A Multi-center, Multi-region Smoking Cessation Study to Understand the Biological and Functional Changes Related to Smoking Cessation in Healthy Smokers Who Are Continuously Abstinent From Smoking for One Year
Conditions: Cigarette Smoking
Sponsor: Philip Morris Products S.A.



 
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 the substantial changes between the Final Version 4.0 study protocol and the first 
amended protocol (Final Version 5.0) dated 30 July 2015 which is to be referred to 
Amendment No. 1. 
 the substantial changes between the Final Version 5.0 study protocol (Amendment No. 
1) and the second amendedprotocol (Final Version 6.0) dated 7 March 2016 which is 
to be referred to Amendment No. 2. 
 the substantial changes between the Final Version 6.0 study protocol (Amendment No. 
2) and the current protocol (Final Version 7.0) dated 21 April 2016 which is to be 
referred to Amendment No. 3. 
 The non-substantial updates between the Final Version 7.0 study protocol dated 21 
April 2016 and its updated version (Final Version 8.0) dated 18 May 2017. 
More precise details on the protocol sections changed are provided. For identification of the 
changes, the previous and the amended texts are provided. The new text has been highlighted 
in bold (e.g. new text) and deleted text has been crossed out (e.g. deleted text). 
 
 

 
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SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Name of Product: 
Not applicable 
Study Title: 
A multi-center, multi-region smoking cessation study to understand the biological and 
functional changes related to smoking cessation in healthy smokers who are continuously 
abstinent from smoking for one year.  
Study Number: 
SA-SCR-01 
Study Short Title: 
A smoking cessation study to understand the biological and functional changes after one 
year of smoking cessation. 

 
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Objectives and Endpoints: 
The objectives and endpoints of this study are: 
1. To describe the clinical, biological and functional changes in smokers who are 
continuously abstinent from smoking. 
Clinical risk endpoints associated with cardiovascular disease at week 13 (V8), week 26 
(V11) and week 52 (V17): 
 White blood cell count (WBC), platelet count, glycosylated hemoglobin (HbA1c), 
and carboxyhemoglobin (COHb) in blood. 
 High and low density 
lipoprotein 
cholesterol (HDL-C, 
and 
LDL-C), 
myeloperoxidase (MPO), soluble intercellular adhesion molecule-1 (sICAM-1), 
apolipoprotein A1 and B (Apo A1 and Apo B), and high sensitivity C-reactive 
protein (hs-CRP) in serum. 
 Fibrinogen, and homocysteine in plasma. 
 Albumin, 11-dehydrothromboxane B2 (11-DTX-B2) and 8-epi-prostaglandin-alpha 
(8-epi-PGF2) in urine (expressed as concentration adjusted to creatinine). 
Clinical risk endpoints associated with respiratory diseases: 
 Spirometry (pre- and post-bronchodilator): Forced expiratory volume in 1 second 
(FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow (FEF 25-
75), at week 13 (V8), week 26 (V11), and week 52 (V17). 
 Lung volume: vital capacity (VC), total lung capacity (TLC), functional residual 
capacity (FRC), inspiratory capacity (IC), at selected sites specialized for lung 
function testing, at week 13 (V8), week 26 (V11), and week 52 (V17). 
 Cough symptoms (intensity and frequency), amount of sputum production and 
bothersomeness of cough symptom from the cough questionnaire at week 13 (V8), 
week 26 (V11) and week 52 (V17). 
Clinical risk endpoint associated with xenobiotic metabolism at week 13 (V8), week 26 
(V11), and week 52 (V17): 
 Cytochrome P450 2A6 (CYP2A6) activity: molar metabolic ratio of trans-3-
hydroxycotinine/cotinine in plasma. 

