A 26-week Extension Study to Determine the Biological and Functional Changes in Healthy Smokers Who Switched From Conventional Cigarettes (CC) to Tobacco Heating System 2.2 (THS 2.2) Compared to Those Who Continued to Smoke CC in the ZRHR-ERS-09-US Study
Phase: NA
Conditions: Smoking
Sponsor: Philip Morris Products S.A.



Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 2 of 115 
 
 
SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
 
Product Name:  
Tobacco Heating System 2.2 (THS 2.2) 
Study Title: 
A 26 week extension study to determine the biological and functional changes in healthy 
smokers who switched from conventional cigarettes (CC) to Tobacco Heating System 2.2 
(THS 2.2) compared to those who continued to smoke CC in the ZRHR-ERS-09-US study. 
Study Number: 
ZRHR-ERS-09-EXT-US 
Short Study Title: 
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. 
Primary Objective and Endpoints: 
The primary objective of this study is: 
1. To determine the changes to the selected clinical risk endpoints (“smokers’ health 
profile”) in smokers who have switched from CC to THS 2.2 as compared to those who 
continued to smoke CC during the extension study. 
Endpoints included in the “smokers’ health profile” measured at V16 (Week 52): 
• High density lipoprotein cholesterol (HDL-C) in serum. 
• White blood cell total count (WBC) in blood. 
• Soluble intercellular adhesion molecule 1 (sICAM-1) in serum. 
• 11-dehydrothromboxane B2 (11-DTX-B2) in urine (expressed as concentration 
adjusted for creatinine). 
• 8-epi-prostaglandin F2α (8-epi-PGF2α) in urine (expressed as concentration adjusted 
for creatinine). 
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
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Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 3 of 115 
 
 
• Carboxyhemoglobin (COHb) in blood. 
• Forced expiratory volume in 1 second (FEV1 post-bronchodilator, expressed as % 
predicted [FEV1 %pred]). 
• Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL) in urine 
(expressed as concentration adjusted for creatinine). 
Secondary Objectives and Endpoints: 
The secondary objectives of this study are: 
2. To evaluate self-reported product use (CC and THS 2.2) over the duration of the study. 
Endpoint (measured daily): 
• Number of CC or THS Tobacco Sticks used daily as reported in the self-reported 
product use electronic diary. 
3. To determine the reduction in exposure to harmful and potentially harmful constituents 
(HPHCs) in smokers who have switched from CC to THS 2.2 as compared to those who 
continued to smoke CC. 
Endpoints  at V16 (Week 52): 
• Biomarker of exposure (BoExp) to carbon monoxide (CO): CO in exhaled breath 
(expressed as ppm). 
• BoExp to N-nitrosonornicotine: total N-nitrosonornicotine (total NNN) in urine 
(expressed as concentration adjusted for creatinine). 
4. To determine the levels of nicotine exposure in smokers who have switched from CC to 
THS 2.2 as compared to those who have continued to smoke CC. 
Endpoints (BoExp to nicotine) over the duration of the study: 
• Nicotine equivalent (Neq): molar sum of free nicotine, nicotine-glucuronide, free 
cotinine, cotinine-glucuronide, free trans-3’-hydroxycotinine, trans-3’-
hydroxycotinine-glucuronide in urine (expressed as concentration adjusted for 
creatinine). 
• Nicotine and cotinine in plasma expressed in ng/mL. 
5. To describe the changes of biological or functional markers associated with respiratory 
diseases and cardiovascular diseases (CVD) in smokers who have switched from CC to 
THS 2.2 as compared to those who have continued to smoke CC. 
Endpoints associated with respiratory diseases measured at V16 (Week 52):  
• Lung function:  
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
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Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 4 of 115 
 
 
• Spirometry pre- and post-bronchodilator: FEV1, forced vital capacity (FVC), 
FEV1/FVC, forced expiratory flow (FEF 25-75) and bronchodilator reversibility in 
FEV1. 
• Lung volume pre-bronchodilator: forced residual capacity (FRC), vital capacity 
(VC), total lung capacity (TLC), and inspiratory capacity (IC). 
• Cough symptoms (intensity and frequency), amount of sputum production, and 
bothersomeness of cough symptom from the cough questionnaire. 
Endpoints associated with CVD measured at V16 (Week 52): 
• Myeloperoxidase (MPO), apolipoprotein A1 and B (Apo A1 and Apo B), high 
sensitivity C-reactive protein (hsCRP), and low density lipoprotein cholesterol 
(LDL-C), in serum. 
• Fibrinogen and homocysteine in plasma. 
• Albumin in urine (expressed as concentration adjusted to creatinine). 
• Platelet count and hemoglobin glycosylated (HbA1c in whole blood). 
• Blood pressure, weight, and waist circumference. 
6. To describe the changes in subjective effects of smoking in smokers who have switched 
from CC to THS 2.2 as compared to those who have continued to smoke CC. 
Endpoint over the duration of the study: 
• Product evaluation: subscales from the modified cigarette evaluation questionnaire 
(MCEQ). 
7. To describe the intention to use THS 2.2 in smokers who have switched from CC to 
THS 2.2. 
Endpoint at V16 (Week 52): 
• Intention to use associated with THS 2.2: item scores from intent to use 
questionnaire for THS 2.2 (ITUQ) only for subjects in the THS 2.2 arm. 
8. To describe the change in tobacco dependence in smokers switching from CC to 
THS 2.2 as compared to those continuing to smoke CC. 
Endpoints at V16 (Week 52): 
• Score from the Fagerström (FTND) questionnaire. 
• Time to first cigarette from the FTND questionnaire. 
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 5 of 115 
 
 
9. To describe the effect of combined product use (dual use) over the study on the 
components of the “smokers’ health profile”.  
Endpoint:  
• The levels of the components in the “smokers’ health profile” and the number of CC 
and THS Tobacco Sticks used daily as reported on the self-reported product use 
electronic diary.  
10. To evaluate the safety profiles associated with THS 2.2 and CC. 
Endpoints over the duration of the study: 
• Adverse events (AEs), serious adverse events (SAEs) and device events, including 
THS 2.2 malfunction/misuse. 
• Vital signs. 
• Electrocardiogram (ECG). 
• Clinical chemistry, hematology and urine analysis safety panel. 
• Physical examination. 
• Concomitant medications. 
 
Study Hypothesis: 
No hypotheses are to be tested. The objective of the study is to determine the effect of 
THS 2.2 compared to CC at week 52 on the components of the “smokers’ health profile” as 
defined by PMI (Table S1), and to provide additional information to the results of the 
original study (ZRHR-ERS-09-US) for a prolonged exposure period.  
Table S1 
The “Smokers’ Health Profile” 
Biomarker 
Measurement of 
Biofluid/Function 
Cardiovascular Disease 
High density lipoprotein cholesterol  
Lipid metabolism 
Serum 
Soluble intercellular adhesion molecule 1  Endothelial dysfunction 
Serum 
White blood cell count  
Inflammation 
Blood 
Carboxyhemoglobin  
Transport of oxygen by 
hemoglobin 
Blood 
11-Dehydrothromboxane B2  
Platelet activation 
Urine 
8-epi-prostaglandin F2α 
Oxidative stress 
Urine 
Respiratory Disease 
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 6 of 115 
 
 
Forced expiratory volume in 1 second  
Lung function 
Lung function 
Genotoxicity 
Total 4-(methylnitrosamino)-1-(3-pyridyl)-
1-butanol  
Exposure to carcinogenic 
HPHC (NNK) 
Urine 
Evaluation criterion:  
The study will target to describe the 95% confidence intervals (CI) of the THS 2.2 effect as 
compared to CC at week 52 on the components of the “smokers’ health profile” estimated 
with a precision of ±75% of the anticipated THS 2.2 effect at week 52. 
Study Design: 
This study is a 26 week extension study of the original study (ZRHR-ERS-09-US), a 
randomized, controlled, open-label, 2-arm, parallel group study design conducted over a 26 
week period. This extension study will be conducted as a separate study, as a follow-up of 
the randomized exposure period of the original study, extending the exposure from V10 
(Week 26) to V16 (Week 52), but will be using the same sites. Subjects will continue to use 
the product they were randomized to in the original study (THS 2.2 arm or CC arm). 
The extension study will be an ad libitum smoking study with unrestricted product use for 
the duration of the study (including during site visits).  
End of Study for whole study is the last subject individual EOS. 
Subjects that terminate the study after enrollment and prior to completion of the extension 
study will undertake early termination procedures (section 9.4).  
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 8 of 115 
 
 
original study. If the subject withdraws or is removed from the study after enrollment, he/she 
will enter the safety follow up period of the extension study (section 9.3). 
The Extended Exposure Period (from Check-out of V10 [Week 26] until Check-out of V16 
[Week 52]): 
Enrolled subjects will continue to use the product they were randomized to in the original 
study (THS 2.2 arm or CC arm) in an ambulatory setting for an additional 26 weeks ad 
libitum, including during the visits. Subjects will continue to capture the number of each of 
the products used including THS Tobacco Sticks, CC (menthol and non-menthol), and other 
nicotine/tobacco containing products on a daily basis in a product use diary.  
After V10, subjects will be required to come for 6 monthly visits to the site for resupply of 
THS 2.2 (except for V16) and for safety assessments. The visits will be scheduled with a 
time window of +/- 5 days respective to V4 of the original study:  
• V11 (30 weeks after V4, 210 days +/- 5 days),  
• V12 (35 weeks after V4, 245 days +/- 5 days),  
• V13 (39 weeks after V4, 273 days +/- 5 days),  
• V14 (43 weeks after V4, 301 days +/- 5 days),  
• V15 (48 weeks after V4, 336 days +/- 5 days),  
• V16 (52 weeks after V4, 364 days +/- 5 days). 
At V15, containers to collect 24 hour urine will be distributed to the subjects. Twenty four-
hour urine collection will start in the morning of the day before V16 and will end 24 hours 
later on the morning of V16. At V16, blood and urine samples from the 24 hour urine 
collection will be collected by the site for the assessments of BoExp and clinical risk 
endpoints.  
Any subject, who wants to make a quit attempt from using tobacco-containing products (e.g. 
THS 2.2 and CC) during the study, will be encouraged to do so and will be referred to 
appropriate services. The subject will not be discontinued from the study, will come to all 
scheduled visits for assessments, and his/her financial compensation will not be affected. A 
subjects in the THS 2.2 arm, who decides to quit using tobacco-containing products (THS 
2.2 and CC), will return all the THS 2.2 components given during the study and will not be 
provided with THS 2.2 anymore, starting from the day the participant intends to quit 
onwards.  
The Safety Follow-up Period (from the Check-out of V16 (Week 52) plus 28 days): 
At the end of the extended exposure period (i.e., or study completion on V16), subjects will 
enter into a safety follow-up period for 28 days. During the safety follow-up period, 
spontaneously reported and ongoing AE/SAEs will be actively monitored by the site. The 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 9 of 115 
 
 
end of study (individual) is defined as the check-out of the subject on V16 or the date of 
early termination of the subject plus a 28 day safety follow-up period, if applicable.  For 
further information on safety follow-up requirements refer to section 9.3. 
Study Population and Main Criteria for Inclusion/Exclusion: 
All subjects who have completed the 26 week randomized exposure period (V10) of the 
original study will be potentially eligible for enrollment into the extension study, depending 
on whether or not they want to participate and if they meet the entry criteria.  
The maximum number of subjects that can be enrolled is pre-defined by the number of 
subjects completing the 26 week period of the original study. Entry criteria for enrollment 
into the extension study are listed below.  
Inclusion criteria:  
• Subject completed V10 of the original study (ZRHR-ERS-09-US). 
• The subject is willing to comply to study procedures and to continue to use the product 
he/she was allocated to during the original study (THS 2.2 or CC) for an additional 26 
weeks at V10. 
• Subject has given written informed consent to enter the 26 week extension study at V10. 
 
Exclusion Criteria: 
• As per judgment of the PI(s) or designee(s), the subject cannot participate in the study 
for any reason (e.g. medical, psychiatric and/or social reason).  
• Any medical conditions that in the opinion of the PI(s) or designee(s) would jeopardize 
the safety of the participant. 
• Subject has made a quit attempt from using tobacco-containing products (e.g. CC and 
THS 2.2) during the original study. 
• Pregnant or breast feeding female at V10. 
• Female who does not agree to use an acceptable method of effective contraception. 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 10 of 115 
 
 
Investigational Products: 
Test Product: 
Tobacco Heating System 2.2 (THS 2.2) which has three major parts: the THS Tobacco Stick, 
the THS Tobacco Stick Holder (Holder), and the Charger. 
Reference Product: 
Subject’s own supply of commercially available own brand CC (manufactured and hand-
rolled). CC will not be provided by the Sponsor. 
Duration of Study: 
The entire extension study duration per subject will be up to 26 weeks of exposure (6 
months) plus 28 days of safety follow-up. 
Statistical Methods: 
The analysis of the “Smokers’ Health Profile” at V16 will compare the two study arms 
according to subjects’ exposure (THS 2.2 or CC) with respect to: 
• Mean difference in each of the following endpoints: FEV1 %pred, HDL-C, and 
WBC at V16. 
• Ratio of the geometric mean levels of each of the following endpoints: 11-DTX-
B2, sICAM-1, 8-epi-PGF2α, COHb, and total NNAL at V16. 
The endpoints will be analyzed using a generalized regression model adjusting for site, sex, 
Baseline value of the endpoint and other endpoint specific covariates. The baseline values 
originate from the original study. 
Descriptive statistics for continuous variables (number of subjects [n], number and percent 
of subjects with missing data, the arithmetic mean, arithmetic standard deviation [SD], 
median, first and third quartiles, minimum and maximum for continuous data, including 
geometric mean and coefficient of variation for data analyzed in the log scale; frequency 
counts and percentages for categorical data) will be presented at each time point, where 
applicable. 
Analyses over time will be descriptive statistics of parameters at each assessment time point, 
together with mean difference from Baseline and 95% confidence intervals (CI). 
Safety will be summarized for the safety population according to study arm and according 
to product exposure. 
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
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Final Version 3.0 / 23 August 2016 
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Sample Size: 
The sample size for this study was defined based on the sample size requirements of the 
original study, for which the sample size was calculated to ensure an overall study power of 
at least 90% while maintaining at least 80% power to detect the expected effect of THS 2.2 
as compared to CC for each individual endpoint of the “Smokers’ health profile”, over 26 
weeks of exposure. This required 475 subjects randomized per group accounting for an 
anticipated 75% of the THS 2.2 arm to be Mostly THS 2.2 users (i.e. report at least 70% 
THS 2.2 use).  
Based on the assumptions that 30% of the 950 subjects will not be enrolled or will drop out 
from the extension study and a potential decrease from 75% to 50% of Mostly THS 2.2 users 
among subjects randomized to THS 2.2, the study will have at least 90% probability to 
determine the effect of THS 2.2 as compared to CC on FEV1 at V16 with a margin of error 
(95% CI) of at most ±1.5 %pred. The anticipated SD of 6.4 %pred was estimated using the 
results of the “Lung Health Study” [1]. 
Following our current understanding of product use data in the main study, the definition of 
the product use categories was redefined and the underlying assumptions re-evaluated so that 
approximately 60% of the subjects in the THS 2.2 arm are expected to be in the THS-use 
category, with an anticipated 20% of subjects dropping out or reporting insufficient product 
use data in the two arms of the main study. Based on the 65% rate of enrollment into the 
extension study observed among subjects randomized in the main study, the extension study 
will have more than 90% probability to determine the effect of THS-use compared to CC-use 
on FEV1 at V16 with a margin of error (95% CI) of at most ±1.5 %pred.  
 
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 12 of 115 
 
 
TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS .........................................................................................................12 
LIST OF IN-TEXT TABLES AND FIGURES .......................................................................15 
LIST OF APPENDICES ..........................................................................................................15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................16 
1 
ETHICS AND REGULATIONS .....................................................................................21 
1.1 
Institutional Review Board Approval ....................................................................21 
1.2 
Ethical Conduct of the Study .................................................................................22 
1.3 
Subject Information and Consent...........................................................................22 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................23 
2 
INTRODUCTION ...........................................................................................................25 
2.1 
Background ............................................................................................................25 
2.2 
Purpose of the Study ..............................................................................................26 
2.3 
Anticipated Benefits and Risks ..............................................................................27 
3 
STUDY OBJECTIVES ....................................................................................................29 
3.1 
Primary Objective and Endpoints ..........................................................................29 
3.2 
Secondary Objectives and Endpoints.....................................................................29 
4 
INVESTIGATIONAL PLAN ..........................................................................................32 
4.1 
Overall Study Design and Plan ..............................................................................32 
4.2 
Rationale for Study Design and Control Groups ...................................................34 
4.3 
Appropriateness of Measurements .........................................................................35 
4.4 
Study Duration .......................................................................................................35 
5 
STUDY POPULATION ..................................................................................................36 
5.1 
Selection of Study Population ................................................................................36 
5.2 
Discontinuation of Subjects from the Study ..........................................................37 
5.3 
Lost to Follow-up ...................................................................................................38 
5.4 
Violation of Selection Criteria ...............................................................................39 
6 
INVESTIGATIONAL PRODUCTS ...............................................................................40 
6.1 
Description of Investigational Products .................................................................40 
6.2 
Use of Investigational Products .............................................................................40 
6.3 
Method for Assigning Subjects to Study Arms .....................................................41 
6.4 
Blinding..................................................................................................................42 
6.5 
Investigational Product Accountability and Adherence ........................................42 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
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Final Version 3.0 / 23 August 2016 
Page 13 of 115 
 
 
6.6 
Restrictions ............................................................................................................43 
6.7 
Concomitant Medications ......................................................................................44 
7 
STUDY PROCEDURES .................................................................................................45 
7.2 
Information on the Risk of Smoking and Smoking Cessation Advice and 
Debriefing ..............................................................................................................45 
7.3 
Clinical Assessments .............................................................................................46 
7.4 
Biomarker Assessment...........................................................................................49 
7.5 
Laboratory Assessments ........................................................................................51 
7.6 
Sampling Handling and Storage ............................................................................52 
7.7 
Other Study Procedures .........................................................................................54 
8 
ADVERSE EVENTS .......................................................................................................57 
8.1 
Definitions..............................................................................................................57 
8.2 
Assessment of Adverse Events ..............................................................................57 
8.3 
Reporting and Follow-Up of Serious Adverse Events ...........................................60 
8.4 
Reporting of Other Events Critical to Safety Evaluations .....................................61 
8.5 
Reporting and Follow-Up of Pregnancies..............................................................62 
8.6 
Adverse Events Leading to Discontinuation..........................................................62 
8.7 
Investigational Device Misuse ...............................................................................62 
8.8 
Investigational Device Malfunction .......................................................................63 
9 
STUDY ACTIVITIES .....................................................................................................64 
9.1 
Visit 10 ...................................................................................................................64 
9.2 
Extended Exposure Period .....................................................................................65 
9.3 
Safety Follow-up Period ........................................................................................70 
9.4 
Early Termination Procedures ...............................................................................70 
10 CONTROL AND QUALITY ASSURANCE .................................................................72 
10.1 
Monitoring .............................................................................................................72 
10.2 
Training of Staff .....................................................................................................72 
10.3 
Audits and Inspections ...........................................................................................73 
11 DATA MANAGEMENT ACTIVITIES..........................................................................74 
11.1 
Data Capture ..........................................................................................................74 
12 PLANNED STATISTICAL METHODS ........................................................................76 
12.1 
General Considerations ..........................................................................................76 
12.2 
Determination of Sample Size and Power Consideration ......................................78 
12.3 
Product Use ............................................................................................................78 
12.4 
Analysis Population ...............................................................................................79 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
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Final Version 3.0 / 23 August 2016 
Page 14 of 115 
 
 
12.5 
Primary Analysis ....................................................................................................81 
12.6 
Secondary Analysis ................................................................................................83 
12.7 
Exploratory Analysis .............................................................................................85 
12.8 
Demographics and Baseline Characteristics ..........................................................85 
12.9 
Interim Analysis .....................................................................................................85 
13 ADMINISTRATIVE CONSIDERATIONS ....................................................................86 
13.1 
Study Administrative Structure..............................................................................86 
13.2 
Subject Confidentiality ..........................................................................................89 
13.3 
Access to Source Documents .................................................................................90 
13.4 
Record Retention ...................................................................................................90 
13.5 
Clinical Study Report .............................................................................................91 
13.6 
Financial Disclosure...............................................................................................92 
13.7 
Publication and Disclosure Policy .........................................................................92 
14 REFERENCE LIST .........................................................................................................93 
15 APPENDICES .................................................................................................................97 
 
 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
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Philip Morris Products SA 
Clinical Study Protocol 
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Final Version 3.0 / 23 August 2016 
Page 15 of 115 
 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1 
The “Smokers’ Health Profile” ..................................................................27 
Table 2 
Blinding Scheme ........................................................................................42 
Table 3 
Clinical Laboratory Parameters for Safety Panel .......................................51 
Table 4 
Time Schedule - V10 (Week 26) ...............................................................64 
Table 5 
Time Schedule – V11 (Week 30), V12 (Week 35), V13 (Week 39), 
V14 (Week 43), V15 (Week 48) ................................................................65 
Table 6 
Time Schedule - V16 (Week 52) ...............................................................67 
Table 7:                 Actual Product Use General Pattern Categories ........................................79 
 
Figure 1 
Study Design ................................................................................................7 
Figure 2 
Overall Study Design .................................................................................32 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events .....................................................................................97 
Appendix 2 
Concomitant Medication and Impact on Clinical Risk Endpoints (With 
Half-Lives) ...............................................................................................103 
Appendix 3 
Participating Laboratories ........................................................................109 
Appendix 4 
Investigational Product and Instructions for Use .....................................111 
Appendix 5 
Abnormal Laboratory Values ..................................................................112 
 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
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Final Version 3.0 / 23 August 2016 
Page 16 of 115 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
11-DTX-B2 
11-dehydro-thromboxane B2 
8-epi-PGF2α 
8-epi-prostaglandine F2 α 
ADL 
Activities of daily living 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
Apo A1 
Apolipoprotein A1 
Apo B 
Apolipoprotein B 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
B 
Blood sample required 
BMI 
Body mass index 
BoExp 
Biomarker(s) of exposure 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CC 
Conventional cigarette 
CD 
Compact disc 
CEMA 
2-cyanoethylmercapturic acid 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTCAE  
Common Terminology Criteria for Adverse Events and Common 
Toxicity Criteria 
CTMS 
Clinical trial management system 
CV (statistics) 
Coefficient of variation  
 
 
 
