140 
2 
 
375 
281 
210 
157 
1023 
3 
 
 
375 
281 
210 
866 
4 
 
 
 
375 
281 
656 
Total 
(person-years) 
375 
1031 
1897 
2920 
3685 
 
This sample size is sufficient to detect for the trajectories analysis, using the assumption of 
20% participants switching to another group, an incidence of 1% of participants switching 
with a precision of less than 1.32% after one year using the first wave at the first analysis and 
up to 0.62% the final analysis. 
 

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TABLE OF CONTENTS 
SYNOPSIS .............................................................................................................................. 33 
TABLE OF CONTENTS ........................................................................................................ 41 
LIST OF IN-TEXT TABLES ................................................................................................. 42 
LIST OF IN-TEXT FIGURES ................................................................................................ 43 
LIST OF APPENDICES ......................................................................................................... 43 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................... 44 
1 
ETHICS AND REGULATIONS .................................................................................... 49 
1.1 
Institutional Review Board (IRB) Approval ......................................................... 49 
1.2 
Ethical Conduct of the Study ................................................................................ 49 
1.3 
Participant Information and Consent .................................................................... 50 
1.4 
Good Epidemiological Practice ............................................................................ 50 
2 
INTRODUCTION .......................................................................................................... 51 
2.1 
Background ........................................................................................................... 51 
2.2 
Study Rationale ..................................................................................................... 53 
2.3 
Anticipated Benefits and Risks ............................................................................. 53 
3 
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 54 
3.1 
Main Study Objectives and Endpoints .................................................................. 54 
4 
INVESTIGATIONAL PLAN ......................................................................................... 57 
4.1 
Overall Study Design and Plan ............................................................................. 57 
4.2 
Rationale for Study Design and Control Group(s) ............................................... 59 
4.3 
Appropriateness of Measurements ........................................................................ 60 
4.4 
Study Duration ...................................................................................................... 60 
4.5 
Study Objectives and Endpoints ........................................................................... 60 
5 
STUDY POPULATION ................................................................................................. 63 
5.1 
Selection of Study Population ............................................................................... 63 
5.2 
Recruitment Strategies and Retention ................................................................... 64 
5.3 
Discontinuation of Participants from the Study .................................................... 64 
5.4 
Loss to Follow-Up ................................................................................................ 65 
5.5 
Violation of Selection Criteria .............................................................................. 65 
6 
RESTRICTIONS AND SUPPORT DURING THE STUDY ........................................ 66 
7 
STUDY PROCEDURES ................................................................................................ 67 
7.1 
Study Assessments ................................................................................................ 67 
8 
SAFETY REPORTING .................................................................................................. 72 

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8.1 
Definitions ............................................................................................................. 72 
8.2 
Assessment of Adverse events .............................................................................. 72 
9 
STUDY ACTIVITIES .................................................................................................... 73 
9.1 
Screening ............................................................................................................... 73 
9.2 
Recruitment Period ............................................................................................... 73 
10 QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 75 
10.1 
Monitoring ............................................................. Error! Bookmark not defined. 
10.2 
Training of Staff .................................................................................................... 75 
10.3 
Audits and Inspections .......................................................................................... 75 
11 DATA MANAGEMENT ACTIVITIES ......................................................................... 76 
11.1 
Data Capture ......................................................................................................... 76 
11.2 
Data Handling ....................................................................................................... 76 
12 PLANNED STATISTICAL METHODS ....................................................................... 78 
12.1 
General Considerations ......................................................................................... 78 
12.2 
Derived and Computed Variables ......................................................................... 82 
12.3 
Analysis Populations ............................................................................................. 84 
12.4 
Study Analysis ...................................................................................................... 84 
12.5 
Interim Analysis .................................................................................................... 88 
13 ADMINISTRATIVE CONSIDERATIONS ................................................................... 89 
13.1 
Study Investigators and Study Administrative Structure ...................................... 89 
13.2 
Participant Confidentiality .................................................................................... 90 
13.3 
Access to Source Documentation ......................................................................... 91 
13.4 
Record Retention .................................................................................................. 91 
13.5 
Study Report ......................................................................................................... 92 
13.6 
Financial Disclosure ............................................... Error! Bookmark not defined. 
13.7 
Publication and Disclosure Policy ........................................................................ 92 
13.8 
Insurance ............................................................................................................... 92 
14 APPENDICES ................................................................................................................ 93 
15 REFERENCE LIST ...................................................................................................... 105 
 
LIST OF IN-TEXT TABLES 
Table 1 
Summary of Person-Years - Pooled for Annual Analyses ........................ 40 
Table 2 
Inclusion Criteria ...................................................................................... 63 
Table 3 
Exclusion Criteria ..................................................................................... 64 

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Table 4 
Current Behaviors Definitions (percentages defined in 12.2)Error! Bookmark not define
Table 5. 
Events Definition ....................................... Error! Bookmark not defined. 
Table 6 
Expected person-time pool for each annual analysis ................................ 83 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ............................................................................................. 57 
Figure 2 
Definition of Annual Waves for IQOS users ............................................ 74 
Figure 3 Definition of Annual waves for CC smokers ..................................................... 74 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .................................................................................... 93 
Appendix 2 
 Core Questionnaires ................................................................................. 95 
Appendix 3 
Socio-Economic Status Questionnaire ...................................................... 96 
Appendix 4 
Cough Assessment Questionnaire ............................................................. 97 
Appendix 5 
MCEQ Questionnaire ................................................................................ 98 
Appendix 6 
QSU-b Questionnaire ................................................................................ 99 
Appendix 7 
Lifestyle Questionnaire ........................................................................... 100 
Appendix 8 
Perceived Risk Instrument (PRI-P) ......................................................... 101 
Appendix 9 
Self-reported Changes Questionnaire ..................................................... 102 
Appendix 10 Fagerström Test for Nicotine Dependence ............................................. 103 
Appendix 11 Signs and Symptoms & Self-Reported Outcomes Questionnaire ........... 104 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
AE 
Adverse event 
AT 
Analysis Time 
BoExp 
Biomarker of exposure 
CASI 
Computer assisted self-interview 
CBi 
Current Behavior 
CC 
Combustible cigarette 
CC-Cessi 
CC Cessation at measurement time i 
CCi 
Current CC smoker at measurement time i 
CCdeci 
CC decrease at measurement time i 
CEi 
Current Events 
CCinci 
CC increase at measurement time i 
COPD 
Chronic obstructive pulmonary disease 
CPDi 
Average CC consumption 
CRE 
Clinical risk endpoint 
CCreli 
CC Relapse at measurement time i 
CRF 
Case report form 
CRO 
Contract research organization 
DU_THS_CCi  
Dual THS – CC at measurement time i 
DU_THS_OTPi 
Dual THS – OTP at measurement time i 
 
 
 
 
EC 
Ethics Committee 
ePDi 
Average daily e-cigarette consumption at measurement 
time i 
FDA 
Food and Drug Administration 
FTND 
Fagerström Test for Nicotine Dependence 
GEP 
Good Epidemiological Practice 

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HnB 
Heat-not-Burn products 
HnBuptakei 
HnB uptake at measurement time i 
HPHC 
Harmful and potentially harmful constituent 
Icci 
CC initiation at measurement time i 
IOTPi 
OTP initiation at measurement time i 
ITHSi 
THS initiation at measurement time i 
ITHSi_brand name 
THS initiation by brand at measurement time i 
IB 
Initial Behavior 
IEA 
International Epidemiological Association 
ICF 
Informed consent form 
IOM 
Institute of Medicine  
IRB 
Institutional Review Board 
 
 
LB 
Last Behavior 
MCEQ 
Modified Cigarette Evaluation Questionnaire 
MRTPs 
Modified risk tobacco products 
MTi 
Measurement Time 
Non_Smokeri 
Non User/Smoker 
Occ_Smokeri 
Occasional User/Smoker at measurement time i 
Occ_THSi 
Occasional THS User at measurement time i 
Occ_THS_CCi 
Occasional THS – CC User at measurement time i 
Occ_THS_CC_OTPi Occasional THS – CC – OTP User at measurement time
i 
Occ_THS_OTPi 
Occasional THS – OTP User at measurement time i 
OTP 
Other tobacco product 
OTP-Cessi 
OTP Cessation at measurement time i 
OTPDi 
Average daily OTP consumption at measurement time 
i 
OTPreli 
OTP Relapse at measurement time i 

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PMI 
Philip Morris International 
PMP 
Philip Morris Products S.A. 
PM-JP 
Philip Morris - Japan 
PRI-P 
Perception Risk Instrument  
PT 
Individual Person Time 
QAj 
Quit Attempt at measurement time i 
QSU-b 
Questionnaire on smoking urges – short form  
Re-Icci 
CC re-initiation at measurement time i 
Re-ITHSi 
THS re-initiation at measurement time i 
QSU-b 
Questionnaire on smoking urges – short form  
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SES 
Socio-economic status 
 
 
Si 
First Switch from Initial Behavior to another Behavior 
SOP 
Standard operating procedure 
SRCQ 
Self-Reported Changes Questionnaire  
STi 
Study Time 
THS 
Tobacco Heating System 
THSPDi 
Average daily THS consumption at MTi 
THS-Cessi 
THS Cessation at measurement time i 
THSdeci 
THS decrease at measurement time i 
THSinci 
THS increase at measurement time i 
THSreli 
THS relapse at measurement time i 
THSuptake 
THS uptake  
WHO 
World Health Organisation 
 
Definitions of Terms 

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Cessation 
Person who: 
 Is not currently using CC or IQOS HeatSticks 
 Has quit using CC and/or IQOS HeatSticks for at least 1 
year 
 Has used at least 100 CC and/or IQOS HeatSticks in their 
lifetime 
Current CC Smoker 
Person who: 
 Is currently using CC 
 Is not currently using IQOS HeatSticks 
 Has used at least 100 CC in their lifetime 
Current IQOS user 
Person who: 
 Is currently using IQOS HeatSticks 
 Has used at least 100 IQOS HeatSticks in their lifetime. 
Current Smoker 
Person who: 
 Is currently using CC or IQOS HeatSticks 
 Has used at least 100 CC and/or IQOS HeatSticks their 
lifetime 
Domain(s) 
A domain is a set or group of questionnaires administered to a 
participant at a specific point in time. 
 
