A Controlled, Open-label, 3-arm Parallel Group, Multi-center Study to Evaluate the Abdominal Aortic Aneurysm (AAA) Growth Rate in Adult Smoking Patients Randomized to Either Cigarette Smoking or IQOS Use and to Compare With the AAA Growth Rate in Patients Who Had Stopped Smoking
Phase: NA
Conditions: Smoking, Abdominal Aortic Aneurysm, IQOS Use
Sponsor: Philip Morris Products S.A.



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SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Name of Product: 
 
IQOS (Tobacco Heating System [THS] with Marlboro Heatsticks) 
Study Title: 
A controlled, open-label, 3-arm parallel group, multi-center study to evaluate the 
Abdominal Aortic Aneurysm (AAA) growth rate in adult smoking patients randomized to 
either cigarette smoking or IQOS use and to compare with the AAA growth rate in patients 
who had stopped smoking. 
Study Number: 
P1-AAA-02-JP 
Patient recruitment:  
In spite of significant efforts undertaken to improve the recruitment of patients into this 
study, the recruitment rate remains low. Indeed, after over a year of recruitment only 32 
patients were enrolled out of 114 planned. Furthermore, the forecast until June 2020 shows 
only 15 new patients potentially eligible to participate in the study. In addition, the recruiting 
sites are reaching the limits of available patients (recruitment is limited to existing patients 
only), and new sites joining the study have more limited pool of patients as compared to the 
originally selected sites. The pool of the new sites to be potentially suitable for patients 
recruitment has also now reached the limits - during the site selection/qualification process 
most promising sites were already contacted. In such a situation, it is not possible to predict 
the length of the recruitment needed to reach 114 patients, if at all possible. Therefore, rather 
than terminating the study, which would result in loss of site’s and patient’s efforts and lack 
of any new scientific knowledge for the broader community, it was decided to stop 
recruitment early and to continue the follow up of patients already recruited. This would 
still allow an evaluation of already collected data to gather evidence of the impact of 
switching to IQOS on the evolution of the disease in patients suffering from abdominal 
aortic aneurysm. 
In addition, to ease the burden for the patients and to avoid potential issues with retention 
rate and missing data, it was also decided to decrease the number of procedures, such as 
those related to co-morbidities, and to shorten the duration of the follow-up from five to 
three years. 

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Objectives and Endpoints 
Primary Objective and Endpoints: 
The primary objective of this study is: 
To evaluate the reduction in the AAA annual growth rate in patients who switch from 
smoking cigarettes (CC) to using IQOS, as compared to patients who continue to smoke 
CC (IQOS arm versus cigarette arm), also as compared to patients who had stopped 
smoking (IQOS arm versus Smoking Cessation (SC) arm), and to evaluate the reduction in 
the AAA annual growth rate in patients who continue to smoke CC as compared to patients 
who had stopped smoking (CC arm versus SC arm). 
Endpoints (to be assessed using all available diameter measurements from V3 to V8): 
• Measurement of the maximum minor-axis AAA diameter in mm 
• AAA annual growth rate (calculated by annualizing the slope of the linear regression 
over the available diameter measurements) 
 
 
Secondary Objectives and Endpoints: 
The secondary objectives of this study are: 
1. To describe the time from diagnosis of the AAA until open surgical AAA treatment or 
AAA endovascular repair or AAA rupture in patients who switch from smoking CC to 
using IQOS, as compared to patients who continue smoking CC and patients who had 
stopped smoking. 
Endpoints (over the entire study period): 
• Date of diagnosis 
• Date of decision to perform open surgical AAA treatment or AAA endovascular 
repair 
• Date of AAA rupture 
 
2. To describe the number of open surgical AAA treatment or AAA endovascular repair 
and AAA rupture in patients who switch from smoking CC to using IQOS, as compared 
to patients who continue to smoke CC and patients who had stopped smoking. 
Endpoints (number per year across all visits): 
• Number of patients with open surgical AAA treatment or AAA endovascular repair 
annually (based on date of decision to perform open surgical AAA treatment or 
AAA endovascular repair) 

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• Number of patients with AAA rupture annually (based on date of AAA rupture) 
 
3. To evaluate the number of AAA growth above 5 mm in 6 months and the number of 
patients with an overall maximum minor-axis AAA diameter >55mm in male patients 
and >50mm in female patients, in patients who switch from smoking CC to using IQOS, 
as compared to patients who continue smoking CC and patients who had stopped 
smoking. 
Endpoints (number per year across all visits): 
• Number of patients with an increase in maximum minor-axis AAA diameter of more 
than 5 mm within 6 months 
• Number of patients with an overall maximum minor-axis AAA diameter >55mm in 
male patients and >50mm in female patients 
 
4. To monitor the safety profiles associated with IQOS use, CC smoking and smoking 
cessation during the study. 
Endpoints (over the entire study period): 
• Incidence of Adverse events (AEs) / serious adverse events (SAEs) 
• Vital signs - change from Baseline (systolic and diastolic blood pressure, pulse rate 
and respiratory rate) 
• Electrocardiogram (ECG) -  change from Screening Visit (V1) used as Baseline 
(Heart rate, PR, QRS, QT, QTcB (Bazett’s correction) and QTcF (Fridericia’s 
correction) intervals) 
• Clinical chemistry, hematology, and urine analysis safety panel 
• Physical examination - changes from Baseline 
• Concomitant medications 
• Incidence of IQOS adverse incidences, malfunctions and misuses 
 
5. To describe nicotine exposure over time in AAA patients who switch from smoking CC 
to using IQOS, patients who continue to smoke CC, and patients who had stopped 
smoking. 
Endpoints (over the entire study period): 
• Nicotine equivalents (NEQ): molar sum of free nicotine, nicotine-glucuronide, free 
cotinine, 
cotinine-glucuronide, 
free 
trans-3’-hydroxycotinine, 
trans-3’-
hydroxycotinine-glucuronide in spot urine (expressed as concentration adjusted to 
creatinine) 

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6. To describe the changes in cardiovascular risk factors and BoExp to selected HPHCs 
over time in AAA patients who switch from smoking CC to using IQOS, patients who 
continue to smoke CC and patients who had stopped smoking.   
Endpoints (over the entire study period): 
1. Cardiovascular risk factors: 
a) Systolic and diastolic blood pressure 
b) Body weight and waist circumference 
 
2. BoExp to selected HPHCs (in spot urine, expressed as concentration adjusted to 
creatinine):  
a) Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL),  
b) Total N-nitrosonornicotine (Total NNN), and 
c) 2-cyanoethylmercapturic acid (CEMA) 
 
Study evaluation criterion: 
This is a descriptive study, designed to gain an understanding on the effect of complete 
switching from cigarettes to IQOS use compared to continued CC smoking on AAA growth 
rate and disease progression. Dual use of IQOS on top of CC will be also investigated. There 
are no formal statistical hypotheses to be tested. 
Study Design: 
This is a controlled, open-label, 3-arm parallel group, multi-center study in patients 
diagnosed with Abdominal Aortic Aneurysm (AAA). 
The overall study design is depicted in Figure 2. 
1. Adult patients currently smoking and not willing to quit smoking at study entry will 
be enrolled to be randomized at V2 with a 1:1 ratio in the CC and IQOS arms. 
Using the CT scan made according to the CT Scan Manual at V1 and assessed by the central 
reading site, patients considered eligible will be randomized according to the following 
stratification criteria: 
i. Aortic maximum minor-axis diameter (male patients: < 40 mm and 
≥ 40 mm; female patients: < 35 mm and ≥ 35 mm)  
ii. Sex (male vs. female) 

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2. Additionally, adult patients who had completely stopped smoking at study entry will 
be enrolled as a non-randomized control SC arm.  
In general, standard of care, as defined by the Guidelines for Diagnosis and Treatment of 
Aortic Aneurysm and Aortic Dissection 1, will be provided to all patients and will be 
supplemented by additional assessments as per this study protocol. As per standard of care, 
all AAA patients eligible for the screening for this study should have already been provided 
with smoking cessation advice at their AAA diagnosis (within the past 60 months). If 
smoking cessation advice was not provided during the last 6 months before the Screening 
Visit, based on the investigator’s judgment, then the respective AAA patient must not be 
screened for this study.  
Based on standard of care, all patients included in the study will be informed about the risks 
of smoking and provided with SC advices by the Investigator at the Screening Visit and all 
following study visits. Both standard of care procedures and procedures related to the study 
will be recorded. 
 
Figure 1 
Study Flow Chart  

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Study Population and Main Criteria for Inclusion: 
Female or male Japanese patients diagnosed with AAA and meeting the following main 
inclusion criteria will be enrolled in the study: 
Main Criteria for Inclusion (all study arms): 
1. Patient is aged ≥ 50 years (to be checked at V1). 
2. Patient is Japanese (to be checked at V1). 
3. Patient diagnosed with AAA (infrarenal, fusiform type) with a current aortic maximum 
minor-axis diameter of 30 to ≤ 49 mm (in male patient) and 30 to ≤ 44 mm (in female 
patient). 
a) Diagnosis of AAA within the past 60 months with at least two computerized 
tomography (CT) assessments since diagnosis. The two CT scans must have 
been done within the last 30 months before the Screening Visit (V1) with a time 
difference of at least 20 weeks and must show an increase of the aortic maximum 
minor-axis diameter between the first and the latter of these 2 CT scans (to be 
checked at V1). 
b) The maximum minor-axis AAA diameter to be used for assessment of eligibility 
is the maximum minor-axis AAA diameter available at the time of enrollment 
(based on the CT scan made according to the CT Scan Manual at V1 and 
assessed by central reading site (to be checked at V2)). 
4. Patient has smoked commercially available and/or roll-your-own CC on a daily basis 
for at least 5 years prior to AAA diagnosis, based on self-reporting (to be checked at 
V1). 
5. Patient is ready to comply with the study protocol (e.g., to use their assigned 
product/regimen during the course of the study) (to be checked at V1 and V2). 
Specific to patients screened for enrollment and randomization to the CC or IQOS arm: 
Female or male Japanese adult smokers with diagnosed AAA meeting the following 
additional main inclusion criteria will be enrolled and randomized in the CC and IQOS arms 
of the study: 
6. Patient has smoked on average > 5 commercially available and/or roll-your-own CC per 
day (no CC brand restriction) for the last 12 months, based on self-reporting (to be 
checked at V1). Intermittent attempts to quit smoking, with or without NRT use during 
these attempts, not exceeding 2 months or short-term interruption of smoking, with or 
without NRT use during the short-term interruption, up to 10 days within the last 12 

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months will be allowed. Smoking status will be verified based on a urinary cotinine test 
(i.e., cotinine ≥ 200 ng/mL) (to be checked at V1 and V2). 
7. Not intending to quit smoking within the next 6 months after having been advised to 
quit smoking (to be checked at V1 and V2). 
Specific to patients screened for enrollment into the SC arm: 
Female or male Japanese adult patients with diagnosed AAA meeting the following 
additional main inclusion criteria will be enrolled in the SC arm of the study: 
8. Patient had completely quitted smoking and stopped the use of any other tobacco or 
nicotine-containing products for at least 6 months prior to the Screening and is still 
abstinent at Screening (V1) and at Baseline (V2). Smoking status will be verified based 
on a urinary cotinine test (i.e., cotinine < 100 ng/mL) (to be checked at V1 and V2). 
Criteria for Exclusion: 
1. Patient is legally incompetent, physically or mentally incapable of giving consent (e.g., 
emergency situation, under guardianship, patient in a social or psychiatric institution, 
prisoner or patient involuntarily incarcerated) (to be checked at V1). 
2. Patient with acute severe cardiovascular events or respiratory diseases (e.g., stroke, 
acute coronary syndrome, cardiovascular-surgical procedures, pulmonary embolism as 
judged by the Investigator), within the last 3 months (to be checked at V1 and V2). 
3. Patient with currently active cancer or history of cancer within the last 5 years (to be 
checked at V1). 
4. Patient is ineligible as judged by the Investigator to participate in the study for any 
reason (e.g., medical, psychiatric and/or social reason) (to be checked at V1). 
5. Patient with dissecting aneurysm(s) of the aorta (to be checked at V1). 
6. Patient with infrarenal pseudo-AAA (false AAA) (to be checked at V1). 
7. Patient with a diagnosis of COPD Stage 3 and 4 in the medical history (to be checked 
at V1). 
8. Patient has used any heat-not-burn tobacco product(s), and/or tobacco vapor product(s) 
on a daily basis for the last 12 months, based on self-reporting (to be checked at V1). 
9. Patient with a recent (within 1 year) or current history of alcohol or other substance 
abuse based on self-reporting (to be checked at V1). 

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10. Female patient who is pregnant or breast-feeding (to be checked at V1 and V2). 
11. Patient with a diagnosis of concomitant genetic diseases such as but not limited to 
Marfan syndrome, Loeys-Dietz syndrome, Vascular Ehlers-Danlos syndrome, Turner 
syndrome, Polycystic kidney disease, Noonan syndrome, Alagile syndrome, Arterial 
tortuosity syndrome and Cutis laxa (to be checked at V1). 
12. Patient is a current or former employee of the tobacco industry or their first-degree 
relatives (parent and child) (to be checked at V1). 
13. Patient is an employee of the investigational site or any other parties involved in the 
study or their first-degree relatives (parent and child) (to be checked at V1). 
14. Patient has been previously screened or enrolled in this study (to be checked at V1). 
15. Patient was enrolled in any clinical study within 3 months prior to V1 (to be checked at 
V1). 
Investigational Products; Dose and Mode of Use:  
Test product: The product tested in this study is the THS with Marlboro Heatsticks, 
marketed in Japan under the brand name IQOS and generally referred to as IQOS in this 
protocol. All versions of IQOS (including Tobacco Heating Devices (THD) with two 
elements: Charger and Holder, and THD with one single element (holder only: e.g., IQOS 3 
Multi)) and Marlboro Heatsticks available for sale in Japan at the time of study start or 
becoming available during the course of the study are allowed to be used in the context of 
this study.  
 
Two IQOS devices and one selection of HeatStick flavor variants available on the Japanese 
market will be supplied either by the site or by a third party courier service to the patients 
randomized to IQOS arm after randomization. The second IQOS device is to be used as 
backup, in case the first one does not work properly. Following this supply, patients allocated 
to IQOS arm will be asked to buy HeatSticks for their own use during the entire 
Investigational Period. HeatSticks will not be provided (except for the first distribution) or 
reimbursed by the Sponsor. Patients will use IQOS ad libitum with no flavor variant 
restrictions. 
Comparator and Baseline product: The patients’ own preferred brand of commercially 
available and/or roll-your-own CC will not be provided by the Sponsor but purchased by the 
patients for their own use for the full duration of the study. Patients will use ad libitum their 
CC with no brand restrictions including no restriction to change preferred brand during the 
study. 

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Smoking Cessation (Reference):  
Patients who had completely quitted smoking will continue to remain abstinent from 
smoking cigarettes or use any tobacco or nicotine containing products, except nicotine 
replacement therapy (NRT), from the Screening Visit onwards and during the Investigational 
Period. 
Study Duration: 
The study duration for each patient will be up to 3 years and 1 month. This includes the 
Screening Period of up to 28 days prior to Visit 2 (Baseline Visit), followed by an 
Investigational Period up to 3 years. 
The end of the study for an individual patient will be defined as V8 or the date of early 
termination. The end of the entire study is the latest date that an individual patient reaches 
the end of the study. 
Independent Data Monitoring Committee (IDMC): 
An Independent Data Monitoring Committee (IDMC) will be established prior to starting 
the recruitment of patients and will meet periodically throughout the study to monitor the 
patients’ safety, to review and evaluate the study data such as disease characteristics, the 
quality of the study conduct, e.g., feasibility, robustness and integrity, and the study progress. 
Members of the IDMC with expertise in the field of the disease and statistics, independent 
of both the sites and the Sponsor, are defined in a separate document, the IDMC Charter. 
The IDMC will organize meetings accordingly to review these study-specific data taking 
into consideration the relevant background knowledge about the disease and the patient 
population being studied. The IDMC Charter will define further details such as the review 
cycles, number of planned IDMC data reviews as well as stopping rules for the study, if 
considered by the IDMC as needed.  
For this study, data reviews by IDMC members will be performed one year and two years 
after the first patient has been randomized. Sponsor will be informed at least with meeting 
minutes. 
 
The Role of IDMC 
1. The IDMC will monitor the safety of the patients and disease progression based on 
clinical parameters listed in the IDMC charter. They will evaluate the risks/benefits for 
the patients based on clear and consistent evidence of higher harm (without formal 
boundaries) in patients randomized to IQOS relative to CC. 
2. The IDMC will also evaluate the quality of study conduct and implication for further 
study course based on parameters described in the IDMC charter.  

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3. The IDMC will not monitor or make any recommendations in regards to effectiveness or 
futility in the study.  
The IDMC may provide recommendations to the Sponsor regarding any identified study-
conduct issues (e.g., protocol deviations), and may make recommendations to the Sponsor 
concerning the continuation or termination of the study based on their evaluation of safety 
(risk /benefit for the patient) and the quality of the study conduct.  
Statistical Methods: 
The Full Analysis Set (FAS) will consist of all enrolled patients in the SC arm who have 
signed the informed consent form (ICF) and who have at least one valid non-safety 
assessment after enrollment as well as all patients randomized to the CC or IQOS arm who 
have signed the ICF, have at least one valid non-safety assessment after randomization and 
have at least one post-randomization product use (IQOS or CC) experience. The FAS will 
be analyzed by enrollment arm (randomization arm for CC or IQOS, or SC arm). 
The Safety Set will consist of all enrolled patients who have signed the ICF and who have 
at least one valid value for a safety assessment during the course of the study. Descriptive 
statistics for continuous variables will include the number of patients, number and percent 
of patients with missing data, the mean and standard deviation, median, first and third 
quartiles, minimum and maximum, and 95% confidence interval (CI) across all patients by 
enrollment arm. In addition, the results may be presented as a stratified summary as defined 
in the Statistical Analysis Plan (SAP). 
Adverse events data will serve as the primary assessment of safety and will be analyzed by 
tabulating the number and percentage of patients in the Safety Set with AEs and SAEs using 
MedDRA®. Concomitant medications, incidence of IQOS malfunction and misuse, 
laboratory parameters, ECG, vital signs, and physical examination, will also be analyzed as 
the safety endpoints. 
Sample Size:  
The sample size of patients is not based on a statistical hypothesis, as this is a descriptive 
study, designed to characterize the growth rate of AAA and the progression of disease, to 
better understand the impact of IQOS relative to CC on the progression of disease. 
Safety Assessments: 
AEs (including SAEs) and product events will be captured. Any AEs (including SAEs) will 
be assessed by the Investigator(s) or designee(s) in order to establish relationship to 
Investigational Products (IPs) and study procedures. AEs and product events will be 
collected from the time when the patients have signed their ICFs until the end of the study. 

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The Investigator must notify the Sponsor of all SAEs and pregnancies within 24 hours of the 
first awareness. 