 
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Clinical risk endpoint associated with genotoxicity at week 13 (V8), week 26 (V11), and 
week 52 (V17): 
 Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL) in urine 
(expressed as concentration adjusted to creatinine). 
2. To describe the changes in biomarkers of exposure (BoExp) to harmful and potentially 
harmful constituents (HPHCs) in smokers who are continuously abstinent from 
smoking. 
BoExp to HPHCs at week 13 (V8), week 26 (V11), and week 52 (V17): 
 BoExp to carbon monoxide (CO): CO in exhaled breath (expressed as ppm).* 
 BoExp to nicotine: cotinine and nicotine in plasma and nicotine equivalents (Neq) in 
urine1.* 
 BoExp to 1,3-butadiene : monohydroxybutenylmercapturic acid (MHBMA).* 
 BoExp to acrolein: 3-hydroxypropylmercapturic acid (3-HPMA).* 
 BoExp to acrylonitrile: 2-cyanoethylmercapturic acid (CEMA).* 
 BoExp to benzo(a)pyrene: 3-hydroxybenzo(a)pyrene (B[a]P).* 
 BoExp to pyrene: Total 1-hydroxypyrene (Total 1-OHP).* 
 BoExp 
to 
crotonaldehyde: 
3-hydroxy-1-methylpropylmercapturic 
acid 
(3-
HMPMA).* 
 BoExp to N-nitrosonornicotine: total N-nitrosonornicotine (Total NNN).* 
 BoExp to 4-aminobiphenyl: 4-aminobiphenyl (4-ABP). 
 BoExp to benzene: S-phenylmercapturic acid (S-PMA). 
 BoExp to 1-aminonaphthalene: 1-aminonaphthalene (1-NA). 
 BoExp to 2-aminonaphthalene: 2-aminonaphthalene (2-NA). 
 BoExp to o-toluidine: o-toluidine (o-tol). 
 BoExp to ethylene oxide: 2-hydroxyethylmercapturic acid (HEMA). 
                                                 
1 Nicotine equivalents (Neq) are defined as molar sum of free nicotine, nicotine-glucuronide, free cotinine, 
cotinine-glucuronide, free trans-3’-hydroxycotinine, trans-3’- hydroxycotinine-glucuronide.  

 
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 BoExp to toluene: S-benzylmercapturic acid (S-BMA). 
All BoExp measured in urine, will be expressed as concentrations adjusted to creatinine. 
Only BoExp marked with “ * ” will be assessed at week 26 (V11) and week 52 (V17). 
3. To describe the rate of continuous smoking abstinence at each visit following the actual 
quit date of smoking cessation (defined as AQD). 
4. To monitor the safety: 
 Adverse events (AEs) / serious adverse events (SAEs). 
 Body weight. 
 Vital signs. 
 Spirometry 
 Electrocardiogram (ECG). 
 Clinical chemistry, hematology and urine analysis safety panel. 
 Physical examination. 
 Concomitant medications. 
Additional study assessments:  
 Prochaska ”Stage of change” questionnaire. 
 Fagerström test for nicotine dependence (FTND, revised version). 
 Socio-economic status (in the following countries: US, UK, Poland, Germany and 
Japan). 
 Lifestyle assessments. 
Study Hypothesis: 
Not applicable 
Evaluation Criterion: 
Not applicable 

 
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Study Design 
This multi-region, multi-center, ambulatory study will be conducted in the US, Japan and 
Europe. Smokers who are motivated to quit smoking within the next 30 days at screening 
will be enrolled to reach approximately 950 subjects continuously abstinent from smoking 
from the actual quit date (AQD) onwards at week 2 (V5) in order to achieve at least 190 
successful quitters to complete the study.  
Smokers who are not continuously abstinent from smoking (i.e., free from tobacco product 
use (e.g., CC, pipes, cigars, snus) or any nicotine containing product (including electronic 
cigarettes) other than nicotine replacement therapy (NRT)), as assessed by the four criteria 
described in section 6.2, from their AQD onwards will be discontinued from the study.  
NRT use will be allowed as per label for up to 3 months (+2 weeks) after the start date of 
NRT to support the subject to remain abstinent from smoking. NRT may be started at any 
time between the TQD and 1 week after the AQD. The start day of NRT will be counted as 
Day 1 of NRT use.  From that day on, the duration of NRT use must not exceed 3 months + 
2 weeks. NRT will be reimbursed. 