Screening Domain: the domain administered after informed consent 
to determine if a participant qualifies for participation in the study. 
Enrollment Domain: the domain administered after screening where 
participants confirm their participation in the study. 
Baseline Domain: the domain administered after the Enrollment 
Domain to capture the baseline information on each participant 
Follow-up Domain: the domain administered to collect the 
participant-reported study assessments at each study time point. 
 
Former CC Smoker 
Person who: 
 Is not currently using CC 
 Has used at least 100 CC in their lifetime. 
Former IQOS user 
Person who: 
 Is not currently using IQOS HeatSticks 
 Has used at least 100 HeatSticks in their lifetime. 

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Former-Smoker 
Person who: 
 Is not currently using CC 
 Is not currently using IQOS HeatSticks 
 Has used at least 100 CC and/or IQOS HeatSticks in their 
lifetime. 
Lost to follow-up 
(date) 
The date of lost to follow-up corresponds to the date of the last 
contact attempt for the participant by 
 Helpdesk. 
 
  
Study completion: 
The study enrollment will be completed once the 4th annual wave is 
closed, and the study will be concluded when 1 year of follow-up is 
complete on the last participant is enrolled. 

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1 
ETHICS AND REGULATIONS 
1.1 
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, the Principal Investigator’s (PI) curriculum vitae and/or other evidence of 
qualificationsand any other documents requested by the Institutional Review Board [IRB]), 
will be submitted for review and approval to the relevant IRB. The IRB shall be 
appropriately constituted 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 IRB approval should be provided to the Sponsor. This should 
identify the study (PI’s name, study number and title) and the documents that have been 
approved by the IRB, with dates and version numbers, as well as the date of approval. The 
composition of the IRB, including the name and occupation of the chairperson, should be 
supplied to the Sponsor. 
The written approval from the IRB will be filed in the Investigator file, and another original 
copy will be filed in the study master file at the Sponsor or designated organization. The 
study must not start before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IRB. 
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the PI. All amendments will be submitted to the 
IRB, and substantial amendments will only be implemented after approval by the IRB. 
These requirements for approval should in no way prevent any action from being taken by 
the PI or sub-Investigator or 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 PI, 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 PI agrees to conduct 
the study in compliance with the protocol agreed upon with the Sponsor and approved by the 
IRB. The PI and the Sponsor must sign the protocol (and protocol amendments, if applicable) 
to confirm this agreement. A copy of the declaration of Helsinki should be located in the PI’s 
study file. 

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1.3 
Participant Information and Consent 
1.3.1 
Informed Consent/ for the Study 
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 the 
 portal for wave 1 participants and once wave 2 
is launched, to the 
 portal to register for the study and give informed consent. The 
ICF will be administered electronically for participants of the Study and it 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 them, will be retained in the 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. They will also be informed about 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/Participant Information Sheet. 
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 PI will, with the support of the Sponsor, ensure 
that the documents have been reviewed and approved by a relevant 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 investigator abide 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 addition, the PI or 
designee will carry out the study in accordance the Ethical Guidelines for Medical and Health 
Research Involving Human Subjects (2). 

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2 
INTRODUCTION 
2.1 
Background 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy 
Tobacco use is a major public health problem worldwide as it is a well-known risk factor for 
many life threatening diseases. Tobacco use leads most commonly to cardiovascular and 
pulmonary disease and is a major risk factor for myocardial infarction, stroke, chronic 
bronchitis, cancers of mouth, throat, voice box and pancreas (4). Half of all long-term 
smokers will die of a tobacco-related condition (5). 
The best way to reduce the adverse health consequences of smoking is to quit smoking (6, 7). 
Because of the impact that smoking has on health and the fact that total smoking cessation is 
difficult to achieve (8, 9), the FDA drafted guidelines for application of modified risk 
tobacco products (MRTPs) that would either have reduced exposure to tobacco toxicants 
and/or reduced risk of developing tobacco-related diseases (10). For those smokers who are 
not willing to quit, Philip Morris Products (PMP) is developing alternative approaches by 
developing products with the potential to reduce the risks of tobacco-related diseases under 
the FDA draft guidelines for MRTP (10). 
PMP’s approach to scientifically assessing the risk-reduction potential of its candidate 
MRTPs is described in the reference document (11). Smoking cessation is the only 
intervention proven to reduce the risk of smoking-related diseases in smokers. Accordingly, 
PMP utilizes smoking cessation/smoking abstinence as the benchmark for assessing the risk 
reduction potential of its candidate MRTPs. The Institute of Medicine (IOM) observed that 
cessation is the “gold standard” for assessing risk reduction, and that “the closer risks and 
exposures from the MRTP are to cessation products, the more confident a regulator can be of 
achieving a net public health benefit” (12). PMP has already conducted studies and plans to 
conduct further clinical studies which observe measurable changes in blood chemistry, risk 
factors and health effects in smokers who switch to a candidate MRTP, comparing the 
changes with those observed in both smokers who continue smoking combustible cigarettes 
(CC) and smokers who stop using tobacco products. 
In order to substantiate clinical study findings PMP according to FDA’s draft guidelines, 
longer-term data from adults who continue to use the candidate MRTP will be needed. This 
is because not only decreased exposure to tobacco toxicants and reduced risk for smoking 
associated diseases need to be ascertained, but because patterns of use of the candidate 
MRTPs are vital to determine population harm. 

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without the written consent of Philip Morris Products S.A. 
2.1.2 
Description of the PMP’s First Candidate MRTP and Scientific Findings 
Thousands of chemicals - “smoke constituents” - are formed when tobacco is burned or 
combusted. More than 5000 smoke constituents have been identified (13, 14), and more than 
100 of them have been categorized as harmful and potentially harmful constituents (HPHCs) 
(15). PMP’s focus has been on the development of products that do not combust tobacco but 
heat tobacco while replicating the “smoking experience” as much as possible. The approach 
being used by heating tobacco at significantly lower temperatures than CC limits pyrolysis 
and combustion. PMP believes that such heat-versus-burn products present the best 
opportunity for reducing harm as they produce vastly lower levels of HPHCs and are more 
likely to be accepted by smokers as substitutes for cigarettes. Important to this effort has been 
providing nicotine in a way that closely parallels CC and closely replicate taste, sensorial 
experience and ritual of that of a CC. 
The product developed by PMP, and to be assessed in this study, is the IQOS Tobacco 
Heating System (THS) (referred to as the IQOS). With this product, the heating of the 
tobacco is maintained below 400°C, a temperature much lower than what is observed for CC, 
which can reach 900°C. The IQOS is composed of the ‘Tobacco Stick Holder’, dedicated 
special IQOS HeatSticks, a Charger, and different accessories. The energy of the IQOS 
Tobacco Stick Holder is sufficient to maintain approximately a 6-minute session. Unlike CC, 
the IQOS HeatSticks do not burn down during their consumption and their lengths remain 
constant after use. 
The non-clinical assessment of IQOS supported the initiation of the clinical studies (16). No 
new or increased toxicological hazard in the product’s aerosol was detected compared with 
CC smoke and aerosol chemistry studies have shown a reduction of up to 90% in HPHC’s 
(16). Several clinical studies have been conducted on an earlier version of IQOS (THS 1.0), 
in Europe, Asia, Africa and the United States. All studies showed reductions in exposure to 
the majority of measured HPHCs from both aerosol fractions, total particulate matter (TPM) 
and gas vapor phase (GVP), in participants using the THS 1.0 as compared to participants 
continuing smoking CC, both, in controlled and ambulatory setting. THS 2.1, the immediate 
predecessor of the non-menthol current IQOS, was tested in two exploratory clinical studies 
to measure the nicotine pharmacokinetic profile (PK) (17) and to assess the reduction of 
exposure to HPHCs when switching from CC to THS 2.1 (18). The observed nicotine PK 
profile for THS 2.1 was similar to CC and there were significant reductions in the exposure 
to the majority of selected HPHCs. In 2013, eight clinical studies were initiated in US, 
Europe, and Japan in order to evaluate the nicotine PK profile, to demonstrate reduced 
exposure, and to determine functional and biological changes following the switching from 
CC to THS in smokers as compared to smokers continuing smoking CC and smoking 
abstinence (SA). The reporting of the results is currently ongoing. 
Clinical studies conducted and ongoing so far on about 3000 participants revealed no safety 
concern for THS 2.2 and its earlier prototypes. 