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TABLE OF CONTENTS 
1 
ETHICS AND REGULATIONS ...................................................................................26 
1.1 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) 
Approval ................................................................................................................26 
1.2 
Ethical Conduct of the Study .................................................................................27 
1.3 
Patient Information and Consent ...........................................................................27 
1.3.1 
Informed Study Consent Form/Patient Information Sheet for 
Participation to the Study .............................................................................27 
1.3.2 
Amendment Informed Consent Forms/ Patient Information Sheet for 
Participation to the Study .............................................................................27 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................28 
2 
INTRODUCTION ..........................................................................................................29 
2.1 
Background ............................................................................................................29 
2.2 
Purpose of the Study ..............................................................................................32 
2.3 
Anticipated Benefits and Risks ..............................................................................32 
2.3.1 
Anticipated Benefits.....................................................................................32 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures .............................32 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Products ..................32 
2.3.4 
Unforeseeable Risks.....................................................................................33 
3 
STUDY OBJECTIVES ..................................................................................................34 
3.1 
Primary Objective and Endpoints ..........................................................................34 
3.2 
Secondary Objectives and Endpoints.....................................................................34 
3.3 
Exploratory Objectives and Endpoints ..................................................................36 
4 
OVERALL STUDY DESIGN AND PLAN ..................................................................37 
4.1 
Rationale for Study Design and Control Group(s) ................................................39 
4.2 
Appropriateness of Measurements .........................................................................41 
4.3 
Study Duration .......................................................................................................43 
4.4 
Patient recruitment .................................................................................................44 
4.5 
Independent Data Monitoring Committee (IDMC) ...............................................44 
5 
STUDY POPULATION .................................................................................................46 
5.1 
Selection of Study Population ................................................................................46 
5.1.1 
Inclusion Criteria .........................................................................................46 
5.1.2 
Exclusion Criteria ........................................................................................47 

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5.2 
Discontinuation of Patients from the Study ...........................................................48 
5.2.1 
Discontinuation from the study ....................................................................49 
5.2.2 
Violation of Selection Criteria .....................................................................50 
5.3 
Lost to Follow-up ...................................................................................................50 
6 
INVESTIGATIONAL PRODUCT(S)/REFERENCE ...................................................51 
6.1 
Description of Investigational Product(s) ..............................................................51 
6.1.1 
Comparator and Baseline Product(s) ...........................................................53 
6.1.2 
Packaging and Labeling ...............................................................................53 
6.2 
Administration of Investigational Product(s) (for CC and IQOS arms) ................53 
6.2.1 
From Screening (V1) to Baseline (V2) ........................................................53 
6.2.2 
Investigational Period ..................................................................................53 
6.3 
SC Arm (Reference) ..............................................................................................54 
6.3.1 
From Screening (V1) to Baseline (V2) ........................................................54 
6.3.2 
Investigational Period ..................................................................................54 
6.4 
Method for Assigning Patients to Study Arms ......................................................54 
6.4.1 
IQOS and CC arms ......................................................................................54 
6.4.2 
SC Arm ........................................................................................................54 
6.5 
Blinding..................................................................................................................55 
6.5.1 
Blinding of the CT-Overreaders ..................................................................55 
6.5.2 
Blinding of data............................................................................................55 
6.6 
Investigational Product Accountability and Adherence ........................................56 
6.6.1 
Dispensing Investigational Product .............................................................56 
6.6.2 
Storage and Accountability ..........................................................................56 
6.6.3 
Investigational Product Retention ................................................................56 
6.6.4 
Product Use Restrictions ..............................................................................56 
6.6.5 
Dietary Restrictions .....................................................................................56 
6.6.6 
Adherence ....................................................................................................57 
6.7 
Concomitant Medication ........................................................................................57 
7 
STUDY PROCEDURES ................................................................................................58 
7.1 
Informed Consent and Guidance ...........................................................................58 
7.2 
Advice on the Risks of Smoking/SC Advice .........................................................58 
7.3 
Debriefing on IQOS ...............................................................................................58 
7.4 
Clinical Assessments .............................................................................................59 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
 
7.4.1 
Demographic Data .......................................................................................59 
7.4.2 
Questions on Smoking History/Habits.........................................................59 
7.4.3 
Intention to Quit Smoking ...........................................................................60 
7.4.4 
Demonstration of IQOS using a video .........................................................60 
7.4.5 
Medical History/Concomitant Disease(s)/Previous and Ongoing 
Medications ..................................................................................................60 
7.4.6 
Physical Examination...................................................................................61 
7.4.7 
Body Height, Body Weight and Waist Circumference ................................61 
7.4.8 
Vital signs ....................................................................................................61 
7.4.9 
Assessments of maximum minor-axis AAA Diameter ................................62 
7.5 
Other Clinical Assessments ...................................................................................62 
7.5.1 
Electrocardiogram ........................................................................................62 
7.5.2 
Chest X ray ..................................................................................................63 
7.6 
Bioanalytical Assessments .....................................................................................63 
7.6.1 
Biomarker of Exposure ................................................................................63 
7.6.2 
Creatinine Analysis ......................................................................................63 
7.7 
Laboratory Assessments ........................................................................................63 
7.7.1 
Clinical Chemistry, Hematology, and Urine analysis for the Safety 
Panel .............................................................................................................63 
7.7.2 
Urine Pregnancy Testing..............................................................................64 
7.7.3 
Cotinine Test ................................................................................................65 
7.8 
Sample Handling, Storage, and Shipment .............................................................65 
7.8.1 
Blood Samples .............................................................................................65 
7.8.2 
Urine Samples ..............................................................................................65 
7.9 
Self-reported Tobacco or Nicotine-Containing Product Use .................................65 
8 
ADVERSE EVENTS/PREGNANCIES/PRODUCT EVENTS.....................................67 
8.1 
Definitions..............................................................................................................67 
8.1.1 
Adverse Events ............................................................................................67 
8.1.2 
Serious Adverse Event .................................................................................67 
8.2 
Assessment of Adverse Events ..............................................................................68 
8.2.1 
Assessment of Adverse Events ....................................................................68 
8.2.2 
Period of Collection .....................................................................................68 
8.2.3 
Intensity of Adverse Event...........................................................................69 

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8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures ....................................................................................................69 
8.2.5 
Expectedness ................................................................................................70 
8.3 
Reporting and Follow-Up of Serious Adverse Events ...........................................70 
8.4 
Reporting of other events critical to safety evaluations .........................................71 
8.4.1 
Abnormal Results of Laboratory Tests ........................................................71 
8.4.2 
Reporting other abnormal findings ..............................................................72 
8.5 
Reporting and Follow-Up of Pregnancies..............................................................72 
8.6 
Adverse Events Leading to Discontinuation..........................................................73 
8.7 
Product Events / Investigational Product Malfunction and Misuse .......................73 
9 
STUDY ACTIVITIES ....................................................................................................74 
9.1 
Screening Visit: V1 ................................................................................................74 
9.2 
Baseline Visit: V2 ..................................................................................................76 
9.3 
Investigational Period (from V3 to V8) .................................................................79 
9.4 
Early Termination Procedures ...............................................................................81 
10 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................83 
10.1 
Monitoring .............................................................................................................83 
10.2 
Training of Staff .....................................................................................................84 
10.3 
Audits and Inspections ...........................................................................................84 
11 
DATA MANAGEMENT ACTIVITIES ........................................................................85 
11.1 
Data Capture ..........................................................................................................85 
11.1.1 
Case Report Forms and Study Records .......................................................85 
11.1.2 
Protocol Deviations ......................................................................................85 
11.2 
Data Handling ........................................................................................................86 
11.2.1 
Data Validation ............................................................................................86 
11.2.2 
Coding ..........................................................................................................86 
11.2.3 
Database Lock ..............................................................................................87 
12 
PLANNED STATISTICAL METHODS .......................................................................88 
12.1 
General Considerations ..........................................................................................88 
12.1.1 
Stratification Criteria ...................................................................................88 
12.1.2 
Definitions for Statistical Data Analysis......................................................89 
12.1.3 
Descriptive Statistics ....................................................................................89 
12.1.4 
Handling of Missing Values and of Values outside the Detection Limits ...89 

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12.1.5 
Significance Level for Inferential Analysis .................................................89 
12.1.6 
Confidence Interval ......................................................................................89 
12.2 
Determination of Sample Size ...............................................................................90 
12.3 
Product Use ............................................................................................................90 
12.4 
Analysis Populations ..............................................................................................90 
12.4.1 
Full Analysis Set (FAS) ...............................................................................90 
12.4.2 
Safety Set .....................................................................................................90 
12.5 
Demographics and Baseline Characteristics ..........................................................91 
12.6 
Primary Analysis ....................................................................................................91 
12.7 
Secondary Analysis ................................................................................................91 
12.8 
Safety Analysis ......................................................................................................92 
12.9 
Exploratory Analysis .............................................................................................93 
12.10 IDMC Analyses .....................................................................................................93 
13 
ADMINISTRATIVE CONSIDERATIONS ..................................................................94 
13.1 
Investigators and Study Administrative Structure .................................................94 
13.1.1 
Investigators .................................................................................................94 
13.1.2 
Sponsor ........................................................................................................94 
13.1.3 
Other Responsibilities ..................................................................................95 
13.2 
Patient Confidentiality ...........................................................................................95 
13.3 
Access to Source Documentation ..........................................................................96 
13.4 
Record Retention ...................................................................................................96 
13.5 
Assessment Study Report ......................................................................................98 
13.6 
Financial Disclosure...............................................................................................98 
13.7 
Publication and Disclosure Policy .........................................................................98 
13.8 
Insurance ................................................................................................................99 
14 
REFERENCE LIST ......................................................................................................100 
 
LIST OF IN-TEXT TABLES 
Table 1 
Test Product (IQOS) ............................................................................................... 52 
Table 2 
Blinding Scheme .................................................................................................... 55 
Table 3  Clinical Laboratory Parameters for Safety Panel ................................................... 64 
Table 4  Schedule - Screening Visit: V1 .............................................................................. 74 
Table 5  Time Schedule – Baseline Visit: V2 ...................................................................... 76 

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Table 6  Time Schedule – V3 to V8 ..................................................................................... 79 
Table 7  Time Schedule – Early Termination Procedures .................................................... 81 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1 Study Flow Chart...................................................................................................... 9 
Figure 2 Study Flow Chart.................................................................................................... 37 
 
LIST OF APPENDICES 
APPENDIX 1 
SCHEDULE OF EVENTS ........................................................................105 
APPENDIX 2 
PARTICIPATING LABORATORIES .....................................................109 
APPENDIX 3 
INVESTIGATIONAL PRODUCT AND INSTRUCTIONS FOR USE ..109 
APPENDIX 4 
STANDARD PROTOCOL TO ASSESS THE MAXIMUM MINOR-
AXIS AAA DIAMETER FROM THE CT SCAN ....................................109 
APPENDIX 5 
LIST OF INVESTIGATORS AND STUDY SITES ................................109 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AAA 
Abdominal Aortic Aneurysm 
 
AE 
Adverse Event  
ALT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BoExp 
Biomarker of Exposure 
BUN 
Blood Urea Nitrogen 
CC 
Cigarette 
CDISC 
Clinical Data Interchange Standards Consortium 
CEMA 
2-Cyanoethylmercapturic Acid 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CT 
Computed Tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
CV 
Coefficient of Variation 
DICOM 
Digital Imaging and Communications in Medicine 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
FAS 
Full Analysis Set 
 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
 
HPHC 
Harmful and Potentially Harmful Constituents  
ICF 
Informed Consent Form  
ICH 
International Council for Harmonization  
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
 

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IP 
Investigational Product 
IRB 
Institutional Review Board 
IXRS 
Interactive Web and Voice Response System 
LDH 
Lactate Dehydrogenase 
LLOQ 
Lower Limit of Qualification 
LOCF 
Last Observation Carried Forward 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NEQ 
Nicotine Equivalents 
NNK 
Nicotine-derived nitrosamine ketone (= 4-(methylnitrosamino)-1-
(3-pyridyl)-1-butanone) 
NRT 
Nicotine Replacement Therapy 
PK 
Pharmacokinetics 
 
PMI 
Philip Morris International 
QC 
Quality Control 
 
RBC 
Red Blood Cell 
 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
 
SC 
Smoking Cessation 
 
SD 
Standard Deviation 
 
SDTM 
Study Data Tabulation Model 
 
SHM 
Sample Handling Manual 
 
SMP 
Safety Management Plan 
 
SOC 
System Organ Class 
 
SOP 
Standard Operating Procedure 
 
SPI 
Summary of Product Information 
 
TC 
Total Cholesterol 
 
TG 
Triglycerides 
 
THD 
Tobacco Heating Device 
 
THS 
Tobacco Heating System 
 

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Total NNAL 
Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanol 
 
Total NNN 
Total N-nitrosonornicotine 
 
ULOQ 
Upper Limit of Qualification 
 
USB 
Universal Serial Bus 
 
WBC 
White Blood Cell 
 
WPI 
Whole Person Impairment 
 
Explanation of terms 
The following special terms are used in this protocol: 
Cigarette  
The term ‘cigarette’ refers to commercially available cigarettes 
(manufactured) and roll-your-own cigarettes. Cigarettes are tobacco rolled in 
paper that is lighted on fire to produce smoke. 
End of study 
 
The end of the study for an individual patient will be defined as Visit 8, or 
the date of early termination of the patient. 
The end of the entire study is defined as the last individual patients’ end of 
the study. 
Enrollment 
 
For the SC Arm: at Visit 2 (V2) for eligible patients after all applicable entry 
criteria have been satisfactorily met. 
For the IQOS and CC Arm: at Visit 2 (V2) for eligible patients after all 
applicable entry criteria have been satisfactorily met. 
HeatSticks 
The HeatStick is designed to be used with IQOS only. The HeatStick is made 
up of: tobacco plug, hollow acetate tube, polymer-film filter, mouth piece 
filter, outer and mouth-end papers. 
IQOS 
Unless otherwise specified, IQOS in this document refers to PMI’s Tobacco 
Heating System (THS) with HeatSticks as available for purchase in the 
Japanese market. No other tobacco sticks should be used with the IQOS 
device. 
Investigator 
Investigator or sub-Investigator. 
Randomization 
 
Assignment to IQOS or cigarette arm. Patients will be randomized and 
informed of their randomized study arm by the study site at Visit 2 (V2, 

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Baseline Visit). All patients will be instructed to continue to solely use their 
assigned product until they complete the study. 
Screen failure  
Patient who signs ICF but was not enrolled. Re-screening of patients who 
did not meet any entry criteria will not be permitted. 

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1 ETHICS AND REGULATIONS 
1.1 
Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) Approval 
Prior to the start of the study, the clinical study protocol, together with its associated documents 
(as applicable, informed consent forms [ICFs] including both patient information sheet and 
consent form, patient recruitment procedures [e.g., advertisements] if applicable, written 
information to be provided to the patients, Summary of Product Information [SPI] 2, the 
Investigator’s curriculum vitae and/or other evidence of qualifications, and any other 
documents requested by the Institutional Review Board [IRB] / Independent Ethics Committee 
[IEC]), will be submitted for review and approval to the relevant IRB / IEC. The IRB / IEC 
shall be appropriately constituted and perform its functions in accordance with the 
International Council for Harmonization of Technical Requirements for pharmaceuticals for 
Human Use (ICH) Tripartite Guidance for Good Clinical Practice (GCP), and Ministerial 
Ordinance on Good Clinical Practice for Drugs and local requirements, as applicable. 
In accordance with GCP, a written confirmation of the IRB / IEC approval should be provided 
to the Sponsor and the Investigator. This should identify the study (Investigator’s name, study 
number and title) and the documents that have been approved by the IRB / IEC, with dates and 
version numbers, as well as the date of approval. The composition of the IRB / IEC, including 
the name and occupation of the chairperson, should be supplied to the Sponsor together with a 
GCP compliance statement. 
The written approval from the IRB / IEC will be filed in the Investigator Site File and a 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 / IEC. 
Any change to this protocol will require a written protocol amendment that must be approved 
by the Sponsor and the Investigator. All amendments will be submitted to the IRB / IEC, and 
substantial amendments will only be implemented after approval by the IRB / IEC. 
These requirements for approval should in no way prevent any action from being taken by the 
Investigator or sub-Investigator (Investigator) or by the Sponsor in order to eliminate 
immediate hazards to the patients. If such a change to the protocol is considered necessary by 
the Investigator, and is implemented for safety reasons, the Sponsor and the IRB / IEC should 
be informed immediately. 
Relevant safety information will be submitted to the IRB / IEC during the course of the study 
in accordance with national regulations and requirements. 

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1.2 
Ethical Conduct of the Study 
The study will follow the principles as defined in the ICH GCP 3, in the Ministerial Ordinance 
on Good Clinical Practice for Drugs (Ministry of Health and Welfare, 1997 (as last amended 
by the Ordinance of Ministry of Health, Labor and Welfare No. 9 of January 22, 2016) 4, in 
the Declaration of Helsinki 5 and other applicable local regulations and guidelines such as 
Japanese-GCP 4. Prior to the initiation of any study procedures, the protocol will be approved 
by an IRB / IEC and the patient will have received information on the study, as well as signed 
the study ICF. 
1.3 
Patient Information and Consent 
1.3.1 
Informed Study Consent Form/Patient Information Sheet for Participation to 
the Study 
Before or at the Screening Visit (V1), the Investigator will ensure each patient is given full and 
adequate oral and written information about the nature, purpose, possible risks and benefits of 
the study, and the Investigator will answer all questions the patient might have to his/her full 
satisfaction. The patient will have sufficient time for consideration of his/her participation in 
the study and will be notified that he/she is free to discontinue his/her participation at any time. 
Once the patient has received all necessary information, and if he/she agrees to participate, this 
will be documented in the ICF by the date, time and signature of both the patient and the person 
who conducted the inform consent discussion. No study-specific procedures will be performed 
before the ICF has been signed. 
The original, dated and signed ICF must be kept in the Investigator file at the site, and a copy 
must be given to the patient. 
The patient will be informed that if he/she withdraws from the study, the data collected until 
the point of withdrawal will be maintained as part of the study data and the samples collected 
prior to withdrawal will be analyzed, unless he/she refuses in writing.  
Furthermore, the patient will be informed that additional data analyses not mentioned in the 
protocol or the statistical analysis plan might be performed with the collected data at a later 
time. If any additional analyses will be performed, they will fully be covered by data 
confidentiality, as for the main analyses described in this protocol. 
1.3.2 
Amendment Informed Consent Forms/ Patient Information Sheet for 
Participation to the Study 
If a protocol amendment is required, an amendment may be required to the ICF. If revision of 
the ICF is necessary, the Investigator or designee will, with the support of the Sponsor or 

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authorized representative, ensure that the documents have been reviewed and approved by the 
IRB / IEC before study participants are required to re-sign and time and date the ICF. 
1.4 
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator abide by the principles of the current version of the ICH 
guidelines on GCP and will carry out the clinical study in accordance with these principles. 
Although these guidelines were written specifically to set a standard for pharmaceutical 
development, they nevertheless provide a robust and ethical framework for conducting clinical 
studies of tobacco products. 
 
 

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2 INTRODUCTION 
2.1 
Background 
Aortic Abdominal Aneurysm (AAA) is a permanent localized dilatation of the abdominal 
aorta. It is usually asymptomatic, almost exclusively occurs in the infrarenal part of the 
abdominal aorta and is incidentally discovered by ultrasound imaging. AAA and aortic 
rupture/dissections are responsible for at least 15,000 deaths annually, and was the 10th leading 
cause of death in white men with 65 to 74 years of age in the U.S. in the year 2000 6. Deaths 
due to aortic aneurysm/dissection are increasing every year in Japan. It was the 9th leading 
cause of death in Japan in 2014 (Statistics of Ministry of Health, Labour and Welfare). The 
limited regional investigational data in Japan indicate that the incidence rate of aortic 
aneurysm/dissection per year to be about 3 per 100,000 in the population 1. 
The Japanese Guidelines for Diagnosis and Treatment of Aortic Aneurysm and Aortic 
Dissection defines AAA as follows: “Aortic aneurysm is a circumferential or local enlargement 
(increased diameter) or protrusion of a part of the aortic wall. Normal diameter in the 
abdominal region is generally 20 mm. When a part of the aortic wall is dilated and thereby 
forms a bump, or when the diameter is increased to a degree at least 1.5-fold greater than 
normal (exceeding 30 mm in the abdominal region) in a fusiform manner, the condition is 
called aneurysm”1. The development of AAA can be observed in 3 steps:  
(1) formation/development, 
(2) expansion, and 
(3) rupture. 
The strongest predictors of developing a AAA are cigarette (CC) smoking, sex, age, family 
history of AAA, hypertension, coronary artery disease, hypercholesterolemia, lower extremity 
peripheral arterial disease, carotid disease, history of cerebrovascular event, overweight or 
obesity, and low high-density lipoprotein cholesterol 7. Cigarette smoking represents an 
independent risk factor for AAA, as it has been shown that there is a 10.1 and 7.5 times higher 
relative risk in male and female smokers, respectively, when compared to never smokers 8. 
Furthermore, the relative risk of an AAA in individuals who have ever smoked is 2.5 times 
greater than that of coronary heart disease in the same patient group. There is a direct dose-
response relationship between AAA and CC smoking (i.e., the risk of AAA rises with the 
increasing exposure to CC smoke and it has been shown that the risk of developing AAA 
gradually decreases with the years of Smoking Cessation (SC) 9-12. 

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Besides its role as the most important risk factor for developing AAA, smoking also 
significantly accelerates the growth of an AAA. The growth rate observed in CC smokers is 
higher than it is in former CC smokers (an increase of approximately 0.4 mm/year) 12,13. 
Through the impact on growth rate, CC smoking also increases the risk of an AAA rupture and 
decreases the time to AAA open surgical/endovascular repair intervention 13,14. Furthermore, 
a larger aneurysm size at diagnosis indicates a more rapid expansion of the aneurysm further 
on and therefore a faster disease progression 10. Abdominal Aortic Aneurysms that reach a 
diameter of ≥ 55 mm in males or ≥ 50 mm in females, as well as AAA that have a growth rate 
of ≥ 5 mm within 6 months are common indicators for open surgical interventional treatment 
or AAA endovascular repair of the AAA 1. 
Philip Morris International (PMI) develops, assesses and commercializes a portfolio of 
innovative products intended to (1) significantly reduce the risk of smoking-related disease 
compared to continued smoking of CC and (2) are accepted by smokers as substitutes for CC. 
More than 6000 smoke constituents have been identified when the tobacco is burned or 
combusted 15, and more than 100 of them have been categorized as harmful and potentially 
harmful constituents (HPHCs) 16. Lowering the temperature and heating the tobacco instead of 
burning it can substantially reduce levels of HPHCs. PMI’s Tobacco Heating System (THS, 
marketed under the brand name of IQOS) is a novel tobacco heating system that heats a 
specifically designed tobacco stick (HeatStick) within a precisely controlled temperature range 
(far lower temperatures than CC) rather than burning it. IQOS replicates the ritual of smoking 
but without combustion. 15,16. 
The Tobacco Heating Device (THD) consists of either two elements (charger and holder) or 
one single element (holder only: e.g., IQOS 3 Multi). IQOS is composed of the Holder and of 
dedicated HeatSticks. In this document, unless otherwise specified, IQOS refers to the device 
with HeatSticks. No other tobacco sticks should be used with the device. The Charger of the 
THD with two elements allows to recharge the Holder after each use. The Holder of the THD 
with one single element must be recharged after approximatively 10 inhalation experiences 
and can be recharged from household power. Unlike CC, the HeatSticks do not burn down 
during their consumption and their lengths remain constant after use. IQOS has been 
commercialized in Japan since November 2014. With this product, the heating of the tobacco 
is maintained below 350°C, a temperature much lower than what is observed for CC, which 
can reach 900°C.  
PMI has undertaken a comprehensive assessment program on IQOS, including pre-clinical and 
clinical studies, aiming to demonstrate that IQOS is a reduced risk product1. The non-clinical 
assessment of IQOS, consisting of the aerosol chemistry analysis, in vitro and in vivo studies, 
supported the initiation of clinical studies, as no new or increased toxicological hazard in the 
product’s aerosol was detected when compared with CC smoke. Results from pre-clinical in 

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vivo studies comparing CC smoke with IQOS aerosol in continuous inhalation show that 
exposure to IQOS aerosol, at multiple concentrations, results in a dramatically lower systemic 
toxicity, extensively reduced lung inflammation and reduced histopathological changes in the 
nasal epithelium as well as lung tissue compared to CC smoking 17,18. Furthermore, exposure 
to IQOS aerosol in mice does not enhance cardiovascular disease or emphysema, as CC smoke 
does, and switching from CC smoke to IQOS aerosol exposure halts, e.g., aortic plaque growth 
in a similar manner as SC 19,20. 
Several clinical studies have been conducted with IQOS, in Europe, Asia and the United States, 
in order to evaluate the nicotine pharmacokinetics (PK) profile 21-24, to demonstrate reduced 
exposure 25-28, and to determine functional and biological changes when adult smokers switch 
from CC to IQOS use compared to smokers continuing smoking CC 27,28. The PK studies 
demonstrated similar nicotine absorption in subjects using IQOS and subjects smoking CC. 
The Reduced Exposure studies showed reductions in the levels of biomarkers of exposure 
(BoExp) to selected HPHCs in subjects using IQOS, when compared to subjects continuing 
smoking CC, close to levels observed when subjects stopped smoking for the duration of the 
study, both in controlled and ambulatory settings, for a duration of up to 3 months. These 
studies also indicated favorable biological and functional changes in clinical risk endpoints 
linked to smoking-related diseases, such as cardiovascular diseases. The number of tobacco 
sticks (= Marlboro Heatsticks) daily used over the entire study period in these studies was not 
increased, when compared to Baseline 29. 
A 6-month exposure study 30, followed by a 6-month extension study 31, with the specific aim 
to demonstrate favorable changes in clinical risk endpoints in smokers switching from CC to 
IQOS compared to smokers continuing smoking CC has been completed and data analysis is 
on-going. Post-marketing studies are initiated, in order to have a better understanding of the 
product use behaviors and first insights in health outcomes 32. Safety data available to date 
show a similar short-term safety profile for IQOS as for CC. PMI is now launching a series of 
new clinical studies to better understand whether switching to IQOS can have beneficial effects 
on health outcomes. Due to the known adverse effects of CC smoking and the benefits of SC 
on cardiovascular diseases (such as AAA), this study is part of this program. Further product 
information such as the nicotine content of each Marlboro HeatStick tested in this study can 
be found in Table 1 (section 6.1) and in the SPI 2. 
1 Reduced risk products (“RRPs”) is the term used by PMI to refer to products that present, are 
likely to present, or have the potential to present less risk of harm to smokers who switch to 
these products versus continued smoking. 