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hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
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CVD 
Cardiovascular disease 
DMP 
Data management plan 
ECG 
Electrocardiogram 
CRF 
Case report form 
ePRO 
Electronic patient reported outcome 
EOS 
End of study 
ERS 
Exposure Response Study 
FAS-EX 
Full analysis set – as exposed  
FAS-AR 
Full analysis set – as randomized 
FDA 
Food and Drug Administration  
FEF 
Forced expiratory flow 
FEV1 
Forced expiratory volume in 1 second 
FTND 
Fagerström test for nicotine dependence 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GVP 
Gas vapor phase 
HbA1c 
Hemoglobin glycosylated A1c 
HDL-C 
High density lipoprotein-C 
HIPAA 
Health Insurance Portability and Accountability Act 
HPHCs 
Harmful and potentially harmful constituents 
hsCRP 
High sensitive C-reactive protein 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IC 
Inspiratory capacity 
IOM 
Institute of Medicine 
IP 
Investigational product 
IRB 
Institutional Review Board 
 
 
 
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ISO 
International Organization for Standardization 
ITUQ 
Intent-to-use questionnaire 
IV 
Intravenous 
IXRS 
Interactive voice and web response system 
LDH 
Lactate dehydrogenase 
LDL-C 
Low density lipoprotein-cholesterol 
LLN 
Lower limit of the normal range 
LLOQ 
Lower limit of quantification 
MCEQ 
Modified cigarette evaluation questionnaire  
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measurements 
MRTP 
Modified risk tobacco product 
MPO 
Myeloperoxidase 
n 
Number of subjects 
Neq 
Nicotine equivalents 
NNAL 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
NNK 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 
NNN 
N-nitrosonornicotine 
NSAID 
Non-steroidal anti-inflammatory drug 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PMI 
Philip Morris International 
PP 
Per-protocol 
PT 
Preferred term 
QC 
Quality control 
RBC 
Red blood cell (count) 
 
 
 
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SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SES 
Socio-economic status (questionnaire)  
sICAM-1 
Soluble intercellular adhesion molecule-1 
SMP 
Safety management plan 
SOC 
System organ class 
SOP 
Standard operating procedure 
TC 
Total cholesterol 
TG 
Triglycerides 
THS 2.2 
Tobacco Heating System 2.2 
THSts 
THS Tobacco Stick 
TLC 
Total lung capacity 
TPM 
Total particulate matter 
U 
Urine sample required 
 
 
ULN 
Upper limit of the normal range 
ULOQ 
Upper limit of quantification 
USB 
Universal serial bus 
VAS 
Visual analog scale 
VC 
Vital capacity 
WBC 
White blood cell (count) 
WHO 
World Health Organization 
 
 
 
 
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Explanation of Terms 
The following special terms are used in this protocol: 
Original study 
Refers to the original study: ZHRH-ERS-09-US 
Extension study 
Refers to the extension study: ZHRH-ERS-09-EXT-US  
End 
of 
study 
(individual) 
Date of the last visit of the subject plus 28 days of Safety Follow-
up Period.  For subjects lost to follow-up the individual end of 
study is the discontinuation date. 
End of study (whole 
study) 
End of Study for whole study is the last subject individual EOS. 
Conventional cigarette 
(CC) 
The term “conventional cigarette” refers to commercially 
available cigarettes (manufactured and hand-rolled) and excludes 
cigars, pipes, bidis, and other nicotine-containing products. 
Screening failure 
Subjects who signed the informed consent form (ICF) at V10 but 
do not meet the entry criteria will be considered as screening 
failure. Once excluded, subject will not be allowed to re-enter the 
study. 
Tobacco Heating 
System 2.2 (THS 2.2) 
THS 2.2 comprises the following components: a THS Tobacco 
Stick, the THS Tobacco Stick Holder (Holder), a Charger, a 
Cleaning Tool, a main power supply, and a USB cable. 
 
 
 
 
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1 
ETHICS AND REGULATIONS 
1.1 
Institutional Review Board Approval 
Prior to the start of the study, the clinical study protocol, together with its associated documents 
(informed consent form [ICF] including the subject information sheet, subject recruitment 
procedures [e.g., advertisements], written information to be provided to the subjects, 
Investigator’s brochure [IB], available safety information, curriculum vitae of the Principal 
Investigator(s) (PI(s)) and designee(s) and/or other evidence of qualifications and any other 
documents requested by an Institutional Review Board [IRB]), will be submitted for review 
and approval to the relevant IRB according to the appropriate provisions found in 21 Code of 
Federal Regulations (CFR) part 50 (“Informed Consent of Human Subjects”) and 21 CFR part 
56 (“Institutional Review Boards”). The IRB shall be appropriately constituted and perform its 
functions in accordance with the International Conference on Harmonization (ICH) Tripartite 
Guidance for Good Clinical Practice (GCP) [2] and local requirements, as applicable. 
In accordance with GCP and 21 CFR part 56, a written confirmation of the IRB approval 
should be provided to the Sponsor. This should identify the study (name of the PI(s) and 
designee(s), study number, and title) and the documents that have been approved by the IRB, 
with dates and version numbers, as well as the date of approval. The composition of the IRB, 
including the name and occupation of the chairperson, will be supplied to the Sponsor together 
with a GCP compliance statement. 
The written approval from the IRB will be filed in the Principal Investigator file, and a copy 
will be filed in the study master file at the Sponsor or designated organization. The study must 
not start at a site before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IRB. 
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the Principal Investigator(s). All amendments will 
be submitted to the IRB, and substantial amendments will only be implemented after approval 
by the IRB. 
These requirements for approval should in no way prevent any action from being taken by the 
PI(s) or designee(s) or by the Sponsor in order to eliminate immediate hazards to the subjects. 
If such a change to the protocol is felt to be necessary by the PI(s) or designee(s), and is 
implemented for safety reasons, the Sponsor and the IRB should be informed immediately. 
The PI(s) is (are) responsible for local reporting (e.g., to the IRB) of serious adverse events 
(SAEs) that occur during the study, according to local regulations. 
Relevant safety information will be submitted to the IRB during the course of the original and 
the extension studies in accordance with national regulations and requirements. Medically 
qualified study personnel will be available during the study. 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
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1.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki [3] and are consistent with ICH/GCP [2] applicable regulatory 
principles. 
The PI(s) or designee(s) agree(s) to conduct the clinical study in compliance with the protocol 
agreed with the Sponsor and approved by the IRB. The PI(s) and the Sponsor must sign the 
protocol (and protocol amendments, if applicable) to confirm this agreement. A copy of the 
Declaration of Helsinki is located in the Investigator’s study file. 
1.3 
Subject Information and Consent 
1.3.1 
Informed Consent Form for Study Participation 
During V10 of the extension study, the PI(s) or designee(s) will ensure that each subject is 
given full and adequate oral and written information about the nature, purpose, possible risks 
and benefits of the extension study, and the PI(s) or the designee(s) will answer all questions 
the subject might have to his/her full satisfaction. The subject will have sufficient time for 
consideration of his/her participation in the study and will be notified that he/she is free to 
withdraw from the study at any time.   
Once the subject has received all the necessary information, and if he/she agrees to participate 
in the study, the subject and the person who conducted the inform consent discussion during 
V10 will both sign, date and time the ICF. The ICF includes both the subject information sheet 
and informed consent. No study-specific procedures will be performed before the ICF has been 
signed (including date and time).  
The original, dated and signed ICF(s) must be kept by the PI(s) and filed in the Principal 
Investigator’s file at the site or with the subject’s files and a copy must be given to the subject. 
The subject will be informed that if he/she 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 disagrees. The subject will be informed that 
additional data analysis not mentioned in the protocol or in the statistical analysis plan (SAP) 
might be performed with the collected data at a later time. Any additional analysis performed 
will be covered by data confidentiality, as for the main analysis described in this protocol. 
1.3.2 
Informed Consent Form for Long-term Biobanking 
In addition to the ICF for the participation in the extension study, only subjects who have 
previously provided consent for biobanking (and did not withdraw it) will be asked to provide 
his/her separate optional consent at V10 for the collection of samples and storage for long-term 
biobanking, which will be performed at V16: 
 
 
 
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• One separate ICF to obtain consent for serum, plasma and urine collection, and long-term 
storage for subsequent analysis of biomarkers of exposure (BoExp) and clinical risk 
endpoints following completion of this study.  
• One separate ICF to obtain consent for collection and long-term storage of blood and 
plasma for further analysis of transcriptomics and lipidomics respectively. 
Each subject will be given full and adequate oral and written information about the nature, 
purpose, possible risks and benefits of biobanking, and the PI(s) or designee(s) will answer all 
questions the subject might have until full satisfaction. The subject will be notified that he/she 
is free to withdraw his consent at any time. Once the subject has received all the necessary 
information, and if he/she agrees to participate, this will be documented by the date, time and 
signature of both, the subject and the PI(s) or designee(s) who conducted the informed consent 
discussion. The subject’s consent to collection of any samples for long-term storage in a 
biobank is not a requirement for his/her participation to the study (section 1.3.1). 
Collection of samples and storage for long-term biobanking performed at V10 is already part 
of the original study, and subjects should have signed the separate optional consent forms at 
V1. 
1.3.3 
Amendment to the Informed Consent Form 
If a protocol amendment is required, or if any new information regarding the risk profile of the 
investigational product (IP) becomes available for any other reason deemed necessary, an 
amendment to the ICF may be required. If a revision of the ICF is necessary, the PI(s) or 
designee(s) will, with the support of the Sponsor, ensure that the documents have been 
reviewed and approved by a relevant IRB before subjects are required to re-sign the ICF 
(including date and time). If new and important safety information is received, subjects who 
already completed or are discontinued from the study will be informed by letters, emails or 
phone calls. 
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, PI(s) or designee(s) abide by the principles of the ICH guidelines on GCP [2]. 
These guidelines apply specifically to pharmaceutical development, but nevertheless provide 
a robust and ethical framework for conducting clinical studies of tobacco products following 
the United States Food and Drug Administration (FDA) guidelines on modified risk tobacco 
product (MRTP) [4]. The study will also be conducted in accordance with the general ethical 
principles outlined in the Declaration of Helsinki [3]. 
 
 
 
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In addition, the PI(s) or designee(s) will carry out the clinical study in accordance with 
applicable national and local laws of the pertinent regulatory authorities. 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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2 
INTRODUCTION 
2.1 
Background 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy 
Cigarette smoking causes pulmonary, cardiovascular diseases and other serious diseases in 
smokers [5]. There is no safe cigarette and the best way for smokers to reduce the adverse 
health consequences of smoking is to quit. Despite the risks which are attributable to smoking, 
some smokers do not manage to quit or decide to continue smoking. To those smokers who 
are not able or not willing to quit, Philip Morris International (PMI) is developing alternative 
approaches by developing products with the potential to reduce the risks of tobacco-related 
diseases. These products are now referred by the FDA as modified risk tobacco products 
(MRTPs) [4]. 
Philip Morris International (PMI) develops candidate MRTPs with the objective to 
substantially reduce the exposure to harmful and potentially harmful constituents (HPHCs) 
while providing an acceptable option to smokers as substitutes for conventional cigarettes 
(CC). The approach to achieve this is by heating tobacco at lower temperatures rather than 
burning tobacco as it is the case for CC. In this way a large spectrum of HPHCs are eliminated 
or reduced, and the PMI clinical program aims to substantiate reduced risk for smoking-related 
diseases with the new heated tobacco products. 
A dose-response relationship exists between cigarette smoking exposure and smoking-related 
diseases such as chronic obstructive pulmonary disease (COPD), cardiovascular disease 
(CVD), and lung cancer. Several functional and biological markers (clinical risk endpoints) 
referring to smoking-related adverse health effects are favorably changed upon smoking 
cessation (SC) and are sufficiently sensitive to smoking status to be used for the risk assessment 
of our candidate MRTP, the Tobacco Heating System 2.2. (THS 2.2) As part of the global 
clinical program to assess the risk reduction using THS 2.2, a smoking cessation study of 1 
year duration (SA-SCR-01) is being conducted in parallel to the ZRHR-ERS-09-US study and 
its extension study, 2-arm parallel randomized studies comparing smokers switching from CC 
to THS 2.2 and smokers continuing smoking CC for 26 weeks and 52 weeks, respectively. The 
observed changes in the clinical risk endpoints and biomarkers of exposure after switching 
from CC to THS 2.2 will be compared to smoking abstinence for a total of 52 weeks (26 weeks 
+ 26 additional weeks) building the basis of the comparative risk assessment between THS 2.2 
and CC.  
2.1.2 
Description of the Product and Scientific Findings 
Thousands of chemicals - “smoke constituents” - are formed when tobacco is burned or 
combusted. More than 6000 smoke constituents have been identified [6], and more than 100 
of them have been categorized as HPHCs [7]. 
 
 
 
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The product developed by PMI, and to be assessed in this study, is the THS 2.2. With this 
product, the heating of the tobacco is maintained below 400°C, a temperature much lower than 
what is observed for CC, which can reach 900°C. THS 2.2 is composed of the THS Tobacco 
Stick Holder, dedicated special THS Tobacco Sticks made of tobacco, a Charger, and different 
accessories. The energy of the THS Tobacco Stick Holder is sufficient to maintain 
approximately a 6-minute session. Unlike CCs, the THS Tobacco Sticks do not burn down 
during their consumption and their lengths remain the same after use. 
The non-clinical assessment of THS 2.2 described in the Investigator’s brochure Edition 4 
(November 2014) supports the conduct of the clinical study ZRHR-ERS-09-US and its 
extension study[8]. No new or increased toxicological hazard in the product’s aerosol was 
detected compared with CC smoke. 
Several clinical studies have been conducted on THS 1.0, an earlier development version of 
THS 2.2, in Europe, Asia, Africa and the United States. All studies showed reductions in 
exposure to the majority of measured HPHCs from both aerosol fractions, total particulate 
matter (TPM) and gas vapor phase (GVP), in subjects using the THS 1.0 as compared to 
subjects continuing smoking CC, both, in controlled and ambulatory setting. THS 2.1, the 
immediate predecessor of the non-menthol THS 2.2, was tested in two exploratory clinical 
studies to measure the nicotine pharmacokinetic profile (PK) [9] and to assess the reduction of 
exposure to HPHCs when switching from CC to THS 2.1 [10]. The observed nicotine PK 
profile for THS 2.1 was similar to CC and there were significant reductions in the exposure to 
the majority of selected HPHCs [11]. In 2013, four clinical studies were initiated in US, 
Europe, and Japan in order to evaluate the nicotine PK profile, to demonstrate reduced 
exposure, and to determine functional and biological changes following the switching from 
CC to non-menthol THS 2.2 in smokers as compared to smokers continuing smoking CC.  
These studies are currently in different phases of finalization and the results will be 
incorporated in the next edition of the Investigator Brochure.  
Clinical studies conducted and ongoing so far on a few hundred of subjects revealed no safety 
concern for THS 2.2 and its earlier prototypes. 
2.2 
Purpose of the Study 
The objective of the study is to determine the effect of THS 2.2 compared to CC at week 52 
on the components of the “smokers’ health profile” as defined by PMI, (Table 1) to provide 
additional information to the results of the original study (ZRHR-ERS-09-US) for a prolonged 
period of time. 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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Table 1 
The “Smokers’ Health Profile” 
Biomarker 
Measurement 
Matrix/ 
Function 
Timeframe of 
Reversibility upon 
Smoking Cessation 
Cardiovascular Disease 
High density lipoprotein 
Cholesterol (reviewed in [12]) 
Lipid Metabolism 
Serum 
Within 3 months 
Soluble intercellular adhesion 
molecule-1 [13-15] 
Endothelial 
Dysfunction 
Serum 
Within 4 weeks 
White blood cell count (total count) 
[16-19] 
Inflammation 
Blood 
Within 6-12 months 
Carboxyhemoglobin [20, 21] 
Transport of 
oxygen by 
hemoglobin 
Blood 
Within 1-7 days 
11-Dehydrothromboxane B2 [22-
24] 
Platelet activation 
Urine 
Within 2-4 weeks 
8-epi-prostaglandin [25, 26] 
Oxidative stress 
Urine 
Within 1-2 weeks 
Respiratory Disease 
Forced expiratory volume in 1 
second [27-30] 
Lung function 
Lung 
function 
Within 6-12 months 
Genotoxicity 
Total 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol) [31, 32] 
Exposure to 
carcinogenic 
HPHC (NNK) 
Urine 
Within 3 months 
Additional clinical risk endpoints related to cardiovascular and respiratory diseases will be 
assessed in this study. 
2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
Advice on health risk associated with tobacco smoking and smoking cessation advice will be 
provided at each visit from V11 to V16. The advice will follow the recommendations of the 
U.S. Public Health Service [33, 34]. Subjects who are motivated to quit using tobacco-
containing products (e.g. THS 2.2 and CC) are to be referred for additional smoking cessation 
counselling.  
 
 
 
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2.3.2 
Anticipated Foreseeable Risks due to Study Procedures. 
• Risks related to blood sampling (e.g., excessive bleeding, fainting, hematoma, paresthesia 
or infection).  
• Risks related to drug application as part of testing procedures (i.e., spirometry with short-
acting bronchodilator).  
• Risk related to spirometry testing procedures (e.g., dizziness or fainting). 
2.3.3 
Anticipated Foreseeable Risks due to the Investigational Products 
(THS 2.2/CC) 
• Change in smoking habits due to study requirements and related concomitant symptoms, 
(e.g., craving, withdrawal symptoms). 
• All risks related to study procedures and IP will be explained in details to the subjects. 
Mitigation will include: 
• Using accepted research and scientific standards, (e.g., blood samples not to exceed 
local blood donation standards). 
• Medical assessment, management of all study participants with follow-up of those who 
have experienced an AE/SAE. 
2.3.4 
Unforeseeable Risks 
A substantial body of evidence already exists on the THS 2.2 and no safety concerns were 
reported. The possibility of unforeseeable events/risks will be explained again at V10 prior to 
signing the ICF of the extension study. Non-expected malfunction of THS 2.2 may lead to 
unforeseeable risks. Subjects will be informed that THS 2.2 is not demonstrated to be less 
harmful than CC. Mitigation will include close monitoring and medical supervision to detect 
any unforeseeable risk or safety signals at the earliest time possible. 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
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3 
STUDY OBJECTIVES 
3.1 
Primary Objective and Endpoints 
The primary objective of this study is: 
1. To determine the changes to the selected clinical risk endpoints (“smokers’ health profile”) 
in smokers who have switched from CC to THS 2.2 as compared to those who continued 
to smoke CC. 
Endpoints included in the “smokers’ health profile” measured at V16 (Week 52): 
• High density lipoprotein cholesterol (HDL-C) in serum. 
• White blood cell total count (WBC) in blood. 
• Soluble intercellular adhesion molecule 1 (sICAM-1) in serum. 
• 11-dehydrothromboxane B2 (11-DTXB2) in urine (expressed as concentration adjusted 
for creatinine). 
• 8-epi-prostaglandin F2α (8-epi-PGF2α) in urine (expressed as concentration adjusted for 
creatinine). 
• Carboxyhemoglobin (COHb) in blood. 
• Forced expiratory volume in 1 second (FEV1 post-bronchodilator, expressed as % 
predicted [FEV1 %pred]). 
• Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL) in urine (expressed 
as concentration adjusted for creatinine).  
3.2 
Secondary Objectives and Endpoints 
The secondary objectives of this study are: 
2. To evaluate self-reported product use (CC and THS 2.2) over the duration of the study. 
Endpoint (measured daily): 
• Number of CC or THS Tobacco Sticks used daily as reported in the self-reported 
product use electronic diary. 
3. To determine the reduction in exposure to HPHCs in smokers who have switched from CC 
to THS 2.2 as compared to those who continued to smoke CC. 
Endpoints at V16 (Week 52): 
• BoExp to CO: CO in exhaled breath (expressed as ppm). 
• BoExp to N-nitrosonornicotine: total N-nitrosonornicotine (total NNN) in urine 
(expressed as concentration adjusted for creatinine). 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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4. To determine the levels of nicotine exposure in smokers who have switched from CC to 
THS 2.2 as compared to those who have continued to smoke CC. 
Endpoints (BoExp to nicotine) over the duration of the study: 
• Nicotine equivalent (Neq): molar sum of free nicotine, nicotine-glucuronide, free 
cotinine, 
cotinine-glucuronide, 
free 
trans-3’-hydroxycotinine, 
trans-3’-
hydroxycotinine-glucuronide in urine (expressed as concentration adjusted for 
creatinine). 
• Nicotine and cotinine in plasma expressed in ng/mL. 
5. To describe the changes of biological or functional markers associated with respiratory 
diseases and cardiovascular diseases (CVD) in smokers who have switched from CC to 
THS 2.2 as compared to those who have continued to smoke CC. 
Endpoints associated with respiratory diseases measured at V16 (Week 52):  
• Lung function:  
• Spirometry pre- and post-bronchodilator: FEV1, forced vital capacity (FVC), 
FEV1/FVC, forced expiratory flow (FEF 25-75) and bronchodilator reversibility in 
FEV1. 
•  Lung volume pre-bronchodilator: forced residual capacity (FRC), vital capacity 
(VC), total lung capacity (TLC), and inspiratory capacity (IC). 
• Cough symptoms (intensity and frequency), amount of sputum production, and 
bothersomeness of cough symptom from the cough questionnaire. 
Endpoints associated with CVD measured at V16 (Week 52): 
• Myeloperoxidase (MPO), apolipoprotein A1 and B (Apo A1 and Apo B), high 
sensitivity C-reactive protein (hs-CRP), and low density lipoprotein cholesterol (LDL-
C), in serum. 
• Fibrinogen and homocysteine in plasma. 
• Albumin in urine (expressed as concentration adjusted to creatinine). 
• Platelet count and hemoglobin glycosylated (HbA1c in whole blood). 
• Blood pressure, weight, and waist circumference. 
6. To describe the changes in subjective effects of smoking in smokers who have switched 
from CC to THS 2.2 as compared to those who have continued to smoke CC. 
Endpoint over the duration of the study: 
• Product evaluation: subscales from the modified cigarette evaluation questionnaire 
(MCEQ). 
 