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2.2 
Study Rationale 
In order to support PMP’s pre-clinical and clinical programs in assessing the exposure and 
risk reduction of the IQOS, post-marketing and in particular observational data is needed to 
collect information on how the product is used in the ‘real world’ (19). This Study will 
therefore allow us to assess the patterns of product use and changes in health status 
associated with the use of the IQOS, compared to CC smokers.  
Originally, the Study included a Clinical Sub-Study which would further assess the 
population level differences in levels of Biomarkers of Exposure to Harmful and Potentially 
Harmful Constituents (HPHC) contained in cigarette smoke, Clinical Risk Endpoints (CREs) 
and self-reported health outcomes and health related events between CC smokers, IQOS 
users and never-smokers. However, as recruitment into this part of the study was extremely 
low and there was little interest in participation from those enrolled in what was called the 
Main Study, it was decided to terminate the Clinical Sub-Study earlier than planned. 
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 to the understanding of how IQOS and other tobacco and nicotine 
containing products are used. 
2.3.2 
Anticipated Foreseeable Risks Due to Study Procedures 
There are no anticipated risks associated with participation in the Study. 
 

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without the written consent of Philip Morris Products S.A. 
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives and Endpoints 
 
1. To characterize and describe patterns of use of tobacco and nicotine containing products 
Endpoints: 
 Mean number of cigarettes smoked (per day and/or per week) over time 
 Mean number of IQOS HeatSticks used (per day and/or per week) over time 
 Mean number of times e-cigarettes are used (per day and/or per week) over time 
 Product use patterns over time (individual and dual/poly use patterns) 
 Rate of increase or decrease in product use over time 
2. To identify intra-individual product use trajectories over time 
Endpoints: 
 Product switching 
 Uptake of new products 
 Rate of tobacco and nicotine product use transitions, within a given timeframe 
3. To describe the cessation rates of tobacco and nicotine containing products including CC 
over time 
Endpoints: 
 Rate of cessation of tobacco or nicotine containing products use, overall as well as by 
consumption within a given timeframe. 
 Rate of cessation from CC use overall as well as by consumption within a given 
timeframe 
4. To identify and assess the motivations for quitting tobacco use and to characterize the 
quit attempts by product use over time 
Endpoints: 
 Rate and number of participants that want to quit 
 Reasons for wanting to quit 
 Rate and number of self-reported quit attempts 
 Characteristics of the quit attempts, including: 
- 
Length of quit attempt 
- 
Type of product used to help in quit attempt (if applicable) 

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- 
Reasons for quit attempt 
- 
Outcome of quit attempt 
5. To characterize the users of tobacco and nicotine containing products over time 
Endpoints: 
 Demographics and socioeconomic characteristics of tobacco and nicotine containing 
products users 
 Smoking history of tobacco and nicotine containing products users 
 Pre- IQOS tobacco and nicotine containing product usage and behaviors 
6. To assess subjective effects including urge to smoke, product reinforcement and self-
observed aesthetic improvements over time 
Endpoints: 
 Total Score and Factor scores from the Questionnaire on Smoking Urges-brief 
version (QSU-brief) by product use 
 Subscales from the Modified Cigarette Evaluation Questionnaire (MCEQ) in IQOS 
users 
 Self-Reported Changes Questionnaire (SRCQ) in IQOS users 
7. To assess the perception of risk associated with tobacco and nicotine containing products 
by product use over time 
Endpoints: 
 Perceived Risk Instrument (PRI-P) to measure perception of risk associated with 
using CC, IQOS and e-cigarettes based on exposure group at the time of assessment 
using the following domains: 
- 
Perceived Health Risk 
- 
Perceived Addiction Risk 
- 
Perceived Harm to Others 
8. To assess the strength of nicotine dependence by product use over time 
Endpoints: 
 Score from the Fagerström test for Nicotine Dependence (FTND) questionnaire. 
9. To describe the rates of self-reported signs, symptoms and diagnoses by product use over 
time 
Endpoints: 
 Signs and symptoms 

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 Cardiovascular disease diagnoses: myocardial infarction, stroke, new diagnoses of 
hypertension, unstable angina, or other cardiovascular diseases 
 Respiratory diseases diagnoses: new diagnoses of chronic obstructive pulmonary 
disease (COPD), or other respiratory diseases, including asthma exacerbations 
 Malignancies diagnoses: all malignancies, including smoking-related malignancies 
(i.e., lung, larynx, and bladder) 
10. To summarize the number of health related events (Hospitalizations) over time 
Endpoints: 
 Rate of prevalence of emergency room visits and/or hospitalization reported by 
product use over time 
 Frequency 
of 
diagnoses 
associated 
with 
emergency 
room 
visits 
and/or 
hospitalizations reported over time 
11. To assess coughing by product 
Endpoints: 
 Cough impact assessed by Visual Analog Scale (VAS), 
 Frequency and intensity of cough using the cough assessment 

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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a prospective open observational cohort study of Japanese adults, legally authorized 
to purchase tobacco products in Japan. The Study will describe the patterns of use of tobacco 
and nicotine containing products and self-reported health outcomes and health related events 
in CC smokers and IQOS users. 
Participants will be recruited into the cohort in 4 annual waves of 1000 participants per year 
(500 IQOS users and 500 CC smokers) until reaching the total study sample size of 4000 
participants (2000 per exposure group). The aim of these annual waves is to ensure the 
recruitment of new IQOS users, as the demographic characteristics of new IQOS users might 
change over time. 
For IQOS users, the date of initiation of IQOS use is the trigger for all study assessments the 
Study. However the process will be different for CC smokers for whom the questionnaire 
timing will be based on the date of enrollment. All participants enrolled in the Study will 
answer the computer assisted self-interviews (CASIs) which will include the following 
questionnaires: demographic information, core questionnaire (which is a questionnaire 
including questions about smoking history, detailed product use and intention to stop tobacco 
and nicotine containing product use), lifestyle assessments, SES, QSU-b, PRI-P, FTND,  
self-reported health outcomes (symptoms and diagnoses) and health related events 
(hospitalizations) questionnaire, and cough assessment questionnaire while IQOS users will 
also be administered the MCEQ and SRCQ. The CASI provider for wave 1 is 
and 
from wave 2 onwards it will be 
. 
Figure 1 
Study Design 

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4.1.1 
Identification of Potential Participants 
IQOS users will be identified via: 1) PM-JP’s consumer database, and/or 2) through 
advertisements, in which potential participants will be directed to the Study Website where 
they can obtain more information on the study and register their interest in participating in 
the study. 
The PM-JP’s consumer database collects information on consumers that buy and/or register 
their IQOS tobacco heating system device. During the registration process consumers can 
record their contact information and agree to the Terms and Conditions of PM-JP’s consumer 
database. Consumers that both provide contact information and have agreed to the Terms and 
Conditions will be contacted via email and invited to participate in the Study. The email will 
contain a link to the Study Website where they will get information about the study and if 
interested in participation they will be able to connect to 
s portal for wave 1 
participants and once wave 2 is launched, to the 
 portal. 
CC smokers will be identified in three ways: 1) PM-JP’s consumer database, 2) through 
market research or other available databases, and 3) through advertisements as previously 
described for IQOS users. CC smokers identified through the other databases will be 
contacted via email/SMS and invited to register for the study. 

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4.1.2 
Enrollment 
The “enrollment domain” is only made available to participants that qualify to enroll in the 
study, it asks participants to confirm their participation in the study. Once a potential 
participant confirms their participation they are considered enrolled in the study. These 
participants will then be administered the “baseline domain” which includes the following 
questionnaires: lifestyle assessments, SES, QSU-b, PRI-P, FTND, core baseline 
questionnaire  self-reported health outcomes (signs, symptoms and diagnoses) and health 
related events (hospitalizations), cough assessment and the MCEQ. All IQOs participants 
will fill their baseline questionnaire at time of entry. After baseline CASI, the next CASI is 
dependent on the exposure time to IQOS.  IQOS participants will not complete a CASI if 
their baseline CASI is within the timeframe (± 4 weeks of the next required CASI).  
  