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2.2 
Purpose of the Study 
The data available in the literature for AAA growth rates in Japanese patients who continue to 
smoke CC and patients who had stopped smoking are scarce. In consequence, a well-informed 
estimate of the expected effect size in the different study groups as well as an evaluation of the 
operational feasibility, in particular the IQOS study group, is difficult.  
Therefore, the purpose of this study is to evaluate the reduction of the AAA annual growth rate 
in patients who switch from smoking CC to using IQOS as compared to patients who continue 
to smoke CC. The study also aims to provide context to the scale of reduction in the growth 
rate, by comparing the AAA annual growth rates for continuing to smoke and switching to 
IQOS with the AAA annual growth rate in smokers who had stopped smoking.  
The data derived from this study will help to close the existing gaps in the literature and inform 
on the appropriate design for further research studies in this field. 
2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
Advice on health risk associated with tobacco smoking and SC advice will be provided at V1 
and then at each visit from V2 to V8. The advice will follow the recommendations of the 
Japanese Circulation Society 33 and of the Ministry of Health, Labour and Welfare 34. Patients 
who are motivated to quit using tobacco or nicotine-containing products (e.g., CC, IQOS or 
any other product) will be provided with SC support as per standard of care in Japan and will 
be referred for additional SC counselling to their General Practitioner. Patients who participate 
in this study will be compensated for their time and any inconvenience and will also benefit 
from repeated, detailed check-ups during the entire study period, which may help to increase 
efficacy of AAA therapy. The exact compensation amount and the schedule of payments will 
be listed in the site specific ICF. 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures 
The risk of study procedures (e.g., computerized tomography [CT] measurement, blood draw, 
etc.) are deemed to be on par with procedures routinely performed during normal or extended 
examinations by the patient’s doctor. 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Products 
A substantial body of evidence already exists on IQOS 2. Adverse events (AEs) reported so far 
seem to be mostly in line with the safety profile of SC pharmacotherapies such as nicotine 
replacement therapy (NRT).  

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2.3.4 
Unforeseeable Risks 
The possibility of unforeseeable events/risks will be explained at V1. Non-expected 
malfunction of IQOS may lead to unforeseeable risks. Patients will be informed that IQOS is 
not demonstrated yet to be less harmful than CC. Mitigation will include close monitoring and 
medical supervision to detect any unforeseeable risks or safety signals at the earliest time 
possible. In case of any disadvantages, the Investigator will take the decision to act 
accordingly. 
 
 

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3 STUDY OBJECTIVES 
3.1 
Primary Objective and Endpoints 
The primary objective of this study is: 
To evaluate the reduction in the AAA annual growth rate in patients who switch from smoking 
cigarettes (CC) to using IQOS, as compared to patients who continue to smoke CC (IQOS arm 
versus CC arm), also as compared to patients who had stopped smoking (IQOS arm versus 
Smoking Cessation (SC) arm), and to evaluate the reduction in the AAA annual growth rate in 
patients who continue to smoke CC as compared to patients who had stopped smoking (CC 
arm versus SC arm).  
Endpoints (to be assessed using all available diameter measurements from V3 to V8): 
• Measurement of maximum minor-axis AAA diameter in mm 
• AAA annual growth rate (calculated by annualizing the slope of the linear regression 
over the available diameter measurements) 
 
3.2 
Secondary Objectives and Endpoints 
The secondary objectives of this study are: 
1. To describe the time from diagnosis of the AAA until open surgical AAA treatment or 
AAA endovascular repair or AAA rupture in patients who switch from smoking CC to 
using IQOS, as compared to patients who continue smoking CC and patients who had 
stopped smoking. 
Endpoints (over the entire study period): 
• Date of diagnosis 
• Date of decision to perform open surgical AAA treatment or AAA endovascular repair 
• Date of AAA rupture 
 
2. To describe the number of open surgical AAA treatment or AAA endovascular repair and 
AAA rupture in patients who switch from smoking CC to using IQOS, as compared to 
patients who continue to smoke CC and patients who had stopped smoking. 
Endpoints (number per year across all visits): 

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• Number of patients with open surgical AAA treatment or AAA endovascular repair 
annually (based on date of decision to perform open surgical AAA treatment or AAA 
endovascular repair) 
• Number of patients with AAA rupture annually (based on date of AAA rupture) 
 
3. To evaluate the number of AAA growth above 5 mm in 6 months and the number of 
patients with an overall maximum minor-axis AAA diameter >55mm in male patients and 
>50mm in female patients, in patients who switch from smoking CC to using IQOS, as 
compared to patients who continue smoking CC and patients who had stopped smoking. 
Endpoints (number per year across all visits): 
• Number of patients with an increase in maximum minor-axis AAA diameter of more 
than 5 mm within 6 months 
• Number of patients with an overall maximum minor-axis AAA diameter >55mm in 
male patients and >50mm in female patients 
 
4. To monitor the safety profiles associated with IQOS use, CC smoking, and SC during the 
study. 
Endpoints (over the entire study period): 
• Incidence of adverse events (AEs) / serious adverse events (SAEs) 
• Vital signs - change from Baseline (systolic and diastolic blood pressure, pulse rate and 
respiratory rate) 
• Electrocardiogram (ECG) - change from Screening Visit (V1) used as Baseline (Heart 
rate, PR, QRS, QT, QTcB (Bazett’s correction) and QTcF (Fridericia’s correction) 
intervals) 
• Clinical chemistry, hematology, and urine analysis safety panel 
• Physical examination – changes from Baseline 
• Concomitant medications 
• Incidence of IQOS adverse incidences, malfunctions and misuses 
 
5. To describe nicotine exposure over time in AAA patients who switch from smoking CC to 
using IQOS, patients who continue to smoke CC, and patients who had stopped smoking. 
Endpoints (over the entire study period): 
• Nicotine equivalents (NEQ): molar sum of free nicotine, nicotine-glucuronide, free 
cotinine, 
cotinine-glucuronide, 
free 
trans-3’-hydroxycotinine, 
trans-3’-

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hydroxycotinine-glucuronide in spot urine (expressed as concentration adjusted to 
creatinine) 
 
6. To describe the changes in cardiovascular risk factors and BoExp to selected HPHCs over 
time in AAA patients who switch from smoking CC to using IQOS, patients who continue 
to smoke CC and patients who had stopped smoking.   
Endpoints (over the entire study period): 
1. Cardiovascular risk factors: 
a) Systolic and diastolic blood pressure 
b) Body weight and waist circumference 
2. BoExp to selected HPHCs (in spot urine, expressed as concentration adjusted to 
creatinine):  
a) Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL),  
b) Total N-nitrosonornicotine (Total NNN), and  
c) 2-cyanoethylmercapturic acid (CEMA) 
 
3.3 
Exploratory Objectives and Endpoints 
Not Applicable. 

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4 OVERALL STUDY DESIGN AND PLAN 
This is a controlled, open-label, 3-arm parallel group, multi-center study in patients diagnosed 
with Abdominal Aortic Aneurysm (AAA).  
Adult patients with diagnosis of AAA currently smoking will be enrolled to be randomized in 
the CC and IQOS arms, and patients who had completely stopped smoking will be enrolled in 
the SC arm.  
In general, standard of care, as defined by the Guidelines for Diagnosis and Treatment of Aortic 
Aneurysm and Aortic Dissection 1, will be provided to all patients and will be supplemented 
by additional assessments as per this study protocol. As per standard of care, all AAA patients 
eligible for the screening for this study should have already been provided with smoking 
cessation advice at their AAA diagnosis (within the past 60 months). If smoking cessation 
advice was not provided during the last 6 months before the Screening Visit, based on the 
investigator’s judgment, then the respective AAA patient must not be screened for this study.  
Based on standard of care, all patients included in the study will be informed about the risks 
of smoking and provided with SC advices by the Investigator at the Screening Visit and all 
following study visits. Both standard of care procedures and procedures related to the study 
will be recorded. 
The overall study design is depicted in Figure 2. 
 
Figure 2 
Study Flow Chart  

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The Screening Period (Screening Visit [V1]): covers a period of up-to 4 weeks prior to Baseline 
Visit (V2) (from Day -28 until on Day -1): 
Patients with AAA diagnosis within the past 60 months with at least two existing CT scans 
will be invited for screening. Prior to the start of any procedure, patients will sign the ICF, and 
screening procedures will be conducted thereafter according to the schedule of events 
(Appendix 1).  
A CT scan will be made at V1 according to the CT Scan Manual and assessed by the central 
reading site at V2 to provide the current the maximum minor-axis AAA diameter for 
assessment of eligibility. 
It is recommended to complete all of the screening procedures in a one-day Screening Visit 
(V1), however it is permissible to complete the procedures over multiple days prior to the 
Baseline Visit (V2), if required.  
The Baseline Visit (V2, Day 1): 
Some eligibility criteria including smoking status will be re-confirmed. Enrollment into the 
SC, IQOS and CC arm occurs at V2 after checking that all eligibility criteria are met. Patients 
who do not meet the eligibility criteria prior to enrollment will be considered as screen failures.  
Spot urine and blood samples will be collected, and further assessments will be performed 
according to the schedule of events (Appendix 1).  
Patients who are current CC smokers and not willing to quit smoking after having been advised 
to quit smoking will be randomized at V2 with a 1:1 ratio within the corresponding stratum (as 
per stratification criteria) into the following study arms: 
• 
IQOS arm: patients, switching to using IQOS 
• 
CC arm: patients, continuing smoking CC 
Using the CT scan made according to the CT Scan Manual at V1 and assessed by the central 
reading site, patients considered eligible for randomization will be randomized according to 
the following stratification criteria: 
• Aortic maximum minor-axis diameter (male patients: < 40 mm and ≥ 40 
mm; female patients: < 35 mm and ≥ 35 mm)  
• Sex (male vs. female) 

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Patients will be informed of their randomized study arm at V2.  
All patients will be advised to use their assigned product until they complete the study.  
The Investigational Period: the ad libitum exposure period from the check-out from V2 until 
the end of V8:  
The Investigational Period will last up to 3 years following V2 and will include up to 61 months 
of retrospective (prior to V2) data collection for all enrolled/randomized patients. 
Each month during the Investigational Period, patients will complete a questionnaire on self-
reported current tobacco and nicotine-containing product consumption (including frequency 
and quantity of product use) over the past month.  
At every visit during the Investigational Period, spot urine and blood samples will be collected. 
CT scans and further assessments will be performed according to the schedule of events 
(Appendix 1). Following the end of their Investigational Period, the patients will be discharged 
from the study. 
At V8, any non-serious AE that is ongoing after completion of discharge procedures at Visit 8 
will be documented as “ongoing”. At that point, the Investigator will assess whether the patient 
should be referred to his/her General Practitioner for further follow-up on their ongoing AEs. 
All SAEs will be followed up by the Investigator until resolution, stabilization (i.e., no 
worsening of the condition), or until an acceptable explanation has been found (e.g., a chronic 
condition). 
Unscheduled visits: 
As a general rule, procedures requested in the protocol should be performed according to the 
visit schedule. However, as this study is focused on treating patients, there may be a number 
of reasons that the patient may visit the investigational site outside of the visit schedule during 
the course of the study. The site should record any site visit and document the reason for the 
visit and the assessments performed during the unscheduled site visit.  
4.1 
Rationale for Study Design and Control Group(s) 
IQOS is designed to provide an acceptable alternative to current adult smokers, with substantial 
reduction of exposure to HPHCs found in CC smoke, considered to cause smoking related 
diseases. PMI has launched a series of studies to demonstrate reduced risk potential of IQOS 
in healthy adult smokers relative to CC smoking. To evaluate the adverse health effects of 
smoking on health outcomes in diseased populations switching from CC to IQOS is the next 
step for assessment.  As it is reported that CC smoking represents an independent risk factor 

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for AAA, and  as it has been shown that there is a 10.1 and 7.5 times higher relative risk in 
male and female smokers, respectively, when compared to never smokers 8, the study will 
enroll patients with AAA diagnosis.  
The minimum age of 50 years old in the inclusion criteria was selected based on:  
• The likelihood to develop AAA, which increases with age and smoking history. 
The rationale for having a minimum of 5 years of smoking history is to not discard long-term 
smokers who might have stopped smoking for some time in their life. 
This study will:  
• Provide a perspective of the effect of switching to IQOS on the reduction of AAA 
growth compared to the continued use of CC as well as SC. 
The study will be a three arm parallel group design with one observational and two randomized 
arms with the following strata:  
• Aortic maximum-minor-axis diameter (male patients: < 40 mm and ≥ 40 mm; female 
patients: < 35 mm and ≥ 35 mm, using the assessment of the CT scan made according 
to the CT Scan Manual at V1 and assessed by the central reading site 
• Sex (male vs. female) 
This selection of stratification criteria is based on: 1) the size and AAA growth rate prior to 
stopping smoking have been shown to affect incidence of open surgical AAA treatment or 
AAA endovascular repair or AAA rupture and 2) sex differences in terms of growth rate and 
indication for open surgical AAA treatment or AAA endovascular repair as well as for the risk 
of rupture exist. 
The choice of the primary and secondary objectives are based on 1) the standard of care 
procedures with regards to AAA diagnosis and follow-up as described in the Guidelines for 
Diagnosis and Treatment of Aortic Aneurysm and Aortic Dissection 1, 2) the most clinically 
relevant endpoints, i.e., AAA diameter and AAA growth within 6 - 12 months’ time periods. 
Although there is evidence that SC alters the growth rate of AAA and therefore seems to delay 
the time to open surgical AAA treatment or AAA endovascular repair and AAA rupture, the 
data available in the literature for AAA growth rates in Japanese patients who continue to 
smoke CC and patients who had stopped smoking are still scarce. Therefore, the assessment 
of these parameters as primary and secondary endpoints will thus provide insight on the effect 
of IQOS on these endpoints in comparison to continued smoking as well as on the effect of 
SC. 

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Cardiovascular risk factors will serve to support understanding of the respective effects of 
continued smoking, stopping smoking or switching to IQOS on the clinically relevant endpoint 
of AAA growth. 
BoExp to nicotine NEQ, Total NNAL, Total NNN, and CEMA will serve as indicators of 
overall exposure of the patients throughout the study. These markers have relatively long half-
lives, and should provide a good estimate of the exposure, even if the patient comes early in 
the morning for his/her visit. Because nicotine is expected to be delivered with IQOS at levels 
comparable to CC, levels of NEQ are not expected to be lower in IQOS users than CC users, 
but it will serve as an overall estimate of exposure to nicotine exposure. Levels of Total NNAL 
and Total NNN as tobacco-specific nitrosamines are expected to be significantly reduced in 
IQOS users compared to CC smokers, close to what is expected when patients stop smoking. 
Urinary excretion of CEMA, a biomarker of acrylonitrile which is generated as an incomplete 
combustion product in CC, is expected to be higher in smokers than in non-smokers and IQOS 
users. Additionally, CEMA levels in smokers are significantly correlated with ISO tar yield, 
daily CC consumption, and other urinary BoExp. Spot-urine collection will be performed, and 
the BoExp levels will be adjusted to creatinine to adjust urinary excretion rates.  
The exclusion of patients with a diagnosis of concomitant genetic diseases such as Marfan 
syndrome, Loeys-Dietz syndrome, Vascular Ehlers-Danlos syndrome, Turner syndrome, 
Polycystic kidney disease, Noonan syndrome, Alagile syndrome, Arterial tortuosity syndrome 
and Cutis laxa is based on the fact that these diseases significantly affect occurrence, location 
and clinical course of AAA development and progression and would therefore not allow a clear 
assessment of the effect of smoking, SC or switching to IQOS on AAA growth rate. 
This study is designed as an ad libitum study without product use restriction in order to mimic 
as closely as possible “real life” conditions.  
All patients will be asked to buy their own CC or HeatSticks, according to their needs for the 
study, in order to minimize any changes in their smoking behavior, and to not promote one 
product over the other. As different brands of commercially available and/or roll-your-own CC 
will be used, neither the nicotine content of each CC is predefined nor the maximum as well 
as the minimum of the CC nicotine content is limited. 
4.2 
Appropriateness of Measurements 
All clinical variables to be measured in this study were selected based on the following criteria:  
1) commonly accepted measures used for AAA diagnosis and monitoring as per standard 
of care as per Guidelines for Diagnosis and Treatment of Aortic Aneurysm and Aortic 
Dissection 1;  

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2) acceptability by patients;  
3) robustness of the method (i.e., index or evaluation criteria are available to assess 
reduction of AAA growth);  
4) clinical relevance to support the objectives of the study.  
The BoExp measured in this study were selected based on the following criteria:  
1) the availability of a validated analytical method;  
2) the measure is known to be directly or indirectly affected by the use of tobacco product;  
3) the measure is readily reversible after SC/abstinence;  
4) the timeframe of reversibility of measure in the perspective of the study duration;  
5) the practicality/acceptability by patients;  
6) the robustness of the method (rapid, simple, accurate).  
Variability of CT scans:  
Various studies have shown that significant variability of maximal aortic aneurysm diameter 
measurements on CT scan exist, especially when the measurement is conducted by different 
observers and without standardized protocol to measure the largest diameter perpendicular to 
the estimated aneurysm centerline from outer aneurysm wall to outer wall. A study by Cayne 
et al. 35 reported a difference in maximal diameter measurements between each observer of 
4.0-5.1 mm (range, 0.0-35.0 mm) on average using an unstandardized method and a mean 
measurement difference with the standardized protocol of on average 2.8-4.4 mm (range, 0.0-
26.0 mm; P < .05). The authors concluded that routine CT maximal diameter measurement of 
AAAs can have substantial inter-observer variability and that a standardized measurement 
protocol can decrease, but not eliminate, this measurement variability. Thus apparent size 
changes based on CT measurements may represent measurement artifact rather than actual 
aneurysm growth or shrinkage, particularly when a standardized system is not used. 
In order to minimize the inter-observer variability on the reading of the CT scans, both the 
Lead CT over-reader and the CT over-reader Delegate will evaluate/assess, independently 
from each other, the maximum minor-axis AAA diameter in mm delivered by each study site. 
The Lead CT over-reader checks the difference between the two readings on the worksheet. If 
the difference between the two readings is less than 5mm, the final reading of the maximum 
minor-axis AAA diameter in mm to be sent to the site is the recorded reading of the Lead CT 
over-reader. This final reading result to be used has to be clearly notified as the final result. 

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If the difference between the two readings is equal or more than 5 mm, the backup over-reader 
will, independently from the Lead CT over-reader and CT over-reader Delegate, repeat the 
process of reading of the maximum minor-axis AAA diameter in mm. The final reading result 
of the AAA diameter in mm to be sent to the site is the one evaluated/assessed by the backup 
over-reader. This final reading result to be used has to be clearly notified as the final result. 
In order to further limit the variability of AAA maximum diameter measurements, all AAA 
diameters used for analysis in this study will be assessed by a single central reading site. 
4.3 
Study Duration 
The study duration for each patient will be up to 3 years and 1 month. This includes the 
Screening Period of up to 28 days prior to Visit 2 (Baseline Visit), followed by an 
Investigational Period up to 3 years. 
The end of the study for an individual patient will be defined as V8 or the date of early 
termination. The end of the entire study is the latest date that an individual patient reaches the 
end of the study. 