 
 
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7. To describe the intention to use THS 2.2 in smokers who have switched from CC to 
THS 2.2. 
Endpoint at V16 (Week 52): 
• Intention to use associated with THS 2.2: item scores from intent to use questionnaire 
for THS 2.2 (ITUQ) only for subjects in the THS 2.2 arm. 
8. To describe the change in tobacco dependence in smokers switching from CC to THS 2.2 
as compared to those continuing to smoke CC. 
Endpoints at V16 (Week 52): 
• Score from the Fagerström (FTND) questionnaire. 
• Time to first cigarette from the FTND questionnaire. 
9. To describe the effect of combined product use (dual use) over the study on the components 
of the “smokers’ health profile’.  
Endpoint:  
• The levels of the components in the “smokers’ health profile” and the number of CC 
and THS Tobacco Sticks used daily as reported on the self-reported product use 
electronic diary.  
10. To evaluate the safety profiles associated with THS 2.2 and CC. 
Endpoints over the duration of the study: 
• Adverse events (AEs), serious adverse events (SAEs) and device events, including THS 
2.2 malfunction/misuse. 
• Vital signs. 
• Electrocardiogram (ECG). 
• Clinical chemistry, hematology and urine analysis safety panel. 
• Physical examination. 
• Concomitant medications. 
 
 
 
 
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The V10 (Week 26): screening and enrollment into the extension  
V10 represents both the last visit of the main study as well as the first of the extension study. 
For subjects willing to participate in the extension study, it also corresponds to the first visit in 
the extension study. Once all V10 assessments from the original study have been performed, 
subjects will be offered to enter into the extension study. The enrollment can only take place 
at V10. 
Enrolled subjects will be informed to continue to use the product they were randomized to in 
the original study as follows: 
• THS 2.2 arm: use of THS 2.2 ad libitum. 
• CC arm: use of their own CC brand ad libitum. 
Subjects who do not sign the ICF for the extension study at V10, will enter the 28 day safety 
follow-up period of the original study. 
Subjects who sign the ICF for the extension study but do not meet the entry criteria will be 
considered as screening failure and will enter the 28 day safety follow-up period of the original 
study. If the subject withdraws or is removed from the study after enrollment, he/she will enter 
the safety follow up period of the extension study (section 9.3). 
 
The Extended Exposure Period (from Check-out of V10 [Week 26] until Check-out of V16 
[Week 52]): 
Enrolled subjects will continue to use the product they were randomized to in the original study 
(THS 2.2 arm or CC arm) in an ambulatory setting for an additional 26 weeks ad libitum, 
including during the visits. Subjects will continue to capture the number of each of the products 
used including THS Tobacco Sticks, CC (menthol and non-menthol), and other 
nicotine/tobacco containing products on a daily basis in a product use diary.  
After V10, subjects will be required to come for 6 monthly visits to the site for resupply of 
THS 2.2 (except for V16) and for safety assessments. The visits will be scheduled with a time 
window of +/- 5 days respective to V4 of the original study:  
• V11 (30 weeks after V4, 210 days +/- 5 days),  
• V12 (35 weeks after V4, 245 days +/- 5 days),  
• V13 (39 weeks after V4, 273 days +/- 5 days),  
• V14 (43 weeks after V4, 301 days +/- 5 days),  
• V15 (48 weeks after V4, 336 days +/- 5 days),  
• V16 (52 weeks after V4, 364 days +/- 5 days). 
 
 
 
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At V15, containers to collect 24 hour urine will be distributed to the subjects. Twenty four-
hour urine collection will start in the morning of the day before V16 and will end 24 hours 
later on the morning of V16. At V16, blood and urine samples from the 24 hour urine collection 
will be collected by the site for the assessments of BoExp and clinical risk endpoints.  
Any subject, who wants to make a quit attempt from using tobacco-containing products (e.g. 
THS 2.2 and CC) during the study, will be encouraged to do so and will be referred to 
appropriate services. The subject will not be discontinued from the study, will come to all 
scheduled visits for assessments, and his/her financial compensation will not be affected. A 
subjects in the THS 2.2 arm, who decides to quit using tobacco-containing products (e.g. THS 
2.2 and CC), will return all the THS 2.2 components he/she was given during the study and 
will not be provided with THS 2.2 anymore, starting from the day he/she intends to quit 
onwards.  
The Safety Follow-up Period (from the Check-out of V16 (Week 52) plus 28 days): 
At the end of the extended exposure period (i.e., or study completion on V16), subjects will 
enter into a safety follow-up period for 28 days. During the safety follow-up period, 
spontaneously reported and ongoing AE/SAEs will be actively monitored by the site. The end 
of study (individual) is defined as the check-out of the subject on V16 or the date of termination 
of the subject plus a 28 day safety follow-up period, if applicable. For further information on 
safety follow-up requirements refer to section 9.3. 
4.2 
Rationale for Study Design and Control Groups 
The extension study will be conducted as a follow-up of the randomized exposure period of 
the original study extending the exposure from V10 (Week 26) to V16 (Week 52).  
In conjunction with the original study, this extension study will: 
• Provide a perspective of product usage in a “real world setting” over a 52 week period, 
where smoking CC in addition to THS 2.2 is expected (dual use). 
• Determine the changes in the components of the “smokers’ health profile” upon THS 2.2 
use over a 52 week period. A particular interest will be given to FEV1, one of the endpoints 
of the “smokers’ health profile”, for which a time frame of 6 months to 3 years is expected 
to observe a favorable change. Additional clinical risk endpoints involved in the 
mechanism of smoking-related diseases will be studied to provide additional scientific 
evidence to strengthen the primary objective. 
The “smokers’ health profile” (Table 1), and used as co-primary endpoints in the original 
study, is a collection of eight, broad-ranging clinical risk endpoints, that together cover the 
biological processes, physiological systems, and mechanisms of actions that are known to 
contribute to smoking-related diseases. Many of the clinical risk endpoints included within the 
“smokers’ health profile” are also mentioned in the 2010 Surgeon General's Report “How 
 
 
 
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Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable 
Disease” [5]. 
Twenty four-hour urine is the standard method to measure the levels of excretion of BoExp 
and will be collected in this study. 
This study is designed as an ad libitum study without product use restriction in order to mimic 
as close as possible “real life” conditions. 
4.3 
Appropriateness of Measurements 
The clinical risk endpoints of the “smokers’ health profile” (Table 1) measured in the original 
and extension studies were selected based on the following criteria: 1) the availability of a 
validated analytical method; 2) measure is known to be directly or indirectly affected by 
smoking; 3) measure is readily reversible after smoking cessation/abstinence; 4) timeframe of 
reversibility of measure in the perspective of the study duration; 5) practicality/acceptability 
by subjects; 6) robustness of the method (rapid, simple, accurate). 
All other clinical risk endpoints or laboratory variables to be measured in these studies were 
selected based on the following criteria 1) the availability of a validated analytical method; 2) 
practicality/acceptability by subjects; 3) robustness of the method (rapid, simple, accurate); 4) 
their clinical relevance to support the primary objective. 
For the extension study a subset of BoExp was selected from the list of the original study, 
including exhaled CO, total NNN and nicotine (Neq in urine, and plasma nicotine and 
cotinine). Exhaled CO was selected to provide information to CO exposure in addition to 
COHb, as acute CO exposure is known to be related to cardiovascular diseases. Total NNN 
was selected based on its specificity to tobacco.  
Questionnaires used in these studies are available as validated questionnaires or will be 
validated before the study will be analyzed (except from questionnaires to assess cough). 
4.4 
Study Duration 
The entire extension study duration per subject will be up to 26 weeks (6 months) plus 28 days 
of safety follow-up.  
 
 
 
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5 
STUDY POPULATION 
5.1 
Selection of Study Population 
All subjects who have completed the 26 week randomized exposure period (V10) of the 
original study will be potentially eligible for enrollment into the extension study, depending 
on whether or not they want to participate and if they meet the entry criteria. 
The maximum number of subjects that can be enrolled is pre-defined by the number of subjects 
completing the 26 week period of the original study. The target population in the original study 
was approximately 950 female or male, healthy adult smokers. All races/ethnicities were 
considered eligible, although a quota was applied to subjects of Caucasian origin (Race is 
White and Ethnicity is Not Hispanic or Latino), as they should not represent more than 75% 
of the randomized subjects. 
5.1.1 
Inclusion Criteria 
At V10, each subject must meet the following criteria to be eligible to enter in the extension 
study: 
Inclusion Criteria 
Screening 
at V10 
1. Subject has completed V10 of the original study (ZRHR-ERS-09-US). 
X 
2. Subject has signed the ICF at V10 and is able to understand the 
information provided in the ICF. 
X 
3. The subject is willing to comply to study procedures and to continue to 
use the product he/she was allocated to during the original study 
(THS 2.2 or CC) for an additional 26 weeks. 
X 
5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the study: 
Exclusion Criteria 
Screening  
at V10 
1. As per judgment of the PI(s) or designee(s), the subject cannot 
participate in the study for any reason (e.g. medical, psychiatric and/or 
social reason).  
X 
 
 
 
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Exclusion Criteria 
Screening  
at V10 
2. Any medical conditions that in the opinion of the PI(s) or designee(s) 
would jeopardize the safety of the participant. 
X 
3. Subject has made a quit attempt* during the original study. 
X 
4. For women only: 
Subject is pregnant (does not have a negative pregnancy test at V10) or is 
breast feeding. 
X 
5. For women only : 
Subject does not agree to use an acceptable method of effective 
contraception**. 
X 
* From using tobacco-containing products (e.g. THS 2.2 and CC). This information will be captured from the original study. 
** e.g., Intrauterine device, intrauterine system, established use of oral/injectable/implantable/transdermal hormonal methods, 
barrier methods of contraception (condoms, occlusive caps) with spermicidal foam/gel/film/suppository, vasectomized 
partner(s), or true abstinence (periodic abstinence and withdrawal are not effective methods) from V10 until V16. 
Hysterectomy, tubal ligation, bilateral oophorectomy or post-menopausal status are reasons for not needing to use birth 
control. Post-menopausal status is defined as women who have not experienced menses for greater than 12 months.  
5.2 
Discontinuation of Subjects from the Study 
Discontinued subjects will include both subjects who withdraw from the study (subject’s 
decision) or subjects who are removed from the study. A subject can only be discontinued from 
the study after enrollment. 
Subjects will be informed that they are free to withdraw from the study (upon decision of the 
subject) at any time. Subjects should be questioned for the reason for withdrawal from the 
study, although they are not obliged to disclose it. If the subject withdraws from the study 
he/she will be asked to confirm at least the following points and this information will be fully 
documented by the PI(s) or designee(s): 
• If applicable, the subject still consents for long-term biobanking (2 ICFs). 
• Whether the subject requested withdrawal of Health Insurance Portability and 
Accountability Act (HIPAA) authorization. 
• The subject agrees to undertake the early termination procedures (section 9.4). 
When a subject is discontinued from the study, early termination procedures (section 9.4) are 
performed within a period of 5 days after the discontinuation date unless the subject refuses to 
perform the assessments. After the date of early termination visit, the subject will enter into 
 
 
 
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the 28 day safety follow-up period. In case an early termination visit is not performed, the 
subject will still enter into the 28 days Safety Follow-up period after the discontinuation date. 
Subjects must be discontinued from the study for any of the following reasons: 
• Withdrawal of informed consent. 
• Any AE or condition (including clinically relevant changes in a laboratory parameter), 
which at the discretion of the PI(s) or designee(s) no longer justifies the subject’s 
participation in this study.  
• Positive pregnancy testing (section 8.5). 
• The Sponsor or PI(s) or designee(s) terminates the study or the study terminates at a 
particular site. If the Sponsor or the PI(s) or designee(s) decides to prematurely terminate 
the study, the subject will be promptly informed. The PI(s) or designee(s) should report the 
fact and the reason in writing to the IRB. 
• Discontinuation is considered to be in the best interest of the subject or the other subjects 
as judged by the PI(s) or designee(s). 
Subjects may be discontinued from the study for the following reason: 
• Non-compliance to the study procedures based on the judgment of the PI(s) or designee(s). 
Use of any tobacco/nicotine containing product different from the allocated product during the 
extended exposure period, will not lead to the discontinuation of the subject from the study. 
Subjects that discontinue the study after enrollment will not be allowed to re-enter the study. 
5.3 
Lost to Follow-up 
The date of the last contact with the subject (e.g. last visit, last phone call) should be recorded 
in the source document.  
After the last contact, reasonable number of attempts to contact the subject (including written 
correspondence and phone calls) should be done and documented in the source documents by 
the site.  
Following the contact attempts, if the PI(s) or designee(s) decides to discontinue the subject 
with the reason of lost to follow-up, the discontinuation date will be recorded. The 
discontinuation date for the subject will be the date the subject was determined to be lost to 
follow-up and will correspond to the date of the end of study of the subject. If the site has lost 
track of the subject, the discontinuation date cannot exceed the maximum number of study 
days (XX), then the PI(s) or designee(s) will discontinue the subject with reason as lost to 
follow-up.  
 
 
 
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5.4 
Violation of Selection Criteria 
Any subject who is willing to participate in the extension study but do not meet the entry 
criteria of the extension study after signing the ICF at V10 will be considered as screening 
failure and will enter in the 28 day safety follow-up period of the original study. 
 
 
 
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6 
INVESTIGATIONAL PRODUCTS 
6.1 
Description of Investigational Products 
6.1.1 
Test Product 
THS 2.2 comprises the following components: a THS Tobacco Stick, a Holder, a Charger, a 
Cleaning Tool, a power supply, and a USB cable (see the user guide - Appendix 4): 
Charger:  
The function of the Charger is to recharge the Holder after use. It 
contains a battery with sufficient capacity to recharge the Holder 
for approximately 20 times.  
THS Tobacco Stick 
Holder (Holder): 
The function of the Holder is to heat the THS Tobacco Stick and 
to deliver an aerosol to the user. The electrical heating is powered 
from an internal battery, which delivers power for about 6 minutes 
(allowing complete use of a single THS Tobacco Stick). 
THS Tobacco Stick 
(Tobacco Stick): 
The THS Tobacco Stick contains tobacco which, when heated, 
generates an aerosol. It is custom-designed to be used with the 
Holder. 
The overall objective of the product design is to provide an acceptable alternative to current, 
adult smokers, in which the exposure to HPHCs in the aerosol is substantially reduced in 
comparison with CC. 
THS 2.2 will be provided by the Sponsor. 
6.1.2 
Reference Product / Baseline Product 
The subject’s own preferred brands of CC will be used as the reference product to THS 2.2. 
There will be no CC brand restriction. CCs will not be provided nor reimbursed by the Sponsor. 
6.1.3 
Packaging and Labeling 
For the THS Tobacco Sticks, the packs and cartons will be labeled “for investigational use 
only” and according to any additional local regulatory requirements. 
6.2 
Use of Investigational Products 
Subjects will not be requested or forced to smoke CC or to use THS 2.2 and will be free to stop 
using their allocated product (THS 2.2 or CC) at any time during the study. THS 2.2 will not 
be promoted for commercial distribution or test market. 
 
 
 
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6.2.1 
Extended Exposure Period 
Subjects will be instructed to use exclusively the product they were randomized to in the 
original study (THS 2.2 arm or CC arm) from check out of V10 until check out of V16. The 
use of THS 2.2 and CC will be allowed on site based on arm allocation. At the check-out of 
each ambulatory visit, subjects in the THS 2.2 arm will be instructed to continue using 
exclusively THS 2.2 until the check-out of V16. 
For subjects in the THS 2.2 and CC arms, the use of other tobacco/nicotine containing products 
will be allowed including during the visits. However, for subjects in the CC arm, the use of 
THS 2.2 will not be allowed. 
From V10 to V15, enrolled subjects in the THS 2.2 arm will be provided with a sufficient 
amount of THS Tobacco Sticks to cover their needs until the next visit; they will be requested 
to bring back THS 2.2 components including the unused and partially used packs of THS 
Tobacco Sticks at each ambulatory visit.  
Any subject, who wants to make a quit attempt from using tobacco-containing products (e.g. 
THS 2.2 and CC) during the study will be encouraged to do so and will be referred to 
appropriate services. The subject will not be discontinued from the study, will come to all 
scheduled visits for assessments, and his/her financial compensation will not be affected. 
Subjects in the THS 2.2 arm who decide to quit using tobacco-containing products (e.g. THS 
2.2 and CC) will not be provided with THS 2.2 anymore, starting from the day they intend to 
quit onwards. 
6.2.2 
Stopping Rules for Investigational Product 
For safety purposes, smoking and THS 2.2 use should be temporarily stopped in the event of 
any signs suggesting nicotine overexposure, (e.g., gastrointestinal disturbance [nausea, 
vomiting, diarrhea, stomach or abdominal pain], cold sweats, headache, dizziness, and 
breathing problems) or any reasons at the discretion of the PI(s) or designee(s). If the study 
product is discontinued, the reasons for discontinuation will be documented in the source 
documents and subjects will undertake early termination procedures (section 9.4). 
6.2.3 
Safety Follow-up Period 
There will be no restrictions of CC use during the safety follow-up period. 
6.3 
Method for Assigning Subjects to Study Arms 
During the extension study, subjects will remain in the study arm they were randomized to in 
the original study (THS 2.2 arm or CC arm in a 1:1 ratio).  
Randomization was done during the original study at V4 through the interactive voice and web 
response system (IXRS).  
 
 
 
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6.4 
Blinding 
This is an open-label study; the subjects and PI(s) or designee(s) were unblinded to the 
subject’s study arm after randomization at V4 during the original study.  
However, and similarly to the original study there will be a limited degree of blinding during 
the conduct of the extension study, including the data review and data analysis process. In 
particular, some members of PMI and contract research organization (CRO) personnel will be 
blinded as summarized in Table 2: 
Table 2 
Blinding Scheme 
Blinded Study Personnel 
Blinded Data 
End of Blinding Period 
PMI and Covance study 
statisticians 
Actual values of 
primary endpoints  
at V161 
After the SAP finalization or database 
lock, whichever comes last 
PMI clinical scientist 
Actual values of 
primary endpoints 
at V161 
After the finalization of PMI blind 
database review1. Can be actively un-
blinded when appropriate. 
1 
To avoid indirect unblinding of the “actual values of primary endpoints” additional data were blinded in the eCRF 
(e.g. adverse event terms). After SAP finalization or database lock of the original study, whichever comes last, the 
whole study team will be unblinded to all data collected in the original study, following the process described in the 
original study protocol. 
2 
As part of the PMI Quality Control (QC) activity, data listings will be reviewed by Covance 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 the above Table 2 will be 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 pre-analysis 
data review as planned in the data review plan. Blinded data will be accessible by the blinded 
study personnel in a masked format or presented independent of the subject identifier so to 
ensure that data cannot be associated within or to a subject. Unblinded data will only be 
reviewed by the unblinded study team. 
6.5 
Investigational Product Accountability and Adherence 
6.5.1 
Dispensing Investigational Product 
CC: 
• From ICF signature at V10 to the end of the study, subject will use their own preferred 
brand of CC ad libitum. 
 
 
 
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THS 2.2: 
• During the extended exposure period: subjects in the THS 2.2 arm will be provided with 
anticipated amount of THS Tobacco Sticks to cover the period until the next study visit. In 
the situation in which a subject needs more THS Tobacco Sticks, extra visits may be 
scheduled. 
6.5.2 
Storage and Accountability 
No accountability will be done for the CC arm. 
A person in the site staff designated by the PI(s) or designee(s) will be responsible for the 
storage and accountability of THS 2.2 components and THS Tobacco Sticks, in accordance 
with the Sponsor’s requirements. 
The THS 2.2 components and THS Tobacco Sticks will be stored in a secured storage site 
within storage specifications with access limited to authorized personnel only. Full 
accountability of THS 2.2 will be ensured by the designated site staff by recording the timing 
and quantities of distribution of THS 2.2 components and THS Tobacco Sticks in appropriate 
logs at each visit. 
6.5.3 
Investigational Product Retention 
No retention will be done for CC. 
The study site will return to the Sponsor any unused and partially used packs of THS Tobacco 
Sticks and THS 2.2 components upon study completion or as required. Retention of THS 2.2 
will be documented in an appropriate log. 
6.5.4 
Adherence to Investigational Product 
From enrolment until V16, the adherence of subjects in the 2 study arms will be based on the 
daily self-reporting of the subject in the product use electronic diary (section 7.7.1). 
6.6 
Restrictions 
6.6.1 
Smoking Restrictions 
To avoid cross-contamination among the 2 study arms subjects will be allowed to use IP in 
areas dedicated to CC or THS 2.2 use during the visits at the site. These product use areas 
could be organized outdoor. On each visit, smoking and product use will be allowed except 
during procedures at the discretion of the site. In general, the performance of scheduled 
procedures has priority over the wish of a subject to use the product. 
 
 
 
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Except for the subjects in the THS 2.2 arm, subjects will not be allowed to use THS 2.2 during 
the extended exposure period. 
6.6.2 
Dietary Restrictions 
Subjects will not be allowed to bring their own food or beverages to the site. During the visits, 
meals and light snacks, fruits and raw vegetables can be distributed to the subjects without 
restrictions at any time during the visit. Consumption of water will be allowed as desired. 
Fasting state has to be observed for at least 10 hours prior to blood draws at V16 for: 
1. Safety laboratory parameters. 
2. Clinical risk endpoints except COHb. 
3. Serum/plasma biobanking samples for further analysis of BoExp and clinical risk 
endpoints. 
4. Blood biobanking for transcriptomics and lipidomics. 
6.7 
Concomitant Medications 
Medications will be allowed during the study and will be carefully monitored by the PI(s) or 
designee(s). The PI(s) or designee(s) is (are) responsible for the medical care including 
medication of the subjects during their participation in the study. Any decisions regarding the 
prescription of medications will be made in the best interest of the subject. All concomitant 
medication ongoing at V10 will be followed up during the extension study. Any use of 
concomitant medication must be fully documented in the source document and recorded into 
the case report form (CRF) (section 7.3.1). 
Any concomitant medication (Appendix 2) which has a potential impact on the “smokers’ 
health profile” including the use of non-steroidal anti-inflammatory drugs (NSAIDs) and 
acetylsalicylic acid (including over-the counter products) should be avoided and carefully 
considered especially when they will be taken prior to V16, as they could interfere with clinical 
risk endpoints such as 11-DTX-B2 (the last dose of the concomitant medication should be at 
least 5 half-lives prior to V16). In case drugs/short-and long-term vitamins listed in Appendix 
2 are taken by the subject during the extension study, they will be recorded as concomitant 
medications (except when salbutamol is used for post-bronchodilator spirometry testing), and 
this will not be a reason to discontinue the subject from the study. Appendix 2 provides an 
overview of selected concomitant medication and their potential impact on clinical risk 
endpoints. Medications containing estrogens (i.e. for contraception and for hormone 
replacement therapy), will be allowed in this study and must be recorded in the CRF. 
 