 
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Abbreviations: CC = conventional cigarettes; NRT = nicotine replacement therapy; SA = smoking abstinence; V = visit; 
W = week. 
Figure 1 
Study Design 

 
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Screening Period 
The Screening Period will take place 1 to 42 days prior to enrolment at V2 (Baseline). 
Eligibility of the subjects to participate in the study will be assessed during the Screening 
Visit (V1). Subjects who are still eligible at the end of V1 will be provided with urine 
containers and instructions for the 24-hour urine home collection. Eligible subjects will be 
contacted prior to V2 to confirm their eligibility and to take an appointment for V2.  
Baseline Visit - V2 (from check-in to check-out from the site) 
Twenty-four-hour urine collection will start in the morning of the day prior to V2 and end 
24 hours later in the morning of V2. Enrolment of the subject will take place after the 
subject’s check-in on site with the cooled urine container(s) filled with his/her 24-hour urine 
and re-check of inclusion criteria n°4 and n°6. All other procedures and data collection will 
be completed following the enrolment of the subject. All subjects will continue smoking 
their preferred brand of CC. 
Before check-out, subjects will be asked to define their target quit date (TQD), the date from 
which the subject will stop smoking. The TQD must be within 14 days after V2. 
From Check-out of V2 to Actual Quit Date (Day 1) 
This period aims to identify subjects who are more motivated and more likely to quit as well 
as to remain continuously abstinent from smoking for the whole duration of the study. The 
period starts from check-out of V2 and ends with the AQD (Day 1) including the TQD, V3 
and the Grace Period. This period might last up to 28 days for each subject. 
The subject will be asked to come to the clinic for V3 within 24 to 48 hours after their defined 
TQD. The goal of this visit will be to ensure that the subject has actually quit smoking and 
to provide him/her with the necessary support. From V3 onwards, smoking cessation (SC) 
counseling and behavioral support will be provided to the subject according to the SC 
support plan. Additional SC support will be offered at any time as requested by the subject. 
A Grace Period of a maximum of 14 days will be allowed after the TQD, during which 
occasional slips of smoking (defined as occasional use of nicotine and/or tobacco-containing 
products) will be accepted. From the AQD onwards, strict abstinence from any tobacco- or 
nicotine-containing product (including electronic cigarettes) other than NRT is required. 
Subjects will be asked to record their AQD and to communicate this date to the site in order 
to schedule following visits. The latest possible day for the AQD to occur is defined as the 
last day of the Grace Period (i.e., TQD + 14 days). 
The Smoking Abstinence Period (from the AQD up to the check-out of V17 [week 52]) 

 
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From the AQD, subjects will be asked to come on site for at week 1 (V4), at week 2 (V5) 
and then on a monthly basis at week 4 (V6 ), at week 9 (V7), at week 13 (V8), at week 17 
(V9), at week 22 (V10), at week 26 (V11), at week 30 (V12), at week 35 (V13), at week 39 
(V14), at week 43 (V15), at week 48 (V16), and at week 52 (V17). Visits will be scheduled 
based on the AQD. A time window of ± 8 days is allowed for the visits, with the exception 
of V4 (± 3 days) and V5 (± 3 days). 
The V8, V11, and V17 will correspond to full assessment visits at site(s) where 24-hour 
urine and blood sampling will be collected for analysis of biomarkers of exposure (BoExp) 
and clinical risk endpoints. The collection of the 24-hour urine will start at home in the 
morning the day before the visit and will end 24 hours later in the morning of the day of the 
visit to the clinic. 
The Safety Follow-Up Period and Phone Contact (28 days after the check-out of V17 [V18 
(±3 days); week 56]) 
A subject who has completed V17, or a subject who has been discontinued from the study 
prematurely (early termination), will enter a 28-days Safety Follow-Up Period during which 
spontaneously reported new AEs/SAEs will be recorded, and the active follow-up of 
ongoing AEs/SAEs will be done by the site. All AEs will be followed-up until resolved, 
stabilized (i.e., no worsening of the event), or a plausible explanation for the event has been 
found until the end of the Safety Follow-Up Period.  
At the end of the Safety Follow-Up Period in Week 56 (V18 (±3 days)), the investigator will 
attempt to contact only the subject who has previously completed V17 by phone to check if 
all AEs/SAEs potentially occurring during the Safety Follow-Up period are fully reported 
and for self-reporting by the subject on continuous smoking abstinence. At the end of the 
Safety Follow-Up Period, all ongoing AEs will be documented as “ongoing” and will not be 
followed-up by the Investigator. At the discretion of the Investigator, the subject will be 
referred to his/her General Practitioner for follow up on ongoing AEs. 
If the investigator can reach the subject who has previously completed V17 by phone at the 
end of the Safety Follow-Up Period in Week 56, the date of this phone call with the subject 
will be recorded as the date of the end of the study of the subject.  
If the investigator cannot reach the subject who has previously completed V17 by phone at 
the end of the Safety Follow-Up Period in Week 56 after a reasonable number of attempts, 
the date of the last contact (e.g., last visit of the subject, last phone call with the subject) will 
be recorded as the date of the end of the study of the subject. 