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4.4 
Patient recruitment 
In spite of significant efforts undertaken to improve the recruitment of patients into this study, 
the recruitment rate remains low. Indeed, after over a year of recruitment only 32 patients were 
enrolled out of 114 planned. Furthermore, the forecast until June 2020 shows only 15 new 
patients potentially eligible to participate in the study. In addition, the recruiting sites are 
reaching the limits of available patients (recruitment is limited to existing patients only), and 
new sites joining the study have more limited pool of patients as compared to the originally 
selected sites. The pool of the new sites to be potentially suitable for patients recruitment has 
also now reached the limits - during the site selection/qualification process most promising 
sites were already contacted. In such a situation, it is not possible to predict the length of the 
recruitment needed to reach 114 patients, if at all possible. Therefore, rather than terminating 
the study, which would result in loss of site’s and patient’s efforts and lack of any new scientific 
knowledge for the broader community, it was decided to stop recruitment early and to continue 
the follow up of patients already recruited. This would still allow an evaluation of already 
collected data to gather evidence of the impact of switching to IQOS on the evolution of the 
disease in patients suffering from abdominal aortic aneurysm. 
In addition, to ease the burden for the patients and to avoid potential issues with retention rate 
and missing data, it was also decided to decrease the number of procedures, such as those 
related to co-morbidities, and to shorten the duration of the follow-up from five to three years. 
4.5 
Independent Data Monitoring Committee (IDMC) 
An Independent Data Monitoring Committee (IDMC) will be established prior to starting the 
recruitment of patients and will meet periodically throughout the study to monitor the patients’ 
safety, to review and evaluate the study data such as disease characteristics, the quality of the 
study conduct, e.g., feasibility, robustness and integrity, and the study progress. Members of 
the IDMC with expertise in the field of the disease and statistics, independent of both the sites 
and the Sponsor, are defined in a separate document, the IDMC Charter. The IDMC will 
organize meetings accordingly to review these study-specific data taking into consideration the 
relevant background knowledge about the disease and the patient population being studied. 
The IDMC Charter will define further details such as the review cycles, number of planned 
IDMC data reviews as well as stopping rules for the study, if considered by the IDMC as 
needed.  
For this study, data reviews by IDMC members will be performed one year and two years after 
the first patient has been randomized. Sponsor will be informed at least with meeting minutes. 
 
 
 

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The Role of IDMC 
 
1. The IDMC will monitor the safety of the patients and disease progression based on clinical 
parameters listed in the IDMC charter. They will evaluate the risks/benefits for the patients 
based on clear and consistent evidence of higher harm (without formal boundaries) in 
patients randomized to IQOS relative to CC. 
2. The IDMC will also evaluate the quality of study conduct and implication for further study 
course based on parameters described in the IDMC charter.  
3. The IDMC will not monitor or make any recommendations in regards to effectiveness or 
futility in the study.  
The IDMC may provide recommendations to the Sponsor regarding any identified study-
conduct issues (e.g., protocol deviations), and may make recommendations to the Sponsor 
concerning the continuation or termination of the study based on their evaluation of safety (risk 
/benefit for the patient) and the quality of the study conduct.  
At a minimum, the following characteristics will be reviewed by the IDMC to evaluate safety 
of the patients and quality of the study (see IDMC charter for further details):  
1) Safety of Patients: 
• Change in the slope of the maximum minor-axis AAA diameter growth rate, 
following change in product use behavior (size of change, and timing of detection of 
the change) 
• Maximum minor-axis AAA diameter growth rate (mm/year) 
• Maximum minor-axis AAA diameter growth of more than 5 mm within 6 months 
• Adverse events (AE)s and SAEs  
• Confounders 
• Number of patients annually undergoing AAA rupture 
• Number of patients annually undergoing an open surgical AAA treatment or AAA 
endovascular repair  
• Product use exposure 
 
 
2) Quality of study conduct: 
• Protocol deviations 
• Patient recruitment rate in the current study 
• Patient retention within each study arm, and switching between study arms 
 
 

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5 STUDY POPULATION  
5.1 
Selection of Study Population 
5.1.1 
Inclusion Criteria 
Each patient to be enrolled must meet the following criteria: 
Study Population and Main Criteria for Inclusion (all study arms): 
Female or male Japanese patients with diagnosed AAA meeting the following main 
inclusion criteria will be enrolled in the study: 
1. Patient is aged ≥ 50 years (to be checked at V1). 
2. Patient is Japanese (to be checked at V1). 
3. Patient diagnosed with AAA (infrarenal, fusiform type) with a current aortic maximum 
minor-axis diameter of 30 to ≤ 49 mm (in male patient) and 30 to ≤ 44 mm (in female 
patient). 
a) Diagnosis of AAA within the past 60 months with at least two computerized 
tomography (CT) assessments since diagnosis. The two CT scans must have been 
done within the last 30 months before the Screening Visit (V1) with a time 
difference of at least 20 weeks and must show an increase of the aortic maximum 
minor-axis diameter between the first and the latter of these 2 CT scans (to be 
checked at V1). 
b) The maximum minor-axis AAA diameter to be used for assessment of eligibility is 
the maximum minor-axis AAA diameter available at the time of enrollment (based 
on the CT scan made according to the CT Scan Manual at V1 and assessed by 
central reading site (to be checked at V2). 
4. Patient has smoked commercially available and/or roll-your-own CC on a daily basis for at 
least 5 years prior to AAA diagnosis, based on self-reporting (to be checked at V1). 
5. Patient is ready to comply with the study protocol (e.g., to use their assigned 
product/regimen during the course of the study) (to be checked at V1 and V2). 
 
 

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Specific to patients screened for enrollment and randomization to the CC or IQOS arms: 
Female or male Japanese adult smokers with diagnosed AAA meeting the following 
additional main inclusion criteria will be enrolled and randomized in the CC and IQOS arm 
of the study: 
6. Patient has smoked on average > 5 commercially available and/or roll-your-own CC per 
day (no CC brand restriction) for the last 12 months, based on self-reporting (to be 
checked at V1). Intermittent attempts to quit smoking, with or without NRT use during 
these attempts, not exceeding 2 months or short-term interruption of smoking, with or 
without NRT use during the short-term interruption, up to 10 days within the last 12 
months will be allowed. Smoking status will be verified based on a urinary cotinine test 
(i.e., cotinine ≥ 200 ng/mL) (to be checked at V1 and V2).  
7. Not intending to quit smoking within the next 6 months after having been advised to quit 
smoking (to be checked at V1 and V2). 
Specific to patients screened for enrollment into the SC arm: 
Female or male Japanese adult patients with diagnosed AAA meeting the following 
additional main inclusion criteria will be enrolled in the SC arm of the study: 
8. Patient had completely quitted smoking and stopped the use of any other tobacco or 
nicotine-containing products for at least 6 months prior to the Screening Visit and is still 
abstinent at Screening (V1) and at Baseline (V2). Smoking status will be verified based 
on a urinary cotinine test (i.e., cotinine < 100 ng/mL) (to be checked at V1 and V2).  
5.1.2 
Exclusion Criteria 
Patients who meet any of the following exclusion criteria must not be enrolled into the study. 
Criteria for Exclusion: 
1. Patient is legally incompetent, physically or mentally incapable of giving consent (e.g., 
emergency situation, under guardianship, patient in a social or psychiatric institution, 
prisoner or patient involuntarily incarcerated) (to be checked at V1). 
2. Patient with acute severe cardiovascular events or respiratory diseases (e.g., stroke, acute 
coronary syndrome, cardiovascular-surgical procedures, pulmonary embolism as judged 
by the Investigator), within the last 3 months (to be checked at V1 and V2).  
3. Patient with currently active cancer or history of cancer within the last 5 years (to be 
checked at V1). 

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4. Patient is ineligible as judged by the Investigator to participate in the study for any reason 
(e.g., medical, psychiatric and/or social reason) (to be checked at V1). 
5. Patient with dissecting aneurysm(s) of the aorta (to be checked at V1). 
6. Patient with infrarenal pseudo-AAA (false AAA) (to be checked at V1). 
7. Patient with a diagnosis of COPD Stage 3 and 4 in the medical history (to be checked at 
V1). 
8. Patient has used any heat-not-burn tobacco product(s), and/or tobacco vapor product(s) on 
a daily basis for the last 12 months, based on self-reporting (to be checked at V1). 
9. Patient with a recent (within 1 year) or current history of alcohol or other substance abuse 
based on self-reporting (to be checked at V1). 
10. Female patient who is pregnant or breast-feeding (to be checked at V1 and V2). 
11. Patient with a diagnosis of concomitant genetic diseases such as but not limited to Marfan 
syndrome, Loeys-Dietz syndrome, Vascular Ehlers-Danlos syndrome, Turner syndrome, 
Polycystic kidney disease, Noonan syndrome, Alagile syndrome, Arterial tortuosity 
syndrome and Cutis laxa (to be checked at V1). 
12. Patient is a current or former employee of the tobacco industry or their first-degree relatives 
(parent and child) (to be checked at V1). 
13. Patient is an employee of the investigational site or any other parties involved in the study 
or their first-degree relatives (parent and child) (to be checked at V1). 
14. Patient has been previously screened or enrolled in this study (to be checked at V1). 
15. Patient was enrolled in any clinical study within 3 months prior to V1 (to be checked at 
V1). 
5.2 
Discontinuation of Patients from the Study 
Discontinued patients will include patients who withdraw from the study (patient’s decision) 
and patients who are discontinued from the study by the decision of the Investigator. A patient 
can only be discontinued from the study after enrollment. 
Patients will be informed that they are free to withdraw from the study at any time. Patients 
should be asked for the reason of withdrawal from the study, although they are not obliged to 
disclose it. 

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If the patient withdraws from the study, he/she will be asked to perform the early termination 
procedures (section 9.4) as soon as possible after the time of withdrawal unless the patient 
refuses to do it in writing.  
The patient will be reminded that the data collected until the point of withdrawal will be 
maintained as part of the study data, and the samples collected prior to withdrawal or during 
the early termination visit will be analyzed after his withdrawal, unless he/she refuses in 
writing.  
All discontinued patients cannot re-enter the study. 
5.2.1 
Discontinuation from the study 
Patients must be discontinued from the study for any of the following reasons: 
• Withdrawal of informed consent. 
• Discontinuation is considered to be in the interest of the patient from a safety 
perspective as judged by the Investigator. 
• Positive or unclear pregnancy test. 
• The Sponsor or Investigator terminates the study or the study terminates at a particular 
investigational site. If the Sponsor or the Investigator decides to prematurely terminate 
the study, the patient will be promptly informed. The investigational site/head of the 
medical institution should report the fact and the reason in writing to the IRB / IEC. 
• Patient has to undergo open surgical AAA treatment or AAA endovascular repair (as 
per the treating physician’s decision based on the standard of care as documented in 
the Guidelines for Diagnosis and Treatment of Aortic Aneurysm and Aortic Dissection 
1).  
• The patient experiences a rupture of his/her AAA. 
• Patient becomes an employee of the investigational site, a tobacco company or any 
other parties involved in the study. 
• Lost to follow-up. 
Patients may be discontinued from the study for the following reasons: 
• Non-compliance to the study procedures based on the judgment of the Investigator. 
If a violation of selection criteria is detected after enrollment, patients might be discontinued 
from the study based on a case-by-case decision of the Investigator.  

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Patients will not be discontinued from the study for the use of tobacco or nicotine-containing 
products other than their assigned product/regimen unless judged by Investigator. 
5.2.2 
Violation of Selection Criteria 
Patients who violate the entry criteria prior to enrollment will be considered as screen failures. 
Re-screening of patients will not be permitted.  
5.3 
Lost to Follow-up 
The date of the last contact with the patient (e.g., last visit, last phone call) should be recorded 
in the source document. After the last contact, a reasonable number of attempts to contact the 
patient (including written correspondence and phone calls) should be made and documented 
in the source documents by the site. Following the contact attempts, if the Investigator(s) or 
designee(s) decides to discontinue the patient with the reason of lost to follow-up, the 
discontinuation date will be recorded. The discontinuation date for the patient will be the date 
the patient was determined to be lost to follow-up and will correspond to the date of the EOS 
of the patient.  
If the site has lost track of the patient, the discontinuation date cannot exceed the maximum 
number of study months (37), then the Investigator(s) or designee(s) will discontinue the 
patient with reason as lost to follow-up. 
 

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6 INVESTIGATIONAL PRODUCT(S)/REFERENCE 
6.1 
Description of Investigational Product(s) 
Test product (IQOS): The product tested in this study is the Tobacco Heating System with 
Marlboro Heatsticks, marketed in Japan under the brand name IQOS and generally referred to 
as IQOS in this protocol. All versions of IQOS (including THD with two elements (Charger 
and Holder), and THD with one single element (holder only: e.g., IQOS 3 Multi)) and 
Marlboro Heatsticks available for sale in Japan at the time of study start or becoming available 
during the course of the study are allowed to be used in the context of this study. IQOS is 
composed of the following components: a tobacco HeatStick, a Holder and a Charger (THD 
with two elements), or a tobacco HeatStick and a holder (THD with one single element) (Table 
1), as well as a cleaning tool, a power supply, and a USB cable. 

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Table 1 
Test Product (IQOS) 
HeatStick: 
The HeatStick is designed to function with the Holder. The 
HeatStick is made up of: tobacco plug, hollow acetate tube, polymer-
film filter, mouth piece filter, outer and mouth-end papers. 
All materials have been evaluated with regards to their toxicological 
potential and have been approved for use. 
The tobacco plug is made from tobacco, glycerin, water, guar gum, 
cellulose, propylene glycol, natural and artificial flavorings. 
The average amount of nicotine in the tobacco plug is 5-6 mg per 
HeatStick. The average amount of nicotine in the aerosol is 1.02-
1.50 mg per HeatStick under the Health Canada Intense (HCI) 
machine-smoking regimen 36.  
Holder: 
The Holder of the THD with two elements is a slim electrical heating 
unit that heats the HeatStick in a controlled manner by using a heater 
blade. 
The Holder stores enough energy for a single experience, delivering 
puffs over a period of about 6 minutes or 14 puffs (whichever comes 
first). A Light Emitting Diode indicates the end of the experience. 
Once this cycle is complete, the Holder must be recharged before a 
new HeatStick can be used. 
The holder of the THD with one single element stores enough energy 
for approximatively 10 inhalation experiences, delivering puffs over 
a period of about 6 minutes or 14 puffs (whichever comes first) for 
each inhalation experience. A LED indicates when the experience 
can start and when the experience ends.  
The Holder of the THD with one single element must be recharged 
after approximatively 10 inhalation experiences and can be 
recharged from household power. 
Charger: 
The power supply for the Holder of the THD with two elements is 
the Charger. 
The Charger holds enough energy for approximately 20 uses of the 
Holder and can be recharged from household power. 
The Charger stores the Holder when not in use, and provides a secure 
environment for the cleaning process of the heater blade. 
The overall objective of the product design is to provide an acceptable experience in which the 
HPHCs levels in the aerosol are substantially reduced in comparison with the smoke of a CC 

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37,38. A summary of description of the product, pre-clinical and clinical data available on IQOS 
is provided in the SPI 2.   
6.1.1 
Comparator and Baseline Product(s) 
The comparator and baseline product will be the patient’s own preferred brand of commercially 
available and/or roll-your-own CC.  
6.1.2 
Packaging and Labeling 
The Sponsor or authorized representative will label the IQOS devices in local language 
ensuring adherence to local regulatory and requirements. This will include at least the 
following information: 
• 
Statement ‘For investigational use only’ 
• 
Name and address of the Sponsor (if the sponsor resides outside Japan, name of the 
sponsor and name of the country where the sponsor is located, and name and address 
of the clinical trial in-country representative) 
6.2 
Administration of Investigational Product(s) (for CC and IQOS 
arms) 
The study is designed as an ad libitum use study. The patients will be allowed to use their 
allocated products (CC or IQOS) according to their need. Patients should be advised that when 
smoking CC or using IQOS, they should temporarily stop using the products in the event of 
any signs suggesting nicotine overexposure, (e.g., gastrointestinal disturbance [nausea, 
vomiting, diarrhea, stomach or abdominal pain], cold sweats, headache, dizziness, breathing 
problems) or any reasons at the discretion of the Investigator. 
6.2.1 
From Screening (V1) to Baseline (V2) 
All adult current CC smokers who do not intend to quit smoking within the next 6 months after 
having been advised to quit smoking will be allowed to continue smoking ad libitum their 
preferred usual brand of CC.  
6.2.2 
Investigational Period 
IQOS Arm 
Patients will be instructed to use exclusively IQOS ad libitum according to their need with no 
flavor variant restrictions on HeatSticks.  
 
 

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CC Arm 
Patients will continue to smoke ad libitum their CC with no brand restrictions including no 
restriction to change preferred brand during the study. 
6.3 
SC Arm (Reference) 
NRT potentially used from the Screening Visit onwards and during the Investigational Period 
will not be provided or reimbursed by the Sponsor.  
6.3.1 
From Screening (V1) to Baseline (V2) 
Patients who had completely quitted smoking will continue to remain abstinent from smoking 
CC or use any tobacco or nicotine containing products, except NRTs. 
6.3.2 
Investigational Period 
Patients who had completely quitted smoking and are allocated to the SC arm are instructed to 
refrain entirely from the use of any tobacco or nicotine-containing product (except NRTs). 
6.4 
Method for Assigning Patients to Study Arms 
6.4.1 
IQOS and CC arms 
At V2, randomization will be done through the Interactive Web and Voice Response System 
(IXRS). Patients eligible for randomization, will be randomized in one of the two randomized 
study arms (IQOS arm and CC arm), in a 1:1 ratio within the corresponding stratum using the 
following strata: 
• 
Aortic maximum-minor-axis diameter (male patients: < 40 mm and ≥ 40 mm; female 
patients: < 35 mm and ≥ 35 mm) 
• 
Sex (male vs. female) 
Patients will be informed of their randomized study arm by the study site at V2.  
6.4.2 
SC Arm  
Patients who had stopped smoking will be enrolled in the SC arm at Baseline Visit (V2) 
through the Interactive Web and Voice Response System (IXRS) without being randomized. 

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6.5 
Blinding  
6.5.1 
Blinding of the CT-Overreaders 
This is an open-label study, however, in order to avoid potential involuntary bias of the CT-
overreaders by the product use status, he/she will be kept blinded to the all study arms (CC, 
IQOS and SC arms). If the CT-overreaders should become unblinded for any reason, including 
accidental disclosure, the unblinding event will be documented. A patient-specific unblinding 
event will not prevent the use of the patient’s data, including those recorded after disclosure.  
6.5.2 
Blinding of data 
There will be an additional, though limited, degree of blinding during the conduct of the study, 
including the data review and data analysis process. In particular, PMI and the contract research 
organization (CRO) personnel involved in this study will be blinded as summarized in Table 
2. 
Table 2 
Blinding Scheme 
Blinded Study 
Personnel 
Blinded Data 
End of Blinding Period  
PMI and 
 study 
statisticians  
Actual values of primary endpoints 
after enrollment / randomization a  
After the SAP finalization or 
database lock, whichever 
comes last. 
PMI clinical scientist  
Actual values of primary endpoints 
after enrollment / randomization b  
After the finalization of PMI 
blind database review. Can be 
actively un-blinded when 
appropriate.  
SAP: Statistical Analysis Plan 
a. 
To avoid indirect unblinding of the “actual values of primary endpoints” additional data were blinded in the CRF (e.g., 
adverse event terms). 
b. 
As part of the PMI Quality Control (QC) activity, data listings will be reviewed by 
 and PMI before database 
lock. Full details will be available in the data review plan. 
 
Any PMI and CRO personnel who are not listed in Table 2 will be unblinded by default 
including the statistician(s) from 
 specifically assigned to provide all the data needed for 
reviews by the IDMC members.  
All IDMC members are unblinded by default.  
Unblinded information will not be shared with the blinded study team, until the end of the 
blinding period (Table 2). PMI will receive blinded and unblinded data for the data review 
prior to database lock or any other analysis as planned in the data review plan. Blinded data 
will be accessible by the blinded study personnel in a masked format or presented independent 

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of the patient identifier so to ensure that data cannot be associated within or to a patient. 
Unblinded data will only be reviewed by the unblinded study team. 
6.6 
Investigational Product Accountability and Adherence 
6.6.1 
Dispensing Investigational Product 
Patients allocated to the IQOS arm will be supplied either by the site or by third party courier 
service with two IQOS devices and one selection of HeatSticks flavor variants available on the 
Japanese market, after randomization has occurred, but will be asked to buy his/her flavor of 
choice of HeatSticks for his/her own use for the entire duration of the study. The second IQOS 
device is to be used as backup, in case the first one does not work properly. In case the device 
needs replacement due to a device malfunction, the patient will need to follow the instructions 
provided by the site in order to have the device replaced. In case a patient decides to purchase 
their own device during the study duration, this will not be replaced in case of failure as part 
of the study requirements. 
Patients allocated to the CC arm will be asked to buy CC for their own use for the entire 
duration of the study. 
6.6.2 
Storage and Accountability 
Proper storage and accountability of the IQOS devices and HeatSticks should be ensured, either 
in case they are stored at and distributed by the sites or by a third party courier service. After 
first distribution, the patients will store the device and HeatSticks according to the IQOS 
manual unless instructed otherwise by the site.  
Because CC will be bought by the patients, CC will not be stored at site or at the third party 
courier service.  
6.6.3 
Investigational Product Retention 
The return of IQOS devices, including replacement devices, upon early discontinuation or at 
V8 will take place according to the instructions in the Investigational Product Handling 
Manual. This does not apply to the devices purchased by the patients. 
6.6.4 
Product Use Restrictions 
There will be no restriction on allocated product use.  
6.6.5 
Dietary Restrictions 
There will be no dietary restrictions for this study. 

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6.6.6 
Adherence 
Based on the numbers of the used Marlboro HeatSticks or the smoked CC as self-reported in 
the diary, and further determinants such as the total duration of use of the respective products 
and the percentages of the respective products over a predefined period, that will be defined in 
the SAP, the adherence to the respective randomized products will be calculated. During the 
scheduled visits, the Investigator will ask the patient whether he/she has been using the 
assigned product (CC and IQOS arms only) and will remind him/her to use exclusively the 
product he/she was randomized to, unless he/she wants to stop using any tobacco or nicotine 
containing products. The investigator should also check and make sure that the product use 
diary is completed by the patient as required.  
Those patients who might change their smoking habits after randomization to an arm or do not 
use their products according to the arm they have been randomized to, will remain during the 
entire study conduct in the arm they have been randomized to. No change of randomization 
arm is allowed for all of the randomized patients after randomization, independent of their 
actual product use.  Section 12.3 provides further details on the statistical analysis according 
to randomization arm. 
6.7 
Concomitant Medication 
Medications will be allowed and carefully monitored during the study by the Investigator or 
designee. The Investigator or designee is responsible for the overall safety and well-being of 
the patient including the overall medical care and medication of the patients during their 
participation in the study. Any decisions regarding the prescribed medications will be made in 
the best interest of the patient. Maintenance or changes in treatment of any pre-existing 
concomitant diseases should be discussed by the Investigator with the treating physician or the 
patients General Practitioner. Any use of concomitant medication must be fully documented 
in the source document and transcribed into the Case Report Form (CRF). 
Records of medication taken including NRT include the drug name (preferably both generic 
and trade name), route of administration (e.g., oral, intravenous), total daily dose/unit (e.g., 
expressed in mg, mL or IU), indication, the start and if applicable, the stop date (day, month 
and year). Any therapy changes (including changes of regimen) during the study have to be 
documented. Any concomitant medication that is still being taken by the patient at the EOS 
will be recorded in the CRF. 
 