 
 
 
 
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7 
STUDY PROCEDURES 
Personnel performing study assessments must have the appropriate and fully documented 
training. If the personnel changes during the study, a new fully documented training must be 
scheduled. An overview of all study assessments is shown in the schedule of events (Appendix 
1). Appropriate medical advice will be provided to the subject in case of any medical findings 
requiring health care. Site personnel will adhere to the site’s standard operating procedures 
(SOPs) for study related procedures. 
7.1 
Informed Consent 
The subject will be asked to provide his/her written consent to participate to the extension 
study (ICF for study participation) at the end of V10, after all the assessments of the original 
study are completed (section 1.3). The V10 assessments of the extension study can start only 
once the subject has signed the ICF.  
In addition to the ICF for the extension study participation, only subjects who have previously 
provided consent for biobanking (and did not withdraw it) will be asked to provide his/her 
separate optional consent at V10 for the further collection of samples and storage for long-term 
biobanking at V16 (section 1.3.2): 
• ICF for the additional biobanking of serum/plasma/urine samples for further 
measurements of BoExp and clinical risk endpoints. 
• ICF for the additional biobanking of blood sample for further transcriptomics and 
lipidomics analysis/sample collection. 
The subject’s participation to the study does not depend on his/her consent for biobanking and 
will be separated from that for study participation. The additional consents will be captured in 
the CRF. 
7.2 
Information on the Risk of Smoking and Smoking Cessation 
Advice and Debriefing 
At each visit from V11 to V16: each subject will be given during the same session 1) 
information on the risks of smoking, 2) smoking cessation advice, and 3) debriefing on THS 
2.2 according to Appendix 1. 
The information on the risk of smoking and the advice on smoking cessation will take the form 
of a brief interview according to the recommendations of the Public Health Service [33, 34]. 
The debriefing of subjects on THS 2.2 will address any intended or unintended beliefs that 
participants may have about THS 2.2. The goal of the debriefing is to help ensure that subjects 
exit the study with an accurate understanding of the product risks, including an understanding 
that THS 2.2 has not been demonstrated to be less harmful than CC. 
 
 
 
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Details of the sessions will be recorded in the source document file. These sessions will be 
given to the subjects on an individual basis during a face-to-face meeting between the subject 
and the PI(s) or designee(s), and may additionally be given in a group session. 
7.3 
Clinical Assessments 
All assessments of the extension study will be performed in the same standardized way as in 
the original study to ensure homogeneity of data collection. During the original study 
demographic data was recorded and subjects were asked questions about their smoking history 
and habits.  
7.3.1 
Concomitant Disease, Previous and Ongoing Medications 
A concomitant disease is defined as any clinically relevant medical condition that was either 
detected at V1, and/or was still ongoing at V1. Any untoward medical occurrence in a subject 
detected during the original and the extension studies, which was not present at V1 of the 
original study, must be documented as an AE. Worsening of a pre-existing condition from V1 
onwards will also be documented as an AE. 
All concomitant medication taken during the extension study (from enrolment at V10 to V16) 
will be documented in the source documents and recorded in the CRF of the extension study. 
Medication which is ongoing at V10 will be considered as a concomitant medication in the 
extension study. This applies to both prescription and over-the-counter products. 
Records of medication taken include the drug name (preferably both generic and trade name), 
route of administration (e.g., oral, intravenous), total daily dose/unit (e.g., expressed in mg, 
mL, or IU), indication, the frequency, the start and (if applicable), the stop date (day, month 
and year). Any therapy changes (including changes of regimen) during the study are to be 
documented. 
7.3.2 
Physical Examination 
Physical examination will be performed according to Appendix 1. 
7.3.3 
Body Height, Weight and Waist Circumference 
Body height was recorded during the original study at V1. 
Body weight will be recorded according to Appendix 1. 
Waist circumference will be recorded according to Appendix 1. 
BMI will be calculated at V13 and V16 from the height (recorded at V1) and body weight 
recorded at V13 and V16 using the following formula: 
 
 
 
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BMI =  
weight in kilograms 
————————  
(kg/m² ) 
height in meters² 
Weight and waist circumference will also be analyzed as CVD clinical risk endpoints. 
Appropriate medical advice will be provided to the subject in case of any medical findings 
requiring health care. 
7.3.4 
Vital signs 
Systolic and diastolic blood pressure, pulse rate and respiratory rate will be recorded according 
to Appendix 1. All measurements will be made after the subject has rested for at least 5 minutes 
in a supine position. 
7.3.5 
Other Clinical Assessments 
7.3.5.1 
Lung Function Testing 
All personnel performing lung function testing must have the appropriate training. In addition 
QC measures should be put into place and be properly documented and filed at the pulmonary 
function laboratory (including the records of the calibration, if applicable). A certified study 
site staff should perform the assessment and the results will be assessed by a pulmonologist. 
The subject will be at rest for at least 15 minutes prior to lung function testing. All lung function 
manoeuvers will be recorded with the subject in a sitting position throughout the study. 
All lung function tests will be managed by a central provider, including the provision of 
equipment and site manual.  
All lung function data will be reviewed by blinded over-readers and the acceptability of the 
overall sessions and individual tests will be provided to the Investigator. 
At the end of each appropriate visit the certified study site staff will be required to send the 
lung function data to the central provider.  
Spirometry Testing 
The spirometry test will be performed in accordance with the 2005 guideline of the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) Joint Task Force on the 
standardization of spirometry [35]. Spirometry predicted values will be standardized to the 
Third National Health and Nutrition Examination Survey (NHANES III) predicted set.  
 
 
 
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The spirometry tests will include the recording of FEV1, FVC, FEV1/FVC ratio and FEF 25-
75. 
All spirometry tests will be performed using the multi-breath (closed circuit) technique, as 
described in the Investigator pulmonary function testing (PFT) site manual. The PFT manual 
will include information on equipment, procedures, subject instructions and precautions. 
All spirometry tests must be performed 1 hour after smoking or using THS 2.2.  
Each subject will need to begin their spirometry tests in a time window of +/- 2 hours respective 
to the time of the spirometry tests done at V3 (Baseline) during the original study. 
Pre- and Post-Bronchodilator Spirometry Testing: 
• At V16: 
Pre- and post-bronchodilator spirometry test will be performed. Values for FEV1, FVC, and 
FEF 25-75 will be recorded. The ratio FEV1/FVC will be calculated from the highest 
acceptable FEV1 and the highest acceptable FVC respectively. At V16, pre- and post-
bronchodilator spirometry will be used to describe the changes in pre- and post-bronchodilator 
spirometry measurements over the duration of the study. 
All post-bronchodilator spirometry testing will be performed 15-30 minutes post 
administration of around 400 µg of salbutamol (usually equivalent to 4 puffs assuming 100 
µg/puff). The time of salbutamol inhalation and time of spirometry assessment will be recorded 
in the source document. 
At V16, in case the value of the pre- and post-bronchodilator spirometry test(s) do not meet 
the ATS/ERS criteria the subject will need to come back within a 7 day window to repeat the 
test(s). 
Lung Volume Measurements Using Multiple Breath Helium Dilution Technique: 
At V16: lung volume measurements will be conducted as part of the lung function tests and 
the following values will be recorded: VC, functional residual capacity (FRC), IC and TLC. 
If required, a second test can be performed. Between tests, a minimum waiting time of 4 
minutes is required. For FRC, the mean value will be used if more than one attempt is 
performed. TLC is evaluated as FRC plus IC. VC will be the highest from FRC-He if more 
than one attempt is performed. RV will be calculated as TLC minus VCmax. VCmax is the highest 
from FRC-He wash in. 
All lung volumes measurements will be done pre-bronchodilator as outlined in Appendix 1. 
The PFT manual will include information on equipment, procedures, subject instructions and 
precautions. 
The helium dilution technique will be used in accordance with the recommendations of the 
ATS/ETS Joint Task Force on the standardization of the measurement of lung volumes [36]. 
This technique is a closed-circuit system where a spirometer is filled with a mixture of helium 
 
 
 
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and oxygen. The closed-circuit rolling seal spirometer will be filled to a starting volume of six 
liters with a mixture of containing helium, oxygen and balance room air. Oxygen will be set to 
30% so that all test subjects will be comfortable; exact contents will be analyzed. The subject 
will be asked to seal their lips around the mouthpiece and breathe normally on the closed-
circuit while the helium mixes and equilibrates. During this time carbon dioxide will be 
removed by a chemical absorber and oxygen will be automatically replaced. Once equilibration 
has occurred, the subject will be asked to perform one or more vital capacity efforts to end the 
test. 
7.3.5.2 
Electrocardiogram 
ECG testing will be performed as per the site’s local practice according to Appendix 1. A 
standard 12-lead ECG will be recorded after the subject 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 PI(s) or designee(s). 
7.4 
Biomarker Assessment 
All bioanalytical assays and laboratory assessments will be carried out using validated methods 
(sections 7.5 and 7.6) according to the laboratory manual. The bioanalytical methods used will 
be documented in the respective bioanalytical plans/reports. A list of laboratories is provided 
in Appendix 2.  
All assessments of the extension study will be performed in the same standardized way as in 
the original study to ensure homogeneity of data collection. 
7.4.1 
Clinical Risk Endpoints Related to Cardiovascular Diseases 
7.4.1.1 
HDL-C, s-ICAM-1, Apo A1 and B, MPO, LDL-C, and hsCRP in serum 
A blood draw for each assay will be collected at this time point according to Appendix 1. 
HDL-C and s-ICAM-1 will be evaluated as part of the “smokers’ health profile.” 
7.4.1.2 
Fibrinogen and Homocysteine in Plasma 
A blood draw for each assay will be collected according to Appendix 1. 
 
 
 
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7.4.1.3 
Carboxyhemoglobin and Hemoglobin Glycosylated A1c in Whole Blood 
A blood draw for each assay will be collected irrespective of product use. COHb will be 
evaluated as part of the “smokers’ health profile.” according to Appendix 1. 
7.4.1.4 
11-DTX-B2 / 8-epi-PGF2α, and Albumin in Urine 
Sampling from 24-hour urine collection to measure 11-DTX-B2, 8-epi-PGF2α and albumin. 
The results will be normalized to creatinine and expressed as concentration adjusted for 
creatinine. 11-DTX-B2 and 8-epi-PGF2α will be evaluated as part of the “smokers’ health 
profile”. The albumin to creatinine ratio will be used to evaluate potential microalbuminuria 
according to Appendix 1. 
7.4.2 
Clinical Risk Endpoints Related to Genotoxicity 
Sampling from 24-hour urine collection to measure total NNAL according to Appendix 1. The 
results will be normalized to creatinine and expressed as concentration adjusted for creatinine. 
Total NNAL will be evaluated as part of the “smokers’ health profile.” 
7.4.3 
Biomarker of Exposure 
7.4.3.1 
Biomarkers of Exposure to CO: 
The CO breath test should be conducted in timely conjunction with the blood sampling for 
COHb where applicable. 
CO Breath Test: CO in exhaled breath will be measured using the Smokerlyzer® device, such 
as the Micro 4 Smokerlyzer® device or similar in the 2 study arms. 
Once a day according to Appendix 1. 
7.4.3.2 
Plasma Nicotine and Cotinine in Plasma 
One blood draw will be collected for the measurement of nicotine and cotinine according to 
Appendix 1. The levels of nicotine and cotinine will be described over the duration of the 
study. 
7.4.4 
 
Other Biomarkers of Exposure 
The following BoExp will be measured in 24-hour urine collection: total NNN and Neq 
according to Appendix 1. The results will be normalized to creatinine and expressed as 
concentration adjusted to creatinine. 
 
 
 
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7.4.5 
Creatinine 
Creatinine will be measured for normalization of urinary BoExp (total NNN, total NNAL and 
Neq) and urinary clinical risk endpoints (11-DTX-B2, 8-epi-PGF2α, albumin and total NNAL) 
according to Appendix 1 . 
7.5 
Laboratory Assessments 
All laboratory assessments of the extension study will be performed in the same standardized 
way as in the original study to ensure homogeneity of data collection. 
7.5.1 
Clinical Chemistry, Hematology, and Urine Analysis for the Safety Panel 
Hematology, clinical chemistry and urine analysis for the safety panel will be measured 
according to Appendix 1. 
Blood samples will be taken after at least 10 hours of fasting (section 6.6.2). The urine test will 
be performed semi-quantitatively as a urine test. Parameters to be measured are listed in Table 
3. Total count of WBC will be evaluated in blood as part of the “smokers’ health profile.” 
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) 
• Glucose 
• Lactate dehydrogenase (LDH) 
• Potassium 
• Sodium 
• Total bilirubin 
• Direct bilirubin 
• Total cholesterol (TC) 
• Triglycerides (TG) 
• pH 
• Bilirubin 
• Glucose 
• Nitrite 
• Red blood cell 
traces 
• Protein 
• Specific gravity 
 
*RBC and WBC morphology tests might be performed in case of abnormal values. 
 
 
 
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7.5.2 
Urine Pregnancy Testing 
A pregnancy test will be done on all female subjects according to Appendix 1. 
Female subjects with a positive pregnancy test at V10 will not be offered to enter in the 
extension study and the PI(s) or designee(s) will inform those subject about the risks associated 
with smoking during pregnancy. All pregnancies detected during the study must be reported 
and handled as described in section 8.5. 
7.6 
Sampling Handling and Storage 
All blood samples will be tested in one of the two central laboratories (Appendix 3). The 
pregnancy tests will be done by the personnel at the study sites. 
Detailed procedures for sample collection and handling of samples are described in the 
laboratory manual. Safety laboratory samples will be destroyed as per the laboratory’s standard 
procedures. For the other samples (except biobanking samples), at least one tube per timepoint 
and per subject should be kept at least up until the finalization of the bioanalytical reports and 
the database is locked unless the stability for analysis is exceeded. 
 
The bioanalytical laboratory(ies) are listed in Appendix 2. 
7.6.1 
Blood Samples 
Venous blood samples will be collected by qualified and trained site personnel. Subjects should 
be in a seated position during blood collection.  
The maximal total volume of blood drawn for each subject for the extension study at V16 will 
be around 80 mL, which includes 13 mL for safety and repeated analysis, 10 mL of blood for 
long-term storage of the biobanking samples for further analysis of BoExp and clinical risk 
endpoints (only if additional consent is given at V10) and 9 mL for long-term storage of the 
biobanking samples for further analysis of transcriptomics and lipidomics (only if additional 
consent is given at V10) (section 7.6.3). 
7.6.2 
Urine Samples 
Spot urine samples will be used for urine pregnancy test and safety urine analysis for each 
visit. 
24-hour urine collection: the day before the visit, subjects will start collection of his/her 24-
hour urine. Subjects will discard their first void in the morning. The collection period will start 
immediately after. After 24-hours ± 1h of urine collection, subjects will empty their bladder 
again in the morning of the visit and this urine will be used as the final portion of the 24-hour 
urine sample. During the collection period, all urine passed must be collected and put into the 
sampling container. No urine should be passed into the toilet. The start and the end time of 
 
 
 
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urine collection will be recorded by the subject and checked by the site staff. The volume of 
24-hour urine will be measured by the site staff upon collection of urine containers from the 
subjects. For assessment of urine BoExp, creatinine, 8-epi-PGF2α and 11-DTX-B2, albumin, 
and for sample biobanking, aliquots from the 24-hour urine collection will be taken. In the 
schedule of events (Appendix 1) for the 24-hour urine collection, the dot corresponds to the 
day on which the 24-hour urine collection period ends.  
The 24-hour urine collection will be collected according to Appendix 1 
7.6.3 
Long-Term Storage (Biobanking) 
The facility at which the samples are stored will follow their procedures for destruction of 
banked samples if a subject withdraws his/her consent for long-term biobanking. 
7.6.3.1 
Long-Term Storage of Serum/Plasma or Urine 
If a subject gives additional consent during V10 for sample biobanking for further analysis of 
BoExp and clinical risk endpoints, additional samples of urine from the 24-hour collection and 
serum/plasma will be collected at V16 as follows:  
• Samples will be collected from the 24-hour urine collections that started one day before 
V16 and ended at V16 (5 tubes of 10 mL each). 
• Serum/plasma will be collected at V16 (10 mL of blood draw in total). This is to obtain 
and store 2X 1 mL of serum and 2X 1 mL of plasma. 
If a subject gives additional consent during V10 for sample biobanking of whole blood for 
further transcriptomics and lipidomics analysis, blood will be collected at V16 as follows: 
• Blood will be collected for transcriptomics at V16 (5 mL in total). The 5 mL will be split 
into two tubes of 2.5 mL of whole blood each. 
• Plasma will be collected for lipidomics at V16 (4 mL in total). The 4 mL will be split into 
two tubes of around 500 µl plasma each. 
The blood samples for transcriptomics and lipidomics and the data related to these samples 
will be anonymized and will be the subject of a separate report. Anonymized data and samples 
are initially single or double coded where the link between the subjects’ identifiers and the 
unique code(s) is subsequently deleted. This is applicable for the blood/plasma biobanking for 
transcriptomics and lipidomics only. 
The samples intended for sample biobanking will be kept frozen; and will be shipped to a 
central storage facility according to the laboratory manual. After the final the clinical study 
report (CSR) is signed, samples of plasma/serum/blood will be stored for a maximum of 
 
 
 
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5 years and samples of urine will be stored for a maximum of 2 years. The blood biobanking 
for transcriptomics and lipidomics will be stored for a maximum of 5 years. 
7.7 
Other Study Procedures 
7.7.1 
Product Use Diary 
The subject will capture the number of THS Tobacco Sticks, CCs (menthol and non-menthol), 
and other nicotine/tobacco containing products used on a daily basis in a product use diary 
from enrollment until the check-out of V16 (including during the visits). Subjects were trained 
by site staff on the use of this diary during the original study. The product use diary was 
supplied by Sponsor and distributed to the subjects by the study site personnel during the 
original study. If paper diary is used, the subjects will receive instructions from the site staff 
on how the diary should be completed. 
The site will schedule at each visit the next appointments at site in the electronic diary. 
7.7.2 
Questionnaires 
The subject questionnaires and the visual analog scale (VAS) used in this study will be entered 
by the subject directly in an electronic diary or on paper copy. If a paper copy is used, the VAS 
scale must be of 100 mm. All subject reported outcome material will be provided in English 
or Spanish and instructions will be provided in the subject’s local language. 
7.7.2.1 
Fagerström Test for Nicotine Dependence Questionnaire 
Subjects will complete themselves the FTND questionnaire according to Appendix 1 in its 
revised version [37] irrespective of the time of product use. 
The questionnaire consists of six questions. The scores obtained on the test permit the 
classification of nicotine dependence into three levels: mild (0-3 points), moderate (4-6 points), 
and severe (7-10 points) [37]. 
7.7.2.2 
Cough Questionnaire 
Subjects will complete themselves the respiratory symptom “cough” on a VAS, on three Likert 
scales, and with an open question irrespective of the time of product use according to Appendix 
1. 
Subjects will be asked if they have experienced a regular need to cough (e.g., whether they 
have coughed several times in the previous 24 hours prior to assessment). If the answer is ‘yes’, 
subjects will be asked to complete a VAS, 3 Likert scales, and to answer the open question. 
On the VAS, subjects will assess how bothersome their cough was during the previous 
24 hours. The VAS ranges from “not bothering me at all” to “extremely bothersome”. 
 
 
 
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Furthermore, subjects will assess the intensity and frequency of cough and the amount of 
sputum production during the previous 24 hours on Likert scales. 
• The intensity of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = very mild – 2 = mild – 3 = moderate – 4 = severe – 5 = very severe. 
• The frequency of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = rarely – 2 = sometimes – 3 = fairly often – 4 = often – 5 = almost always. 
• The amount of sputum production will be assessed on a 4-point Likert scale ranging from 
0 to 3, with 0 = no sputum – 1 = a moderate amount of sputum – 2 = a larger amount of 
sputum – 3 = a very large amount of sputum. 
Symptoms or worsening of symptoms documented in the VAS do not need to be documented 
as additional AEs because the VAS will be analyzed as part of the final report. However, it is 
at the discretion of the PI(s) or designee(s) to decide whether to document such symptoms as 
additional AEs. The main source for AE collection will be the face-to-face interview between 
the subject and study site staff, using open, non-directive questions (section 8.2). 
7.7.2.3 
Modified Cigarette Evaluation Questionnaire 
Subjects will complete themselves the modified cigarette evaluation questionnaire (MCEQ) 
[38] according to Appendix 1 . 
The MCEQ assesses the degree to which subjects experience the reinforcing effects of 
smoking, by measuring: 
• Smoking satisfaction (satisfying, tastes good, and enjoys smoking). 
• Psychological rewards (calms down, more awake, less irritable, helps concentrate, reduces 
hunger). 
• Aversion (dizziness, nauseous). 
• Enjoyment of respiratory tract sensations (single-item assessment). 
• Craving reduction (single-item assessment). 
7.7.2.4 
Intention to Use THS 2.2 Questionnaire 
Subjects in the THS 2.2 arm will complete themselves the questionnaire on their intention to 
use THS 2.2 using the ITUQ according to Appendix 1. The ITUQ comprises two sets of items: 
• 1 item assessing intention to use THS 2.2 on a regular, ongoing basis to be rated on an 
ordinal scale with 6 timeframe categories. Only subjects who provide answer different from 
“definitely not” to this item will be asked to answer the next 6 items. 
 
 
 
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• 6 items assessing several intentions to use THS 2.2 on a regular, ongoing basis to be rated 
on a 6-point scale ranging from “definitely not” to “definitely” with higher scores 
indicating greater likelihood to use THS 2.2. 
 