 
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The individual end of the study for a subject who has previously completed V17 is defined 
as V18. 
The individual end of the study for a subject who has been discontinued from the study 
prematurely (early termination) is defined as the date of the early termination of the subject 
plus 28 days of the Safety Follow-Up Period.  
The EOS of the entire study is the end of the Safety Follow-Up Period of the last subject. 
Study Population and Main Criteria for Inclusion/Exclusion: 
Female or male currently smoking, healthy adult subjects meeting the following main 
criteria without any restriction on race and ethnicity: 
Inclusion criteria:  
 Subject is aged from 30 to 65 years old (inclusive). 
 Positive urine cotinine test at both screening and V2 (cut-off ≥ 200 ng/mL). 
 Has smoked for at least the last 10 years prior to screening.  
 Smokes  10 cigarettes/day on average over the past year prior to screening and V2 as 
reported by the subject. 
 Is willing to quit smoking within the next 30 days, as assessed by the Prochaska’s stages 
of change questionnaire. 
Exclusion criteria:  
 Clinically relevant gastrointestinal, renal, hepatic, neurological, hematological, 
endocrine, oncological, urological, pulmonary, immunological, psychiatric or 
cardiovascular disorders or any other conditions that in the opinion of the investigators 
would jeopardize the safety of the participant or affect the validity of the study results.  
 Abnormal findings on physical examination, in the medical history, or in clinical 
laboratory results deemed clinically relevant by investigators (as per the common 
terminology criteria for adverse events [CTCAE]).  
 Acute illness (e.g., upper-respiratory-tract infection, viral infection etc.) requiring 
treatment within 42 days prior to enrolment in the study.  

 
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 Use of any prescribed or over-the-counter systemic medication listed in Table 1 within 
the last 42 days prior to enrolment in the study (except for vitamins, hormonal 
contraceptives and hormone-replacement therapy). 
 The subject has (FEV1/FVC) < 0.7 and FEV1 < 80% predicted value at post-
bronchodilator spirometry. 
 The subject has (FEV1/FVC) < 0.75 (post-bronchodilator) and reversibility in FEV1 (that 
is both > 12% and > 200 mL from pre- to post-bronchodilator values). 
 Pregnant or breast-feeding female. 
Investigational Product; Dose; and Mode of Administration: 
No investigational product will be used in this study. 
Duration of Study: 
The maximum total duration of the study for a subject will be 66 weeks. A Screening Period 
of up to 42 days will be followed by V2, plus a period of a maximum of 28 days until the 
AQD including the TQD visit and the Grace Period, followed by a 52-week smoking 
abstinence period in an ambulatory setting and a 28-days Safety Follow-Up Period ending 
after a phone contact with successful quitters in Week 56 (V18 (±3 days)).  The EOS of the 
entire study is the end of the Safety Follow-Up Period of the last subject. 
Statistical Methods:  
Descriptive statistics (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 (CV) for data analyzed in the log scale; frequency counts and 
percentages for categorical data) will be presented overall and at each time point, where 
applicable. BoExp data will be analyzed in the logarithmic scale and summary estimates will 
be back-transformed to provide results in the original scale. 
Descriptive analysis will be conducted in the population of continuous abstainers with no 
major protocol deviations. In subjects failing to abstain from smoking, only endpoint data 
assessed prior to the date of relapse will be included in the analysis.  
Descriptive statistics will be provided for endpoint parameters and baseline characteristics 
of the population retained in the study at each assessment time point. Summary statistics of 
endpoints will also include the mean change from baseline, together with 95% confidence 

 
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interval (CI). Absolute and percent change from baseline will be summarized for endpoints 
analyzed in the real and logarithmic scale, respectively. 
 