4.1.3 
Follow-up 
During the Main Study the follow-up CASIs will be administered: 
Quarterly (every 3 months ± 4 weeks) for the first 18 months (up to 6 times), at Months 3, 6, 
9, 12, 15 and 18, 
 Bi annually (every 6 months ± 4 weeks) for the second 18 months (up to 3 times), at 
Months 24, 30, and 36, 
 Annually (every 12 months ± 4 weeks), for the last 2 years (up to 2 times), at Months 48, 
and 60. 
The follow-up domain will include the following questionnaires: core follow-up 
questionnaire , lifestyle assessments, SES, QSU-b, PRI-P, the FTND, self-reported health 
outcomes (signs, symptoms and diagnoses) and health related events (hospitalizations) 
questionnaire, cough assessment questionnaire and for IQOS users the MCEQ and the SRCQ 
as defined in the Schedule of Events. 
Participants will complete the follow-up domains online, without the need to attend the 
Clinical Site or a data collection center. 
4.2 
Rationale for Study Design and Control Group(s) 
This study is part of PMP’s assessment program for IQOS, providing information on how 
this product is used in “real life”. This includes consideration of areas such as the expected 
rates of use of the tobacco product by current tobacco users, the use of the tobacco product in 
conjunction with other tobacco products”. 
This study will: 

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 Provide a perspective of product use in a “real world setting”, where smoking CC in 
addition to IQOS is likely to occur (dual use). 
 Describe the incidence of smoking related diseases and symptoms in the different 
exposure groups. 
4.3 
Appropriateness of Measurements 
 
Endpoints related to subjective effects are selected based on their relevance as clinical 
phenomena connected to smoking or smoking cessation 
The questionnaires included in this study, for which there is an associated scoring algorithm, 
have been validated by other parties and have been reported in the literature (QSU-b, MCEQ, 
FTND) or have been validated internally (PRI-P). The different instruments and standalone 
items included in this study will undergo cognitive debriefing and linguistic validation prior 
to administration in the study. 
4.4 
Study Duration 
This study is an open cohort which will have a follow-up duration of up to 5 years. With a 
minimum follow-up per participant of 1 year. 
The cohort will remain open for enrollment for the first 4 years, with annual waves of 500 
IQOS users and 500 CC smokers for the Study.  
4.5 
Study Objectives and Endpoints 
The objectives and endpoints of the  Study are: 
1. To characterize and describe patterns of use of tobacco and nicotine containing products 
Endpoints: 
 Mean number of cigarettes smoked (per day and/or per week) over time 
 Mean number of IQOS HeatSticks used (per day and/or per week) over time 
 Mean number of times e-cigarettes are used (per day and/or per week) over time 
 Product use patterns over time (individual and dual/poly use patterns) 
 Rate of increase or decrease in product use over time 
2. To identify intra-individual product use trajectories over time 
Endpoints: 
 Product switching 

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 Uptake of new products 
 Rate of tobacco and nicotine product use transitions, within a given timeframe 
3. To describe the cessation rates of tobacco and nicotine containing products including CC 
over time 
Endpoints: 
 Rate of cessation of tobacco or nicotine containing products use, overall as well as by 
consumption within a given timeframe. 
 Rate of cessation from CC use overall as well as by consumption within a given 
timeframe 
4. To identify and assess the motivations for quitting tobacco use and to characterize the 
quit attempts by product use over time 
Endpoints: 
 Rate and number of participants that want to quit 
 Reasons for wanting to quit 
 Rate and number of self-reported quit attempts 
 Characteristics of the quit attempts, including: 
- 
Length of quit attempt 
- 
Type of product used to help in quit attempt (if applicable) 
- 
Reasons for quit attempt 
- 
Outcome of quit attempt 
5. To characterize the users of tobacco and nicotine containing products over time 
Endpoints: 
 Demographics and socioeconomic characteristics of tobacco and nicotine containing 
products users 
 Smoking history of tobacco and nicotine containing products users 
 Pre- IQOS tobacco and nicotine containing product usage and behaviors 
6. To assess subjective effects including urge to smoke, product reinforcement and self-
observed aesthetic improvements over time 
Endpoints: 
 Total Score and Factor scores from the Questionnaire on Smoking Urges-brief 
version (QSU-brief) by product use 
 Subscales from the Modified Cigarette Evaluation Questionnaire (MCEQ) in IQOS 
users 

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 Self-Reported Changes Questionnaire (SRCQ) in IQOS users 
7. To assess the perception of risk associated with tobacco and nicotine containing products 
by product use over time 
Endpoints: 
 Perceived Risk Instrument (PRI-P) to measure perception of risk associated with 
using CC, IQOS and e-cigarettes based on exposure group at the time of assessment 
using the following domains: 
- 
Perceived Health Risk 
- 
Perceived Addiction Risk 
- 
Perceived Harm to Others 
8. To assess the strength of nicotine dependence by product use over time 
Endpoints: 
 Score from the Fagerström test for Nicotine Dependence (FTND) questionnaire. 
9. To describe the rates of self-reported signs, symptoms and diagnoses by product use over 
time 
Endpoints: 
 Signs and symptoms 
 Cardiovascular disease diagnoses: myocardial infarction, stroke, new diagnoses of 
hypertension, unstable angina, or other cardiovascular diseases 
 Respiratory diseases diagnoses: new diagnoses of chronic obstructive pulmonary 
disease (COPD), or other respiratory diseases, including asthma exacerbations 
 Malignancies diagnoses: all malignancies, including smoking-related malignancies 
(i.e., lung, larynx, and bladder) 
10. To summarize the number of health related events (Hospitalizations) over time 
Endpoints: 
 Rate of prevalence of emergency room visits and/or hospitalization reported by 
product use over time 
 Frequency 
of 
diagnoses 
associated 
with 
emergency 
room 
visits 
and/or 
hospitalizations reported over time 
11. To assess coughing by product 
Endpoints: 
 Cough impact assessed by Visual Analog Scale (VAS), 
 Frequency and intensity of cough using the cough assessment 

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5 
STUDY POPULATION 
5.1 
Selection of Study Population 
4000 participants will be enrolled in the Study, including 2000 IQOS users and 2000 CC 
smokers. 
The study will be an observational open cohort of Japanese adults legally authorized to buy 
tobacco products in Japan. 
5.1.1 
Inclusion Criteria 
At the screening, in order for each participant to be enrolled must meet the following criteria: 
Table 12 
Inclusion Criteria 
Inclusion Criteria 
 
18. Adults legally authorized to buy tobacco products in Japan (20 
years of age) 
 
19. Japanese 
 
20. Participant is able to understand the information provided in the 
informed consent form (ICF). 
 
21. Signed informed consent form 
 
22. Willing to participate in the study and has access to the internet 
 
23. For IQOS users: 
o 
Is currently using IQOS HeatSticks 
o 
Has used at least 100 IQOS HeatSticks in their lifetime; and 
o 
Has used IQOS HeatSticks for at least 2 months 
NOTE: The use of IQOS HeatSticks defines the user as an IQOS 
user, regardless of other tobacco or nicotine product use 
 
24. For CC smokers: 
o 
Is currently using CC 
o 
Is not currently using IQOS HeatSticks, and 
o 
Has used at least 100 CC in their lifetime 
 
 
 
5.1.2 
Exclusion Criteria 
Participants who meet any of the following exclusion criteria at screening must not be 
enrolled into the study. 

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Table 13 
Exclusion Criteria 
Exclusion Criteria 
 
1. Tobacco industry employees 
 
2. Employed by the Sponsor, CRO or Clinical Site 
 
3. For IQOS users: 
o 
More than 12 months of IQOS use 
 
4. For former smokers: 
o 
Is not currently using CC 
o 
Is not currently using IQOS HeatSticks, and 
o 
Has used at least 100 CC and/or IQOS HeatSticks in their 
lifetime 
 
o  
 
5.2 
Recruitment Strategies and Retention 
As described in section 4.1.1, participants will be recruited into this study using: 
 The PM-JP’s consumer database (for both IQOS users and CC smokers) 
 Market research or other available databases (specifically CC smokers) 
 Study Website advertisements and optimization, and advertisements in public locations, 
which direct potential participants to the Study Website where they can obtain more 
information on the study and register their interest in participating in the study. 
The retention strategies will focus on contacting participants on a regular basis to keep them 
engaged in the study as well as payment for continued participation. Every time a CASI is 
completed the participant will be reimbursed for their time and effort. Participants will be 
provided a reward code for obtaining Rakuten tokens of appreciation to redeem for purchases 
at the Rakuten website. 
. 
Enrollment and attrition rates will be monitored during the study. In particular, the 
enrollment strategy may be adapted and sample size may be increased, depending on the 
actual attrition rate observed during the study conduct. 
5.3 
Discontinuation of Participants from the Study 
Participants will be informed that they are free to withdraw from the Study at any time. 
Participants can log into the Study Website at any time to discontinue from the Study. They 
will be asked to record the reason for discontinuation, although they are not obliged to 

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disclose it. Data collected for enrolled participants prior to the participant’s withdrawal will 
still be used in the analysis. 
Participants may be discontinued from the Study for any of the following reasons: 
 Withdrawal of informed consent 
 The Sponsor terminates the study. If the Sponsor decides to prematurely terminate the 
study, the participants and IRB will be promptly informed. Lost to follow-up 
Participants that discontinue from the study cannot re-enter the study. 
5.4 
Loss to Follow-Up 
 Helpdesk will perform a reasonable number of attempts to contact the 
participant including email correspondence and phone calls should be done and documented. 
The date of the last completed follow-up domain will be recorded and can be used as 
required for the analyses. 
5.5 
Violation of Selection Criteria 
Eligibility for the Study is assessed using the self-report participant information recorded in 
the screening domain. Participants not meeting the enrollment criteria will not be enrolled 
into the Study. 

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6 
RESTRICTIONS AND SUPPORT DURING THE STUDY 
Not Applicable 
 

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7 
STUDY PROCEDURES 
An overview of all study procedures is shown in the schedule of events (Appendix 1). In this 
section, only the expected/planned time points for the various measurements are described. 
As not all participants will undergo a procedure at the same time, adequate time windows are 
given for each study procedure and each time point (Appendix 1).  
7.1 
Study Assessments 
7.1.1 
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 1 for the time points of assessment. 
7.1.1.1 
Demographics 
Demographic data corresponding to inclusion/exclusion criteria (i.e., sex, age, ethnicity) will 
be recorded in the screening domain, at this stage potential participants will also be asked 
how they heard about the study (i.e., invite from PM-JP’s consumer database, 
advertisements, market research or other available databases). Additional demographic 
questions will be administered in the baseline domain. 
See Appendix 1 for the time points of assessment. 
7.1.1.2 
Core Questionnaires (Baseline and Follow-Up) 
The Core Questionnaire is composed of a set of multiple questions (47 questions in the Core 
Baseline Questionnaire and 151 in the Core Follow-up Questionnaire) ( Appendix 2). These 
questions will be administered specifically based on the subject’s product use. These 
questions include the following domains: 
 Detailed tobacco and nicotine containing product use. 
 Smoking History 
 Intention to stop using tobacco and nicotine containing products 
  
See Appendix 1 for the time points of assessment. 