 

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7 STUDY PROCEDURES 
Personnel performing or recording study measurements must have appropriate and fully 
documented training. Quality control (QC) measures must be defined, implemented and 
documented. All study procedures are provided as an overview in the schedule of events 
(Section 15.1, Appendix 1 – Schedule of Events).  
Site personnel will adhere to the site’s standard operating procedures (SOPs) or other 
applicable SOPs and study-specific manuals for all activities relevant to the quality of the study. 
Appropriate medical advice will be provided to the patients in case of any medical findings 
requiring health care. 
7.1 
Informed Consent and Guidance 
Prior to any study assessment being performed, the patient will be asked to provide his/her 
written consent to participate in the study and for the collection, storage and subsequent 
analysis of samples (ICF). All the assessments must start after the time of ICF signature by the 
patient before study participation. During the consent process, the Investigator or designee 
obtaining consent must inform each patient of the nature, risks and benefits of, and alternatives 
to study participation. In addition, each patient must review the ICF and must have sufficient 
time to understand and have adequate opportunity to ask questions. The ICF must be signed 
and dated (date and time) prior to undertaking any study-specific procedures. A copy of the 
signed ICF must be given to the patient. 
7.2 
Advice on the Risks of Smoking/SC Advice  
All patients, screened for the study will be first advised that the best way of preventing further 
AAA disease progression is to stop smoking and will be given advice on risk of smoking and 
SC advice at V1.  
From V1 onwards, all patients screened to be enrolled into CC, IQOS and SC arms will receive 
information on the risks of smoking, and the advice to quit smoking or to be abstinent from 
smoking will be given to all patients as described in Appendix 1 – Schedule of Events. This 
will take the form of a brief interview according to WHO recommendations 39.  
Any patient who is willing to attempt quitting CC or IQOS or use of any tobacco or nicotine-
containing products at any time during the study will be encouraged to do so. He/She will be 
referred to appropriate medical services, and the standard of care to support SC will be applied.  
7.3 
Debriefing on IQOS  
Smokers screened to be enrolled in the IQOS arm and CC arms only will receive a debriefing 
on IQOS at V1, and if they are randomized to IQOS or CC arm, at each visit from V1 onwards 

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as described in Appendix 1 – Schedule of Events - to address any intended or unintended 
beliefs participants may have about IQOS. The goal of the debriefing is to ensure that patients 
have an accurate understanding of the current scientific knowledge about IQOS and the risks 
related to using IQOS. Any updates to the IQOS debriefing script will be submitted and 
approved by an IRB / IEC prior to be used in the study.  
No information on IQOS will be given to patients eligible to the SC arm. 
7.4 
Clinical Assessments 
7.4.1 
Demographic Data 
Demographic data (sex, date of birth, ethnicity) will be recorded at V1 (all patients). 
7.4.2 
Questions on Smoking History/Habits 
All patients will be asked by the Investigator questions about their smoking history/habits 
(based on self-reporting) at V1, and the answers will be recorded: 
1. Have you smoked cigarettes for at least the past 5 years prior to AAA diagnosis? (Yes/No)  
1a. On average, how many cigarettes per day have you smoked over the past 5 years prior 
to AAA diagnosis? (numeric response, 2 digits) 
2. Have you been smoking cigarettes in the last 12 months? (Yes/No) 
2a. On average, how many cigarettes per day have you smoked over the last 12 months? 
(numeric response, 2 digits) 
3. Have you been using any heat-not-burn tobacco product(s), for example IQOS or GLO, in 
the last 12 months? (Yes/No) 
3a. On average, how many tobacco HeatSticks / tobacco sticks per day have you used over 
the last 12 months? (numeric response, 2 digits) 
4. Have you been using any tobacco vapor product(s), for example PLOOM Tech, in the last 
12 months? (Yes/No) 
4a. On average, how many tobacco capsules per day have you used over the last 12 
months? (numeric response, 2 digits) 
5. Have you completely quit smoking cigarettes or completely stopped using any other tobacco 
or nicotine-containing products 6 months ago or even longer? (Yes/No)   

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3a. Are you still abstinent now? (Yes/No) 
This information will be used to assess the patients’ eligibility for inclusion in the different 
study arms. 
7.4.3 
Intention to Quit Smoking 
The investigator must also ensure that as according to standard of care, smoking cessation 
advice had been provided to the patients at and after his/her AAA diagnosis and that he/she 
had had an adequate time period of approximately 6 months to attempt to stop smoking before 
coming to the Screening Visit.  
In addition, smokers who are screened for enrollment and randomization to the IQOS and CC 
arms will be provided with SC advice at the Screening and Baseline Visit before being enrolled 
into the study, and will be asked about their intention to quit smoking within the next 6 months 
after having been advised to quit smoking. This must be clearly documented by the Investigator 
at V1 and V2.  
7.4.4 
Demonstration of IQOS using a video  
IQOS demonstration using a video will only be made to smokers screened for enrollment and 
randomization to the IQOS and CC arms only at the time of V1. A video presenting IQOS 
including HeatSticks will be shown to currently smoking male patients by the Investigator or 
study collaborator. With respect to female patients, the video presenting IQOS will be shown 
to these patients whose pregnancy test was negative or where post-menopausal status is 
confirmed (see section 7.7.2).   
No demonstration of IQOS will be given to AAA patients screened for the SC arm. 
7.4.5 
Medical History/Concomitant Disease(s)/Previous and Ongoing Medications 
Relevant medical history, any concomitant disease, and previous and ongoing medications will 
be documented at V1 for all patients. It will be responsibility of the Investigator or designee to 
collect the relevant medical records for each patient necessary for the purposes of this study. 
Medical history is defined as any condition that started and ended prior to Screening. A 
concomitant disease is defined as any condition that started prior to ICF signature and is still 
ongoing at the end of V1. After V1, each concomitant disease will be followed-up at each visit 
to check if it is still ongoing or not. 
Previous medication taken within 3 months prior to screening and any ongoing medication at 
screening needs to be documented. Any medication which is started prior to Screening and is 
still being taken by the patient at screening or thereafter will be considered as concomitant 
medication. This applies to both prescription and over-the-counter products.  

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Any use of a concomitant medication must be fully documented in the Source Document and 
CRF. Therapy changes (including changes of regimen) during the study have to be 
documented. If a concomitant medication is still being taken by the patient at the end of the 
study, this will be recorded in the CRF. 
7.4.6 
Physical Examination 
Physical examinations including palpation on abdomen will be conducted at V1 to V8 (all 
patients).  
7.4.7 
Body Height, Body Weight and Waist Circumference 
Body height will be measured only at V1. Body weight will be recorded at V1 to V8. Waist 
circumference will be measured at V1 to V8. Appropriate medical advice will be provided to 
the patient in case of any medical findings requiring health care (all patients). 
Body mass index (BMI) will be calculated at V2 to V8 from the body weight and height using 
the following formula: 
 
BMI =  
weight in kilograms 
————————     ( kg/m² ) 
height in meters² 
 
Body weight and waist circumference will also be analyzed as cardiovascular risk factors. 
7.4.8 
Vital signs 
Systolic and diastolic blood pressure, pulse rate and respiratory rate will be measured at V1 to 
V8 (all patients). All measurements will be made after the patient has rested for at least 5 
minutes. For every measurement in patients in the CC or IQOS arms, it will be documented, if 
applicable, that the last CC smoked or the last IQOS used was at least 15 minutes prior to the 
measurement. 
Systolic and diastolic blood pressures will also be analyzed as cardiovascular risk factors. 

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7.4.9 
Assessments of maximum minor-axis AAA Diameter   
The assessment of the current maximum minor-axis AAA diameter on the CT scan which is 
made according to the CT Scan Manual at V1 at individual study sites will be performed at a 
single specifically assigned central clinical site (further referred to central reading site) 
following a standard protocol to assess the maximum minor-axis AAA diameter from the CT 
scan (Appendix 4) in all patients. All digital imaging data (DICOM files) of the CT scans 
performed during the up to 30 month period prior to V1 (minimum 2 CT scans) will be sent to 
the central reading site for assessment. The maximum minor-axis AAA diameter 
measurements used to assess patient eligibility for enrollment in the study (V1-CT scan) and 
all AAA diameter measurements used for the calculation of the AAA growth rate and related 
analysis in this study will be the measurements as assessed by the central reading site.  
Although the determination for clinical treatment of a patient and therefore also the decision 
to perform open surgical AAA treatment or AAA endovascular repair will be based on the 
site’s assessment of the CT scan, the maximum minor-axis AAA diameter recorded in the CRF 
at the time point of the decision to perform open surgical AAA treatment or AAA endovascular 
repair will be the maximum minor-axis AAA diameter as assessed by the over-reader at the 
central reading site.  
Further details with regards to the assessment and handling of CT scans and the associated 
measurements will be described in the CT scan manual. 
7.5 
Other Clinical Assessments 
7.5.1 
Electrocardiogram 
An Electrocardiogram (ECG) will be recorded in a supine position at V1, V4, V6, and V8 (all 
patients). ECG testing will be performed as per the site’s local practice. A standard 12-lead 
ECG will be recorded after the patient has rested for at least 5 minutes in a supine position. 
The following parameters will be documented: heart rate, PR interval, QRS interval, QT 
interval, and QT interval corrected according to Bazett’s formula and Fridericia’s formula. 
Every ECG has to be assessed as normal, abnormal – clinically not relevant, or abnormal – 
clinically relevant. A diagnosis has to be provided on the CRF for all ECGs assessed as 
abnormal – clinically relevant. All ECG print-outs will be interpreted by a qualified physician. 
Any print-outs of ECGs on thermo-sensitive paper must be photocopied and stapled together 
for inclusion in the source documents and signed by the Investigator or designee(s). 

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7.5.2 
Chest X ray 
At V1, a chest X-ray (upright position with anterior-posterior and left lateral views) will be 
assessed to exclude patients with relevant pulmonary diseases. No new examination is required 
if the patient can present at V1, a chest X-ray not older than 6 months with upright position 
with anterior-posterior and left lateral views.  
7.6 
Bioanalytical Assessments 
All bioanalytical assessment assays will be carried out using validated methods (Section 7.8). 
The bioanalytical methods used will be documented in the Bioanalytical Plans/Reports. A list 
of laboratories is provided in Appendix 2. 
7.6.1 
Biomarker of Exposure  
 
Total NNAL, Total NNN, CEMA, and NEQ in Urine 
At V2 to V8: spot urine collection to measure biomarkers of exposure (expressed as 
concentration adjusted to creatinine): 
• total NNAL, a biomarker for NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone),  
• total NNN, a biomarker for NNN (N-nitrosonornicotine), 
• CEMA, a biomarker for acrylonitrile, and  
• NEQ, a biomarker to nicotine. 
7.6.2 
Creatinine Analysis 
At V2 to V8: Creatinine will be measured for normalization of urinary BoExp 
7.7 
Laboratory Assessments 
Laboratory analyses will conducted according to Good Clinical Practice (GCP). 
7.7.1 
Clinical Chemistry, Hematology, and Urine analysis for the Safety Panel 
Hematology, clinical chemistry and urine analysis for the safety panel will be measured at V1 
to V8. The urine test will be performed semi-quantitatively as a urine test. Parameters to be 
measured are listed in the following Table 3.  

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Table 3  
Clinical Laboratory Parameters for Safety Panel 
 
Hematology 
 
Clinical Chemistry 
Urine analysis 
- Hematocrit 
- Hemoglobin 
- Mean corpuscular hemoglobin 
(MCH) 
- Mean corpuscular hemoglobin 
concentration (MCHC) 
- Mean corpuscular volume 
(MCV) 
- Platelet count 
- Red blood cell (RBC) count  
- White blood cell (WBC) count 
- Differential WBC count:  
• 
Neutrophils 
• 
Basophils  
• 
Eosinophils  
• 
Lymphocytes 
• 
Monocytes 
 
 
- Albumin* 
- Total protein 
- Alkaline phosphatase (AP) 
- Alanine aminotransferase (ALT) 
- Aspartate aminotransferase 
(AST) 
- Blood urea nitrogen (BUN) 
- Creatinine* 
- Gamma-glutamyl transferase 
(GGT) 
- Fasting Glucose 
- Lactate dehydrogenase (LDH) 
- Potassium  
- Sodium 
- Total bilirubin 
- Direct bilirubin 
- Total cholesterol 
- Triglycerides 
- pH 
- Bilirubin 
- Glucose 
- Nitrite 
- Red blood cell traces 
- Protein 
- Specific gravity 
 
* The albumin to creatinine ratio will be used to evaluate potential microalbuminuria. 
7.7.2 
Urine Pregnancy Testing 
All female patients (with the exception of women in post-menopausal status, see below) will 
undergo urine pregnancy testing at all Visits. 
Female patients with a urine positive pregnancy test at V1 cannot be enrolled and will be 
considered a screening failure. In any case of a positive urine pregnancy test, the Investigator 
will inform the patient about the risks associated with smoking during pregnancy. In case, the 
urine pregnancy test at screening is unclear, the patient cannot be enrolled. After enrollment, 
an unclear pregnancy test would lead to discontinuation of the patient. 
The post-menopause is formally defined as the time after which a woman has experienced 12 
consecutive months of amenorrhea (lack of menstruation) without a period. If a woman claims 
she is post-menopausal, but has had her menses within 12 months, a follicle stimulating 
hormone test must be performed and must be within acceptable limits of the post-menopausal 
status. Once post-menopause is confirmed no further pregnancy test needs to be conducted 
during the course of this study. 

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All pregnancies detected during the study must be reported and handled as described in Section 
8.5. 
7.7.3 
Cotinine Test 
A urine cotinine test will be performed at V1 and V2 in all patients considered for enrollment 
in order to confirm the patient’s smoking status. The test must be able to detect cotinine with 
a cotinine level of ≥ 200 ng/mL (e.g., One-Step Cotinine Test 008A086, Ultimed, Belgium) in 
current smokers, and < 100 ng/mL (e.g., NicAlert TM Urine, JAN, California, USA) in the 
former smokers group.  
7.8 
Sample Handling, Storage, and Shipment 
The urine pregnancy tests and urine cotinine tests will be done by personnel at the study sites. 
Participating laboratories for the analyses of clinical samples are listed in Appendix 2. Detailed 
procedures for handling of samples are described in a separate Laboratory Manual / Sample 
Handling Manual (SHM). All samples will be destroyed post database lock or post finalization 
of the bioanalytical reports depending on which one is coming the latest or when the stability 
end date of the sample has been reached.  
7.8.1 
Blood Samples 
Arterial blood sampling should be avoided in any case. Venous blood samples will be collected 
by qualified and trained site personnel. Patients should be in a seated position (if feasible; 
otherwise supine) during blood collection. The maximal total volume of blood drawn from 
each patient during the full study duration will be around 80 mL (From V1 to V8: 10 mL at 
every single visit, i.e. not more than a blood donation every 3 months.  
7.8.2 
Urine Samples 
Spot urine will be collected for analysis of BoExp, creatinine, safety analysis, cotinine test, 
and pregnancy test. 
  
7.9 
Self-reported Tobacco or Nicotine-Containing Product Use 
At V2, a diary on current tobacco and nicotine-containing product use will be distributed to 
the patients, and patients will be provided with instructions from study staff so that they can 
then fill the diary. Each diary contains 6 questionnaires for 6 months between the visits. The 
sites will call the patients to remind them to fill the questionnaires in the diary monthly to 
record their self-reported tobacco and nicotine-containing product consumption (including 
frequency and quantity of product use) over the past month. In this case, a “month” is to be 

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considered as 30 days, however a “calendar month” window is acceptable. A flexibility of ± 2 
day is allowed, whichever definition of the month is used. The first questionnaire in the diary 
will be completed one month after V2. The Investigator or study collaborator will collect the 
completed diaries at every visit from V3 onwards, and the diary data will be transcribed into 
the CRF by the site staff.  
 
 

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8 ADVERSE EVENTS/PREGNANCIES/PRODUCT EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
According to ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting 40, an adverse event (AE) is defined as any untoward medical 
occurrence in a patient administered an IP (including the comparator product: CC), which does 
not necessarily have a causal relationship with the IP (including the comparator product: CC). 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an IP, 
whether or not it is considered related to the IP. 
Worsening of the AAA parameters (maximum minor-axis AAA diameter in mm, AAA annual 
growth rate, maximum minor-axis AAA diameter growth of above 5 mm in 6 months) will not 
be considered as an AE, as clinical assessments will capture any worsening of the condition. 
Patients experiencing unexpected worsening of the disease will be treated according to 
Investigator’s judgement, which will be recorded. 
8.1.2 
Serious Adverse Event 
An SAE is defined as, but not limited to, any untoward medical occurrence that: 
• 
Results in death. 
• 
Is life-threatening. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity,  
• 
Is a congenital anomaly/birth defect, or 
• 
Is an important medical event. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, they 
may jeopardize the patient or the patient may require medical or surgical intervention to 
prevent one of the outcomes listed in the above definition. 
Any pre-planned hospitalizations that are known at the time of signing the study participation 
ICF will not be recorded as SAEs (they will be recorded only as AEs). However, any AE that 
occurs during this pre-planned hospitalization will be considered according to the above 
definitions. 

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8.2 
Assessment of Adverse Events 
The Investigator is responsible for obtaining, assessing and documenting all AEs during the 
study. 
8.2.1 
Assessment of Adverse Events 
Adverse event information will be collected from the time of signature of the ICF onwards 
until the end of Investigational Period either by the Investigator via spontaneous reporting or 
by the use of consistent, open, non-directive questions from study site collaborators (e.g., 
“Have you had any health problems since the previous visit/How have you been feeling since 
you were last asked?”). The main source for AE collection will be face-to-face interview(s) 
with the patient.  
Information recorded will include: verbatim description of the AE, start and stop dates and 
times, seriousness, severity (intensity), action taken (e.g., whether or not the AE led to the 
patient’s discontinuation from the study), and outcome (e.g., resolved, discontinuation due to 
AE). 
For each AE, the intensity (severity) will be graded on a 3-point intensity scale (mild, moderate, 
severe) using the definitions provided in Section 8.2.3.  
Any exacerbation/worsening of an AE or pre-existing condition shall be evaluated and 
recorded.  
Correct medical terminology/concepts are preferred when recording AE terms, and 
abbreviations must be avoided. Wherever possible, a diagnosis is to be used to describe an AE 
rather than individual signs and symptoms (e.g., record ‘pneumonia’ rather than ‘fever,’ 
‘cough,’ ‘pulmonary infiltrate,’ or ‘septicemia,’ rather than ‘fever’ and ‘hypotension’ 
following blood sample). 
Any AE that meets the serious criteria must be recorded both on the AE report form of the 
CRF and on a separate SAE report form (Section 8.3). 
Information regarding AEs related to product events should be actively collected during the 
study visits.  
8.2.2 
Period of Collection 
Any AEs (including SAEs) will be captured by the study site collaborators and assessed by the 
Investigator(s) or designee(s) in order to establish relationship to IP and study procedures. AEs 
(including SAEs) will be collected from the time the patients have signed their ICFs until the 
end of the Investigational Period. 
All collected AEs will be reported in the clinical study report (CSR) as described below and in 
accordance with the respective local regulatory guidelines. 

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Screening Period 
All existing health conditions identified during the Screening Visit and judged by the 
Investigator as a preexisting condition will be recorded as concomitant disease and the patient’s 
eligibility for admission to the study will be reviewed. Any AEs which occur during the 
Screening period will be captured by the study site staff and assessed by the Investigator(s) or 
designee(s) in order to establish relationship or relatedness in respect to study procedures. For 
screen failure patients, only the study procedure-related AEs will be reported in the CRF and 
in accordance with respective regulatory guidelines. 
 
From ICF signature until the End of Study 
Any new, clinically relevant, abnormal finding or worsening of a pre-existing 
condition/concomitant disease detected during the study will be documented as an AE and/or 
SAE and assessed by the Investigator or designee.  
SAEs will be reported by the Investigator as described in this document and the safety 
management plan (SMP).  
At the end of the Investigational Period, all ongoing non-serious AEs will be documented as 
“ongoing” and no follow-up information will be sought for them anymore by the Investigator 
or designee. At that point, the Investigator will assess whether the patient should be referred to 
his/her General Practitioner to have their ongoing AEs addressed accordingly.  
All SAEs will be followed-up by the Investigator, despite their continuation after the end of 
the Investigational Period, until their resolution, stabilization (i.e., no worsening of the 
condition), or until an acceptable explanation has been found (e.g., a chronic condition). 
8.2.3 
Intensity of Adverse Event 
For each AE, the intensity will be graded by the Investigator on a 3-point intensity scale (mild, 
moderate, severe) using the following definitions: 
Mild: The AE is easily tolerated and does not interfere with daily activity.  
Moderate: The AE interferes with daily activity, but the patient is still able to function.  
Severe: The AE is incapacitating and requires medical intervention. 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures 
In general, all AEs and/or SAEs will be assessed by the Investigator as either ‘related’ or ‘not 
related’ to IP or comparator product as described below. In addition to the assessment of the 
relationship of the clinical event to the IP, the Investigator shall document a potential 
relationship of the clinical event to any particular study procedure. 