Exploratory Analysis 
For the clinical risk endpoints, the smoking abstinence (SA) effect over time will be 
predicted by a model of the change from baseline adjusted for relevant population 
characteristics. The pattern and form of the change over time will be modeled using repeated 
measurement random-effects models. Sex, age, region, and other baseline variables will be 
considered for inclusion in the model using a backward elimination approach. Goodness of 
fit will be evaluated by the analysis of residuals (model diagnostics) and by comparing the 
values predicted versus the observed parameter changes (calibration). Least square estimates 
of the effect of variables included in the model and the intercept will be reported together 
with the 95% CI. 
Safety Analysis 
Adverse event data will serve as the primary assessment of safety. Safety data will be listed 
and tabulated for the enrolled population. 
Sample Size: 
Smokers willing to quit smoking within the next 30 days will be enrolled in this study. 
Enrolment will be allowed until approximately 950 subjects successfully abstain from 
smoking for at least two weeks after AQD. Unsuccessful quitters (i.e., subjects that smoke 
after the AQD) will be discontinued from the study.  
The sample size of this study is based on our current understanding of the effect and 
variability of SC from the results of the Lung Health Study [1] in the subject intending to 
quit smoking at Baseline, since no data on the attrition rate at 12 months after 2 weeks of 
smoking cessation are available. 
In particular, approximately 190 subjects are needed to estimate the mean increase from 
Baseline of 1.98 [% pred.] [1] in FEV12 at V17, with a 90% probability of obtaining a margin 
of error (95% CI) of at most ±1 [% pred.]. The anticipated SD of the change from Baseline 
of 6.4 [% pred.] was estimated using the results of the Lung Health Study [1] and includes 
an inflation of 10% in order to account for additional sources of variability, including the 
                                                 
2 Sample size calculations are driven by FEV1. Other endpoints are assumed to exhibit a larger effect size than 
FEV1 and thus would result in smaller sample size estimates.  

 
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multi-national nature of the study. As the primary population for analysis will be successful 
quitters, this sample size was increased to 950, to account for a predicted continuous 
abstinence rate of 20% expected at week 52 for subjects that successfully abstain from 
smoking for at least two weeks after. This is based on an assumed increase of 5% from the 
15% abstinence rate at week 52 expected for subjects at enrolment [2]. 

 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES .....................................................................................................2 
SYNOPSIS ...............................................................................................................................13 
TABLE OF CONTENTS .........................................................................................................25 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................29 
1 
ETHICS AND REGULATIONS .....................................................................................35 
1.1 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) 
Approval ................................................................................................................35 
1.2 
Ethical Conduct of the Study .................................................................................36 
1.3 
Subject Information and Consent...........................................................................36 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................38 
2 
INTRODUCTION ...........................................................................................................39 
2.1 
Background ............................................................................................................39 
2.2 
Purpose of the Study ..............................................................................................40 
2.3 
Anticipated Benefits and Risks ..............................................................................40 
3 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................42 
4 
INVESTIGATIONAL PLAN ..........................................................................................45 
4.1 
Overall Study Design and Plan ..............................................................................45 
4.2 
Rationale for Study Design ....................................................................................49 
4.3 
Appropriateness of Measurements .........................................................................50 
4.4 
Study Duration .......................................................................................................50 
5 
STUDY POPULATION ..................................................................................................51 
5.1 
Selection of Study Population ................................................................................51 
5.2 
Recruitment Strategies and Retention ....................................................................53 
5.3 
Discontinuation of Subjects from the Study ..........................................................54 
5.4 
Assessments at Visit 17 to be performed if Total NNAL is above the cut-off at 
Visit 11 ...................................................................................................................56 
5.5 
Lost to Follow-up ...................................................................................................56 
5.6 
Violation of Selection Criteria ...............................................................................57 
6 
RESTRICTIONS AND SUPPORT DURING THE STUDY .........................................58 