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7.1.1.3 
Socio-Economic Status (SES) 
As part of the characterization of the study population it is important to measure variables 
that have been shown to be related to nicotine dependence and tobacco product reinforcing 
value. Based on prior tobacco research these factors include age, gender, tobacco use history, 
educational as well as socio-economic status. 
SES information is recorded in similar manner in the clinical program, in behavioral research 
and in this study it will be assessed in the post-market setting. 
At screening the participants will be informed in details about the exams and evaluations 
planned during the study, and similarly notified about the SES assessments which will be 
done at enrollment after they provided informed consent and were enrolled in the study. 
Participants will be asked a series of questions related to their education, occupational status, 
size and annual income of their household (Appendix 33). If the participant does not want to 
answer the questionnaire, he/she will not be withdrawn from the study. 
See Appendix 1 for the time points of assessment. 
7.1.1.4 
Cough Assessment Questionnaire 
Participants will be asked to assess the respiratory symptom ‘cough’ on a VAS, on three 
Likert scales, and with an open question. Assessment of cough will be conducted irrespective 
of the time. Participants will be asked if they have experienced a regular need to cough, e.g., 
whether they have coughed several times in the previous 24 hours prior to assessment. If the 
answer is ‘yes’, participants will be asked to complete a VAS, 3 Likert scales and to answer 
the open question (Appendix 44). 
On the VAS, participants will assess how bothersome their cough was during the previous 24 
hours (Appendix 44). The VAS ranges from ‘not bothering me at all’ to ‘extremely 
bothersome.’ Furthermore, participants will assess the intensity and frequency of cough and 
the amount of sputum production during the previous 24 hours on Likert scales. 
The intensity of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 1 
=very mild – 2 = mild – 3 = moderate – 4 = severe – 5 = very severe. 
The frequency of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = rarely – 2 = sometimes – 3 = fairly often – 4 = often – 5 = almost always. 
The amount of sputum production will be assessed on a 4-point Likert scale ranging from 0 
to 3, with 0 = no sputum – 1 = a moderate amount of sputum – 2 = a larger amount of sputum 
– 3 = a very large amount of sputum. 
See Appendix 1 for the time points of assessment. 

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7.1.1.5 
Modified Cigarette Evaluation Questionnaire 
Product evaluation will be assessed using the Modified Cigarette Evaluation Questionnaire 
(MCEQ) (20) (Appendix 5). The MCEQ assesses the degree to which participants experience 
the reinforcing effects of smoking, by measuring: 
 Smoking satisfaction (satisfying, tastes good, enjoys smoking) 
 Psychological rewards (calms down, more awake, less irritable, helps concentrate, 
reduces hunger) 
 Aversion (dizziness, nauseous) 
 Enjoyment of respiratory tract sensations (single-item assessment) 
 Craving reduction (single-item assessment) 
The MCEQ will be completed by IQOS users through the CASI. 
See Appendix 1 for the time points of assessment. 
7.1.1.6 
Questionnaire of Smoking Urges (QSU-b) 
To assess the urge-to-smoke, all participants will be asked to fill-in a 10-item brief version of 
the QSU (21) (Appendix 6). The QSU-b items are rated on a 7-point scale, ranging from 1 
(strongly disagree) to 7 (strongly agree). Higher scores in this questionnaire indicate a higher 
urge to smoke. 
The QSU-b will be completed by the participant through the CASI. 
See Appendix 1 for the time points of assessment. 
7.1.1.7 
Lifestyle Assessment 
The lifestyle questionnaire consists of 8 questions on different dietary and physical activity 
habits (Appendix 7). 
 Question 1 frequency of fast food consumption 
 Question 2 frequency of alcoholic beverage intake 
 Questions 3 and 4 frequency and amount of physical activity 
 Question 5 inquires about length of sleep 
 Question 6 asks if the household includes a CC smoker 
 Questions 7 and 8 self-reported height and weight 
Details about when this questionnaire will be administered can be found on the schedule of 
events (Appendix 1) 

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7.1.1.8 
Perceived Risk Instrument (PRI-P) 
The PRI-P is a self-report instrument that has been developed by PMP to assess the perceived 
risks associated with the use of tobacco and nicotine containing products such as CC, 
Electronic nicotine devices (ENDs), Modified Risk Tobacco Products (MRTPs). More 
specifically, the PRI-P aims at assessing the perceived risks to the individual respondent. The 
PRI-P is comprised of three domains (Appendix 8): 
 Perceived Health risk 
 Perceived Addiction risk 
 Perceived Harm to others 
Details about when this questionnaire will be administered can be found on the schedule of 
events (Appendix 1) 
7.1.1.9 
Fagerström Test of Nicotine Dependence 
The Fagerström Test for Nicotine Dependence is a standard instrument for assessing the 
intensity of physical addiction to nicotine. The test was designed to provide an ordinal 
measure of nicotine dependence related to cigarette smoking. It contains six items (Appendix 
9). This questionnaire consists of 6 questions which will be answered by the subject 
himself/herself. The scores obtained on the test permit the classification of nicotine 
dependence into 3 levels: mild (0-3 points), moderate (4-6 points) and severe (7-10 points) 
(22). 
 How soon after waking does the participant have their first cigarette 
 Difficulty in refraining from smoking 
 Their ability to give up specific a smoking experience 
 Number of cigarettes smoked 
 Intensity of smoking during the day 
 Smoking during illness 
Details about when this questionnaire will be administered can be found on the schedule of 
events (Appendix 1). 
7.1.1.10 Self-reported Changes Questionnaire (SRCQ) 
The SRCQ will be administered at enrollment and then throughout the first year of follow-up 
until month 12 within the CASI. The SRCQ will focus on self-observed aesthetic changes 
seen after adopting IQOS HeatSticks. It is composed of 6 questions about: 
 Skin appearance 

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 Ease of exercise 
 Sense of smell 
 Sense of taste 
 Own and/or Spouse’s perception of participant’s breath 
 Teeth appearance 
This questionnaire can be found in (Appendix 10) 
7.1.1.11 Self-Reported Health Outcomes and Events Questionnaire 
A self-reported health outcomes questionnaire will be administered at enrollment, annually as 
well as Months 9 and 30 within the CASI. The self-reported outcomes and events 
questionnaire will focus on signs, symptoms and diagnoses of smoking-related diseases as 
well as on health related events such as hospitalizations. The self-reported health 
questionnaire can be found in Appendix 11.  

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8 
SAFETY REPORTING 
8.1 
Definitions 
 For adverse events for tobacco products: an AE is any health-related event associated 
with the use of tobacco product in humans, which is adverse or unfavorable, whether or 
not it is considered related to the tobacco product. 
 Serious adverse event – A serious adverse event is an adverse event that results in any of 
the following: death; a life-threatening condition or event; persistent or substantial 
disability or incapacitation; hospitalization or prolonged hospitalization; or a congenital 
anomaly or birth defect. 
8.2 
Assessment of Adverse events 
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. IQOS users will be reminded of 
the product quality complaints (including AEs) hotline that has been established for all users 
of IQOS in Japan. 
The PMP hotline information is printed on the packaging and included in the product 
information. Study personnel will be informed about the PMP hotline. Calls to the Study 
hotline by IQOS participants reporting spontaneously adverse events will be transferred to 
the PMP hotline. 

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9 
STUDY ACTIVITIES 
A detailed schedule of assessments can be found in Appendix 1. 
9.1 
Screening 
Screening will be done entirely online as defined in section 4.1.2. 
9.2 
Recruitment Period 
This cohort will be open for recruitment for about 4 years. Recruitment will be performed in 
4 annual waves. Each annual wave will span a one year period, however, the definition of an 
annual wave will vary for IQOS users and CC smokers.  
For IQOS users, an annual wave is defined by when the IQOS users start using IQOS. The 
first wave (i.e., the pilot wave) will cover IQOS users who initiate IQOS within 6 months 
prior to the launch of the study. Enrollment for IQOS users will remain open for any given 
wave until the wave is full (500 IQOS users) or 12 months after the last possible initiation 
date for the annual wave. Additionally, for wave 2 a new CASI system will be launched and 
the wave definition for IQOS users will start 4 months prior to the system launch. . The 
question flow of the new CASI system is dynamic. In order to ensure collecting consistent 
data, the questions asked depend of answers provided during the current and during the last 
CASI. Therefore wave 1 data that are required to display dynamically in order to administer 
the questions of wave 2 CASI will be transferred and classified. During this transition period 
there will be no enrollment into the Study. Subsequent waves will follow sequentially. A 
graphic representation of the waves can be found in Figure 2.  
For CC smokers, an annual wave is defined by the date of enrollment into the study. The first 
wave will start with study launch and run for a period of 12 months. This means only 1 wave 
can be open for enrollment at a given time for CC smokers. In the event that enrollment is 
met in less than 12 months for a CC wave, the next annual wave will open for enrollment in 
alignment with the IQOS wave. A graphic representation of the waves can be found in Figure 
3. 
In general, although the study is open to all participants that register, because of the timing of 
the product launch and the start of the study the pilot wave will, by definition, target IQOS 
users in Nagoya, and therefore the recruitment plan will reflect this to ensure equal 
considerations are given to the CC participants registering into the study.  