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Not related: The temporal relationship of the clinical event to IP administration or to a study 
procedure makes a causal relationship unlikely, or, concomitant medication, 
therapeutic interventions, or underlying conditions provide a sufficient 
explanation for the observed event. 
Related: 
The temporal relationship of the clinical event to study IP administration or to a 
certain study procedure makes a causal relationship possible, and concomitant 
medication, therapeutic interventions, or underlying conditions do not provide a 
sufficient explanation for the observed event. 
8.2.5 
Expectedness 
Any AE assessed as related to the IP will be assessed for its expectedness. An AE will be 
regarded as ‘unexpected’ if its nature or severity is not consistent with information already 
known about the IP, and is not listed in the current SPI 2.  
8.3 
Reporting and Follow-Up of Serious Adverse Events 
Any SAEs reported or observed during the study, whether or not attributable to the IP, or to 
any study procedures must be reported by the Investigator within 24 hours after first 
awareness by any party involved in the study to the Sponsor via email, having the SAE form 
attached as detailed in the Safety Management Plan (SMP).  
An SAE report form must be e-mailed as an attachment to: 
 
 
 
 
 
 
 
 
Sponsor: 
 
 
 
 
E-mail: 
 
 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube 
5 Quai Jeanrenaud 
2000 Neuchâtel 
Switzerland 
The Investigator/head of the investigational site is responsible for local reporting (i.e., to the 
IRB / IEC) of SAEs that occur during the study, according to local regulations.  
Any additional/follow-up information that becomes available after the initial SAE report form 

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has been completed will be forwarded to the Sponsor within 24 hours after first awareness 
by any person at the site using a new SAE report form and indicating that this is a follow-up 
report. 
The follow-up SAE report form must include the minimum information required for form 
completion and only changed/new information needs to be specified. Information provided in 
the follow-up SAE report form supersedes any information that was initially reported.  
All SAEs will be followed up by the Investigator until their resolution or until the Investigator 
considers the event to be stabilized (i.e., no worsening of condition), or until an acceptable 
explanation has been found (e.g., a chronic condition). The details of the SAE management 
will be provided in a separate document, namely the safety management plan (SMP) for this 
study. 
The SAE report form to be used in this study is provided as a separate document. All SAEs 
will be recorded on the relevant CRF page, in addition to the SAE report form. 
The Investigator or designee is responsible for submitting the relevant reports of SAEs that 
occur during the study to the IRB, according to local regulations and in accordance with the 
respective safety management plan (SMP). 
8.4 
Reporting of other events critical to safety evaluations 
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator and assessed for clinical significance. 
In addition, any clinical safety laboratory test result that is outside of the normal reference 
range will be assessed for severity by the Investigator using the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 grading system. Whenever that grading scheme is 
not available for the laboratory result of concern, the Investigator should assess the severity of 
that result using his/her medical judgment. 
Abnormal laboratory test results detected at the Screening Visit and deemed clinically 
significant are usually concomitant disease or a manifestation of one and must be recorded 
accordingly.  
Abnormal laboratory test results detected after the Screening Visit and deemed clinically 
significant must be either recorded as AEs or linked to a concomitant disease or to an already 
reported AE. 
If there is no diagnosis available to record an AE or a concomitant disease corresponding to a 

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clinically significant abnormal laboratory test result, it will be recorded as “increased <lab 
parameter>” or “decreased <lab parameter>” to ensure consistency of recording/coding. 
8.4.2 
Reporting other abnormal findings 
The other abnormal findings discovered during different clinical assessments (e.g., ECG, 
physical examination, vital signs) should be evaluated for the clinical significance by the 
Investigator/designee based on his/her medical judgement. All abnormal clinical significant 
test results or clinical examination findings can, at the discretion of the Investigator, be 
reported as AEs. 
8.5 
Reporting and Follow-Up of Pregnancies 
For pregnancies detected between the time of signature of the study participation ICF and the 
enrollment of the patient, the patient will be considered as a screen failure. In that situation, 
the pregnancy will not be reported to the Sponsor, however, the identified pregnancy(ies) must 
be captured in the screen failure CRF. No pregnancy form will be filled. 
For pregnancies detected between enrollment and prior to randomization (IQOS and CC arm 
only), patients will be discontinued, and reported as “enrolled but not randomized” patients. 
Early termination procedures shall apply. No pregnancy form will be filled. 
Any pregnancy detected after enrollment for the SC arm and after randomization for CC and 
IQOS arm, must be reported by the Investigator to the Sponsor within 24 hours of the first 
awareness and must be followed-up for up to 8 weeks after the pregnancy outcome is reached. 
This also includes pregnancies spontaneously reported to the Investigator after the end of the 
study for a patient. 
The pregnancy form to be used in this study is provided as a separate document.  
The procedure to report a pregnancy and provide any additional/follow-up information to the 
Sponsor must be followed in the same manner and within the same timelines as described for 
an SAE (Section 8.3). No invasive procedures must be done in such patients after the discovery 
of pregnancy. If pregnancies are to be followed-up, they will be followed-up until an outcome 
is reached (e.g., normal delivery, spontaneous abortion, or voluntary termination) and also until 
8 weeks after delivery.  
Any pregnancy complication, adverse pregnancy outcome, or maternal complications will be 
recorded as an AE (or SAE).  
The Investigator/head of the investigational site is responsible for informing the IRB / IEC of 
any pregnancy that occurs during the study and its outcome, according to local regulations. 

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8.6 
Adverse Events Leading to Discontinuation 
Patients who are discontinued from the study because of an AE will undergo the early 
termination procedure, as described in Section 9.4, as soon as possible. The Investigator will 
follow-up these AEs as described in Section 8.2.2.  
8.7 
Product Events / Investigational Product Malfunction and Misuse 
Any occurrences of product events, including IQOS malfunction (e.g., holder does not charge 
when inserted into the charger), misuse by a patient (use not in accordance with its label and 
instruction) or events related to HeatSticks, will be documented by the Investigator or his/her 
designated collaborator using a product issue log developed by the site.  
Investigational product misuse may result in use-related hazards (Section 2.3.4).  
Furthermore, any misuse or malfunction of IQOS that leads to an AE/SAE will follow the same 
processes as described above for the reporting of the AE/SAE. 
 
 

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9 STUDY ACTIVITIES 
A detailed schedule of assessments can be found in Appendix 1. 
Measurements not conducted at the exact time point, but conducted within the given time 
window (if applicable) do not constitute a protocol deviation but an accepted variability for the 
given time point. In general, if no start time for the procedures is provided, then the procedure 
can be performed at any time during the day. Assessment during the study visits will be 
performed by qualified and trained personnel.  
9.1 
Screening Visit: V1 
The Screening Visit (V1) will be scheduled within 4 weeks (Day -28 to -1) prior to the Baseline 
Visit (V2).  
Patient will sign the study participation ICF before the start of any study procedure, and will 
enter Screening. When/if the ICF is signed (date and time), screening procedures can be 
performed in the order deemed most practical. While it is recommended to complete as many 
screening procedures as possible in one day, it is permissible to complete those over more than 
one day. Smoking is allowed at V1 unless otherwise instructed by the site.  
Table 4 shows the assessments that will be performed at the Screening Visit: all the 
assessments described below have to be conducted in all patients unless specified otherwise. 
All the samples will be collected, stored, and shipped according to the laboratory/sample 
handling manual. 
Table 4  
Schedule - Screening Visit: V1 
Time 
Sample 
collection 
Procedures 
Additional information 
Start of procedure 
 
Screening 
 
Start of the visit 
 
ICF procedure and signature 
Informed consent for study 
participation  
After ICF signature, 
during the visit 
 
Advice on the risks of smoking/SC 
advice  
 
 
 
Check of eligibility criteria 
 
 
 
Demographics data 
Sex, date of birth, ethnicity 
 
 
Medical history, including history of 
recent and current alcohol and 
substance abuse (only history of 
recent and current alcohol and 
substance abuse is based on self-
reporting) 
 

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Time 
Sample 
collection 
Procedures 
Additional information 
Start of procedure 
 
Screening 
 
Concomitant diseases  
 
 
 
Previous medication and/or 
concomitant medication 
 
 
 
Retrospective CT scan evaluation 
within the last 30 months prior to V1 
2 CT scans to be sent to 
central reading for 
evaluation 
 
 
Intention to quit smoking in the next 6 
months after having been advised to 
quit smoking  
Smoking patients only  
During the visit  
 
  
 
 
U 
Spot urine collection for pregnancy 
and cotinine tests 
 
Pregnancy test (all females, 
except when menopause is 
confirmed): at the study 
site. 
Cotinine test: test at the 
study site. The cut-off 
value of urine cotinine 
Screening test in smoking 
patients: ≥ 200 ng/ml, in all 
former CC smokers: < 100 
ng/ml. 
 
 
IQOS demonstration and debriefing 
For smoking patients only. 
For female smoking 
patients, only after 
pregnancy test was tested 
negative. 
 
 
Smoking history/habits questions 
 
 
 
Readiness to comply to study 
procedures 
 
 
 
Clinical assessments: 
Vital signs: at least 15 min 
after having smoked CC or 
used IQOS 
 
Vital signs 
 
Physical examinations 
 
Electrocardiogram 
 
Chest X ray 
 
Body height and weight 

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Time 
Sample 
collection 
Procedures 
Additional information 
Start of procedure 
 
Screening 
 
 
Waist circumference 
 
B/U 
Hematology, clinical chemistry, urine 
analysis 
 
 
 
Judgment on eligibility 
All eligibility criteria must 
be checked. 
 
 
AE/SAE recording 
 
 
 
CT scan for abdominal aorta 
Recommended as last 
assessment once all other 
assessments are done, and 
all of other eligibility 
criteria are checked. To be 
made at V1 and to be sent 
to the central reading site 
(can also be organized after 
V1). 
End of the visit 
 
 
 
Abbreviations: AAA = Abdominal Aortic Aneurysm; AE = Adverse event; B = Blood/Plasma; CT = Computed 
Tomography; SAE = Serious adverse event; SC = Smoking Cessation; U = Urine. 
9.2 
Baseline Visit: V2 
Table 5 shows the assessments that will be performed at Baseline Visit (V2): all the 
assessments described below have to be conducted in all patients unless specified otherwise. 
All the samples will be collected, stored, and shipped according to the laboratory/sample 
handling manual. 
Table 5  
Time Schedule – Baseline Visit: V2 
Time 
Sample 
collection 
Procedures 
Additional information 
 
Start of 
procedure 
 
 
 
Start of the 
visit 
 
Advice on the risks of 
smoking/SC advice 
 
Prior to 
enrollment 
 
Re-check of applicable 
eligibility criteria 
CT scan assessment for 
eligibility  
 
 
 
Made at V1, sent to the central 
reading site for assessment, to be 
checked at V2 for eligibility.    

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Time 
Sample 
collection 
Procedures 
Additional information 
 
Start of 
procedure 
 
 
 
Spot urine for pregnancy and  
cotinine tests  
  
Pregnancy test (all females, except 
when menopause is confirmed): at 
the study site. Cotinine test: test at 
the study site. The cut-off value of 
urine cotinine test in all smoking 
patients: ≥ 200 ng/ml, in all former 
smokers: < 100 ng/ml. 
 
 
Intention to quit smoking in the 
next 6 months after having 
been advised to quit smoking 
Smoking patients only 
 
 
Concomitant medication 
Follow-up on concomitant 
diseases (ongoing or not) 
 
 
 
Assessment of concomitant 
diseases 
 
 
 
 
 
 
 
Readiness to comply to study 
procedures 
 
 
 
Judgment on eligibility 
 
 
 
 
 
Enrollment 
 
Enrollment of eligible patients 
for the IQOS and CC arm in 
IXRS 
Smoking patients only. 
 
 
Enrollment of eligible patients 
into the SC arm in IXRS  
Former smoker patients only. 
After 
enrollment 
 
Distribution of the diary for 
tobacco or nicotine-containing 
product use self-reporting 
Patients will be provided with 
information on how to fill the diary 
 
 
 
 
 
U 
Spot urine collection for 
collection of samples for total 
NNN, total NNAL, CEMA, 
NEQ, creatinine 
 
 
 
 
B/U 
Blood/Urine: Hematology, 
clinical chemistry, urine 
analysis 
Blood samples have to be taken 
after at least 10 hours of fasting.  
 
 
 
 
 

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Time 
Sample 
collection 
Procedures 
Additional information 
 
Start of 
procedure 
 
 
 
 
 
Clinical assessments: 
 
 
 
Vital signs 
Vital signs: at least 15 min after 
having smoked CC or used IQOS. 
Systolic and diastolic blood 
pressure also assessed as 
cardiovascular risk factors 
 
 
Physical examinations 
 
 
 
Body weight 
Assessed as cardiovascular risk 
factor 
 
 
Waist circumference 
Assessed as cardiovascular risk 
factor 
 
 
 
 
 
 
AE/SAE recording 
 
 
 
Debriefing on IQOS 
Smoking patients only.  
 
 
Randomization 
Smoking patients only 
 
 
Patients are informed of their 
randomized study arm. 
Smoking patients only 
 
 
Distribution of the IQOS 
supplies as per site process 
Smoking patients randomized to 
IQOS arm only 
 
 
 
Any other assessment as per 
standard of care for AAA 
patients and deemed necessary 
by the Investigator 
 
End of the 
visit 
After check 
out 
 
 
 
Patients start using their 
allocated product 
 
 
IQOS and CC arm only 
Abbreviations: AAA = Abdominal Aortic Aneurysm; AE = Adverse event; ; B = Blood/Plasma; CEMA = 2-
Cyanoethylmercapturic Acid; CT = Computed Tomography;  NEQ = nicotine equivalents, consisting of the molar 
sum of free nicotine, nicotine-glucuronide, free cotinine, cotinine-glucuronide, free trans-3’-hydroxycotinine and 
trans-3’-hydroxycotinineglucuronide; NNAL = 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol; NNN = N-
nitrosonornicotine; SAE = Serious adverse event; SC = Smoking Cessation; U = Urine; . 
 

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9.3 
Investigational Period (from V3 to V8) 
All the assessments described in the tables have to be conducted in all patients unless specified 
otherwise. All the samples will be collected, stored, and shipped according to the 
laboratory/sample handling manual. 
V3 will be scheduled 6 months after V2 with a flexibility of ± 14 days. All subsequent visits 
until Visit 8 will be conducted every 6 months with a flexibility of ± 14 days since the previous 
visit.  
Table 6 shows the assessments that will be performed at: 
• 6 month Visit: V3 
• 12 month Visit: V4 
• 18 month Visit: V5 
• 24 month Visit: V6 
• 30 month Visit: V7 
• 36 Month Visit: V8 
Electrocardiogram is to be performed at V4, V6, and V8 only. 
Table 6  
Time Schedule – V3 to V8 
Time 
Sample 
collection 
Procedures 
Additional information 
 
Start of 
procedure 
 
 
 
Start of the visit 
 
Advice on the risks of smoking/SC advice 
 
 
 
Debriefing on IQOS 
IQOS and CC arm only. 
During the visit 
 
Tobacco or nicotine-containing product 
use self-reporting diary 
Collection of the Diaries 
from the previous visit, and 
distribution of the diaries for 
the next visit  
 
 
Concomitant medication 
Follow-up on concomitant diseases 
(ongoing or not) 
 
 
U 
Spot urine collection for pregnancy, and 
collection of samples for NEQ, total NNN, 
total NNAL, CEMA, creatinine 
Pregnancy test (all females, 
except when menopause is 
confirmed): at the study site 
 
 
B/U 
Blood/Urine: Hematology, clinical 
chemistry, urine analysis 
Blood samples have to be 
taken after at least 10 hours 

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Time 
Sample 
collection 
Procedures 
Additional information 
 
Start of 
procedure 
 
 
 
of fasting.  
 
 
Clinical assessments: 
 
 
 
Vital signs 
Vital signs: at least 15 min 
after having smoked CC or 
used IQOS. Systolic and 
diastolic blood pressure also 
assessed as cardiovascular 
risk factor 
 
 
Physical examinations 
 
 
 
Body weight 
Assessed as cardiovascular 
risk factor 
 
 
Waist circumference 
Assessed as cardiovascular 
risk factor 
 
 
 
CT scan 
CT scan to be made at site 
and to be sent to the central 
reading site for assessment 
by the central reading site 
following standardized 
protocol. 
 
 
 
 
 
 
Assessment of concomitant diseases  
 
 
 
 
 
 
 
 
 
 
 
Any other assessment as per standard of 
care for AAA patients and deemed 
necessary by the Investigator  
 
 
 
 
Record of the date of open surgical AAA 
treatment or AAA endovascular repair if 
applicable 
 
 
 
 
Electrocardiogram 
 
At V4, V6, and V8 only 
 
 
Return of IQOS device, replacement of 
devices as appropriate 
For IQOS arm only: at V8 
or when the device needs 
replacement due to a device 
malfunction according to 
the instructions in the 

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Time 
Sample 
collection 
Procedures 
Additional information 
 
Start of 
procedure 
 
 
 
Investigational Product 
Handling Manual 
End of the visit 
 
AE/SAE/product event recording 
 
 
 
Discharge 
At V8 only 
Abbreviations: AAA = Abdominal Aortic Aneurysm; AE = Adverse event; B = Blood/Plasma; CEMA = 2-
Cyanoethylmercapturic Acid; CT = Computed Tomography; NEQ = nicotine equivalents, consisting of the molar 
sum of free nicotine, nicotine-glucuronide, free cotinine, cotinine-glucuronide, free trans-3’-hydroxycotinine and 
trans-3’-hydroxycotinineglucuronide; NNAL = 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol; NNN = N-
nitrosonornicotine; SAE = Serious adverse event; SC = Smoking Cessation;  U = Urine; . 
At the end of V8, patients will be discharged from the study. The procedures prior to discharge 
of the patient will also apply in case of early termination of the patient. 
9.4 
Early Termination Procedures 
For patients who terminate the study early, the procedure of discharge planned for V8 will be 
performed as an early termination (Table 7).  
Table 7  
Time Schedule – Early Termination Procedures 
 
Time 
Sample 
collection 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
 
During the visit 
 
Advice on the risks of smoking/SC 
advice 
Follow-up on concomitant diseases 
(ongoing or not) 
 
During the visit 
U 
Spot urine collection for pregnancy  
Pregnancy test (all females, 
except when menopause is 
confirmed): at the study site 
 
B/U 
Blood/Urine: Hematology, clinical 
chemistry, urine analysis 
Blood samples have to be 
taken after at least 10 hours 
of fasting. 
 
 
Clinical assessments: 
Electrocardiogram  
Physical examinations 
 
At least 5 minutes in supine 
position 

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Return of IQOS device 
For IQOS arm only upon 
early discontinuation 
End of the visit 
 
AE/SAE/product event recording 
 
Abbreviations: AE = Adverse event; SAE = Serious adverse event. 
 
If the patient withdraws from the study, or is discontinued based on Investigator judgment, 
he/she will be asked to perform the early termination procedure as soon as possible after the 
time of discontinuation unless the patient refuses to do so (section 5.2).  
 
 

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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
The Clinical Research Associate (“Monitor”) will be responsible for the monitoring of the 
study. Monitoring will be performed according to CRO’s Standard Operating Procedures 
(SOPs) and as per the agreed monitoring plan with the Sponsor. 
The Investigator/head of the investigational site shall permit the Monitor to review study data 
as frequently as considered necessary to ensure that data are being recorded in an adequate 
manner and that protocol adherence is satisfactory. 
The Investigator shall access medical records for the Monitor in order that entries in the CRFs 
may be verified. The Investigator, as part of his/her responsibility, is expected to ensure that 
the study adheres to GCP requirements. 
An Investigator’s meeting will be held prior to the site initiation visit. During this meeting, a 
general training on the study procedures and specific training on selected procedures will be 
done and documented. 
After the Investigator’s meeting, and before the first patient is screened into the study, a site 
initiation visit will be conducted by the Monitor and, if necessary, with the Sponsor or its 
authorized representative. The purpose of the site initiation visit will be detailed in the 
monitoring plan. 
Communication by telephone, mail, and e-mail may be used as needed to supplement site 
visits. The Investigator and study personnel will cooperate with the Monitor, provide all 
appropriate documentation, and will be available to discuss the study. 
The Monitor and the Sponsor’s personnel will be available between visits, should the 
Investigator or other study collaborator at the sites need information and advice. 
Site visits will be made at regular intervals during the study. The frequency of the monitoring 
visits will be defined in the monitoring plan agreed with the Sponsor. 
The Investigator, or a designated member of the Investigator’s study collaborator, must be 
available during the monitoring visit to review the data and resolve any queries, and to allow 
direct access to the patient’s records for source data verification. 

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10.2 Training of Staff 
A formal meeting (Investigator’s meeting) will be conducted prior to site initiation. During 
this meeting, the Sponsor or its authorized representative will discuss the requirements of the 
clinical study protocol and related documents and will also provide training in the relevant 
systems and other study-specific procedures. The activities of the Investigator’s meeting will 
be described in the monitoring plan. 
In addition to the Investigator’s meeting, the Investigator will ensure that appropriate training 
relevant to the study is provided to all study collaborators involved in the study, and that any 
new information relevant to the performance of this study is forwarded in a timely manner to 
the study collaborator. The record of all individuals involved in the study will be maintained 
in the Site Investigator File. 
10.3 Audits and Inspections 
Good Clinical Practice guidelines require that there are independent inspections of clinical 
program activities. Such inspections may be performed at any time before, during and/or after 
the study. 
Authorized representatives of the Sponsor, regulatory agencies and/or the IRB / IEC may 
perform audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, ICH/GCP guidelines, and any 
applicable regulatory requirements. The Investigator/head of investigational site will contact 
the Sponsor or the authorized representative immediately, if contacted by a regulatory agency 
about an inspection at their site. 
The Investigator and study collaborators are responsible for maintaining a comprehensive and 
accurate filing system of all study-related documentation that will be suitable for inspection at 
any time by the Sponsor, its authorized representative, and/or regulatory agencies. In signing 
this protocol, the Investigator understands and agrees to provide access to the necessary 
documentation and files. 
 