 
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6.1 
Smoking Cessation Support ...................................................................................58 
6.2 
Compliance ............................................................................................................58 
6.3 
Restrictions ............................................................................................................59 
6.4 
Concomitant Medication ........................................................................................59 
7 
STUDY PROCEDURES .................................................................................................62 
7.1 
Informed Consent and Guidance ...........................................................................62 
7.2 
Information on the Risk of Smoking and Smoking Cessation Advice ..................62 
7.3 
Smoking Cessation Support ...................................................................................62 
7.4 
Clinical Assessments .............................................................................................63 
7.5 
Laboratory Assessments ........................................................................................67 
7.6 
Biomarkers of Assessments ...................................................................................71 
7.7 
Other Study Procedures .........................................................................................73 
8 
ADVERSE EVENTS .......................................................................................................77 
8.1 
Definitions..............................................................................................................77 
8.2 
Assessment of Adverse Events ..............................................................................77 
8.3 
Reporting of Serious Adverse Events ....................................................................79 
8.4 
Reporting of Other Events Critical to Safety Evaluations .....................................81 
8.5 
Reporting and Follow-Up of Pregnancies..............................................................82 
8.6 
Adverse Events Leading to Discontinuation..........................................................82 
9 
STUDY ACTIVITIES .....................................................................................................83 
9.1 
Screening Visit (V1) ..............................................................................................83 
9.2 
Baseline Visit (V2) ................................................................................................85 
9.3 
Visit 3 (V3) ............................................................................................................88 
9.4 
Actual Quit Date ....................................................................................................89 
9.5 
Smoking Abstinence Period (V4 to V17) ..............................................................89 
9.6 
Safety Follow-Up Period and Phone Contact (V18)..............................................92 
9.7 
Early Termination Procedures ...............................................................................93 
10 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................95 
10.1 
Monitoring .............................................................................................................95 
10.2 
Training of Staff .....................................................................................................96 

 
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10.3 
Audits and Inspections ...........................................................................................96 
11 DATA MANAGEMENT ACTIVITIES..........................................................................97 
11.1 
Data Capture ..........................................................................................................97 
11.2 
Data Handling ........................................................................................................98 
12 PLANNED STATISTICAL METHODS ........................................................................99 
12.1 
General Considerations ..........................................................................................99 
12.2 
Determination of Sample Size and Power Consideration ....................................100 
12.3 
Analysis Populations ............................................................................................101 
12.4 
Demographics and Baseline Characteristics ........................................................101 
12.5 
Study Endpoint(s) ................................................................................................101 
12.6 
Safety Endpoint(s) ...............................................................................................102 
12.7 
Interim Analysis ...................................................................................................103 
13 ADMINISTRATIVE CONSIDERATIONS ..................................................................104 
13.1 
Subject Confidentiality ........................................................................................104 
13.2 
Access to Source Documentation ........................................................................104 
13.3 
Record Retention .................................................................................................105 
13.4 
Clinical Study Report ...........................................................................................106 
13.5 
Financial Disclosure.............................................................................................106 
13.6 
Publication and Disclosure Policy .......................................................................107 
14 REFERENCE LIST .......................................................................................................108 
 
LIST OF IN-TEXT TABLES 
Table 1 
Concomitant Medication and Impact on Clinical Risk Endpoints .............60 
Table 2 
Hematology and Clinical Chemistry Parameters (Safety) .........................68 
Table 3 
Time Schedule – Screening Visit (V1) ......................................................83 
Table 4 
Time Schedule – Baseline Day (V2) .........................................................85 
Table 5 
Time Schedule – Target Quit Date (V3) ....................................................89 
Table 6 
Time Schedule – Visits V4, V5, V6, V7, V9, V10, V12, V13, V14, 
V15 and V16 ..............................................................................................89 