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Figure 2 
Definition of Annual Waves for IQOS users 
 
 
Figure 3 Definition of Annual waves for CC smokers 
 
 

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10 QUALITY CONTROL AND QUALITY ASSURANCE 
 
Not Applicable. 
10.1 Training of Staff 
Not Applicable. 
10.2 Audits and Inspections 
Good Epidemiological Practice guidelines do not specify independent inspections of clinical 
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 PI 
or designee will contact the Sponsor or the authorized representative immediately if 
contacted by a regulatory agency about an inspection at their site. 

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11 DATA MANAGEMENT ACTIVITIES 
All data management activities will be described in details in the data management plan 
(DMP) and documents specified therein. The electronic systems used and CASI, to collect 
participant data will be FDA 21 CFR Part 11 compliant. 
11.1 Data Capture 
11.1.1 
Data Capturing Tool and Study Records 
All questionnaires including screening and enrollment domains will be provided in electronic 
form (through the data capturing tool) to the participant in Japanese. The participants’ 
questionnaires and the VAS will be entered by the participants directly in their computer or 
electronic device. The data capturing tool allows participants to use different devices to 
submit their entries on the device they are using at the time of receiving the reminder to 
complete a (set of) questionnaire(s).The participants will enter surveys via the link embedded 
in the survey reminder message they will receive once enrolled and the subsequent 
questionnaire is due. 
11.1.2 
Protocol Deviations 
Protocol deviations at the individual participant level should be minimal in an observational 
study such as this one, but erroneous inclusions and other deviations from protocol could 
potentially take place.  In addition, deviations in the execution of the study (such as not 
following the sampling procedure outlined in the protocol) could affect the outcomes or 
interpretability of the study, even though they are not associated with a particular 
subject.  For this matter, the statistical analysis plan (SAP) will detail the documentation of 
eligibility protocol deviations from the data received from 
. Any other 
protocol deviations identified during the study will be recorded into the Protocol Deviation 
tracker.  
 
The overall procedure for managing protocol deviations is described in the SOPs and/or 
agreed upon procedure of the CRO team.  
11.2 Data Handling 
All study data, collected with 
 CASI system will be managed by the 
data management team and the statistical team at the CRO. The overall procedures for 
quality assurance of clinical study data are described in the SOPs of the CRO data 
management team. The data management team at the CRO will prepare a DMP, to be 
reviewed and approved by the Sponsor, prior to the go life of systems used to capture study 

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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. 
11.2.1.1 Data Validation 
The data will be validated as defined in the DMP and Data Validation Specifications. 
Discrepancies will be reported as defined in DMP and Data Validation Plan. 
11.2.1.2 Data Reconciliation 
The wave 1 participants will be migrated to the new wave 2 
 CASI system. Only 
data used for participant identification and the data used for dynamic question flow will be 
migrated from wave 1 CASI to wave 2 new CASI. Therefore the reconciliation of the data 
extracted out of the 2 CASI system will be done outside the CASI systems by the CRO data 
management team. The data reconciliation process will be defined in the DMP. 
 
11.2.1.3 Database Lock 
When all outstanding Data Management issues have been resolved and all validation, quality 
review, and cleaning activities are complete, the database or selected data is/are declared soft 
locked. Access to change data in the soft-locked database or to change selected data at this 
time is limited. 
After the data is reviewed by the Sponsor, resolution of all raised queries and QC of the 
changed data, database, or selected data upon Sponsor approval as applicable, is declared 
locked. 
Any changes to the database after that time can only be made by written agreement between 
the Sponsor and the Data Management and Statistical Team at the CRO. Any of those 
changes must be documented in the database log file. 
After study completion, the Study database will be transferred to the Sponsor in the format 
specified in the DMP in Clinical Data Interchange Standards Consortium’s Study Data 
Tabulation Model Data Structure Specifications. 

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12 PLANNED STATISTICAL METHODS 
12.1 General Considerations 
The results from this study will be analyzed by annual wave and overall (including all 
available waves) and will be reported annually. 
Full details of the statistical analysis will be given in a statistical analysis plan (SAP). Any 
changes to the planned statistical methods will be documented in the study report. The 
statistical evaluation will be performed using SAS®, version 9.2 or later. 
12.1.1 
Definitions 
Independent of recruitment waves, calendar time will be translated into study time (STi) 
ranging from the start of the study (0) to  60 months. 
Measurement times (MT) are in STi (study entry, 3 months, 6 months …) as defined in 
Appendix 1. 
Individual person time (PT) is the total duration that an individual has spent in the study at 
any MTi. Of note, for IQOS users product use periods prior to entering the study are added to 
their person-time. 
Current behavior at MTi (i being ST in months), will be denoted CBi and will be defined as 
described 
 
.. Additional CBi or sub-category CBi may 
be added during data analysis which will be specified in the SAP. 
 
Table 14 
Current Behaviors Definitions (percentages defined in 12.2) 
 
CB(i) 
Notation at MT(i) 
Definition 
Daily THS 
Daily THSi  
 THS ≥ 1/day,  
 each OTP <1/day,  
 CC < 1/day 
Daily CC Smoker 
Daily CCi 
 THS = 0/day, 
 CC ≥ 1/day, 
 each OTP < 1/day 
Daily OTP user 
Daily OTPi 
 THS = 0/day, 
 0 ≤ CC < 1/day, 
 At least one OTP ≥ 1/day 
Dual THS – CC 
DU_THS_CCi 
 THS ≥ 1/day,  

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CB(i) 
Notation at MT(i) 
Definition 
 
 CC ≥ 1/day,  
 each OTP <1/day 
Dual THS – OTP 
 
DU_THS_OTPi 
 THS ≥ 1/day, 
 At least one OTP≥ 1/day,  
 CC < 1/day  
THS – CC-OTP 
PU_THS_CC_OTPi 
 THS ≥ 1/day, 
 at least one OTP ≥ 1/day,  
 CC≥ 1/day 
Occ THS 
Occ_ THSi 
 THS < 1/day,  
 all OTP <1/day,  
 CC < 1/day 
Occ THS-CC-OTP 
 
Occ_THS_CC-OTPi 
 THS < 1/day,  
 CC ≥ 1/day 
 at least one OTP ≥ 1/day 
Occ THS-CC 
 
Occ_THS_ CCi 
 THS < 1/day,  
 CC ≥ 1/day 
 all OTP < 1/day 
Occ THS-OTP 
 
Occ_THS_ OTPi 
 THS < 1/day,  
 at least one OTP ≥ 1/day 
 CC < 1/day 
Non User/Smoker 
Non_Smokeri 
 THS = 0/day,  
 CC = 0/day, 
 each OTP = 0/day, 
Occ User/Smoker 
Occ_Smokeri 
 THS = 0/day,  
 0 ≤ CC < 1/day,  
 each OTP must be: 0 ≤ OTP 
<1/day 
 not (CC=0 and OTPs=0) 
Note: OTP includes other Heat-not-Burn products (HnB) except THS 
Note: ePD is considered as one of the other tobacco product (OTP) when we determine the 
CB. 
Last behavior (LB) is the behavior at assessment time. When MTi=AT, LB=CBi 
The behavior at study entry will be named initial behavior (IB). IB will be either C0 or I0 for 
the participants enrolled as CC smoker or IQOS user respectively. 

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Events assessed at MTi (i being ST in months), will be denoted Current Events (CEi) and 
will be defined as described 
 . Additional CEi may be 
added during data analysis which will be specified in the SAP. 
Table 15. 
Events Definition 
 
CEi 
Notation at MT(i) 
Definition 
Switching 
 
 
First Switch from Initial 
Behavior to another 
Behavior 
Si 
CBi≠CBi-1 | for any j<i CBj=IB 
Initiation 
 
 
CC Initiation 
ICCi 
CPDi≥1| for any j<i CPDj<1 
Has not used  100 CC in their lifetime 
THS Initiation  
ITHSi 
THSPDi≥1| for any j<i THSPDj<1 
Has not used 100 THS (heatsticks) products in 
their lifetime 
THS Initiation by brand 
ITHSi_brand name  
THSPDi≥1(stratified by brand) 
Has not used  100 THS (HeatSticks) products in 
their lifetime  
OTP Initiation 
IOTPi 
OTPDi≥1  
Has used OTP less than daily used or not used 
(wave 1)  
Has not ever used OTP or not used regularly 
(wave 2 and following waves)   
Has not used 100 Ploom capsules  in their 
lifetime (Wave2 and following waves) 
Has not used 100 Glo Neostiks® in their life 
(Wave2 and following waves) 
CC Re-Initiation  
Re-ICCi 
CPDi≠0|CPDk=0, for any k in [j; i-1] where i and 
j differ by more than 12 months. 
THS Re-Initiation  
Re-ITHSi 
THSPDi≠0|THSPDk=0, for any k in [j; i-1] where 
i and j differ by more than 12 months. 
Quitting attempt/cessation/relapse 
Quit Attempt 
QAi 
A quit attempt is defined according to the 
participant’s answer to the intention to stop and 
quit attempt questionnaire at MT(i) 
CC Cessation 
CC-Cessi 
CPDk=0|CPDj≠0, for any k in (j; i] where i and j 
differ by more than 12 months. 