 

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11 DATA MANAGEMENT ACTIVITIES 
All Data Management activities will be described in detail in the Data Management Plan 
(DMP) and documents specified therein. 
11.1 Data Capture 
11.1.1 Case Report Forms and Study Records 
Data Collection Procedures: 
The results from the clinical assessments will be recorded in the source data file by the 
Investigator or their authorized designee and then captured in the CRFs. 
Trained study personnel will be responsible for capturing the data from the observations, tests, 
and assessments specified in the protocol and in the source documents, and transferring the 
data to the CRF according to the CRF Completion Guidelines. 
The Investigator has ultimate responsibility for the collection and reporting of all data related 
to the clinical study and ensuring that the data are accurate, authentic/original, legible, timely 
(contemporaneous), enduring, and available when required. The CRF must be signed by the 
Investigator to attest that the data contained on the CRF are true and accurate. Any corrections 
made to source documents must be clearly recorded, without obscuring the original values and 
be accompanied by the date of change, reason for change, and identification of the person 
making the change. The CRF data will be verified against the source documents at the study 
site by the clinical research associate. Instances of missing or unclear data will be discussed 
with the Investigator for resolution. 
11.1.2 Protocol Deviations 
All protocol deviations will be entered into the Clinical Trial Management System (CTMS) or 
other approved format. 
Information from the source documents will represent the primary source of protocol 
deviations. Information following site monitoring and other manual reviews will be 
documented in the site visit reports, follow-up letters, audit documentation, or other manual 
review and will be recorded and tracked in the CTMS or other approved format. 
Telecommunications and other verbal communications regarding deviations will be considered 
and handled as important communication, and documented and tracked as protocol deviations, 
as necessary. 

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Individual entries for protocol deviations that are recorded in the CTMS, or other approved 
format, following site monitoring and other manual reviews will be reviewed against the 
individual data points in the CRF database but will not be formally reconciled with the CRF 
database (e.g., their description or occurrence date). The overall procedures for managing 
protocol deviations are described in the SOPs of the CRO Data Management Team. All 
deviations will be reviewed periodically, as determined at study start, to identify trends to 
improve monitoring and/or potential impact on the statistical analysis. 
11.2 Data Handling 
All study data will be managed by the Data Management Team at the CRO. The overall 
procedures for quality assurance of clinical study data are described in the SOPs of the CRO 
Data Management Team. The Data Management Team at CRO will prepare a DMP, to be 
reviewed and approved by the Sponsor, prior to the start of the study. This document will 
describe, in detail, the Data Management related procedures and processes. 
All data of all patients enrolled and screening failures who experience an AE during the study 
(from time of informed consent) will be captured. 
All data collected during the study is property of the Sponsor, irrespective of the location of 
the database and the Data Management CRO. 
11.2.1 Data Validation 
The data will be validated as defined in the DMP and Data Validation Specifications. 
Discrepancies will be reported as defined in DMP and Data Validation Specifications. 
Data queries will be raised for discrepant or missing data. All changes to data will be captured 
in the database with a comprehensive audit trail. 
11.2.2 Coding 
AEs, medical/surgical history, and prior/concomitant medication will be classified according 
to the terminology of the latest version of the following Dictionaries, at time of coding the first 
entry: 
Medical history: 
Medical Dictionary for Regulatory Activities (MedDRA®) 
Adverse events: 
MedDRA® 
Medications: 
WHODrug Global 
IQOS device issues 
and/or malfunctions: 
C54451/Medical_Device_Problem_Codes_FDA_CDRH 

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11.2.3 Database Lock 
When all outstanding Data Management issues have been resolved and all validation, quality 
review, and cleaning activities are complete, the database or selected data is/are declared soft 
locked. Access to change data in the soft-locked database or to change selected data at this 
time is limited. 
After the data is reviewed by the Sponsor, resolution of all raised queries and QC of the 
changed data, database, or selected data upon Sponsor approval as applicable, is declared 
locked. 
Any changes to the database after that time can only be made by written agreement between 
the Sponsor and the Data Management and Statistical Teams 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 and compliant with Clinical Data Interchange Standards Consortium 
(CDISC) Study Data Tabulation Model (SDTM).  
 
 
 

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12 PLANNED STATISTICAL METHODS 
12.1 General Considerations 
This study is following the International Conference on Harmonization (ICH) guidelines and 
Good Clinical Practices (GCP) [3] ensuring that there is a complete traceability and auditability 
of the data from the CRF until final database and statistical analysis. Monitoring ensures that 
correct data from the CRF are entered in the database, and as soon as the data are entered in 
the database, that there is a complete audit trail of these data (any update, change, deleting are 
traced). Any audit or regulatory inspection should be able to retrieve any statistical results from 
the raw data (CRF data). 
The data management, statistical analysis and reporting of the data will be performed according 
to the international guidelines on clinical studies.  
During the study, study statisticians are blinded to data related to the primary endpoints. The 
Statistical Analysis Plan is written in a blinded manner without seeing the data. The Statistical 
Analysis Plan has to be signed before the database lock and before receiving the final data for 
the analysis. As soon as the Statistical Analysis Plan is signed, all analyses described in the 
Statistical Analysis Plan have to be performed accordingly. 
Full details of the statistical analysis will be given in the Statistical Analysis Plan (SAP). Any 
changes to the planned statistical methods will be documented in the CSR. The statistical 
evaluation will be performed using SAS®, version 9.2 or later. 
 
12.1.1 Stratification Criteria 
For the primary analysis of AAA annual growth rate, the following stratification criteria will 
be used: 
• Aortic maximum-minor-axis diameter (male patients: < 40 mm and ≥ 40 mm; female 
patients: < 35 mm and ≥ 35 mm, using the CT scan made at V1 and assessed by the 
central reading site 
• Sex (male vs. female) 
Although smokers who had stopped smoking will be enrolled in the SC arm without 
randomization, they will be analyzed based on the defined stratification criteria. Additional 
stratified presentations (e.g., pack years of history of smoking) may be defined in the SAP. 

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disclosed without the written consent of Philip Morris Products S.A. 
 
12.1.2 Definitions for Statistical Data Analysis 
In general, baseline value for any given variable will be the last assessment prior to 
randomization for the patients randomized to either IQOS or CC smoking. For the patients in 
the SC arm, baseline value for any given variable will be the assessment of any given variable 
performed at V2 (e.g., CT scan made at V1 and assessed by the central reading site and 
available at V2). Further details will be described in the SAP. 
12.1.3 Descriptive Statistics 
Data will be presented in listings, patient, and study visit, unless otherwise specified. 
For continuous data, summary statistics will include the number of patients [n], number and 
percent of patients with missing data, the mean and standard deviation (SD), median, first and 
third quartiles, minimum and maximum, and 95% confidence interval (CI). Log-normally 
distributed data (e.g., BoExp data) will also include the geometric mean and coefficient of 
variation (CV) in addition to the mean and SD. For categorical data, frequency counts and 
percentages will be presented. 
12.1.4 Handling of Missing Values and of Values outside the Detection Limits 
For BoExp parameters: 
• Values below the lower limit of quantification (LLOQ) will be imputed using LLOQ/2. 
For values above the upper limit of quantification (ULOQ), the ULOQ will be imputed.  
• The number of values below LLOQ or above ULOQ will be presented in each summary 
table. If more than 50% of the data are below LLOQ, only the number and percentage 
of values below LLOQ will be reported in the summary together with the minimum 
and maximum values. 
For self-reported tobacco or nicotine-containing product use:  
• Only available data will be included in the product use summaries. 
12.1.5 Significance Level for Inferential Analysis 
This study is of exploratory nature and therefore no statistical hypothesis is to be tested.  
12.1.6 Confidence Interval 
All confidence intervals will be 95% CIs. 

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12.2 Determination of Sample Size 
The sample size of patients is not based on a statistical hypothesis, as this is a descriptive study, 
designed to characterize the growth rate of AAA and the progression of disease, to better 
understand the impact of IQOS relative to CC on the progression of disease. Patients will be 
enrolled/randomized per study arm.  
12.3 Product Use 
Although patients are being requested to use solely the product allocated to their respective 
study arm, it is considered that not all patients randomized to the IQOS arm or to continue 
smoking CC will exclusively use the randomized product at all times during the study. For 
instance, patients may concomitantly use IQOS and CC (dual use). Similarly, it is expected 
that some patients in the SC arm who had stopped smoking after AAA diagnosis may relapse 
to the use of tobacco or nicotine-containing products (e.g., CC or IQOS). Those patients who 
might change their smoking habits after randomization to an arm (e.g., who have been allocated 
to the IQOS arm but restart smoking CC) will remain for the statistical analysis in the arm they 
have been randomized to.  
12.4 Analysis Populations 
The main population for non-safety analyses will be the Full Analysis Set.  
Safety will be analyzed using the Safety Set. 
12.4.1 Full Analysis Set (FAS) 
The Full Analysis Set (FAS) will consist of all enrolled patients in the SC arm who have signed 
the ICF and who have at least one valid non-safety assessment after enrollment as well as all 
patients randomized to the CC or IQOS arm who have signed the ICF, have at least one valid 
non-safety assessment after randomization and have at least one post-randomization product 
(IQOS or CC) use experience. The FAS will be analyzed by enrolled arm (randomization arm 
for CC or IQOS, or SC arm). 
12.4.2 Safety Set 
Safety Set consists of all the patients enrolled with signed ICF who have at least one valid 
value for a safety assessment during the course of the study. The Safety Set will be analyzed 
by enrollment arm and in patients exposed but not randomized.  

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disclosed without the written consent of Philip Morris Products S.A. 
 
12.5 Demographics and Baseline Characteristics 
The demographic variables will be summarized by enrollment arm for the Full Analysis Set.. 
No inferential analyses will be presented for the demographics and baseline characteristics. 
12.6 Primary Analysis 
The primary analysis will be a descriptive analysis of patients who were randomized to IQOS 
use as compared to patients who were randomized to continue to smoke CC (IQOS arm versus 
CC arm) in the Full Analysis Set of AAA patients. 
The primary endpoint is the comparison of the annualized mean growth rates in patients 
diagnosed with AAA between patients who were randomized to IQOS use and patients who 
continue to smoke CC. The growth rate is calculated as the slope of the linear regression fit to 
the maximum minor-axis AAA diameter values over the time by randomization arm.  
Descriptive statistics for maximum minor-axis AAA diameter will be summarized at each visit 
and overall (across all patients). The primary endpoint will also be summarized by strata 
(maximum-minor-axis AAA diameter, CC consumption, sex). 
Study evaluation criterion: 
This is a descriptive study, designed to gain an understanding on the effect of complete 
switching from cigarettes to IQOS use compared to continued CC smoking on the AAA growth 
rate and disease progression. Dual use of IQOS on top of CC will be also investigated. There 
are no formal statistical hypotheses to be tested. 
Evaluation Criteria: 
No formal evaluation criterion is applied since this is a descriptive study. 
12.7 Secondary Analysis 
Descriptive statistics for the maximum minor-axis AAA diameter will be summarized at each 
visit and overall (across all patients). The endpoints will also be summarized by strata 
(maximum-minor-axis AAA diameter, CC consumption, sex). 
Urinary NEQ, and Total NNAL, Total NNN, and CEMA levels (concentration data adjusted 
for creatinine will be analyzed on a logarithmic scale) using an MMRM with the logarithmic 
transformation. 
Descriptive statistics for the secondary endpoints shown below, will be summarized at each 
visit, except for vital signs (systolic and diastolic blood pressure) which will be summarized 

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every 12 months, by exposure group and overall (across all patients) in the FAS (unless 
otherwise defined): 
• Time from diagnosis of AAA until open surgical AAA treatment or endovascular repair 
• Time from diagnosis of AAA until AAA rupture 
• Annual growth rate of AAA 
• Nicotine equivalents (NEQ): molar sum of free nicotine, nicotine-glucuronide, free 
cotinine, 
cotinine-glucuronide, 
free 
trans-3’-hydroxycotinine, 
trans-3’-
hydroxycotinine-glucuronide in spot urine (expressed as concentration adjusted to 
creatinine) 
• Systolic and diastolic BP 
• Body weight and waist circumference 
 
For the secondary endpoints shown below, the number at each visit and overall (across all 
patients) will be described: 
• Number of patients with open surgical AAA treatment or endovascular repair annually 
(based on date of decision to perform open surgical AAA treatment or AAA 
endovascular repair) 
• Number of patients with a AAA rupture annually (based on date of AAA rupture) 
• Number of patients with an increase in maximum minor-axis AAA diameter of more 
than 5 mm within 6 months 
• Number of patients with an overall maximum minor-axis AAA diameter >55mm in 
male patients and >50mm in female patients 
•  
• Incidence of IQOS malfunctions and misuses 
• Number of tobacco products used, (including CC and HeatSticks) based on self-
reporting 
12.8 Safety Analysis 
In general, safety data will be provided in listings by study arm, site, patient, visit and time-
point if applicable. The data will be tabulated on the Safety Set by study arms. Adverse events 
data will serve as the primary assessment of safety. 
The number and percentage of patients in the Safety Set  with AEs and SAEs will be tabulated 
by using the MedDRA® system organ class (SOC) and preferred term (PT), summarized 
annually for the Safety Set. Summaries will also be presented for AEs leading to 
discontinuation of the patients due to AE, AEs leading to death, AEs by relatedness to CC or 
IQOS, and AEs by severity.  

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Incidence and frequency of concomitant medications and product events will be tabulated by 
study arms. 
Tabulations will be performed for both the number of patients experiencing an event and the 
number of events. 
The number and percentage of patients in the Safety Set with clinical findings will be tabulated 
by study arms and exposure group for laboratory safety parameters, ECG, physical 
examinations and vital signs. Shift tables showing change from Baseline of clinical findings 
will be provided for ECGs (for ECGs: change from Screening Visit (V1) used as Baseline), 
physical examinations, and laboratory parameters (both shifts in normal ranges and toxicity 
grades). Descriptive statistics will be summarized by visit and change from Baseline for 
laboratory parameters, ECG (for ECGs: change from Screening Visit (V1) used as Baseline), 
and vital signs (systolic and diastolic blood pressure will be summarized every 12 months). 
Abnormal values of laboratory parameters will be shown in the listing. Individual laboratory 
parameters will be plotted over time. 
12.9 Exploratory Analysis  
Not Applicable. 
12.10 IDMC Analyses 
For this study, data reviews by IDMC members will be performed one year and two years after 
the first patient has been randomized. Sponsor will be informed at least with meeting minutes. 
All data reviews by IDMC members will focus on safety, study quality, product use exposure, 
and disease characteristics and progression. 

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13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Investigators and Study Administrative Structure 
13.1.1 Investigators 
See Appendix 5. 
13.1.2 Sponsor 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Phone: +41 (58) 242 2111 
Fax: +41 (58) 242 2811 
Clinical Scientist 
 PhD, Clinical Scientist 
 
 
 
Study Biostatistician 
, Senior Scientist, Biostatistics, 
Study Biostatistician 
  
 
 
 
Medical Safety Officer 
 
 
, MD, MSc, Medical Safety 
Officer 

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Clinical Study Manager 
, PhD, Associate Clinical Study 
Manager 
 
 
 
 
13.1.3 Other Responsibilities 
 is the CRO designated by PMI to perform duties and have responsibilities transferred 
to 
 by PMI as defined in the agreement signed between the two parties. 
 does not 
have any interests in sponsor activities related to the Test Product (IQOS).  
 
 
 
 
 
 
 
 
13.2 Patient Confidentiality 
All information obtained during the conduct of the study with respect to the patients, and their 
state of health, will be regarded as confidential. A statement to this effect will be included in 

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the information provided to the patient. An agreement to disclose any such information will be 
obtained from the patient in writing and signed by the patient, in compliance with all local and 
national data protection and privacy legislation. 
The anonymity of patients participating in this study will be maintained. Patients will be 
identifiable by the Sponsor (or Sponsor’s authorized representative) on CRFs and other 
documents by their patient (or randomization) number/code, sex and date of birth, but not by 
name, initial, or any other details relating to an identifiable person (e.g., address, health 
insurance ID card, medical chart number, etc.). The assignment of a patient number/code for 
patient identification will be based on the appropriate data protection rules. 
Any documents that allow full identification of the patient (e.g., the patient’s signed study 
participation ICF) must be maintained in confidence by the Investigator. If any document 
relating to this study shows a patient’s name or any other details relating to an identifiable 
person (e.g., address, health insurance ID card, medical chart number, etc.), the name or other 
identifiable details must be obscured before a copy of that document is supplied to the Sponsor 
or the Sponsor’s authorized representative. 
13.3 Access to Source Documentation 
Patients will be informed that, during the course of the clinical study, the Sponsor, any 
authorized representatives of the Sponsor, IRB / IEC, or regulatory authorities may inspect 
their medical records to verify the information collected, and ensure that all personal 
information made available for inspection is handled in the strictest confidence and in 
accordance with national and local data protection and privacy legislation. 
The Investigator/head of the investigational site and all study site trial collaborators involved 
with the study must permit direct access to source data/documents for study related monitoring, 
audits, IRB / IEC review, and regulatory inspection(s). 
13.4 Record Retention 
All records of data, source data and source documents (original records or certified copies), in 
any form (including, but not limited to, written, electronic, magnetic, optical records and scans) 
that describe or record the methods, conduct, and/or results of the study, the factors affecting 
the study, and the actions taken will be maintained by the Investigator/head of investigational 
site for the study, as required by ICH GCP and any other applicable local or national 
regulations.  
Essential study documents/records, which individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced, are described in Article 41 of 

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Ministerial Ordinance on GCP (Ordinance of the Ministry of Health and Welfare No. 28 of 
March 27, 1997 (as last amended by the Ordinance of Ministry of Health, Labour and Welfare 
No. 161 of December 28, 2012). Essential documents must be retained by the Investigator/head 
of investigational site for a minimum of: 
• At least 15 years after completion or discontinuation of the study, or 
• At least 2 years depending on, for example, the circumstances, or 
• After formal discontinuation of clinical development of the IP. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. 
Examples of essential records/documents include, but are not limited to: 
• Signed informed consent documents for all patients and study participation ICF. 
• Patient identification code list, Screening Log and Enrollment Log (if applicable). 
• Record of all communications between the Investigator and the IRB / IEC, composition 
of the IRB / IEC. 
• Record of all communications/contact between the Investigator, Sponsor, and its 
authorized representatives. 
• List of sub-Investigators and other appropriately qualified persons to whom the head 
of the investigational site has delegated significant study-related duties, together with 
their roles in the study. 
• Investigator Logs. 
• CRFs, study-specific questionnaires (and associated data/scoring), patient diaries. 
• AE reports and details of follow-up investigations, details of concomitant medication. 
• All other source documents or any electronically captured study source data. 
• Original medical/hospital records, if applicable (the medical files of study patients must 
be retained in accordance with local legislation and in accordance with the maximum 
period of time permitted by the hospital or study site). 
• Record of any body fluids or tissue samples collected and retained. 
• Device Issue Log, IP Accountability Logs, dispensing records. 
• Information regarding patients’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the Investigator/head of investigational site as 
to when these documents no longer need to be retained. 
The Investigator/head of investigational site must take measures to prevent accidental or 
premature destruction of these documents. 

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If the head of the investigational site wishes to assign the study records to another party or 
move them to another location, the Sponsor must be notified in advance. 
The head of the investigational site must obtain written approval from the Sponsor before 
destruction of any records. Normally, these records will be held in the Investigator’s archives. 
If the head of the investigational site is unable to meet this obligation, they must ask the 
Sponsor for permission to make alternative arrangements. Details of these arrangements must 
be documented. 
The Sponsor will maintain documentation relating to the study as long as the IP is on the market 
and three years after its discontinuation or for 15 years after the CSR has been finalized 
whichever is longer. 
13.5 Assessment Study Report 
The Sponsor must ensure that a CSR for this study is prepared regardless of whether the study 
is completed or prematurely terminated, and whether the study succeeds to evaluate/describe 
the study objectives or not.  
The CSR will be written based on standards of the ICH Guideline for the Structure and Content 
of Clinical Study Reports. In certain circumstances, an abbreviated CSR may be acceptable. 
Submission of the CSR to the IRB / IEC will be complied with as requested by local 
requirements. 
The results of the additional variables for analysis will be presented in reports separate from 
the CSR. 
13.6 Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor. In 
addition, the Investigators must provide to the Sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 1 year 
following the completion of the study. 
13.7 Publication and Disclosure Policy 
This document contains data, information and trade secrets that are confidential and proprietary 
to the Sponsor. This document is being provided solely for the purpose of evaluation and/or 
conducting this clinical study for the Sponsor. Disclosure of the content of this document is 
allowed only to study personnel, IRB / IEC, or duly authorized representatives of regulatory 
agencies for this purpose under the condition that confidentiality is maintained. The contents 
of this document may not be used in any other clinical study or disclosed to any other person 

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hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
 
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 will disclose details of the study protocol as well as study results, according to 
applicable local regulations, on a web-based, publicly available, clinical trial register database 
(e.g., ClinicalTrials.gov). 
13.8 Insurance 
The Sponsor is responsible for AEs and health damage to the patients who are associated with 
the IQOS product which are used during the study, except for AEs and health damage to the 
patients caused by a negligent or an intentional misconduct and/or significant deviation to 
the protocol of the Investigator or the clinical study site or the patients. The Sponsor has taken 
out insurance to cover any bodily injury and property damage caused by the operations carried 
out by the insured. 
 