 
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Table 7 
Time Schedule – Visits V8, V11, and V17 ................................................90 
Table 8 
Time Schedule – Visit V18 ........................................................................93 
Table 9 
Time Schedule – Early Termination Procedures .......................................94 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ..............................................................................................18 
Figure 2 
Study Design ..............................................................................................46 
 
LIST OF APPENDICES 
Appendix 1 
Study Assessments ...................................................................................111 
Appendix 2 
Medications with Impact on Clinical Risk Endpoints (with Half-Lives) 118 
Appendix 3 
Prochaska “Stage of Change” Questionnaire ...........................................124 
Appendix 4 
Summary of Clinical Risk Endpoints ......................................................125 
Appendix 5 
Summary of Biomarkers of Exposure to HPHC ......................................127 
Appendix 6 
Abnormal Laboratory Values ..................................................................129 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
1-NA 
1-aminonaphthalene 
1-OHP 
1-hydroxypyrene 
2-NA 
2-aminonaphthalene 
3-HPMA 
3-hydroxypropylmercapturic acid 
4-ABP 
4-aminobiphenyl 
8-epi-PGF2α 
8-epi-prostaglandin F2α 
11-DTX-B2 
11-dehydrothromboxane B2 
AE 
Adverse event 
AP 
Alkaline phosphatase 
Apo A1 
Apolipoprotein A1 
Apo B 
Apolipoprotein B 
ATS/ERS 
American Thoracic Society/European Respiratory Society 
AQD 
Actual quit date 
B[a]P 
3-hydroxybenzo(a)pyrene 
BMI 
Body mass index 
BoExp 
Biomarker of exposure 
BS 
Behavioral support 
BUN 
Blood urea nitrogen 
CC 
Conventional cigarette 
CEMA 
2-cyanoethylmercapturic acid 
CI 
Confidence interval 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case report form 

 
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CRO 
Contract research organization 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria for adverse events 
CTMS 
Clinical trial management system 
CV 
Coefficient of variation 
CVD 
Cardiovascular disease 
CYP2A6 
Cytochrome P450 2A6 
Dn 
Day n (nth study day) 
DMP 
Data management plan 
ECG 
Electrocardiogram 
EOS 
End of study 
ERS 
Exposure response study 
FDA 
Food and Drug Administration  
FEF 25-75 
Forced expiratory flow 25-75 
FEV1  
Forced expiratory volume in one second 
FRC 
Functional residual capacity 
FTND 
Fagerström test for nicotine dependence 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HbA1c 
Glycosylated hemoglobin 
HDL-C 
High density lipoprotein-cholesterol 
HEMA 
2-hydroxyethylmercapturic acid 
HIV 
Human immunodeficiency virus 
HMPMA 
3-hydroxy-1-methylpropylmercapturic acid 
HPHC 
Harmful and potentially harmful constituent 
Hs-CRP 
High sensitivity C-reactive protein 
IC 
Inspiratory capacity 

 
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ICF 
Informed consent form 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LDL-C 
Low density lipoprotein-cholesterol 
LLOQ 
Lower limit of quantification 
LOQ 
Limit of quantification 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHBMA 
Monohydroxybutenylmercapturic acid 
MPO 
Myeloperoxidase 
MRTP 
n 
Modified risk tobacco product 
Number of subjects 
Neq 
Nicotine equivalents 
NNAL 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
NNN 
N-nitrosonornicotine 
NNK 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 
NRT 
Nicotine replacement therapy 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
o-tol 
o-toluidine 
PFT 
Pulmonary function testing 
PMI 
Philip Morris International 
RBC 
Red blood cell (count) 
SA 
Smoking abstinence 
SAE 
Serious adverse event 