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CEi 
Notation at MT(i) 
Definition 
Has used at least 100 CCs in their lifetime 
THS Cessation 
THS-Cessi 
THSPDk=0|THSPDj≠0, for any k in (j; i] where i 
and j differ by more than 12 months. 
Has used at least 100 THS (heatsticks) in their 
lifetime  
OTP Cessation 
OTP-Cessj 
OTPDk=0|OTPDj≠0, for any k in (j; i] where i 
and j differ by more than 12 months. 
Has used OTP daily (wave 1) 
Has used at least 100 heatsticks in their lifetime 
(wave 1) 
Has used regularly OTP (wave 2 and following 
waves) 
Has used at least 100 other HnB products (except 
THS) in their lifetime (wave 2 and following 
waves) 
CC Relapse 
CCreli 
CPDi≠0|CPDk=0, for any k in [j; i-1] where i and 
j differ by strictly less than 12 months. 
THS Relapse 
THSreli 
THSPDi≠0|THSPDk=0, for any k in [j; i-1] where 
i and j differ by strictly less than 12 months. 
OTP Relapse 
OTPreli 
OTPDi≠0|OTPDk=0, for any k in [j; i-1] where i 
and j differ by strictly less than 12 months. 
Consumption changes 
 
 
CC Increase 
CCinci 
(CPDi-CPDi-1)/ CPDi-1≥10% 
CC Decrease 
CCdeci 
(CPDi-1-CPDi)/ CPDi-1≥10% 
THS Increase 
THSinci 
 (THSPDi-THSPDi-1)/ THSPDi-1≥10% 
THS Decrease 
THSdeci 
(THSPDi-1-THSPDi)/ THSPDi-1≥10% 
Product uptake 
 
 
THS uptake  
THSuptakei 
The new THS product one participant uses at 
specific timepoint and was not used in the 
previous timepoint based on product use 
questionnaire 
THSPDi≠0, THSPDi-1=0 
HnB uptake  
HnBuptakei 
The new HnB products one participant uses at 
specific timepoint and was not used in the 
previous timepoint based on product use 
questionnaire 
HnBPDi≠0, HnBPDi-1=0   
Note: CPDi, THSPDi, HnBPDi and OTPDi are defined in section 12.2.1 

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Note: The CC Initiation is defined for THS user cohort participants; the THS Initiation is defined for CC smoker 
cohort participants. 
 
12.1.2 
Descriptive Statistics 
Descriptive statistics for continuous variables will include number of participants [n], number 
and percent of participants with data, mean, standard deviation [SD], median, first and third 
quartile, minimum and maximum. For categorical variables absolute and relative [%] 
frequency for categorical data) will be presented. 
12.1.3 
Handling of Missing Values and of Values outside the Detection Limits 
For questionnaire data, total scores and domain or subscale scores may be derived using 
imputation by averaging across neighboring non-missing variables. 
Product use at MT(i) if missing, can be interpolated by averaging across neighboring product 
use at MT(i-1) and MT(i+1). There will be no imputation for missing CE(i). Only the 
reported CE(i) will be used in the analysis.  
Further details will be provided in the SAP. 
12.1.4 
Significance Level for Inferential Statistics 
 No inferential statistics are planned. 
12.2 Derived and Computed Variables 
12.2.1 
Product use 
Percent consumption of THS, CC, OTP, e-cig and HnB, respectively, with respect to 
THSPD, CPD, ePD and OTPD will be calculated at MTi based on THS Tobacco Sticks, CC, 
e-cigarettes and OTP reported in Product use questionnaire as: 
i
i
i
i
OTPD
CPD
THSPD
THS



i
THSPD
*
100
%
 
i
i
i
i
OTPD
CPD
THSPD
CC



i
CPD
*
100
%
 
i
i
i
i
OTPD
CPD
THSPD
OTP



i
OTPD
*
100
%
 
i
i
i
i
OTPD
CPD
THSPD
cig
e




i
ePD
*
100
%
 

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i
i
i
i
OTPD
CPD
THSPD
HnB



i
HnBD
*
100
%
 
 
where CPDi is the average daily Cigarettes consumption at MTi, THSPDi is the average daily 
THS consumption (Marlboro Heatsticks with iQOS device), OTPDi is the average daily other 
tobacco products consumption, HnBPDi is the average daily HnB products consumption and 
ePDi is the average daily e-cigarette products consumption, which is part of the other tobacco 
products consumption will also be calculated. 
Additional percent consumption of tobacco products may be added and will specified in the 
SAP. 
 
 
12.2.2 
Definition of Product Use Categories 
Product use pattern categories over a period ending at MTi are defined in Table 4 above. 
12.2.3 
Sample Size 
A total of 4000 participants will be enrolled in the Study. Enrolment will happen in four 
annual waves. 
Assuming an annual drop-out rate of 5% and a maximum of 20% of participants changing 
from CC smoker or IQOS user to another behavior per year, the person-time pool in each 
group will be for each annually analysis as described in Table 16: 
Table 16 
Expected person-time pool for each annual analysis 
Wave 
Year 1 
Report 
Year 2 
Report 
Year 3 
Report 
Year 4 
Report 
Year 5 
Report 
1 
375 
281 
210 
157 
117 
2 
 
375 
281 
210 
157 
3 
 
 
375 
281 
210 
4 
 
 
 
375 
281 
Total (Person-Years) 
375 
1031 
1897 
2920 
3685 
This sample size and the study duration is sufficient for an assumed 1% of participants for a 
particular period (CBi; CBi-1) to estimate this behavior with a precision of less than 1.32% at 
the first annual analysis and up to less than 0.62% at the final annual analysis. 

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12.3 Analysis Populations 
All participants that enroll in the Study and complete at least one baseline questionnaire (at a 
minimum the product use questionnaire) as part of the enrollment process will be included 
and reported as the Study Population. 
. 
12.4 Study Analysis 
12.4.1 
Study Endpoints 
See section “Study Objectives and endpoints”  for a description of the Study endpoints. 
12.4.2 
Baseline Comparability 
Not applicable. 
12.4.3 
User Group and Product Use Behavior 
See section 12.1.2 “Descriptive Statistics” for a description of the methodology for 
descriptive statistics in the study. 
12.4.3.1 Demographics and Baseline Characteristics 
 
All data will be presented in listings, ordered by baseline usage group and subject, unless 
otherwise specified. Demographic data include age, sex, occupation, etc. 
 
Descriptive statistics for continuous variables (number of subjects [n], number and percent of 
subjects with missing data, mean, standard deviation, median, first and third quartiles, minimum 
and maximum for continuous data, and the n and absolute and relative (%) frequency for 
categorical data) will presented by usage group and overall at each time point, where applicable.  
 
12.4.3.2 Product Use Level 
 
To assess objective 1, the following analysis will be conducted. 
Summary tables of use of tobacco and nicotine containing products over time for all enrolled 
participants will be presented by Cohort at baseline, by CB (i) group and overall participants 
at MT (i) at post baseline, including: 

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 Mean number of cigarettes smoked (per day) -  CPD(i) 
 Mean number of  THS Tobacco Sticks used (per day)- THSPD(i) 
 Mean number of  Heat-not-Burn products used (per day)- HnBPD(i) 
 Mean number of  other cigarettes product used (per day)- OTPD(i) 
 Mean number of  e-cigarettes used (per day)- ePD(i) 
 Percent of THS Tobacco Sticks used (%THS) 
 Percent of cigarettes used (%CC) 
 Percent of other cigarettes product used (%OTP) 
 Percent of e-cigarettes used (%e-cig) 
 Percent of Heat-not-Burn products used (%HnB) 
The table will be repeated by sex, age group and enrollment wave in the Study. Tables will 
also be presented by CB. 
The following figures will be provided at each measurement time. 
-  Bar chart of CPD(i), THSPD(i), ePD(i) and OTPD(i) with 95% CI by CB(i-1) and 
CB(i) group at each measure time MT(i). 
Additional statistical analyses will be specified in the SAP. 
Corresponding information is provided in participant data listings.  
 
12.4.3.3 Product Use Patterns 
The table of current behavior, CB(i), at MT(i) will provide the information of product use 
patterns. 
Summary table of the product use patterns will be evaluated by CE(i) and presented by CB(i) 
group at MT(i). The product use patterns includes product switching, initiation, re-initiation, 
quitting attempt, cessation, relapse, consumption changes and product uptake. Additional 
product transition table will also be provided between CB(i-1) and CB(i). Participants who 
have tobacco and nicotine product use transitions will be tabulated by previous and current 
behavior at each study year. The median of time to first product use transitions (behavior 
switch) will be calculated via Kaplan-Meier estimators and presented by cohort, IB and CB.  
The following outputs will be repeated by sex, age group and enrollment: 
-   Descriptive Statistics of Current Behavior  
-   Descriptive Statistics of Current Event by Current Behavior  
-   Descriptive Statistics of Uptake of HnB Products by Current Behavior  
-   Descriptive Statistics of Transitions Across Behaviors  
Additional statistical analyses will be specified in the SAP. 

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The following figure will also be provided: 
-   Bar chart of CB(i) group at each measurement time MT(i). 
 Corresponding information is provided in participant data listings. 
 