 

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14 REFERENCE LIST 
1. 
JCS Joint Working Group. Guidelines for diagnosis and treatment of aortic aneurysm 
and aortic dissection (JCS 2011). Circulation Journal. 2013;77(3):789-828. 
2. 
Philip Morris Products S.A. Unpublished on file data: Summary of product 
information (SPI) - iQOS with HeatSticks. Version 1.0. 2017. 
3. 
ICH E6 (R2). Integrated addendum to ICH E6 (R1): guideline for good clinical 
practice - Current Step 4 version dated 9 November 2016. 2016; Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
6/E6_R2__Step_4.pdf (Accessed on 30 Jan 2017). 
4. 
Ministry of Health and Welfare. Ministerial ordinance on good clinical practice for 
drugs. Ordinance of the Ministry of Health and Welfare No. 28 of March 27, 1997, as 
last amended No. 161 of December 28, 2012. Provisional Translation (as of March 
2013). 2013; Available from: 
http://www.pmda.go.jp/english/service/pdf/ministerial/20130329No_28.pdf 
(Accessed on 22 April 2014). 
5. 
World Medical Association (WMA). Declaration of Helsinki - Ethical principles for 
medical research involving human subjects. 2013; Available from: 
http://www.wma.net/en/30publications/10policies/b3/ (Accessed on 16 March 2017). 
6. 
Heron M, Smith B. National Vital Statistics Reports, Deaths: Leading causes for 
2010. In. Vol 56: Center for Disease Control; 2007:9. 
7. 
Kent KC, Zwolak RM, Egorova NN, et al. Analysis of risk factors for abdominal 
aortic aneurysm in a cohort of more than 3 million individuals. Journal of vascular 
surgery. 2010;52(3):539-548. 
8. 
Carter BD, Abnet CC, Feskanich D, et al. Smoking and mortality--Beyond 
established causes. N Engl J Med. 2015;372(7):631-640. 
9. 
Wilmink TB, Quick CR, Day NE. The association between cigarette smoking and 
abdominal aortic aneurysms. Journal of vascular surgery. 1999;30(6):1099-1105. 
10. 
Powell JT, Greenhalgh RM. Small abdominal aortic aneurysms. New England 
Journal of Medicine. 2003;348(19):1895-1901. 
11. 
Lederle FA, Johnson GR, Wilson SE, et al. The aneurysm detection and management 
study screening program: validation cohort and final results. Archives of internal 
medicine. 2000;160(10):1425-1430. 
12. 
Brady AR, Thompson SG, Fowkes FG, Greenhalgh RM, Powell JT. Abdominal 
aortic aneurysm expansion: risk factors and time intervals for surveillance. 
Circulation. 2004;110(1):16-21. 
13. 
Bhak RH, Wininger M, Johnson GR, et al. Factors associated with small abdominal 
aortic aneurysm expansion rate. JAMA surgery. 2015;150(1):44-50. 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
 
14. 
Solberg S, Singh K, Wilsgaard T, Jacobsen B. Increased growth rate of abdominal 
aortic aneurysms in women. The Tromsø study. European journal of vascular and 
endovascular surgery. 2005;29(2):145-149. 
15. 
Rodgman A, Perfetti TA. The chemical components of tobacco and tobacco smoke. 
2nd ed: CRC Press, Taylor & Francis Inc (United States); 2013. 
16. 
U.S. Department of Health and Human Services, FDA (Food and Drug 
Administration). [Docket No. FDA-2012-N-0143]: harmful and potentially harmful 
constituents in tobacco products and tobacco smoke; established list. Federal 
Register. 2012;77(64):20034-20037. 
17. 
Wong ET, Kogel U, Veljkovic E, et al. Evaluation of the Tobacco Heating System 
2.2. Part 4: 90-day OECD 413 rat inhalation study with systems toxicology endpoints 
demonstrates reduced exposure effects compared with cigarette smoke. Regulatory 
toxicology and pharmacology : RTP. 2016;Suppl 2. Available from: 
http://www.sciencedirect.com/science/article/pii/S027323001630304X (Accessed on 
03 May 2017):S59-81. 
18. 
Oviedo A, Lebrun S, Kogel U, et al. Evaluation of the Tobacco Heating System 2.2. 
Part 6: 90-day OECD 413 rat inhalation study with systems toxicology endpoints 
demonstrates reduced exposure effects of a mentholated version compared with 
mentholated and non-mentholated cigarette smoke. Regulatory toxicology and 
pharmacology : RTP. 2016;Suppl 2. Available from: 
http://www.sciencedirect.com/science/article/pii/S0273230016303324 (Accessed on 
03 May 2017):S93-122. 
19. 
Titz B, Boue S, Phillips B, et al. Effects of cigarette smoke, cessation and switching 
to two heat-not-burn tobacco products on lung lipid metabolism in C57BL/6 and 
Apoe-/- mice - an integrative systems toxicology analysis. Toxicological sciences : an 
official journal of the Society of Toxicology. 2015. 
20. 
Phillips B, Veljkovic E, Boue S, et al. An 8-month systems toxicology 
inhalation/cessation study in Apoe-/- mice to investigate cardiovascular and 
respiratory exposure effects of a candidate modified risk tobacco product, THS 2.2, 
compared with conventional cigarettes. Toxicological sciences : an official journal of 
the Society of Toxicology. 2016;149(2):411-432. 
21. 
Philip Morris Products S.A. Nicotine pharmacokinetic profile and safety of the 
Tobacco Heating System 2.2 (THS 2.2)[ZRHR-PK-01-EU]. In: ClinicalTrials.gov 
[Internet]. Bethesda (MD): National Library of Medicine (US). 2013-2014 [cited 
2015 Jun 16]. Available from: http://clinicaltrials.gov/show/NCT01967732 NLM 
Identifier: NCT01967732. 
22. 
Philip Morris Products S.A. A single-center, open-label, randomized, controlled, 
crossover study to investigate the nicotine pharmacokinetic profile and safety of THS 

Philip Morris Products SA 
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2.2 following single use in smoking, healthy subjects compared to conventional 
cigarettes and nicotine gum [ZRHR-PK-02-JP]. In: ClinicalTrials.gov [Internet]. 
Bethesda (MD): National Library of Medicine (US). 2013-2014 [cited 2015 Aug 26]. 
Available from: http://clinicaltrials.gov/show/NCT01959607 NLM Identifier: 
NCT01959607. 
23. 
Philip Morris Products S.A. A single-center, randomized, controlled, crossover study 
to investigate the nicotine pharmacokinetic profile and safety of THS 2.2 Menthol 
following single use in smokers compared to menthol conventional cigarettes and 
nicotine gum [ZRHM-PK-05-JP]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): 
National Library of Medicine (US). 2013-2014 [cited 2016 Jan 03]. Available from: 
http://clinicaltrials.gov/show/NCT01967706 NLM Identifier: NCT01967706. 
24. 
Philip Morris Products S.A. A single-center, randomized, controlled, crossover study 
to investigate the nicotine pharmacokinetic profile and safety of THS 2.2 Menthol 
following single use in smokers compared to menthol conventional cigarettes and 
nicotine nasal spray [ZRHM-PK-06-US]. In: ClinicalTrials.gov [Internet]. Bethesda 
(MD): National Library of Medicine (US). 2013-2014 [cited 2015 Jun 16]. Available 
from: http://clinicaltrials.gov/show/NCT01967719 NLM Identifier: NCT01967719. 
25. 
Philip Morris Products S.A. A randomized, controlled, open-label, 3-arm parallel 
group, single center study to demonstrate reductions in exposure to selected smoke 
constituents in smoking, healthy subjects switching to the THS 2.2 or smoking 
abstinence, compared to continuing to use conventional cigarettes, for 5 days in 
confinement (ZRHR-REXC-03-EU). In: ClinicalTrials.gov [Internet]. Bethesda 
(MD): National Library of Medicine (US). 2013-2014 [cited 2015 Jun 16]. Available 
from: http://clinicaltrials.gov/show/NCT01959932 NLM Identifier: NCT01959932. 
26. 
Philip Morris Products S.A. A controlled, 3-arm parallel group study to demonstrate 
reductions in exposure to smoke constituents in smoking subjects switching to THS 
2.2 or to smoking abstinence, compared to smoking conventional cigarettes for 5 days 
in confinement [ZRHR-REXC-04-JP]. In: ClinicalTrials.gov [Internet]. Bethesda 
(MD): National Library of Medicine (US). 2013-2014 [cited 2015 Jun 16]. Available 
from: http://clinicaltrials.gov/show/NCT01970982 NLM Identifier: NCT01970982. 
27. 
Philip Morris Products S.A. Reduced exposure study using the Tobacco Heating 
System 2.2 (THS 2.2) Menthol for 91 days in confinement and ambulatory [ZRHM-
REXA-08-US]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of 
Medicine (US). 2013-2015 [cited 2015 Jun 16]. Available from: 
http://clinicaltrials.gov/show/NCT01989156 NLM Identifier: NCT01989156. 
28. 
Philip Morris Products S.A. A randomized, controlled, multi-center study to 
demonstrate reductions in exposure to selected smoke constituents in smokers 
switching to THS 2.2 Menthol or smoking abstinence compared to smoking menthol 
conventional cigarettes, for 90 days [ZRHM-REXA-07-JP]. In: ClinicalTrials.gov 

Philip Morris Products SA 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
 
[Internet]. Bethesda (MD): National Library of Medicine (US). 2013-2014 [cited 
2015 Jun 16]. Available from: http://clinicaltrials.gov/show/NCT01970995 NLM 
Identifier: NCT01970995. 
29. 
Ludicke F, Picavet P, Baker G, et al. Effects of switching to the Tobacco Heating 
System 2.2 menthol, smoking abstinence, or continued cigarette smoking on 
biomarkers of exposure: a randomized, controlled, open-label, multicenter study in 
sequential confinement and ambulatory settings (part 1). Nicotine & tobacco research 
: official journal of the Society for Research on Nicotine and Tobacco. 2017. 
30. 
Philip Morris Products S.A. Evaluation of biological and functional changes in 
healthy Smokers after switching to THS 2.2 for 26 weeks [ZRHR-ERS-09-US]. In: 
ClinicalTrialsgov [Internet] Bethesda (MD): National Library of Medicine (US) 
2015- [cited 2015 Aug 26] Available from: 
https://clinicaltrialsgov/ct2/show/NCT02396381?term=NCT02396381&rank=1 NLM 
Identifier: NCT02396381. 
31. 
Philip Morris S.A. A 26-week extension of the ZRHR-ERS-09-US study evaluating 
biological and functional changes in healthy smokers after switching to THS 2.2 
[ZRHR-ERS-09-EXT-US]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): 
National Library of Medicine (US). 2015- [cited 2016 Jun 01]. Available from: 
http://clinicaltrials.gov/show/NCT02649556 NLM Identifier: NCT02649556. 
32. 
Philip Morris Products S.A. 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 THS 2.2 Tobacco Heating System [P1-PMC-01-JP]. In: 
ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 
2016- [cited 2017 Jan 16]. Available from: 
https://clinicaltrials.gov/ct2/show/NCT03020667 NLM Identifier: NCT03020667. 
33. 
Japanese Circulation Society Joint Working Group. Guidelines for smoking cessation 
(JCS 2010) - Digest version. Availble from: 
https://www.jstage.jst.go.jp/article/circj/76/4/76_CJ-88-0021/_pdf (Accessed on 14 
July 2017=. Circulation journal : official journal of the Japanese Circulation Society. 
2012;76(4):1024-1043. 
34. 
Ministry of Health, Labour and Welfare. [Smoking cessation support manual (2nd 
edition)] Japanese. 2013; Available from: http://www.mhlw.go.jp/topics/tobacco/kin-
en-sien/manual2/dl/manual2.pdf (Accessed on 14 July 2017). 
35. 
Cayne NS, Veith FJ, Lipsitz EC, et al. Variability of maximal aortic aneurysm 
diameter measurements on CT scan: significance and methods to minimize. Journal 
of vascular surgery. 2004;39(4):811-815. 
36. 
Philip Morris Products S.A. Unpublished on file data: Summary of product 
information (SPI) - iQOS with HeatSticks. Version 6.0. 2019. 

Philip Morris Products SA 
Assessment Study Protocol 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
 
37. 
Schaller JP, Pijnenburg JP, Ajithkumar A, Tricker AR. Evaluation of the Tobacco 
Heating System 2.2. Part 3: influence of the tobacco blend on the formation of 
harmful and potentially harmful constituents of the Tobacco Heating System 2.2 
aerosol. Regulatory toxicology and pharmacology : RTP. 2016;Suppl 2. Available 
from: http://www.sciencedirect.com/science/article/pii/S0273230016303051 
(Accessed on 03 May 2017):S48-58. 
38. 
Schaller J-P, Keller D, Poget L, et al. Evaluation of the Tobacco Heating System 2.2. 
Part 2: Chemical composition, genotoxicity, cytotoxicity, and physical properties of 
the aerosol. Regulatory Toxicology and Pharmacology. 2016;Suppl 2. Available 
from: http://www.sciencedirect.com/science/article/pii/S0273230016302902 
(Accessed on 03 May 2017):S27-47. 
39. 
Raw M, Anderson P, Batra A, et al. WHO Europe evidence based recommendations 
on the treatment of tobacco dependence. Tobacco control. 2002;11(1):44-46. 
40. 
ICH E2A. Clinical safety data management: definitions and standards for expedited 
reporting - Guideline. 1994; Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
2A/Step4/E2A_Guideline.pdf (Accessed on 17 July 2014). 
 

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Appendix 1 
Schedule of Events 
 
 
Screening 
Visit 
Baseline 
Investigational Period 
Visit (time 
window) 
Visit 1 
Visit 2 
Visit 3 
(± 14 
days) 
Visit 4 
(± 14 
days) 
Visit 5 
(± 14 
days) 
Visit 6 
(± 14 
days) 
Visit 7 
(± 14 
days) 
Visit 8 
(± 14 
days) 
Study Month 
Day -28 to 
Day -1 
Day 1 
 6 
months  
after 
Visit 2 
12 
months 
after 
Visit 2  
18 
months 
after 
Visit 2 
24 
months 
after 
Visit 2 
30 
months 
after 
Visit 2 
36 
months 
after 
Visit 2 
Informed consent 
for study 
participation  
● 
 
 
 
 
 
 
 
Information on the 
risk of smoking, SC 
advice a  
● 
● 
● 
● 
● 
● 
● 
● 
IQOS 
demonstration b 
● 
 
 
 
 
 
 
 
Debriefing on 
IQOS  
for smoking 
patients only 
● 
● 
● 
● 
● 
● 
● 
● 
Inclusion/exclusion 
criteria  
● 
● 
 
 
 
 
 
 
Readiness to 
comply with study 
protocol 
● 
● 
 
 
 
 
 
 
Enrollment c 
 
●  
 
 
 
 
 
 
Randomization 
procedures 
 
● 
 
 
 
 
 
 
Allocation to study 
arms d 
 
● 
 
 
 
 
 
 
Distribution of 
Diary 
 
● 
 
 
 
 
 
 
Demographics,  
medical history 
(including history 
of  recent and 
current alcohol and 
substance abuse) 
● 
 
 
 
 
 
 
 
Concomitant 
diseases at V1, and 
follow-up of 
● 
● 
● 
● 
● 
● 
● 
● 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
 
 
Screening 
Visit 
Baseline 
Investigational Period 
Visit (time 
window) 
Visit 1 
Visit 2 
Visit 3 
(± 14 
days) 
Visit 4 
(± 14 
days) 
Visit 5 
(± 14 
days) 
Visit 6 
(± 14 
days) 
Visit 7 
(± 14 
days) 
Visit 8 
(± 14 
days) 
Study Month 
Day -28 to 
Day -1 
Day 1 
 6 
months  
after 
Visit 2 
12 
months 
after 
Visit 2  
18 
months 
after 
Visit 2 
24 
months 
after 
Visit 2 
30 
months 
after 
Visit 2 
36 
months 
after 
Visit 2 
concomitant 
diseases after V1 
Previous 
medication/Concom
itant medication 
● 
● 
● 
● 
● 
● 
● 
● 
Questions about 
smoking 
history/habits 
● 
 
 
 
 
 
 
 
Intention to quit 
smoking in the next 
6 months  
● 
● 
 
 
 
 
 
 
Tobacco or 
nicotine-containing 
product use self-
reporting (1 month 
retrospective) 
 
 
● 
● 
● 
● 
● 
● 
Urine: Pregnancy 
test (all females) e 
● 
● 
● 
● 
● 
● 
● 
● 
Urine cotinine 
screening test in 
smoking patients f 
● 
● 
 
 
 
 
 
 
Urine cotinine 
screening test in 
former smokers g  
● 
● 
 
 
 
 
 
 
Vital signs h  
● 
● 
● 
● 
● 
● 
● 
● 
Physical 
examination 
● 
● 
● 
● 
● 
● 
● 
● 
Body height and 
weight i   
● 
● 
● 
● 
● 
● 
● 
● 
Waist 
circumference j   
● 
● 
● 
● 
● 
● 
● 
● 
Electrocardiogram 
● 
 
 
● 
 
● 
 
● 
Chest X-ray k   
● 
 
 
 
 
 
 
 
Retrospective CT 
scan evaluation 
● 
 
 
 
 
 
 
 

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disclosed without the written consent of Philip Morris Products S.A. 
 
 
Screening 
Visit 
Baseline 
Investigational Period 
Visit (time 
window) 
Visit 1 
Visit 2 
Visit 3 
(± 14 
days) 
Visit 4 
(± 14 
days) 
Visit 5 
(± 14 
days) 
Visit 6 
(± 14 
days) 
Visit 7 
(± 14 
days) 
Visit 8 
(± 14 
days) 
Study Month 
Day -28 to 
Day -1 
Day 1 
 6 
months  
after 
Visit 2 
12 
months 
after 
Visit 2  
18 
months 
after 
Visit 2 
24 
months 
after 
Visit 2 
30 
months 
after 
Visit 2 
36 
months 
after 
Visit 2 
from the 30 months 
prior to V1 l 
CT for abdominal 
aorta m 
● 
 
● 
● 
● 
● 
● 
● 
Record of the date 
when the decision 
of an open surgical 
AAA treatment or 
AAA endovascular 
repair is made 
 
 
● 
● 
● 
● 
● 
● 
Blood/Urine: 
Hematology, 
clinical chemistry, 
urine analysis n  
● 
● 
● 
● 
● 
● 
● 
● 
Urine: Total 
NNAL, Total NNN, 
NEQ, CEMA, 
creatinine in spot 
urine 
 
● 
● 
● 
● 
● 
● 
● 
AE/SAE recording 
o 
● 
● 
● 
● 
● 
● 
● 
● 
Abbreviations: AAA = Abdominal Aortic Aneurysm; AE = Adverse event; CEMA = 2-Cyanoethylmercapturic 
Acid; CT = Computed Tomography; NEQ = nicotine equivalents, consisting of the molar sum of free nicotine, 
nicotine-glucuronide, free cotinine, cotinine-glucuronide, free trans-3’-hydroxycotinine and trans-3’-
hydroxycotinineglucuronide; NNAL = 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol; NNN = N-
nitrosonornicotine; SAE = Serious adverse event; SC = Smoking Cessation 
a: Information on the risk of smoking and SC advice will be provided at every visit.  
b: IQOS demonstration will be given to smoking patients only. For females, the demonstration will take place 
only after negative pregnancy test. 
c: SC, IQOS, and CC arm = Enrollment at V2. 
d: SC, IQOS and CC arm at V2. 
e: Except post-menopausal women. The post-menopause is formally defined as the time after which a woman 
has experienced 12 consecutive months of amenorrhea (lack of menstruation) without a period. If a woman 
claims she is post-menopausal, but has had her menses within 12 months, a follicle stimulating hormone test 
must be performed and must be within acceptable limits of the post-menopausal status. 

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disclosed without the written consent of Philip Morris Products S.A. 
 
f: The cut-off value of urine cotinine Screening test in all smoking patients eligible for the CC and IQOS arms: 
≥ 200 ng/ml. 
g: The cut-off value will be < 100 ng/ml for former smoker patients eligible for the SC arm.  
h: Systolic and diastolic blood pressure, pulse rate, and respiratory rate. Systolic and diastolic blood pressure 
will also be analyzed as cardiovascular risk factors at Visit 2 to Visit 8. 
i: Including height (only at the Screening Visit). Body weight will also be analyzed as cardiovascular risk 
factor at Visit 2 to Visit 8. 
j: Waist circumference will also be analyzed as cardiovascular risk factor at Visit 2 to Visit 8. 
k: Chest X-ray performed within 6 months prior to V1 will be used for checking eligibility. If chest X-ray has 
not been performed, then it has to be performed.  
l: All patients (SC arm, IQOS and CC arm) at V1. 
m: CT scan made at V1 will be send to central reading site to provide the current the maximum minor-axis 
AAA diameter for assessment of eligibility at V2. The CT scan is recommended to be made as the last 
assessment at the end of V1 which can also be scheduled after V1.  
n: Samples have to be taken after at least 10 hours of fasting, except at V1. 
o:  Spontaneous reporting of new AEs/SAEs by the patients and follow-up of ongoing AEs/SAEs by the site, as 
described in section 8. 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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disclosed without the written consent of Philip Morris Products S.A. 
 
Appendix 2 
Participating Laboratories 
The following laboratories will be used in the study: 
Laboratory for analysis of NEQ, total 
NNAL, total NNN, CEMA, and 
creatinine in urine: 
  
 
Lincoln, NE 68502  
USA 
 
Switzerland:  
  
  
8320 Fehraltorf  
Switzerland 
 
(referred to as 
) 
Laboratory for the assessment of 
clinical chemistry, hematology, and 
urine analysis in the safety panel 
 
 
 
  
Tokyo 101-8517 
Japan 
 
Telephone +81-
 
Appendix 3 
Investigational Product and Instructions for Use 
The product user guide will be provided as a separate document.  
Appendix 4 
Standard protocol to assess the maximum minor-axis 
AAA diameter from the CT scan 
The standard protocol to assess the maximum minor-axis AAA diameter from the CT scan will 
be provided in a separate document. 
Appendix 5 
List of Investigators and Study Sites 
The list of Investigators and study sites will be provided in a separate document.