 
 
 
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8 
ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
The FDA MRTP guideline [4] specifies this definition towards tobacco products, as follows: 
“An AE is any health-related event associated with the use of a tobacco product in humans, 
which is adverse or unfavorable, whether or not it is considered tobacco-product related”. 
8.1.2 
Serious Adverse Events 
A serious adverse event (SAE) is defined as, but not limited to, any untoward medical 
occurrence that: 
• Results in death. 
• Is life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, they 
may jeopardize the subject or the subject may require medical or surgical intervention to 
prevent one of the outcomes listed in the above definitions. 
Any pre-planned hospitalizations that are known at the time of signing the ICF will not be 
recorded as SAEs, however they will be recorded as AEs only. Any AE that occurs during this 
pre-planned hospitalization will be considered according to the above definitions. 
8.2 
Assessment of Adverse Events 
The PI(s) or designee(s) is (are) responsible for obtaining, assessing, and documenting all AEs 
during the study. 
8.2.1 
Collection of Information 
Adverse event information will be collected from the time of signature of the ICF at V10 
onwards until the end of the extension study for the subject either by the PI(s) or designee(s) 
via spontaneous reporting or by the use of consistent, open, non-directive questions from study 
site staff (e.g., “Have you had any health problems since the previous visit/How are you feeling 
 
 
 
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since you were last asked?”). At the discretion of the PI(s) or designee(s), the collection of AE 
information may also be triggered from the review of the subject questionnaires and the VAS. 
However, during the visits, the main source for AE collection will be face-to-face interview(s) 
with the subject. 
Information recorded will include: verbatim description of the AE, start and stop dates and 
times, seriousness, severity (intensity), action taken (e.g., whether or not the AE led to the 
subject’s withdrawal from the study), and outcome (e.g., resolved, withdrawal due to AE). 
For each AE, the intensity will be graded on a 3-point intensity scale (mild, moderate, severe) 
using the definitions provided in section 8.2.3. 
Any exacerbation/worsening or increased frequency of an AE or pre-existing condition shall 
be evaluated and recorded. 
Correct medical terminology/concepts are preferred when recording AE terms, and 
abbreviations must be avoided. Wherever possible, a diagnosis is to be used to describe an AE 
as a diagnosed medical condition 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). 
8.2.2 
Period of Collection 
From the time of signature of the ICF of the extension study (at V10) until the end of the study 
(EOS), all AEs (includes SAEs) will be collected by the study site staff as described below. 
Any AE ongoing at V10 will be followed up during the extension study. 
8.2.2.1 
From Enrollment until the End of the Study 
Any new, clinically relevant, abnormal finding or worsening of a pre-existing 
condition/concomitant disease detected during the study including the safety follow-up period 
will be documented as an AE and/or SAE. 
During the safety follow-up period spontaneously reported AEs and/or SAEs will be recorded 
in the CRF. Any AEs/SAEs ongoing during the 28 day safety period will be actively followed 
up by the PI(s) or designee(s) until they have been resolved, stabilized (i.e., no worsening of 
condition), or until an acceptable explanation has been found. 
Upon/after the end of the safety follow-up period for all ongoing AEs, the PI(s) will refer the 
subject to his General Practitioner for follow up of those AEs (section 8.3) until they have been 
resolved, stabilized (i.e., no worsening of condition), or until an acceptable explanation has 
been found. All ongoing SAEs at the end of the study will be followed up by the PI(s). 
 
 
 
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8.2.3 
Intensity of Adverse Event 
For each AE, the intensity will be graded by the PI(s) 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 subject is still able to 
function. 
Severe: 
 
The AE is incapacitating and requires medical intervention. 
According to CIOMS (Council for International Organizations of Medical Sciences) VI 
Working group, changes in severity (Intensity) and maximum intensity of AEs must be 
documented. 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures 
It is difficult to establish a firm method to distinguish an adverse reaction (that is AE that is 
causally related to the IP) from a clinical adverse event that is temporally associated to the use 
of an IP. 
In general, all AEs and/or SAEs will be assessed by the PI(s) or designee(s) as either “related” 
or “not related” to IP as described below. In addition to the assessment of the relationship of 
the clinical event to the IP, the PI(s) or designee(s) shall document a potential relationship of 
the clinical event to any particular study procedure. 
 
Not related: The temporal relationship of the clinical event to IP administration 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 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 IB. The IB provides further detail on signs 
or symptoms that might be expected with the use of the IP, including information relating to 
device malfunction or misuse. 
 
 
 
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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, or any SAE related to the product and spontaneously reported after the 
safety follow-up must be reported by the Principal Investigator or designee within 24 hours 
after first awareness by any party involved in the study to 
 
 
 and to the Sponsor. 
An SAE report form must be faxed or e-mailed as an attachment to: 
 
 
Fax number: 
 
E-mail: 
 
 
Address: 
 
 
 
 
Sponsor Contact: 
  MD  
Medical Safety Officer 
Phone: 
 
 
 
 
E-mail 1: 
E-mail 2: 
@pmi.com 
@pmi.com  
 
 
 
The PI(s) or designee(s) is (are) responsible for local reporting (e.g., to the IRB) of SAEs that 
occur during the study, according to local regulations. 
Any SAE will be reported by the Sponsor to the FDA Center for Tobacco Products Office of 
Science within 15 business days after the report is received by the Sponsor. 
Any additional/follow-up information that becomes available after the initial SAE report form 
has been completed will be forwarded to 
 
 and the Sponsor within 24 hours after 
first awareness by any person at the site using a follow-up to the existing SAE report form. 
The follow-up SAE report form must include the minimum information required as described 
in the safety management plan (SMP) 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 PI(s) or designee(s) and/or 
 until their 
resolution or until the PI(s) or designee(s) consider(s) the event to be stabilized (i.e., no 
 
 
 
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worsening of condition), or an acceptable explanation has been found (e.g., a chronic 
condition). 
The SAE report form to be used in this study is provided as a separate document and included 
in the Investigator site file. All SAEs will be recorded, in addition to the SAE report form. 
8.4 
Reporting of Other Events Critical to Safety Evaluations 
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the PI(s) or designee(s) and assessed for clinical relevance. If the subject is 
enrolled in the extension study and, if the abnormal laboratory result is detected after signature 
of the extension study ICF at V10 onwards, and is considered clinically relevant (see below), 
this should be recorded as an AE in the CRF of the extension study. If the subject is not enrolled 
(e.g. screen failure), the AE should be recorded in the CRF of the original study.  
The grading scheme described in the Common Terminology Criteria for Adverse Events and 
Common Toxicity Criteria [CTCAE] version 4.03 (Appendix 5) will be used by the PI(s) or 
designee(s) to assess abnormal laboratory AEs as follows: 
• All Grade 1 abnormal laboratory values will be evaluated by the PI(s) or designee(s) with 
respect to Baseline value (V3 of the original study) and clinical relevance. If considered to 
be clinically relevant the Investigator or designee must report it as an AE. All Grade 2 and 
higher abnormal laboratory values must be reported as, or linked to, an AE/concomitant 
disease.  
• If there is any worsening in grade from Grade 2 and above during the study the PI(s) or 
designee(s) must report this worsening as an AE. 
• Where there is no grading available, the abnormal laboratory value will be evaluated by 
the PI(s) or designee(s) and assessed for clinical relevance. If considered to be clinically 
relevant, the PI(s) or designee(s) will report it as an AE.  
• Any other abnormal clinical laboratory result (including those that are not part of the core 
safety assessments) can, at the discretion of the PI(s) or designee(s), be reviewed and 
assessed. Even if they do not meet the criteria of the CTCAE grading scheme (please see 
above), the PI(s) or designee(s) may consider them to be of clinical relevance and, if they 
are, must report them as AEs. 
• In general, laboratory values will be recorded as ‘increased <lab parameter>’ or ‘decreased 
<lab parameter>’ to ensure consistency of recording/coding. 
All other information (e.g., relationship to IP, intensity, seriousness, outcome) will be assessed 
as for other AEs. 
 
 
 
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8.5 
Reporting and Follow-Up of Pregnancies 
For pregnancies detected at V10, subject will not be offered to enter in the extension study. A 
pregnancy form will be filled during V10 as part of the original study assessments. The 
diagnosed pregnancy will be captured in the CRF of the original study only, and not in the 
CRF of the extension study, as it will be considered as an event from the original study. 
Any pregnancy having occurred after enrollment in the extension study, potentially associated 
with exposure the IP, including pregnancies spontaneously reported to the PI(s) or designee(s) 
after the EOS must be reported by the PI(s) or designee(s) and followed up until the pregnancy 
outcome is reached. Potentially associated with exposure to the IP is defined as the pregnancy 
where a conception date being calculated as the date after first exposure and before the last 
exposure to the IP. In case the conception occurs before the enrollment in the extension study 
but the pregnancy test is negative at V10, the occurrence of the pregnancy will be captured in 
the CRF of the extension study only once the pregnancy is diagnosed.   
The PI(s) or designee(s) will complete a pregnancy form (provided as a separate document) 
for all pregnancies diagnosed after enrollment in the extension study (including positive urine 
pregnancy tests). 
The procedure to report a pregnancy and provide any additional/follow-up information to 
 
 and the Sponsor must be followed in the same manner and within the same timelines as 
described for an SAE (section 8.3). No invasive study procedures, including drawing of blood 
must be done in such subjects after the discovery of pregnancy. 
 
 will follow up pregnancies until an outcome is reached (e.g. normal delivery, 
spontaneous abortion or voluntary termination). Any pregnancy complication, adverse 
pregnancy outcome or maternal complications will be recorded. 
The PI(s) or designee(s) is(are) responsible for informing the IRB of any pregnancy that occurs 
during the study and its outcome, according to local regulations. 
8.6 
Adverse Events Leading to Discontinuation 
Enrolled subjects who are discontinued from the extension study because of an AE will 
undergo early termination procedures (section 9.4) within 5 days after the day of 
discontinuation and enter the safety follow-up period of the extension study. The PI(s) or 
designee(s) will follow-up these AEs until they have been resolved, stabilized (i.e., no 
worsening of condition), or until an acceptable explanation has been found. All ongoing AEs 
at the end of the study will be managed as described in section 8.2.2.1. 
8.7 
Investigational Device Misuse 
Any occurrence of THS Tobacco Stick Holder or THS Charger misuse (use not in accordance 
with its label and instruction) by a subject will be documented by the PI(s) or designee(s) using 
a device issue log. 
 
 
 
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Investigational device misuse may result in use-related hazards. 
Use-related hazards are derived from the US Food and Drug Administration Medical Device 
Use - Safety Guidance [39]: 
• Hazards caused specifically by how a device is used. 
• Unanticipated use scenarios (e.g., modification of charging unit, applying any chemicals, 
using CCs, mechanical damage of the unit, etc.) that result in hazards must be documented 
and reported by the PI(s) or designee(s). 
8.8 
Investigational Device Malfunction 
Any occurrences of malfunction of the THS Tobacco Stick Holder or THS Charger will be 
documented by the PI(s) or designee(s) using a device issue log. 
Furthermore, any malfunctions of the THS Tobacco Stick Holder or THS Charger that lead to 
an AE/SAE will follow the same processes as described above. 
 
 
 
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9 
STUDY ACTIVITIES 
A detailed schedule of assessment can be found in Appendix 1. All assessments of the 
extension study will be performed in the same standardized way as in the original study to 
ensure homogeneity of data collection. 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 a procedure is provided, then the procedure can be performed at 
any time during the day. 
9.1 
Visit 10 
V10 corresponds to the last visit of the original study. For subjects willing to participate in the 
extension study, it also corresponds to the first visit in the extension study. Once all V10 
assessments from the original study have been performed, subjects will be offered to enter into 
the extension study. After subjects give their written informed consent, screening procedures 
of the extension study can be performed. If eligibility criteria of the extension study are met 
subjects will be enrolled. All assessments done at V10 in the context of the original study do 
not need to be repeated for the extension study. The assessments done as part of the original 
study at V10 are given in Appendix 1. 
Table 4 shows the extension study assessments that will be performed during V10. 
Table 4 
Time Schedule - V10 (Week 26) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Visit 10 
 
At the end of 
V10 
 
Subject will be offered to enter 
into the extension study 
After all V10 assessments of the 
original study have been 
performed according to Appendix 
1. 
Only if female subject have a 
negative pregnant test 
During 
Screening  
 
Informed consent form for 
extension study participation and 
two additional informed consent 
forms for biobanking 
 
During 
screening  
 
Readiness to comply to 
extension study procedures 
(e.g., willingness to use THS 2.2 
for an additional 26 weeks) 
 
 
 
 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Visit 10 
 
During 
screening  
 
Inclusion/exclusion criteria 
check for the enrollment into the 
extension study 
 
During the visit 
 
AE/SAE questioning; 
Concomitant medication 
At any time during the day 
End of 
screening  
 
Enrollment into the extension 
study after all V10 procedures 
completed 
If all eligibility criteria are met 
After 
enrollment 
 
Enrolled subjects are informed 
to continue in their assigned 
study arm (THS 2.2 or CC) 
 
After 
enrollment 
 
THS Tobacco sticks are 
distributed to subjects in THS 
2.2 arm 
 
After 
enrollment 
 
Check-out from site / beginning 
of extended exposure period 
 
Abbreviations:  
AE = Adverse event; CC = Conventional cigarette(s); SAE = Serious adverse event; THS = Tobacco Heating System. 
The sequence of assessments/events is given just for illustrative purposes. The sequence will 
be at the discretion of the site after signature of the ICF. If the inclusion and exclusion criteria 
are met, the subject will be enrolled into the extension study. However, enrollment can only 
take place at V10. 
9.2 
Extended Exposure Period 
Table 5 shows the assessments that will be performed at V11, V12, V13, V14, and V15: 
Table 5 
Time Schedule – V11 (Week 30), V12 (Week 35), V13 (Week 39), V14 
(Week 43), V15 (Week 48) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V11, V12, V13, V14, and V15 
 
Start of the 
visit  
 
Check-in at site 
Product use will be allowed on 
site in the THS 2.2 and CC arms 
 
 
 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V11, V12, V13, V14, and V15 
 
The use of THS 2.2 in subjects 
randomized to CC will be 
forbidden 
During the visit 
 
Return of unused and partially 
used packs of THS Tobacco 
Sticks by the subject randomized 
to THS 2.2 arm 
 
During the visit 
 
Urine pregnancy test (females 
only) 
 
During the visit 
 
AE/SAE questioning; 
Concomitant medication 
At any time during the day 
During the visit 
 
Weight and calculation of BMI 
At V13 only 
 
During the visit 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
After resting for at least 5 
minutes in supine position 
At any time during the day 
During the visit 
 
Information on the risk of 
smoking/smoking cessation 
advice and debriefing on THS 
2.2 
 
During the visit 
 
Dispensing of THS 2.2 
THS 2.2 arm only 
During the visit 
 
Distribution of the 24-hour urine 
containers 
At V15 only 
End of the visit 
 
Check-out from site 
 
Abbreviations: 
AE = Adverse event; CC = Conventional cigarette(s); SAE = Serious adverse event; THS = Tobacco Heating System.  
 
 
 
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Table 6 shows the assessments that will be performed at V16: 
Table 6 
Time Schedule - V16 (Week 52) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V16 
 
Start of the 
visit  
 
Check-in at site 
Product use will be allowed on 
site in the THS 2.2 and CC arms 
The use of THS 2.2 in smokers 
randomized to CC will be 
forbidden 
 
 
 
 
Prior to 
breakfast 
 
Receipt of the subject’s 
containers filled with 24-hour 
urine 
The urine is collected for 24-
hours ±1 hour. The start of urine 
collection is at subject’s home the 
day before the visit and the end is 
in the morning of the visit 
Prior to 
breakfast 
 
Urine pregnancy test (females 
only) 
 
Prior to 
breakfast 
√ 
Clinical laboratory parameters* 
(hematology, clinical chemistry) 
Has to be done after at least 
10 hours of fasting 
* WBC from safety will be also 
evaluated as part of the 
“smokers’ health profile” 
Prior to 
breakfast 
√ 
Clinical risk endpoints: HDL-C, 
LDL-C, sICAM-1, Apo A1, Apo B, 
MPO, homocysteine, hsCRP, 
HbA1c, fibrinogen 
Has to be done after at least 
10 hours of fasting 
Prior to 
breakfast 
√ 
Blood sampling for biobanking 
for transcriptomics and lipidomics 
If consent is obtained 
Has to be done after at least 
10 hours of fasting 
Prior to 
breakfast 
√ 
Biobanking for BoExp/clinical risk 
endpoints in serum/plasma 
If consent is obtained 
Has to be done after at least 
10 hours of fasting 
During the 
visit 
 
Breakfast 
 
During the 
visit 
 
Urine sampling to be taken from 
the 24-hour urine V16 container 
as appropriate 
BoExp (all BoExp and Neq), and 
creatinine, in 24-hour urine 
Clinical risk endpoints: 11-DTX-
B2, 8 epi-PGF2α, albumin 
 
 
 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V16 
 
Biobanking for BoExp/clinical risk 
endpoints (if additional consent is 
obtained) 
During the 
visit 
 
AE/SAE questioning; 
concomitant medication 
At any time during the day 
During the 
visit 
 
Physical examination 
 
During the 
visit 
 
 
Lung function: 
• 
spirometry pre- 
salbutamol first,  
• 
lung volume using 
helium dilution technique pre-
salbutamol, then,  
• 
spirometry post-
salbutamol 
Has to be done at least after 1 
hour without smoking or using 
THS 2.2 
Subject at rest for at least 15 
minutes prior to lung function 
testing 
In sitting position 
All post-salbutamol spirometry 
testing will be performed 15-30 
minutes post administration of 
salbutamol 
For an individual subject, the start 
of his/her spirometry should be 
organized within the time window 
of +/- 2 hours respective to the 
time of his/her spirometry tests 
that was performed at V3 
Baseline. 
During the 
visit 
√ 
Nicotine and Cotinine in plasma 
Irrespective of cc use 
During the 
visit 
 
CO breath test 
Has to be done in conjunction 
with COHb blood sampling 
Irrespective of product use. 
During the 
visit 
√ 
COHb in blood 
Has to be done in conjunction 
with CO breath test 
Irrespective of product use 
During the 
visit 
 
Lunch 
 
During the 
visit 
 
Urine safety analysis 
 
 
 
 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V16 
 
During the 
visit 
 
Weight, calculation of BMI, and 
waist circumference 
Weight and waist circumference 
to be evaluated also as clinical 
risk endpoints 
During the 
visit 
 
Vital signs (blood pressure, pulse 
rate, respiratory rate) 
After resting for at least 5 minutes 
in supine position 
At any time during the day 
Systolic and diastolic blood 
pressure to be evaluated also as 
clinical risk endpoints. 
During the 
visit 
 
ECG 
After resting for at least 5 minutes 
in supine position prior to 
recording 
During the 
visit 
 
MCEQ questionnaire 
 
During the 
visit 
 
Assessment of cough (VAS) 
 
During the 
visit 
 
ITUQ questionnaire THS 2.2 
THS 2.2 arm only 
During the 
visit 
 
Information on the risk of 
smoking/smoking cessation 
advice and debriefing on THS 
2.2 
 
During the 
visit 
 
FTND 
 
During the 
visit 
 
Return of eDiary to the site staff 
 
In the 
morning 
 
Return of THS 2.2 in addition to 
the unused and partially used 
packs of THS Tobacco Sticks by 
the subject randomized  to THS 
2.2 
 
At the end of 
the visit 
 
Check-out from the site / 
beginning of follow up safety 
period  
 
Abbreviations: 
8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTX-B2 = 11-dehydro-thromboxane B2; AE = Adverse event; Apolipoprotein 
A1= Apo A1; Apolipoprotein B = Apo B; BMI = Body mass index; BoExp = Biomarkers of exposure; CC = Conventional 
cigarette(s); CO = Carbon monoxide; COHb = Carboxyhemoglobin; ECG = Electrocardiogram; FTND = Fagerström test 
 
 
 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V16 
 
for nicotine dependence; HbA1c = Hemoglobin glycosylated A1c; HDL-C = High density lipoprotein; hs-CRP = high 
sensitivity C-reactive protein; ITUQ = Intent-to-use questionnaire LDL-C = Low density lipoprotein; MCEQ = Modified 
cigarette evaluation questionnaire; MPO = Myeloperoxidase; Neq = nicotine equivalents; SAE = Serious adverse event; 
sICAM-1 = soluble intercellular adhesion molecule; THS = Tobacco Heating System; WBC = White blood cell count. 
9.3 
Safety Follow-up Period 
After V16, subject will enter the 28 day safety follow-up period of the extension study. If a 
subject discontinues from the study prior to V16, he/she will also enter the 28 day safety 
follow-up period at the time of discontinuation unless he/she is lost to follow-up. 
During the 28 day safety follow-up period, there will be spontaneous reporting by the subject 
of new AEs and new SAEs. Any ongoing AEs/SAEs will be actively followed-up by the site. 
Any AEs or SAEs that are ongoing at the end of the 28 day safety follow-up period will be 
managed as described in section 8. 
9.4 
Early Termination Procedures 
The following early termination procedures will be performed within 5 days of the date of 
study discontinuation, if a subject is discontinued from the study: 
• AE/SAE recording. 
• Clinical laboratory parameters (hematology, clinical chemistry, and urine safety analysis). 
• Physical examination. 
• Lung function (spirometry pre-bronchodilator and spirometry post-bronchodilator). In case 
the value of the test(s) do not meet the criteria the subject will need to come back within a 
7 day window to repeat the test(s). 
• Urine pregnancy. 
• Vital signs. 
• ECG. 
• Information on the risk of smoking, smoking cessation advice, and debriefing on THS 2.2. 
If the early termination visit occurs on the same day than a planned visit (e.g. the subject wants 
to withdraw or is discontinued in the middle of V12), all assessments that have been performed 
during the planned visit should not be conducted again for the ET procedures. In case an early 
 
 
 
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termination visit is not performed, the subject will still enter into the 28 days Safety Follow-
up Period after the discontinuation date. 
 