 
12.4.3.4 Quit Attempts 
 
To characterize the quit attempts by cohort at study entry and by CB(i) group at each MT(i) 
post baseline,, the following information will be presented in the:  
 Rate and number of self-reported quit attempts 
 Characteristics of the quit attempts, including: 
- 
Length of quit attempt 
- 
Type of product used to help in quit attempts (if applicable)  
- 
Reasons for quit attempt 
- 
Outcome of quit attempt (Success or Restart using  tobacco products) 
More detail will be given in the Statistical Analysis Plan. 
12.4.3.5 Perceived Risks 
To assess the perception of risk associated with using CC, MRTPs and ENDs, the related 
information based on cohort at baseline and CB(i) group at post baseline will be presented in 
tables at each MT(i) using the following domains: 
 Perceived health risk scale  
 Perceived addiction risk scale  
 Perceived harm to others single items 
The tables will be provided separately for CCs, MRTPs and ENDs. 
The details of score calculation rule are specified in SAP.  
 
Summary statistics will be also provided by current behavior regardless of time point in table 
for perception of risk associated with using CC, MRTPs and ENDs. 
12.4.3.6 Strength of Nicotine Dependence 
The strength of nicotine dependence of the Main Study will be analyzed by  cohort at 
baseline and by CB(i) group according to the behavior at MT(i) post baseline as follows: 

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 Total score from the Fagerström Test for Nicotine Dependence (FTND) questionnaire 
The tables will be repeated by CB(i), CB(i-1) and CB(i), sex, age group and enrollment 
wave.  
Summary statistics will be also provided by current behavior regardless of timepoint for total 
score from FTND. 
Corresponding information is provided in participant data listings. 
 
12.4.3.7 Self-Reported Signs and Symptoms and Hospitalizations 
The self-reported signs and symptoms including cough and the hospitalizations of the Study 
will be analyzed by CB(i)  group.  One participant can be counted only once with the worse 
scenario under overall category. 
The cough result will be analyzed by cohort at baseline and by CB(i) group and overall in 
participants at post baseline MT(i). 
 
To describe the rates of self-reported signs, symptoms and diagnoses from health outcome 
questionnaire, the following information will be presented: 
 Signs and symptoms: It is counted when any kind of symptoms or diseases reported 
associated with cardiovascular or respiratory disease, or cancer. It can be from the 
conditions/diseases or symptoms. 
 Cardiovascular disease diagnoses: myocardial infarction, stroke, new diagnoses of 
hypertension, unstable angina, or other cardiovascular diseases 
 Respiratory diseases diagnoses: new diagnoses of chronic obstructive pulmonary 
disease (COPD), or other respiratory diseases, including asthma exacerbations 
 Malignancy diagnoses: all malignancies, including smoking-related malignancies 
(i.e., lung, larynx, and bladder) 
To summarize the number of health related events (hospitalizations) from health outcome 
questionnaire, the following information will be presented: 
 Rate of prevalence of emergency room visits and/or hospitalization reported by 
product use over time 
 Frequency 
of 
diagnoses 
associated 
with 
emergency 
room 
visits 
and/or 
hospitalizations reported over time 
To assess coughing by product use from cough assessment questionnaire, the following two 
tables will be provided: 
 Frequency and intensity of cough using the cough assessment 
 Cough impact assessed by Visual Analog Scale (VAS) 

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If there is more than one response of specific participant during study from cough 
assessment, the worst response (worst answer or highest score) will be used in the overall 
summary. 
The tables will be repeated by sex, age group and enrollment wave for self-reported signs and 
symptoms, health related events (hospitalizations) and cough assessment questionnaire.  
 
Corresponding information is provided in participant data listings. 
12.4.4 
Inferential Analyses 
All analyses in this study are descriptive. Therefore, no inferential analysis is planned. 
12.5 Interim Analysis 
There will be annual descriptive interim reports on the study objectives but no decision will 
be made based on the results. In addition to the specified analyses, additional administrative 
evaluation of study progress may be conducted. 

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13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Study Investigator and Study Administrative Structure 
13.1.1 
Principal Investigator – Main Study 
Name: Dr 
 
Institution: 
 
Address: 
, 
Nagoya, 
 Japan 
Phone: +81
 
Email:
 
 
13.1.2 
Sponsor 
Sponsor: 
Philip Morris Products S.A 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Tel: + 41 (58) 242 21 11 
Fax: + 41 (58) 242 28 11 
, PhD 
Study Scientist  
Phone: +41 (58) 
 
Mobile: +41 (79) 
 
E-mail: z
 
, MEng, MSc 
Study Statistician 
Phone: +41 58 
 
Mobile: +41 (79) 
 
E-Mail:  
 
, MD 
Medical Safety Officer 
Phone: +41 (58) 
 
Mobile: +41 (79) 
 
E-mail: 
 
, MSc 
Clinical Study Manager 
Phone: +41 (58) 
 
Mobile: +41 (79) 
 
E-Mail: 
 

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Clinical Data Manager 
Phone: +41 (58) 
 
Mobile: +41 (79) 
 
E-Mail:
 
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. 
 
 
 
 
 
  
 
 
      
 
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 in compliance with all local and national data protection and privacy legislation. 
Participants will sign the agreements electronically  
The anonymity of participants participating in this study will be maintained. Participants will 
be identifiable by the Sponsor (or Sponsor’s authorized representative) on pertaining 
documents by their participant number/code, sex and date of birth, but not by name, initial, or 
any other details relating to identifiable person (e.g., address, health insurance ID card, 
medical chart number, etc.). The assignment of a participant number/code for participant 
identification will be based on the appropriate data protection rules. 
 Helpdesk and 
 or 
 will have access to email, geographical 
data and phone number. This is in order to be able to contact the participants to remind them 
to complete their CASIs, or to discuss with them any other information/query. 

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In the exceptional case where an IQOS user a) is recruited into the study through PM-JP’s 
consumer database, and b) communicates in one of the follow-up CASIs of his/her intention 
to quit smoking or using IQOS. His/Her email address will be shared with PM-JP 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 
NA. 
13.4 Record Retention 
Essential study documents/records, which individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced must be retained by the PI or the 
head of the investigational site for a minimum of: 
 At least 15 years after completion or discontinuation of the study, or 
 At least 2 years depending on, for example, the circumstances, or 
 After formal discontinuation of clinical development of the IP. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. 
Examples of essential records/documents include, but are not limited to: 
 Record of all communications between the PI and the IRB, composition of the IRB 
 Record of all communications/contact between the PI, Sponsor, and its authorized 
representatives 
 Study specific questionnaires (and associated data/scoring) 
 All other source documents or any electronically captured study source data 
 Information regarding participants’ discontinuation and any follow-up 
It is the responsibility of the Sponsor to inform the PI/head of investigational site as to when 
these documents no longer need to be retained. 
The PI/head of investigational site must take measures to prevent accidental or premature 
destruction of these documents. 
If the head of the investigational site wishes to assign the study records to another party or 
move them to another location, the Sponsor must be notified in advance. 

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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
The Sponsor or Sponsor’s authorized representative will maintain documentation relating to 
the study for 15 years after the CSR has been finalized. 
13.5 Study Report 
The Sponsor must ensure that a study report for this study is prepared regardless of whether 
the study is completed or prematurely terminated. In certain circumstances, an abbreviated 
study report may be acceptable. Submission of the 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 study report. 
 
13.6 Publication and Disclosure Policy 
This document contains data, information and trades secretes that are confidential and 
proprietary to the Sponsor. This document is being provided solely for the purpose of 
evaluation and/or conducting this 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). 
13.7 Insurance 
For the conduct of this type of study, an insurance plan is not necessary. 

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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 Appendix 2 
 Core Questionnaires 
The “Smoking History Questionnaire” will be provided in a separate document. 

Philip Morris International 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Appendix 3 
Socio-Economic Status Questionnaire 
The “Socio-Economic Status Questionnaire” will be provided in a separate document. 

Philip Morris International 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Appendix 4 
Cough Assessment Questionnaire 
The “Cough Assessment Questionnaire” will be provided in a separate document. 

Philip Morris International 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Appendix 5 
MCEQ Questionnaire 
The “MCEQ Questionnaire” will be provided in a separate document. 

Philip Morris International 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Appendix 6 
QSU-b Questionnaire 
The “QSU-b Questionnaire” will be provided in a separate document. 

Philip Morris International 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Appendix 7 
Lifestyle Questionnaire 
The “Lifestyle Questionnaire” will be provided in a separate document. 

Philip Morris International 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Appendix 8 
Perceived Risk Instrument (PRI-P) 
The “Perceived Risk Instrument (PRI-P) Questionnaire” will be provided in a separate 
document. 

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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Appendix 9 
Self-reported Changes Questionnaire 
The “Self-reported Changes questionnaire” will be provided in a separate document. 
 

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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Appendix 10 
Fagerström Test for Nicotine Dependence 
The “Fagerström Test for Nicotine Dependence Questionnaire” will be provided in a separate 
document. 
 

Philip Morris International 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Appendix 11 
Signs and Symptoms & Self-Reported Outcomes 
Questionnaire 
The “Signs and Symptoms & Self-Reported Outcomes Questionnaire” will be provided in a 
separate document. 
 
 
 

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commercial information, and the legal protections provided to such trade secrets and confidential information 
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without the written consent of Philip Morris Products S.A. 
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Observational Study Protocol 
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"Final Version 5.0"  
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
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