 
 
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10 CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
The Clinical Research Associate (“Monitor”) of the contract research organization (CRO) will 
be responsible for the monitoring of the study. Monitoring will be performed according to 
CRO’s SOPs and as per the agreed monitoring plan with the Sponsor. 
The PI(s) or designee(s) 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 met. 
The PI(s) or designee(s) shall access medical records for the Monitor in order that entries in 
the CRFs may be verified. As part of his/her(their) responsibilities, the PI(s) or designee(s) 
is(are) expected to ensure that the study adheres to GCP requirements [2]. 
An Investigator’s meeting will be held prior to the site initiation visit. During this meeting, the 
general training of the study procedures and specific training on selected procedures will be 
completed and documented. 
Subsequent to the Investigator’s meeting, and before the first subject is screened into the study, 
the site initiation visit will be conducted by the Monitor and, if necessary, together with the 
Sponsor or its authorized representative. The purpose of the site initiation visit is described in 
the monitoring plan. 
During the study, the Monitor will have regular contact with the study site, including interim 
monitoring visits. The purpose of these visits is described in the monitoring plan. 
Communication by telephone, mail, and e-mail may be used as needed to supplement site 
visits. The Principal 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 Principal 
Investigator or other staff 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 PI(s) or designee(s), must be available during the monitoring visit to review the data, 
resolve any queries and to allow direct access to the subject’s records for source data 
verification. 
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 to the relevant 
 
 
 
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systems and other study-specific procedures. The activities of this meeting will be described 
in the monitoring plan. 
Further to the Investigator meeting, the PI(s) or designee(s) will ensure that appropriate 
training relevant to the study is provided to all staff involved in the study, and that any new 
information relevant to the performance of this study is forwarded in a timely manner to the 
staff involved. The PI(s) or designee(s) will maintain a record of all individuals involved in the 
study. 
10.3 Audits and Inspections 
Good Clinical Practice regulations require that there are independent inspections of clinical 
program activities. Such inspections may be performed at any time before, during and/or after 
the study. 
Authorized representatives of the Sponsor, regulatory agencies and/or an IRB may perform 
audits or inspections, including source data verification. The purpose of an audit or inspection 
is to systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted and data were recorded, analyzed, and 
accurately reported according to the protocol, ICH/GCP guidelines [2], and any applicable 
regulatory requirements. The PI(s) or designee(s) will contact the Sponsor or the authorized 
representative immediately if contacted by a regulatory agency about an inspection at their site. 
The PI(s) or designee(s) is(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 PI(s) or designee(s) understand(s) and agree(s) 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. The electronic systems used to collect subject data, CRF and 
electronic patient reported outcome (ePRO), will be FDA 21 CFR Part 11 compliant. 
11.1 Data Capture 
11.1.1 
Case Report Forms and Study Records 
Data from the extension study will be collected in a new CRF separate from the CRF of the 
original study. The CRF of the extension study will contain some data collected during the 
original study, which will be integrated from the CRF of the original study into the CRF of the 
extension study (e.g. medical history, ongoing concomitant medications, ongoing AEs, etc.). 
Subjects in the extension study will have the same identification number used during the 
original study. 
With the exception of subject-reported outcome data, all results from the clinical assessments 
will be recorded in the source documents by the PI(s) or designee(s) and then captured in the 
CRFs at the study site. The subject questionnaires, the cough-VAS and the product use diary 
(tobacco and nicotine containing products) will be entered by the subject directly in an 
electronic diary or on paper copy. Trained study personnel will be responsible for capturing 
the data from the observations, tests and assessments specified in the protocol in the source 
documents, and then for transferring the data into the CRF according to the CRF Completion 
Guidelines. 
The Principal Investigator(s) has(have) ultimate responsibility for the collection and reporting 
of all data related to the clinical study and for ensuring that the data are accurate, 
authentic/original, legible, timely (contemporaneous), enduring, and available when required. 
The CRF must be electronically signed by the PI(s) to attest that the data are true and accurate. 
Any corrections made to source documents and/or CRFs must be clearly recorded, without 
obscuring the original values and must be accompanied by the date of change, reason for 
change, and identification of the person making the change. The CRF for each subject will be 
checked against the source documents at the study site by the Monitor. Instances of missing or 
unclear data will be discussed with the Investigator for resolution. For the electronic diary, all 
subject reported outcome data will be provided in English and Spanish and instructions will be 
provided in the subject’s local language. A CRF will be generated for all subjects who have 
signed the ICF of the extension study. Every subject who signed the ICF of the extension study 
at V10 will be attributed the same number as in the original study.  
 
 
 
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11.1.2 
Protocol Deviations 
Protocol deviations are defined as deviations from the study procedures as defined in this 
document, including but not limited to, as any violation of inclusion/exclusion criteria, 
assessments not performed or performed outside the scheduled time windows, or use of drugs 
that are known to affect components of the “smokers’ health profile”. 
All protocol deviations will be documented into the clinical trial management system (CTMS) 
or other approved format following site monitoring and other manual review. 
Information from the source documents will represent the primary source of protocol 
deviations. Information following site monitoring and other manual reviews will be 
documented in the site visit reports, follow-up letters, audit documentation, or other manual 
review and will be recorded and tracked in the CTMS or other approved format. 
Telecommunications and other verbal communications regarding deviations will be considered 
and handled as important communication, documented and tracked as protocol deviations, as 
necessary. 
The protocol deviations from the CTMS (or other approved format) will be reviewed against 
the individual data points in the CRF database. The overall procedure for managing protocol 
deviations is described in the SOPs and/or documented in the DMP. 
11.1.3 
Data Handling 
All study data will be managed by the data management team at the CRO responsible for this 
study. The overall procedures for quality assurance of clinical study data are described in the 
SOPs of the CRO data management team. The data management team at the CRO will prepare 
a DMP, to be reviewed and approved by the Sponsor, prior to the start of data entry. This 
document will describe, in details, the data management-related procedures and processes. 
Data of all subjects who sign the ICF, including screening failures will be captured in the 
source documents. All AEs will be entered in the study database (CRF). 
All data collected during the study is declared property of the Sponsor, irrespective of the 
location of the database and the data management CRO. 
Additional details are covered in the DMP. 
 
 
 
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12 PLANNED STATISTICAL METHODS 
12.1 General Considerations 
Full details of the statistical analysis are given in a SAP. Any changes to the planned statistical 
methods will be documented in the clinical study report. The statistical evaluation will be 
performed using SAS®, version 9.2 or later. 
For analysis purposes, data collected in this study will be pooled with relevant data from the 
original study as indicated in the following sections, with reference to Baseline and data 
collected during visits V1 to V10.  
12.1.1 
Stratification Criteria 
For the primary analysis of the endpoints in the “smokers’ health profile”, the following 
stratification criteria will be used: 
1. Sex (male; female). 
2. Site. 
12.1.2 
Definitions for Statistical Data Analysis 
Baseline: 
In general, Baseline value will be the last assessment at or prior to the V3. 
Adherence to product allocation: 
Adherence to THS 2.2 is defined as at least 70% THS 2.2 use, with no more than 5 CC during 
each single day of the randomized exposure period of the main study. The same criteria will 
be adopted for the extended 6-month period. Subjects in the CC arm will be considered 
adherent to the randomized product. For both the THS 2.2 and CC arm, any subjects reporting 
to having quit using tobacco-containing products (e.g. THS 2.2 and CC) will be considered not 
adherent to the study product allocated. Product adherence will be used for the definition of 
the per-protocol (PP) population (section 12.4.4). 
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by product arm, product use pattern category 
(section 12.4.2), subject, and study visit, unless otherwise specified. 
For continuous data, summary statistics will include the number of subjects (n), the number 
and percent of subjects with missing data, the arithmetic mean, arithmetic standard deviation 
(SD), median, first and third quartiles, minimum, maximum, and number; for log-normal data 
the geometric mean and geometric CV will also be presented. For categorical data, frequency 
 
 
 
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counts and percentages will be presented. For the calculation of summary statistics and 
statistical analysis, unrounded data will be used. 
12.1.4 
Handling of Missing Values and of Values Outside the Detection Limits 
For laboratory 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 50% or more data are below LLOQ or above ULOQ, only the number (%) of value 
below LLOQ or above ULOQ will be reported in the summaries, together with minimum 
and maximum of the observed values. 
For daily product use data: 
• Only available data will be included in the product use summaries. 
• For product use categorization purposes, missing product use data will be interpolated 
using a moving average centered on the missing data.  If more than one third of the product 
use data is still missing after this imputation process, the product use category will be set 
to missing. 
• Only available product use data collected since the first day after randomization (Day 2) 
up until V16 (Day 16 excluded) will be considered, with the exclusion of inconsistent 
records and outliers. Further details will be provided in the SAP. 
• If the number of subjects classified as Missing product use category is greater than 10% of 
the total FAS-EX population, a sensitivity analysis will be produced for the FAS-EX, by 
reanalysing the primary endpoints re-classifying all subjects based on the available data in 
the diary. 
 
For MCEQ questionnaire data, total scores and domain or subscale scores will be derived by 
averaging the individual non-missing item scores if at least 50% are non-missing, otherwise 
they will be set to missing.  
The FTND total score will be derived by summing the individual item scores if all items are 
non-missing; if any items are missing the total score will be set to missing. 
Further details are provided in the SAP. 
 
 
 
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12.1.5 
Significance Level for Inferential Analysis 
This study has no formal pre-specified hypotheses associated with the study objectives. 
Estimates of THS 2.2 effect will be presented However, 95% CI will accompany all effect 
estimates, with no multiplicity adjustment. 
12.2 Determination of Sample Size and Power Consideration 
The sample size for this study was defined based on the sample size requirements of the 
original study, for which the sample size was calculated to ensure an overall study power of at 
least 90%, while maintaining at least 80% power to detect the expected effect of THS 2.2 as 
compared to CC for each individual endpoint of the “smokers’ health profile”, over 26 weeks 
of exposure. This required 475 subjects randomized per group accounting for an anticipated 
75% of the THS 2.2 arm to be Mostly THS 2.2 users (i.e. report at least 70% THS 2.2 use).  
Based on the assumptions that 30% of the 950 subjects will not be enrolled or will drop out 
from the extension study and a potential decrease from 75% to 50% of Mostly THS 2.2 users 
among subjects randomized to THS 2.2, the study will have at least 90% probability to 
determine the effect of THS 2.2 as compared to CC on FEV1 at V16 with a margin of error 
(95% CI) of at most ±1.5 %pred. The anticipated SD of 6.4 %pred was estimated using the 
results of the “Lung Health Study” [1]. 
Following our current understanding of product use data in the main study, the definition of 
the product use categories was redefined and the underlying assumptions re-evaluated so that 
approximately 60% of the subjects in the THS 2.2 arm are expected to be in the THS-use 
category, with an anticipated 20% of subjects drop-out or reporting insufficient product use 
data in the two arms of the main study. Based on the 65% rate of enrollment into the extension 
study observed among subjects randomized in the main study, the extension study will have 
more than 90% probability to determine the effect of THS-use compared to CC-use on FEV1 
at V16 with a margin of error (95% CI) of at most ±1.5 %pred.  
 
12.3 Product Use 
Although subjects are being requested to use solely the product allocated to their respective 
study arm, it is considered that not all subjects that were randomized to the THS 2.2 arm in the 
original study will exclusively use THS 2.2 at all times during the study. Subjects may 
concomitantly use THS 2.2 and CC (dual-use). To assess dual use of THS 2.2 and CC, PMI 
has defined categories of pattern of product use. 
Product use pattern categories within an analysis period will be calculated based on the 
percentage of product use that is THS 2.2 product use of the overall product use, including 
THS Tobacco Sticks and conventional cigarettes (CC). During each analysis period, the 
percentage of THS 2.2 product use will be calculated as:  
 
 
 
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= 100 ×
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑇𝑇𝑇𝑇𝑇𝑇 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑇𝑇𝑇𝑇𝑇𝑇 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆+ 𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝐶𝐶𝐶𝐶 
General product use pattern categories are defined as in Table 7. General product use 
categories will be used for both safety summaries and non-safety analysis.  More granular 
product exposure categories will be used for the detailed description of the product use patterns 
observed in the study.  Full details of the product use categories derivation are reported in the 
SAP. 
 
Table 7: Actual Product Use General Pattern Categories 
Category Label 
General Description 
THS-use 
• 
≥ 1 THSts or CC and 
• 
≥ 70% THSts use in the analysis period and 
• 
≥ 70% THSts use on ≥ 50% of the days in the analysis period 
 
Dual-use 
• 
≥ 1 THSts or CC and 
• 
1% ≤  THSts < 70% in the analysis period  
or 
• 
THS-use and CC-use don’t apply due to < 50% of the days 
 
CC-use 
• 
≥ 1 THSts or CC and 
• 
< 1% THSts in the analysis period and 
• 
< 1% THSts on ≥ 50% of the days in analysis period 
 
Other-use  
General category encompassing subjects with missing product use, or 
subjects using e-cigarettes or other tobacco products, subjects who quit, 
or subjects who switched across different use patterns between 
consecutive analysis periods.  
Rules applied over 6-mont analysis periods. Details of combined 12-month the product use categories are 
reported in the SAP. THSts = THS Tobacco Stick; THS=Tobacco Heating System; CC= Conventional 
Cigarette. 
 
12.4 Analysis Population 
The Full Analysis Set – as Exposed (FAS-EX) will be the primary analysis set for clinical risk 
endpoints, BoExp, and questionnaires, based on the overall product use pattern categories. 
 
 
 
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Supportive analyses will be run on the per-protocol (PP) population and a sensitivity analysis 
will be conducted on the Full Analysis Set – as Randomized (FAS-AR).  
The primary population for the assessment of safety will be the safety population. Safety will 
be summarized and presented by randomization arm and according to product use pattern 
categories. 
12.4.1 
Full Analysis Set - as Randomized (FAS-AR) 
The FAS-AR consists of all the randomized subjects with signed ICF who have both a valid 
baseline and at least one valid post-randomization value for one of the primary endpoints.  
Subjects enrolled at sites that are terminated due to findings of non-compliance with GCP 
and/or with the protocol will be excluded from the FAS-AR. 
Subjects included in the FAS-AR are analyzed as per randomized arm. 
12.4.2 
Full Analysis Set - as Exposed (FAS-EX) 
The FAS-EX consists of all subjects in FAS-AR who have at least one record of reported 
product use diary post randomization. 
The exposure assignment for the FAS-EX will be actual product exposure, as defined by the 
product use pattern categories estimated during the 12 month period ]V4, V16[.  The product 
use pattern categories are defined in section 12.3. 
12.4.3 
Per-Protocol Population 
The PP population is a subset of FAS-EX and includes all subjects who: 
• Have a product use pattern category THS-use if randomized to THS 2.2 or have product 
use pattern category CC-use if randomized to CC. 
• Were included in the PP population in the original study. 
• Do not make a quit attempt. 
• Have no major protocol deviations that impact the overall subject evaluability (as detailed 
in the SAP). 
• Have data for at least one endpoint of the “smoker’s health profile” which is not missing 
or excluded from the PP analysis at V7, V10, or V16, because of a major protocol deviation 
impacting evaluability. 
 
 
 
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12.4.4 
Safety Population 
The safety population consists of all the subjects enrolled with signed ICF who have at least 
one valid value for a safety assessment. This analysis set excludes all subjects enrolled in sites 
terminated due to findings of non-compliance with GCP and/or with the protocol. In general, 
the exposure assignment for the full safety population will be by randomization arm and 
according to product use pattern categories as defined in section 12.3. 
12.5 Primary Analysis 
12.5.1 
Primary Endpoint Analysis Variables 
The “smokers’ health profile” endpoints to be analyzed at V16 are: 
• HDL-C. 
• WBC. 
• sICAM-1. 
• 11-DTX-B2. 
• 8-epi-PGF2α. 
• COHb. 
• FEV1. 
• Total NNAL. 
See section 3.1. 
Study Hypothesis: 
No hypotheses are to be tested. The objective of the study is to determine the effect of THS 2.2 
compared to CC at week 52 on the components of the “smokers’ health profile” and to provide 
additional information to the results of the original study (ZRHR-ERS-09-US) for a prolonged 
exposure period.  
Exploratory statistical hypothesis testing will be conducted to assess baseline comparability 
(see Section 12.5.2 “Baseline Comparability”) and to evaluate the THS 2.2 effect on selected 
endpoints (as detailed in the SAP). All the THS 2.2 effect estimates will be accompanied by 
95% CI. 
 
 
 
 
 
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Evaluation Criterion: 
The study will target to describe the 95% confidence intervals (CI) of the THS 2.2 effect as 
compared to CC at week 52 on the components of the “smokers’ health profile” estimated with 
a precision of ±75% of the anticipated THS 2.2 effect at week 52. 
12.5.2 
Baseline Comparability 
There will be no formal comparison of Baseline data, however exploratory statistical 
hypothesis testing will be conducted to assess the characteristics of the subjects enrolling in 
the extension study. Baseline comparability will be assessed between subjects enrolled and not 
enrolled in the study among subjects who completed V10, by means of analysis of variance 
method and chi-square tests for continuous and categorical variables, respectively. 
12.5.3 
Descriptive Analysis 
Primary endpoints will be summarized at Baseline, V7, V10 and at V16 for the product use 
categories at V16 of FAS-EX, and by randomization arm for the FAS-AR and PP population. 
12.5.4 
Confirmatory Analysis 
No formal confirmatory analysis is foreseen in this study.  
FEV1, HDL-C, and WBC will be analyzed in the real scale. Other clinical risk endpoints, which 
will be analyzed in the logarithmic scale, will be back-transformed to provide relative effects. 
The primary analysis for the “smokers’ health profile” endpoints will be based on a mixed 
model for repeated measurements (MMRM). The model will include the endpoint value as the 
dependent variable, product use pattern category, visit (V7, V10, and V16), and exposure by 
visit interaction as fixed effects, with adjustment for site, sex, and Baseline endpoint value. In 
order to adjust for potential residual confounding, covariates found to be not balanced between 
THS-use and CC-use will be included in the final model. Modeling assumptions will be 
evaluated and model fit assessed by the analysis of residuals (model diagnostics) and by 
comparing the values predicted versus the observed endpoint values (calibration). 
The point and interval estimate of the contrast of THS-use versus CC-use at V16 will be 
tabulated for the FAS-EX.  
Supportive analysis will be conducted on the FAS-AR and PP set. 
The detailed analysis methods, including subgroup analyses, are given in the SAP. 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
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Final Version 3.0 / 23 August 2016 
Page 83 of 115 
 
 
12.6 Secondary Analysis 
12.6.1 
Secondary Endpoint Analysis Variables 
See section 3.2. 
The details on derivation rules are provided in the SAP. 
12.6.2 
Descriptive Analysis 
The number of CC or THS Tobacco Sticks used daily (as reported on the self-reported product 
use electronic diary) will be described over time on FAS-AR, FAS-EX, and on the safety 
population. 
The levels of the BoExp and nicotine exposure level and their percent change from Baseline 
will be listed and summarized over the 12-month study period for the FAS-AR, FAS-EX and 
PP population.  
The levels of lung function and CVD clinical risk endpoints will be summarized for the 
FAS-EX over the 12-month study period, along with change from baseline. 
A supportive analysis will be conducted on the “smokers’ health profile” endpoints for the 
FAS-EX, FAS-AR, and PP population to compare the THS-use versus CC-use, and Dual-use 
versus CC-use at V16 by means of the MMRM approach used for the primary analysis. The 
estimates of the difference/percent reduction (and 2-sided p-values) will be presented together 
with 95% CI for THS-use versus CC-use and Dual-use vs CC-use. The same approach will be 
adopted for the analysis of BoExp, lung function, and CVD risk endpoints. 
The number and percentage of subjects reporting a cough will be summarized for FAS-EX 
over the 12-month study period. A logistic regression model will be used to evaluate the 
differences between incidence rates (with 2-sided p-values) and 95% CI for the need to cough 
between THS-use and CC-use at V16. The models will only include terms for visit, baseline 
level and its interaction with visit, sex, Caucasian origin, and product use pattern category and 
its interaction with visit. The point and 95% CI of LS means of the incidence rates and their 
difference (with 2-sided p-values) will also be produced for Dual-use versus CC-use. The 
responses to the individual items, including the VAS score and change from Baseline, and 3 
Likert scales measuring the intensity and frequency of cough, and the amount of sputum 
production will be listed and summarized for all subjects who filled in the questionnaire. 
The change from Baseline will be calculated for the five domain scores of the MCEQ for the 
FAS-AR, FAS-EX and PP population over the 12-month study period.  Scores and changes 
from baseline will be listed and summarized. 
The FTND score and the number and percent of subjects in each category of the FTND score and 
of the response to the first item of the FTND will be summarized for FAS-EX and PP population 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

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Page 84 of 115 
 
 
during the 12-month period The change from V1 in the FTND score category and for response to 
the first item of the FTND will be presented in a shift table.  
The number and proportion of subject responses to items of the ITUQ will be summarized. Changes 
in response categories will also be summarized in shift tables by product use pattern groups for 
FAS-EX and PP during the 12-month period. 
The distribution of dual use will be summarized by cross-tabulation of the frequency (number 
and percent) of subjects for the categories of the following two variables for the FAS-EX 
population: average number of CC smoked over a 6 month period and the average number of 
THS Tobacco Sticks used over a 6 month period. To describe the effect of dual use on the 
components of the “smokers’ health profile” the exposure-response relationship between the 
CC and THS 2.2 exposure and the “smokers’ health profile” endpoints level is evaluated by 
means of the following approach based on method proposed by Follmann [40]. The details on 
the analysis method are described in the SAP. 
12.6.3 
Inferential Analysis 
See section 12.1.5. 
12.6.4 
Safety Analysis 
All safety data collected during the study will be provided in listings by randomization arm, 
site, subject and product use pattern category defined over the 12-month period.  Safety study 
periods are defined as follows: 
• Screening: 
[Screening to V3] 
• Product Trial: 
]V3 to V4]  
• Exposure: 
]V4 to V16] 
• Safety Follow-up: 
[Start to End of Safety Follow-up] 
Summaries of safety parameters will be conducted on the safety population. Unless otherwise 
specified, summaries will be produced by randomization arm and product use pattern 
categories over the relevant safety exposure periods. 
Adverse event data will serve as the primary assessment of safety. Other safety variables 
monitored in this study include: respiratory symptoms (cough assessment VAS and Likert 
scales); vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate); 
electrocardiogram (ECG) data; clinical chemistry, hematology, concomitant medications, and 
urine analysis safety panel; physical examination. 
The number and percentage of subjects with AEs and SAEs will be tabulated by the Medical 
Dictionary for Regulatory Activities (MedDRA), system organ class (SOC) and preferred term 
(PT) for the safety population overall, and in analysis time intervals. Summaries will also be 
presented for AEs leading to withdrawal, AEs leading to death, AEs by relatedness to product 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

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Clinical Study Protocol 
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Final Version 3.0 / 23 August 2016 
Page 85 of 115 
 
 
exposure and AEs by severity. Tabulations will be performed for both the number of subjects 
experiencing an event and the number of events for the Safety population. 
The number and percentage of subjects with clinical findings will be summarized for the safety 
population. Shift tables showing change from Baseline of clinical findings will be provided 
for: ECGs, COPD categories, 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, physical examination, ECG, respiratory symptoms, and vital signs. 
12.7 Exploratory Analysis 
12.7.1 
Exploratory Endpoint Analysis Variables 
Not applicable. 
12.7.2 
Descriptive Analysis 
Not applicable. 
12.8 Demographics and Baseline Characteristics 
The demographic variables age, sex, race, body weight, height, BMI and waist circumference 
will be summarized by product use pattern categories and by sex for the FAS-EX. Other 
baseline characteristics including scores for SES questionnaire, smoking history, and subjects’ 
answer to product preference will also be included in the table. 
Demographic and other baseline characteristics will also be summarized for the FAS-AR, 
safety and PP population. All data will be listed by randomization arms. 
No inferential analyses will be presented for the demographic and baseline characteristics. 
12.9 Interim Analysis 
There are no planned interim analyses. 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

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Clinical Study Protocol 
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Final Version 3.0 / 23 August 2016 
Page 86 of 115 
 
 
13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Study Administrative Structure 
13.1.1 
Sponsor 
 
 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Phone: + 41 (0) 58 242 2111 
Fax: + 41 (0) 58 242 2811 
 
Clinical Scientist 
Phone: +41 
 
E-mail: 
@pmi.com 
, PhD 
Study Statistician 
Phone: +41
 
Mobile: +41 
 
E-mail: 
@pmi.com 
, MD  
Medical Safety Officer 
Phone: +41 
 
E-mail 1: 
@pmi.com 
E-mail 2: 
@pmi.com  
, PhD 
Clinical Study Manager 
Phone: +41 
 
Mobile: +41 
 
E-mail: 
@pmi.com 
 
13.1.2 
Other Responsibilities 
All duties and responsibilities transferred to Covance by PMI will be defined in the agreement 
signed between the two parties. 
The name of all sites is listed below: 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
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Final Version 3.0 / 23 August 2016 
Page 87 of 115 
 
 
• 
 
 
Tempe, AZ 85283 
• 
  
 
Clearwater, FL 33765 
• 
  
 
Daytona Beach, FL 32117 
• 
  
 
Orlando,  FL 32806 
 
• 
  
 
Tampa,  FL 33603 
• 
 
 
      The Villages, FL 32162 
• 
  
 
Lexington,  KY 40509 
• 
  
 
Lincoln,  NE 68502 
• 
  
 
Raleigh,  NC 27609 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
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Final Version 3.0 / 23 August 2016 
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• 
  
 
Charlotte,  NC 28209 
• 
 
 
Wilmington,  NC 28401 
• 
  
 
Cary,  NC 27518 
• 
 
      
 
      Dayton, OH 45417 
• 
 
 
Bristol,  TN 37620 
• 
 
 
Knoxville,  TN 37920 
• 
 
 
San Angelo,  TX 76904 
• 
 
 
Austin,  TX 78705 
• 
 
 
Fort Worth, TX 76135 
• 
 
 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

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      Richmond, VA 
 
Any SAEs or pregnancies will be handled by: 
 
 
 
Switzerland 
Phone:  
+41 
 
Fax: 
 
+41 
 
E-mail: 
 
Details of the laboratories conducting the clinical safety laboratory services, biopharmaceutical 
analyses and the analyses of BoExp are shown in Appendix 2. 
13.2 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects' state of 
health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subject in writing and signed by the subject, in compliance with all local and 
national data protection and privacy legislation. 
The anonymity of subjects participating in this study will be maintained. Subjects will be 
identifiable by the Sponsor (or Sponsor’s authorized representative) on CRFs and other 
documents by their subject (or randomization) number/code, sex, and date of birth, but not by 
name, initial, or any other details relating to identifiable person (e.g., address, social security 
number, medical chart number, etc.). The assignment of a subject number/code for subject 
identification will be based on the appropriate data protection rules. 
The blood samples for transcriptomics and lipidomics the data related to these samples will be 
anonymized. Anonymized data and samples are initially single or double coded where the link 
between the subjects’ identifiers and the unique code(s) is subsequently deleted. This is 
applicable for the blood biobanking for transcriptomics and lipidomics. 
Any documents that allow full identification of the subject (e.g., the subject’s signed ICF) must 
be maintained in confidence by the Principal Investigator or designee. If any document relating 
to this study shows a subject’s name or any other details relating to an identifiable person (e.g., 
address, social security number, medical chart number, etc.), it is the responsibility of the 
Principal Investigator or designee to ensure that the name or other identifiable details be 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
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Final Version 3.0 / 23 August 2016 
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obscured before a copy of that document is supplied to the Sponsor or the Sponsor’s authorized 
representative. 
13.3 Access to Source Documents 
Subjects will be informed that, during as well as after the course of the clinical study, the 
Sponsor, any authorized representatives of the Sponsor, IRB, or regulatory authorities may 
inspect their medical records to verify the information collected, and ensure that all personal 
information made available for inspection is handled in the strictest confidence and in 
accordance with national and local data protection and privacy legislation. 
The PI(s) and all study site staff involved with the study must permit direct access to source 
data/documents for study related monitoring, audits, IRB review, and regulatory inspection(s). 
13.4 Record Retention 
All records of data, source data and source documents (original records or certified copies), in 
any form (including, but not limited to, written, electronic, magnetic, optical records and scans, 
and ECGs) that describe or record the methods, conduct, and/or results of the study, the factors 
affecting the study, and the actions taken will be maintained by the Investigator/study site for 
the study, as required by ICH GCP [2] 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 Section 8 of the 
ICH Tripartite Guideline for Good Clinical Practice [2]. 
Essential documents must be retained by the Investigator 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. 
• After formal discontinuation of clinical development of the IP. 
These documents should be retained for a longer period, however, if required by applicable 
regulatory requirements or by an agreement with the Sponsor. 
Examples of essential records/documents include, but are not limited to: 
• Signed informed consent documents for all subjects and master ICF. 
• Subject identification code list, screening log, and enrollment log (if applicable). 
• Record of all communications between the Investigator and the IRB, composition of the 
IRB. 
• Record of all communications/contact between the PI(s) or designee(s), Sponsor, and its 
authorized representatives. 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
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• List of sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in the 
study, curricula vitae, and their signatures. 
• Investigator logs. 
• CRFs, study specific questionnaires (and associated data/scoring), subject diaries. 
• AE reports and details of follow-up investigations, details of concomitant medication. 
• All other source documents (e.g., ECGs, consultation reports, physical examination, 
laboratory records) or any electronically captured study source data. 
• Clinical laboratory reports, laboratory normal ranges. 
• Original medical/hospital records, if applicable (the medical files of study subjects must be 
retained in accordance with local legislation and in accordance with the maximum period 
of time permitted by the hospital or study site). 
• Record of any body fluids or tissue samples collected and retained. 
• Device issue log, IP accountability logs, dispensing records. 
• Information regarding subjects’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the PI(s)/study site(s) as to when these 
documents no longer need to be retained. 
The PI(s)/study site(s) must take measures to prevent accidental or premature destruction of 
these documents. 
If the PI(s) wish(es) to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
The PI(s) or designee(s) must obtain written approval from the Sponsor before destruction of 
any records. Normally, these records will be held in the archives of the PI(s). If a Principal 
Investigator is unable to meet this obligation, he/she must ask the Sponsor for permission to 
make alternative arrangements. Details of these arrangements must be documented. 
The Sponsor or Sponsor’s authorized representative will maintain documentation relating to 
the study as long as the IP is on the market, and/or for 15 years after the CSR has been finalized. 
13.5 Clinical Study Report 
The Sponsor must ensure that a CSR for this study is prepared regardless of whether the study 
is completed or prematurely terminated. 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

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The CSR will be written based on standards of the ICH Guideline for the structure and content 
of clinical study reports [41]. In certain circumstances, an abbreviated CSR may be acceptable. 
Submission of the CSR to the IRB will be complied with as requested by local requirements. 
The results of the additional variables for analysis will be presented in reports separate from 
the study CSR. 
13.6 Financial Disclosure 
Principal Investigator(s) is (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 information that is confidential and proprietary to the Sponsor. This 
information is being provided solely for the purpose of evaluation and/or conducting this 
clinical study for the Sponsor. Disclosure of the content of this document is allowed only to 
study personnel, IRB, or duly authorized representatives of regulatory agencies for this purpose 
under the condition that confidentiality is maintained. The contents of this document may not 
be used in any other clinical study, disclosed to any other person or entity without the prior 
written permission of the Sponsor. The foregoing shall not apply to disclosure required by any 
regulations; however, prompt notice will be given to the Sponsor prior to any such disclosure. 
The Sponsor plans to disclose details of the study protocol on a web-based, publicly available, 
clinical trial register database (e.g., ClinicalTrials.gov). 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
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14 REFERENCE LIST 
[1] 
Scanlon PD, Connett JE, Waller LA, Altose MD, Bailey WC, Buist AS. Smoking 
cessation and lung function in mild-to-moderate chronic obstructive pulmonary 
disease. The Lung Health Study. Am J Respir Crit Care Med. 2000;161(2 Pt 1):381-
90. 
[2] 
ICH E6 (R1). Guideline for Good Clinical Practice. 1996; Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
6/E6_R1_Guideline.pdf (Accessed on 14 August 2014). 
[3] 
World Medical Association (WMA). WMA Declaration of Helsinki - Ethical principles 
for medical research involving human subjects. 2013. 
[4] 
FDA (Food and Drug Administration). Guidance for industry - Modified risk tobacco 
product applications - Draft Guidance. 2012. 
[5] 
U.S. Department of Health and Human Services. How tobacco smoke causes disease: 
the biology and behavioral basis for smoking-attributable disease: a report of the 
Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers 
for Disease Control and Prevention, National Center for Chronic Disease Prevention 
and Health Promotion, Office on Smoking and Health. 2010. 
[6] 
Rodgman A, Perfetti TA. The chemical components of tobacco and tobacco smoke. 
2nd ed: CRC Press, Taylor & Francis Inc (United States); 2013. 
[7] 
U.S. Department of Health and Human Services. Docket No. FDA-2012-N-0143: 
harmful and potentially harmful constituents in tobacco products and tobacco smoke; 
established list. Fed Regist. 2012;77(64):20034-7. 
[8] 
Philip Morris Products S.A. Unpublished on file data: Investigator's Brochure for 
Tobacco Heating System 2.2 Regular. Edition 4. 2014. 
[9] 
Philip Morris Products S.A. A single-center, open-label, randomized, controlled, 
crossover study to explore the nicotine pharmacokinetic profile and safety of Tobacco 
Heating System (THS) 2.1 compared to conventional cigarettes following single and 
ad libitum use in smoking, but otherwise healthy subjects [ZRHX-PK-02]. In: 
ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 
2013- 
[cited 
2013 
May 
03]. 
Available 
from: 
http://clinicaltrials.gov/show/NCT01780688 NLM Identifier: NCT01780688. 
[10] 
Philip Morris Products S.A. A single-center, open-label, randomized, controlled, 2-arm 
parallel group study to evaluate the exposure to selected smoke constituents in 
smoking, but otherwise healthy subjects switching from conventional cigarettes to the 
Tobacco Heating System (THS) 2.1 [ZRHX-EX-01]. In: ClinicalTrials.gov [Internet]. 
Bethesda (MD): National Library of Medicine (US). 2013 -[cited 2013 May 03]. 
Available 
from: 
http://clinicaltrials.gov/show/NCT01780714 
NLM 
Identifier: 
NCT01780714. 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
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Final Version 3.0 / 23 August 2016 
Page 94 of 115 
 
 
[11] 
Philip Morris Products S.A. Unpublished on file data: Investigator's Brochure for 
Tobacco Heating System 2.2 Regular. Edition 3. 2014. 
[12] 
Forey BA, Fry JS, Lee PN, Thornton AJ, Coombs KJ. The effect of quitting smoking 
on HDL-cholesterol - a review based on within-subject changes. Biomark Res. 
2013;1(1):26. 
[13] 
Palmer RM, Stapleton JA, Sutherland G, Coward PY, Wilson RF, Scott DA. Effect of 
nicotine replacement and quitting smoking on circulating adhesion molecule profiles 
(sICAM-1, sCD44v5, sCD44v6). Eur J Clin Invest. 2002;32(11):852-7. 
[14] 
Scott DA, Stapleton JA, Wilson RF, Sutherland G, Palmer RM, Coward PY, et al. 
Dramatic decline in circulating intercellular adhesion molecule-1 concentration on 
quitting tobacco smoking. Blood Cells Mol Dis. 2000;26(3):255-8. 
[15] 
Tsai JS, Guo FR, Chen SC, Lue BH, Lee LT, Huang KC, et al. Changes of serum 
adiponectin and soluble intercellular adhesion molecule-1 concentrations after smoking 
cessation. Clin Chem Lab Med. 2012;50(6):1063-9. 
[16] 
Hammett CJ, Prapavessis H, Baldi JC, Ameratunga R, Schoenbeck U, Varo N, et al. 
Variation in blood levels of inflammatory markers related and unrelated to smoking 
cessation in women. Prev Cardiol. 2007;10(2):68-75. 
[17] 
Haustein KO, Krause J, Haustein H, Rasmussen T, Cort N. Effects of cigarette smoking 
or nicotine replacement on cardiovascular risk factors and parameters of 
haemorheology. J Intern Med. 2002;252(2):130-9. 
[18] 
Jensen EJ, Pedersen B, Frederiksen R, Dahl R. Prospective study on the effect of 
smoking and nicotine substitution on leucocyte blood counts and relation between 
blood leucocytes and lung function. Thorax. 1998;53(9):784-9. 
[19] 
Lee PN, Forey BA, Fry JS, Thornton AJ, Coombs KJ. The effect of quitting smoking 
on white blood cell count - A review based on within-subject changes [Internet]. 2014; 
Available from: http://www.pnlee.co.uk/documents/refs/lee2014D.pdf (Accessed on 
15 May 2014). 
[20] 
Ergüder IB, Ergüder T, Ozkan C, Bozkurt N, Soylu K, Devrim E, et al. Short-term 
effects of smoking cessation on blood antioxidant parameters and paraoxonase activity 
in healthy asymptomatic long-term cigarette smokers. Inhal Toxicol. 2006;18(8):575-
9. 
[21] 
Kambam JR, Chen LH, Hyman SA. Effect of short-term smoking halt on 
carboxyhemoglobin levels and P50 values. Anesth Analg. 1986;65(11):1186-8. 
[22] 
Saareks V, Ylitalo P, Alanko J, Mucha I, Riutta A. Effects of smoking cessation and 
nicotine substitution on systemic eicosanoid production in man. Naunyn 
Schmiedebergs Arch Pharmacol. 2001;363(5):556-61. 
[23] 
Rangemark C, Ciabattoni G, Wennmalm A. Excretion of thromboxane metabolites in 
healthy women after cessation of smoking. Arterioscler Thromb. 1993;13(6):777-82. 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 95 of 115 
 
 
[24] 
Roethig HJ, Zedler BK, Kinser RD, Feng S, Nelson BL, Liang Q. Short-term clinical 
exposure evaluation of a second-generation Electrically Heated Cigarette Smoking 
System. J Clin Pharmacol. 2007;47:518. 
[25] 
Pilz H, Oguogho A, Chehne F, Lupattelli G, Palumbo B, Sinzinger H. Quitting cigarette 
smoking results in a fast improvement of in vivo oxidation injury (determined via 
plasma, serum and urinary isoprostane). Thromb Res. 2000;99(3):209-21. 
[26] 
Chehne F, Oguogho A, Lupattelli G, Palumbo B, Sinzinger H. Effect of giving up 
cigarette smoking and restarting in patients with clinically manifested atherosclerosis. 
Prostaglandins Leukot Essent Fatty Acids. 2002;67(5):333-9. 
[27] 
Bake B, Oxhoj H, Sixt R, Wilhelmsen L. Ventilatory lung function following two years 
of tobacco abstinence. Scand J Respir Dis. 1977;58(6):311-8. 
[28] 
Buist AS, Sexton GJ, Nagy JM, Ross BB. The effect of smoking cessation and 
modification on lung function. Am Rev Respir Dis. 1976;114(1):115-22. 
[29] 
Willemse BW, ten Hacken NH, Rutgers B, Lesman-Leegte IG, Postma DS, Timens W. 
Effect of 1-year smoking cessation on airway inflammation in COPD and 
asymptomatic smokers. Eur Respir J. 2005;26(5):835-45. 
[30] 
Lee PN, Fry JS. Systematic review of the evidence relating FEV1 decline to giving up 
smoking. BMC Med. 2010;8:84. 
[31] 
Goniewicz ML, Havel CM, Peng MW, Jacob P, 3rd, Dempsey D, Yu L, et al. 
Elimination kinetics of the tobacco-specific biomarker and lung carcinogen 4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanol. Cancer Epidemiol Biomarkers Prev. 
2009;18(12):3421-5. 
[32] 
Carmella SG, Chen M, Han S, Briggs A, Jensen J, Hatsukami DK, et al. Effects of 
smoking cessation on eight urinary tobacco carcinogen and toxicant biomarkers 
(Erratum in Chem Res Toxicol. 2012 Mar 19;25(3):763). Chem Res Toxicol. 
2009;22(4):734-41. 
[33] 
U.S. Department of Health and Human Services. Treating tobacco use and dependence: 
2008 
update. 
Clinical 
practice 
guideline. 
2008;Available 
from: 
http://bphc.hrsa.gov/buckets/treatingtobacco.pdf (Accessed on 18 July 2014). 
[34] 
U.S. Department of Health and Human Services. Helping smokers quit. A guide for 
clinicians. 2008. 
[35] 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
[36] 
Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, et al. 
Standardisation of the measurement of lung volumes. Eur Respir J. 2005;26(3):511-22. 
[37] 
Fagerstrom K, Russ C, Yu CR, Yunis C, Foulds J. The Fagerstrom Test for Nicotine 
Dependence as a predictor of smoking abstinence: a pooled analysis of varenicline 
clinical trial data. Nicotine Tob Res. 2012;14(12):1467-73. 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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[38] 
Cappelleri JC, Bushmakin AG, Baker CL, Merikle E, Olufade AO, Gilbert DG. 
Confirmatory factor analyses and reliability of the modified cigarette evaluation 
questionnaire. Addict Behav. 2007;32:912–23. 
[39] 
FDA (Food and Drug Administration). Implementation Specifications, reporting 
medical device problems (C54451/Medical_Device_Problem_Codes_FDA_CDRH). 
2012; 
Available 
from: 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequ
irements/ReportingAdverseEvents/EventProblemCodes/ucm134761.htm 
(Accessed 
on 01 December 2014). 
[40] 
Follmann DA. On the effect of treatment among would-be treatment compliers: an 
example of the multiple risk factor intervention trial. Journal of the American Statistical 
Association 2000; 95: 1101-09. 
[41] 
ICH E3. Structure and content of clinical study reports. 1995; Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
3/E3_Guideline.pdf (Accessed on 17 July 2014). 
[42]  
U.S. Department of Health and Human Services. Common terminology criteria for 
adverse 
events. 
2010; 
Available 
from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf (Accessed on 23 April 2014)(CTCAE v4.03). 
 
 
 
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Page 97 of 115 
 
 
15 APPENDICES 
Appendix 1 
Schedule of Events 
Table A1 
Study Assessments  
Visits  
Assessments 
ZRHR-ERS-09-US 
ZRHR-ERS-09-EXT-US 
Extended Exposure Period 
Safety 
Follow-Up g 
V3 
(Baseline) 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
28 days 
ERS 
EXT 
Study week (W) 
- 
W26 
W30 
W35 
W39 
W43 
W48 
W52 
 
Informed consent and additional ICFs for 
biobanking for ZRHR-ERS-09-EXT-US 
 
 
● 
 
 
 
 
 
 
 
Inclusion / exclusion check for ZRHR-ERS-09-
US 
● V1+V3 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion check for ZRHR-ERS-09-
EXT-US 
 
 
● 
 
 
 
 
 
 
 
Readiness to comply with study procedures 
and to use THS 2.2 for 26 additional weeks 
 
 
● 
 
 
 
 
 
 
 
Enrollment of ZRHR-ERS- 09-US 
● 
 
 
 
 
 
 
 
 
 
Enrollment of ZRHR-ERS-09-EXT-US 
 
 
● 
 
 
 
 
 
 
 
Information on the risk of smoking, advice on 
smoking cessation (SC), and debriefing on 
THS 2.2 
● 
● 
 
● 
● 
● 
● 
● 
● 
 
Concomitant medication 
● 
 ● 
● 
● 
● 
● 
● 
● 
● 
 
 
 
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Final Version 3.0  / 23 August 2016 
Page 98 of 115 
 
 
Visits  
Assessments 
ZRHR-ERS-09-US 
ZRHR-ERS-09-EXT-US 
Extended Exposure Period 
Safety 
Follow-Up g 
V3 
(Baseline) 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
28 days 
ERS 
EXT 
U: Pregnancy test (females) 
● 
● 
 
● 
● 
● 
● 
● 
● 
 
B/U: Clinical chemistry, hematology, urine 
analysis a 
● 
● 
 
 
 
 
 
 
● 
 
ECG 
 
● 
 
 
 
 
 
 
● 
 
Vital signs b 
● 
● 
 
● 
● 
● 
● 
● 
● 
 
Waist circumference 
● 
● 
 
 
 
 
 
 
● 
 
Weight and body mass index (BMI) c 
● 
● 
 
 
 
● 
 
 
● 
 
Physical examination 
● 
● 
 
 
 
 
 
 
● 
 
Dispensing of THS 2.2 
● 
 
● 
● 
● 
● 
● 
● 
 
 
CO breath test d 
● 
● 
 
 
 
 
 
 
● 
 
U: BoExp in urine (Table A2) 
● 
● 
 
 
 
 
 
 
● 
 
U: CVD clinical risk endpoints in urine (Table 
A2) 
● 
● 
 
 
 
 
 
 
● 
 
B: CVD clinical risk endpoints (Table A3) 
● 
● 
 
 
 
 
 
 
● 
 
B: BoExp in blood (Table A3) 
● 
● 
 
 
 
 
 
 
● 
 
Pre-bronchodilator spirometry testing e 
 
● 
 
 
 
 
 
 
● 
 
Post-bronchodilator spirometry testing e 
● 
● 
 
 
 
 
 
 
● 
 
Lung volume e 
● 
● 
 
 
 
 
 
 
● 
 
 
 
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Philip Morris Products SA 
Clinical Study Protocol 
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Final Version 3.0  / 23 August 2016 
Page 99 of 115 
 
 
Visits  
Assessments 
ZRHR-ERS-09-US 
ZRHR-ERS-09-EXT-US 
Extended Exposure Period 
Safety 
Follow-Up g 
V3 
(Baseline) 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
28 days 
ERS 
EXT 
Cough questionnaire 
● 
● 
 
 
 
 
 
 
● 
 
MCEQ questionnaire 
● 
● 
 
 
 
 
 
 
● 
 
Product use diary (daily) f 
● 
 
● 
● 
● 
● 
● 
● 
● 
 
FTND 
 
● 
 
 
 
 
 
 
● 
 
Intent to use THS 2.2 questionnaire (ITUQ) h 
 
● 
 
 
 
 
 
 
● 
 
AE/SAE recording i 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
U: Biobanking (Table A2) j 
● 
● 
 
 
 
 
 
 
● 
 
B: Biobanking for BoExp and clinical risk 
endpoints (Table A3) j 
● 
● 
 
 
 
 
 
 
● 
 
B: Biobanking for transcriptomics and 
lipidomics (Table A3) j 
● 
● 
 
 
 
 
 
 
● 
 
Abbreviations: AE = Adverse event; B: Blood sample required; BMI = Body mass index; BoExp = Biomarkers of exposure; CC = Conventional cigarette(s); CO = Carbon monoxide; 
COHb = Carboxyhemoglobin; CVD = Cardiovascular disease; ECG = Electrocardiogram; FTND = Fagerström test for nicotine dependence; MCEQ = Modified cigarette evaluation 
questionnaire; SAE = Serious adverse event; THS = Tobacco Heating System; U = Urine sample required; VAS = Visual analog scale 
a 
Safety laboratory parameters will be evaluated in at least 10 hours of fasting conditions. 
Hematology: hematocrit, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, platelet count, red blood cell 
count, white blood cell count, differential white blood cell count. Platelet count, white blood cell count from hematology will be evaluated as clinical risk endpoints. Urine 
analysis: pH, bilirubin, glucose, nitrite, red blood cell traces, protein, specify gravity. Clinical chemistry: albumin, total protein, alkaline phosphatase, alanine aminotransferase, 
aspartate aminotransferase, blood urea nitrogen, creatinine, gamma-glutamyl transferase, glucose, lactate dehydrogenase, potassium, sodium, total bilirubin, direct bilirubin, 
total cholesterol, triglycerides. White blood cell count (WBC) will also be evaluated as part of the “smokers’ health profile”. 
b 
Systolic and diastolic blood pressure, pulse rate, and respiratory rate. Vital signs will be assessed after at least 5 minutes in supine position. 
c 
Height will be transferred from the original study 
 
 
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d 
CO breath test: the test will be conducted once and should be done in conjunction with COHb blood where applicable. 
e 
Lung function assessments must be performed in the following sequence: 
• 
Pre-bronchodilator spirometry testing. 
• 
Pre-bronchodilator lung volume using helium dilution (only at V10 and V16). 
• 
Post-bronchodilator spirometry testing. 
f 
Use of any tobacco/nicotine containing products will be captured in the ediary. 
g 
Early termination procedures will be conducted in subjects who terminate from the study earlier. 
h 
At V16, only subjects in the THS 2.2 arm will answer to the ITUQ. 
i 
 During the safety follow-up period, spontaneous reporting of new AEs/SAEs by the subject will be done. 
j 
Once at every visit. Samples will only be taken if additional ICF for sample biobanking is signed by the subject. 
All assessments done at V10 in the context of the original study do not need to be repeated for the extension study. 
 
 
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Table A2 
Schedule for 24-hour Urine Collection Assessments 
 
 
ZRHR-ERS-09-US 
ZRHR-ERS-09-EXT-US 
 
V3 
(Baseline) 
V10 
V16 
ERS 
EXT 
Exposure 
BoExp in urine a 
● 
● 
 
● 
CVD Clinical Risk Endpoints 
11-DTXB2, 8-epi-PGF2α,  albumin 
● 
● 
 
● 
Others 
Creatinine 
● 
● 
 
● 
Biobanking for BoExp and clinical 
risk endpoints b 
● 
● 
 
● 
Abbreviations: BoExp = Biomarker(s) of exposure; CVD = Cardiovascular disease; 8-epi-PGF2α = 8-epi-prostaglandine F2α; 11-DTXB2 = 11-
dehydrothromboxane B2.  
a 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL), total N-nitrosonornicotine (total NNN), nicotine equivalents (Neq). 
b 
Samples will only be taken if additional ICF for biobanking is signed by the subject 
All assessments done at V10 in the context of the original study do not need to be repeated for 
the extension study. 
 
 
 
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Clinical Study Protocol 
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Final Version 3.0 / 23 August 2016 
Page 102 of 115 
 
 
Table A3 
Schedule 
for 
Blood/Serum/Plasma 
Assessments 
(Except 
Hematology and Clinical Chemistry) 
 
ZRHR-ERS-09-US 
ZRHR-ERS-09-EXT-US 
 
V3 
(Baseline) 
V10 
V16 
ERS 
EXT 
Blood 
CVD clinical risk endpoints (COHb 
and HbA1c a 
● 
● 
 
● 
Biobanking b 
● 
● 
 
● 
Plasma 
CVD clinical risk endpoints 
(fibrinogen and homocysteine)  
● 
● 
 
● 
Biobanking b 
● 
● 
 
● 
BoExp: nicotine and cotinine 
● 
● 
 
● 
Serum 
CVD clinical risk endpoints c 
● 
● 
 
● 
Biobanking b 
● 
● 
 
● 
Abbreviations: BoExp = Biomarker(s) of exposure; CVD = Cardiovascular disease; COHb = Carboxyhemoglobin; HbA1c = Hemoglobin 
glycosylated A1c 
a 
WBC and platelet count will be taken from the laboratory safety parameters. 
b 
Samples must only be taken if additional ICF for biobanking is signed by the subject. 
c 
sICAM-1, MPO, LDL-C, HDL-C, hs-CRP, Apo A1 and Apo B. 
All assessments done at V10 in the context of the original study do not need to be repeated for 
the extension study. 
 
 
 
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Appendix 2 
Concomitant Medication and Impact on Clinical 
Risk Endpoints (With Half-Lives) 
Drug 
Biological or 
Elimination 
Half-Life (h) 
Last Dose Applied 
in Hours Prior to 
Lab Value Tested 
(5 x Half-Life)  
Impact on 
Endpoint 
Vitamins+ 
Pyridoxine (Vitamin B6) 
2 - 5 
10 - 25 
HDL-C 
Cyanocobalamin (Vitamin B12) 
approx. 24 - 48 
120 - 240 
(≈ 5 - 10 days) 
HDL-C 
Thiamine Chloride (Vitamin 
B1) 
4 - 6 
20 - 30 
HDL-C 
Nicotinic acid (Vitamin B3) 
approx. 24 
120 
(≈ 5 days) 
HDL-C 
Ascorbic acid (Vitamin C) 
2.9 
14.5 
HDL-C 
Alpha-Tocopherol (Vitamin E) 
approx. 5 - 7 
days 
approx. 25 - 35 days 
PGF2α 
Systemic and Inhaled Drugs Affecting Spirometry 
Anticholinergic/Antimuscarinic 
Ipratropiumbromide 
3.6 
18 
FEV1 
Tiotropium 
120 - 144 
(≈ 5 - 6 days) 
600 - 720 
(≈ 25 - 30 days) 
FEV1 
Aclidinium bromide 
2 - 3 
10 - 15 
 
Short-acting β-agonists, orally taken 
Terbutaline sulfate 
Plasma 
t1/2: 3 - 4 
Plasma 
t1/2: 15 - 20 
FEV1 
Bambuterol 
22 - 24 
110 - 120 
(≈ 4.6 - 5 days) 
FEV1 
Inhaled short-acting β-agonists 
Salbutamol sulfate 
Plasma 
t1/2: 2.7 - 5 
Plasma 
t1/2: 13.5 - 25 
FEV1 
Fenoterol 
approx. 3 
approx. 15 
FEV1 
 
 
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Drug 
Biological or 
Elimination 
Half-Life (h) 
Last Dose Applied 
in Hours Prior to 
Lab Value Tested 
(5 x Half-Life)  
Impact on 
Endpoint 
Inhaled long-acting β-agonists 
Formoterol fumarate 
approx. 5 
approx. 25 
FEV1 
Indacaterol maleate 
40 - 52 
200 - 260 
(≈ 8.3 - 10.8 days) 
FEV1 
Salmeterol 
n.a. no systemic 
effect 
n.a 
FEV1 
Inhaled Glucocorticosteroids 
Beclomethasone 
2.8 
14 
FEV1 
Budesonide 
2 - 3 
10 - 15 
FEV1 
Ciclesonide 
6 - 7 
30 - 42 
(≈ 1.25 - 1.75 days) 
FEV1 
Fluticasone propionate 
16 - 21.3 
80 - 106.5 
(≈ 3.3 - 4.4 days) 
FEV1 
Systemic broncholytic drugs 
Montelukast 
Plasma 
t1/2: 2,7 – 5,5  
13.5 - 27.5 
FEV1 
Aminophylline,  
Theophylline 
7 - 9 
35 - 45 
FEV1 
Roflumilast 
Plasma 
t1/2: 17 
85 
(≈ 3.5 days) 
FEV1 
β-blockers 
Atenolol 
6 -10 
30 – 50 
(≈1.25 - 2 days) 
FEV1 
Metoprolol 
3 - 5 
15 - 25 
FEV1 
Bisoprolol 
17 ± 5 
85 
(≈3.5 days) 
FEV1 
Antiplatelet agents 
Phenprocoumon 
165 
(≈ 6.9 days) 
825 
(≈ 34 days) 
PGF2α 
 
 
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Drug 
Biological or 
Elimination 
Half-Life (h) 
Last Dose Applied 
in Hours Prior to 
Lab Value Tested 
(5 x Half-Life)  
Impact on 
Endpoint 
Apixaban 
12 
60 
(≈ 2.5 days) 
PGF2α 
Warfarin 
Plasma 
t1/2: 
approx. 35 - 45 
175 - 225 
(≈ 7.3 - 9.4 days) 
PGF2α 
Rivaroxaban 
5 - 13 
(age - 
dependent) 
25 - 65 
(≈ 1 - 2.7 days) 
PGF2α 
Acetylsalicylic acid 
2 - 30 (dose - 
dependent) 
10 - 150 
(up to 6.25 days) 
PGF2α 
Antidiabetic drugs 
Acarbose 
9,6 ± 4,4 
48 
(≈ 2 days) 
11-DTX-B2 
Metformin 
6.5 
32.5 
(≈ 1.3 days) 
11-DTX-B2 
Vildagliptin 
3 
15 
11-DTX-B2 
Saxagliptin 
26.9 
134.5 
(≈ 5.6 days) 
11-DTX-B2 
Repaglinide 
4 - 6 
20 - 30 
(up to 1.25 days) 
11-DTX-B2 
Glyburide 
8 - 10 
40 - 50 
(≈ 1.7 - 2.1 days) 
11-DTX-B2 
Glimepiride 
5 - 8 
20 - 40 
(up to 1.7 days) 
11-DTX-B2 
Pioglitazone 
16 - 23 
80 - 115 
(≈ 3.3 - 4.8 days) 
HDL-C 
NSAIDs 
Celecoxib 
8 - 12 
40 - 60 
(≈ 1.7-2.5 days) 
WBC, 11-DTX-B2 
Diclofenac 
approx. 2 
approx. 10 
WBC, 11-DTX-B2 
 
 
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Drug 
Biological or 
Elimination 
Half-Life (h) 
Last Dose Applied 
in Hours Prior to 
Lab Value Tested 
(5 x Half-Life)  
Impact on 
Endpoint 
Indometacin 
2; terminal 
phase: 4 - 11 
10; terminal phase: 
20-55 (up to 2.3 
days) 
WBC, 11-DTX-B2 
Meloxicam 
approx. 20 
approx. 100 
(≈ 4.2 days) 
WBC, 11-DTX-B2 
Piroxicam 
approx. 50 
250 
(≈ 10.4 days) 
WBC, 11-DTX-B2 
Ibuprofen 
1.8 - 3.5 
9 - 17.5 
WBC, 11-DTX-B2 
Ketoprofen 
1.5 - 2.5 
(up to 8) 
7.5 - 12.5 
(up to 40) 
WBC, 11-DTX-B2 
Naproxen 
10 - 18 
50 - 90 
(≈ 2.1 - 3.75 days) 
WBC, 11-DTX-B2 
Angiotensin-converting enzyme inhibitors 
Enalapril 
at least 24 
at least 120 
(at least 5 days) 
11-DTX-B2 
Quinapril 
approx. 26 
approx. 130 
(≈ 5.4 days) 
11-DTX-B2 
Ramipril 
13 - 17 
65 - 85 
(≈ 2.7 - 3.5 days) 
11-DTX-B2 
Lisinopril 
12.6 
63 
(≈ 2.6 days) 
11-DTX-B2 
Antidepressant Drugs 
Bupropion 
20 
100 
(≈ 4.2 days) 
WBC 
Selective serotonin reuptake 
inhibitors (SSRIs) 
 
 
 
Citalopram 
35 
175 
(≈ 7.29 days) 
WBC 
Escitalopram 
27 – 32 
135 – 160 
(up to 6.67 days) 
WBC 
 
 
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Drug 
Biological or 
Elimination 
Half-Life (h) 
Last Dose Applied 
in Hours Prior to 
Lab Value Tested 
(5 x Half-Life)  
Impact on 
Endpoint 
Fluoxetine 
Initial: 24 - 72 
Chronic: 96 – 
144 
Initial: 120 – 360 
(up to 15 days) 
Chronic: 480 – 720 
(up to 30 days) 
WBC 
Fluvoxamine 
16 
80 
(≈ 3.33 days) 
WBC 
Paroxetine 
21 
105 
(≈ 4.38 days) 
WBC 
Sertraline 
26 
130 
(≈ 5.42 days) 
WBC 
Serotonin–norepinephrine 
reuptake inhibitors (SNRIs)  
 
 
WBC 
Venlafaxine 
5 ± 2 
25 ± 10 
( ≈ 1.0 ± 0.4 days) 
 
Tricyclic antidepressants 
 
 
WBC 
Tricyclic clomipramine 
20 - 26 
100 - 130 
(≈ 4.2 - 5.4 days) 
 
Non-specified 
antidepressant drug class 
 
 
WBC 
Nefazodone 
11 - 24 
55 - 120 
(≈ 2.3 - 5 days) 
WBC 
Lipid lowering drugs 
Fibrate 
Fenofibrate 
Plasma 
t1/2: approx. 20 
approx. 100 
(≈ 4.2 days) 
HDL-C, total 
cholesterol (TC), 
triglycerides (TG) 
Gemfibrozil 
1.3 - 1.5 
6.5 - 7.5 
HDL-C, 
apolipoproteins 
Bile acid sequestrants 
Cholestyramine 
no absorption 
into blood 
stream 
n.a. 
HDL-C 
 
 
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Drug 
Biological or 
Elimination 
Half-Life (h) 
Last Dose Applied 
in Hours Prior to 
Lab Value Tested 
(5 x Half-Life)  
Impact on 
Endpoint 
Statins 
Atorvastatin 
20 - 30 
100 - 150 
(≈ 4.2 - 6.25 days) 
HDL-C, 11-DTX-B2 
Simvastatin 
approx. 2-3 
10 - 15 
HDL-C, 11-DTX-B2 
Rosuvastatin 
approx. 19 
95 
HDL-C, 11-DTX-B2 
Fluvastatin 
2.3 ± 0.9 
11.5 ± 4.5 
HDL-C, 11-DTX-B2 
* n.a. = not applicable 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 109 of 115 
 
 
Appendix 3 
Participating Laboratories 
 
 
  
 USA  
 
USA: 
 
 
 USA 
Tel: 
 
Fax: 
 
Geneva: 
 
 
Tel: +41 
 
Fax: +41 
 
 (USA and Switzerland) 
USA: 
 
  
68502, USA 
 
Switzerland: 
 
 
Switzerland 
 
More details will be found in the study laboratory manuals. 
 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 110 of 115 
 
 
For biobanking of samples: 
BIOSTORAGE TECHNOLOGIES 
Germany: 
 
 
 
Germany 
USA: 
 
 
  
 USA 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 111 of 115 
 
 
Appendix 4 
Investigational Product and Instructions for Use 
The product user guide was provided as a separate document during the original study. 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 112 of 115 
 
 
Appendix 5 
Abnormal Laboratory Values 
ABNORMAL LABORATORY VALUES RATING: SERUM CHEMISTRY PARAMETERS 
Serum Chemistry * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
(Grade 4) 
Sodium - 
Hyponatremia 
(mmol/L) 1 
< LLN - 130 
- 
< 130 - 120 
< 120 
Sodium – 
Hypernatremia 
(mmol/L) 1 
> ULN - 150 
> 150 - 155 
> 155 - 160 
hospitalization 
indicated 
> 160 
Potassium – 
Hyperkalemia 
(mmol/L) 1 
> ULN - 5.5 
> 5.5 - 6.0 
> 6.0 -7.0; 
hospitalization 
indicated 
> 7.0 
Potassium – 
Hypokalemia 
(mmol/L) 1 
< LLN - 3.0 
< LLN - 3.0; 
symptomatic; 
intervention indicated 
< 3.0 - 2.5 
hospitalization 
indicated 
< 2.5 
Glucose - 
Hypoglycemia 1 
(mg/dL) 
(mmol/L)  
< LLN - 55 
< LLN - 3.0 
< 55 - 40 
< 3.0 - 2.2 
< 40 - 30 
< 2.2 - 1.7 
< 30 
< 1.7 
Glucose - 
Hyperglycemia: 1 
Fasting (mg/dL) 
(mmol/L) 
> ULN - 160 
> ULN - 8.9 
> 160 - 250 
> 8.9 - 13.9 
> 250 - 500 
> 13.9 - 27.8 
hospitalization 
indicated 
> 500 
> 27.8 
Creatinine increase 1 
> 1 - 1.5 x Baseline 
> ULN - 1.5 x ULN 
> 1.5 - 3.0 x Baseline 
> 1.5 - 3.0 x ULN 
> 3.0 x Baseline 
> 3.0 - 6.0 x ULN 
> 6.0 x ULN 
Albumin - 
Hypoalbuminemia 1  
(g/dL) 
(g/L) 
< LLN - 3; 
< LLN - 30 
< 3 - 2; 
< 30 - 20 
< 2 
< 20 
- 
- 
Alkaline phosphatase 
increased 1 
> ULN - 2.5 x ULN 
> 2.5 - 5.0 x ULN 
> 5.0 - 20.0 x ULN 
> 20.0 x ULN 
ALT/AST increase 1 
> ULN - 3.0 x ULN 
> 3.0 - 5.0 x ULN 
> 5.0 - 20.0 x ULN 
> 20.0 x ULN 
Gamma-glutamyl 
transferase (GGT) 
increased 1 
> ULN - 2.5 x ULN 
> 2.5 - 5.0 x ULN 
> 5.0 - 20.0 x ULN 
> 20.0 x ULN 
Blood bilirubin 
increased  
(total and direct) 1 
> ULN - 1.5 x ULN 
> 1.5 - 3.0 x ULN 
> 3.0 - 10.0 x ULN 
> 10.0 x ULN 
 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
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Final Version 3.0 / 23 August 2016 
Page 113 of 115 
 
 
Serum Chemistry * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
(Grade 4) 
Cholesterol high 1 
(mg/dL) 
(mmol/L) 
> ULN - 300 
> ULN - 7.75 
> 300 - 400 
> 7.75 - 10.34 
> 400 - 500 
> 10.34 - 12.92 
> 500 
> 12.92 
Triglycerides - 
Hypertriglyceridemia 1 
(mg/dL) 
(mmol/L) 
150 - 300 
1.71 - 3.42 
> 300 - 500 
> 3.42 - 5.70 
> 500 – 1,000 
> 5.70 - 11.40 
> 1,000 
> 11.4  
Abbreviations: 
ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; BUN = Blood urea nitrogen; GGT = Gamma-glutamyl transferase; 
LLN = Lower limit of the normal range; ULN = Upper limit of the normal range. 
Data source: 
1  
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. U.S. Department of Health and Human Services, FDA,  
National Institutes of Health 
National Cancer Institute -. [42] 
* The parameters that are not listed and do not have grading categories in the CTCAE will be reviewed by the Principal Investigator or 
designee and will only be reported as an AE if considered to be clinically relevant. 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 114 of 115 
 
 
ABNORMAL LABORATORY VALUES RATING: HEMATOLOGY PARAMETERS 
Hematology * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
(Grade 4) 
Anemia 
(Hemoglobin) 1 
(g/dL) 
(mmol) 
g/L 
< LLN - 10.0 
< LLN - 6.2 
< 100 
< 10 - 8.0 
< 6.2 - 4.9 
< 100 - 80 
< 8.0 
< 4.9 
< 80 Transfusion 
indicated 
Life threatening 
consequences; 
urgent 
intervention 
indicated 
Hemoglobin increase 
(g/dL) 1 
Increase in 
> 0 - 2 above 
ULN or above 
Baseline if 
Baseline is above 
ULN 
Increase in > 2 - 4 
above ULN or 
above Baseline if 
Baseline is above 
ULN 
Increase in > 4 above 
ULN or above 
Baseline if Baseline is 
above ULN 
- 
WBC Decrease 
(cell/mm3) 1 
10-9/l 
< LLN – 3,000 
< LLN - 3.0 
< 3,000 - 2,000 
< 3.0 - 2.0  
< 2,000 - 1,000 
< 2.0 - 1.0  
< 1,000 
< 1.0  
Lymphocytes increase 
(cell/mm3) 1 
- 
> 4,000 - 20,000 
> 20,000 
- 
Lymphocytes 
decrease 
(cell/mm3) 1 
10-9/l  
< LLN - 800 
< LLN - 0.8 
< 800 - 500 
< 0.8 - 0.5 
< 500 - 200 
< 0.5 - 0.2 
< 200 
< 0.2 
Neutrophils decrease 
(cell/mm3) 1 
10-9/l  
< LLN - 1500 
< LLN - 1.5 
< 1500 - 1,000 
< 1.5 - 1.0 
< 1000 - 500 
< 1.0 – 0.5 
< 500 
< 0.5 
Platelets decrease - 
(cell/mm3) 1 
10-9/l  
< LLN – 75,000 
< LLN – 75.0 
< 75,000 – 50,000 
< 75.0 – 50.0 
< 50,000 – 25,000 
< 50.0 – 25.0 
< 25,000 
< 25.0 
Abbreviations: 
LLN = Lower limit of the normal range; ULN = Upper limit of the normal range; WBC = White blood cell. 
Data source: 
1 Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. U.S. Department of Health and Human Services, FDA,  
National Institutes of Health National Cancer Institute [42] 
* The parameters that are not listed and do not have grading categories in the CTCAE will be reviewed by the Principal Investigator or 
designee and will only be reported as an AE if considered to be clinically relevant. 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
ZRHR-ERS-09-EXT-US 
Final Version 3.0 / 23 August 2016 
Page 115 of 115 
 
 
ABNORMAL LABORATORY VALUES RATING: URINALYSIS PARAMETERS 
Urine* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-Threatening 
(Grade 4) 
Protein 1 
1+ proteinuria; 
urinary protein 
< 1.0 g/24 hours 
2+ proteinuria; 
urinary protein 
1.0 - 3.4 g/24 hours 
Urinary protein 
≥ 3.5 g/24 hours 
- 
Abbreviations:  
ADL = Activities of daily living; IV = Intravenous. 
Data source: 
1 Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. U.S. Department of Health and Human Services, FDA,  
National Institutes of Health National Cancer Institute [42] 
* The parameters that are not listed and do not have grading categories in the CTCAE will be reviewed by the Principal Investigator or 
designee and will only be reported as an AE if considered to be clinically relevant. 
 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A.