 
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SAP 
Statistical analysis plan 
S-BMA 
S-benzylmercapturic acid 
SC 
Smoking cessation 
SD 
Standard deviation 
SES 
Socio-economic status/situation 
ILM 
Investigator Laboratory Manual 
sICAM-1 
soluble inter-cellular adhesion molecule-1 
SOP 
Standard operating procedure 
S-PMA 
S-phenylmercapturic acid 
SRO 
Subject report outcome 
TLC 
Total lung capacity 
TQD 
Target quit date 
UBC 
United BioSource Corporation 
ULOQ 
Upper limit of quantification 
Vn 
Visit n 
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: 
Baseline  
Baseline Visit is defined as V2.  
Baseline value 
Unless specified, baseline is defined as the last available value prior 
to TQD or AQD, whichever comes first. 
Actual quit date 
The AQD is the date recorded in the source document on which the 
subject actually quits smoking and from which onwards total SA is 
expected. AQD corresponds to the first day without any 
tobacco/nicotine use (except NRT). 
End of study 
The individual end of the study for a subject who has previously 
completed V17 is defined as V18. 
The individual end of the study for a subject who has been 
discontinued from the study prematurely (early termination) is 
defined as the date of the early termination of the subject plus 28 
days of the Safety Follow-Up Period.  
The EOS of the entire study is the individual end of the study of the 
last subject. 
Lost to follow-up (date) When the PI(s) or designee(s) declare(s) a subject is lost to follow-
up, the lost to follow-up date will be recorded and will correspond 
to the date of the end of study of the subject.  
If the site has lost track of the subject but the subject has reached the 
maximum number of study days (465 days), then the PI(s) or 
designee(s) will declare the subject lost to follow-up at this date. 
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. 
Nicotine replacement 
therapy 
The NRT consists of nicotine-containing products such as nicotine 
gum, lozenge, patches, inhaler or nasal spray. The NRT should be 
used as per country label for up to 3 months (+2 weeks) after the 
start date of NRT. NRT may be started at any time between the TQD 
and 1 week after the AQD. 

 
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Target quit date 
Date from which the smoker intends to quit smoking and may start 
treatment with his/her preferred NRT as per country label, if any and 
where applicable. 
Study completion 
The study will be completed once the last successful quitter has 
reached V18. 
Successful quitter 
A successful quitter is defined as a subject that was continuously 
abstinent from smoking from AQD to V17, as assessed by the four 
criteria described in section 6.2. 
Unsuccessful quitter 
An unsuccessful quitter is defined as a subject that was not 
continuously abstinent from smoking from AQD to V17, as assessed 
by the four criteria described in section 6.2. 

 
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1 
ETHICS AND REGULATIONS 
1.1 
Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) Approval 
Prior to the start of the study, the clinical study protocol, together with its associated documents 
(informed consent form [ICF], subject information sheet, subject recruitment procedures [e.g., 
advertisements], written information to be provided to the subjects, available safety 
information, the Investigator’s and designee curriculum vitae and/or other evidence of 
qualifications and any other documents requested by an Institutional Review Board [IRB] or 
Independent Ethics Committee [IEC]), will be submitted for review and approval to the 
relevant IRB/IEC. The IRB/IEC shall be appropriately constituted and perform its functions in 
accordance with the International Conference on Harmonisation (ICH) Tripartite Guidance for 
Good Clinical Practice (GCP) and local requirements, as applicable. 
Where applicable, and 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 (Principal 
Investigator and designee’s name, study number, and title) and the documents that have been 
approved by the IRB, with dates and version numbers, as well as the date of approval. The 
composition of the IRB, including the name and occupation of the chairperson, will be supplied 
to the Sponsor together with a GCP compliance statement. 
The written approval from the IRB/IEC will be filed in the 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/IEC. 
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the Investigator. All amendments will be submitted 
to the IRB/IEC, and substantial amendments will only be implemented after approval by the 
IRB/IEC. 
These requirements for approval should in no way prevent any action from being taken by the 
Investigator or designee or by the Sponsor in order to eliminate immediate hazards to the 
subjects. If such a change to the protocol is felt to be necessary by the Investigator or designee, 
and is implemented for safety reasons, the Sponsor and the IRB/IEC should be informed 
immediately. 
The Investigator is responsible for local reporting (e.g., to the IRB/IEC) of serious adverse 
events (SAEs) that occur during the study, according to local regulations. 

 
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Relevant safety information will be submitted to the IRB/IEC during the course of the study in 
accordance with national regulations and requirements. 
Medically qualified study personnel will be available during the study. Separate ICFs will be 
signed by the subject for the collection and storage of bio-banking samples and their 
subsequent analysis. 
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 is consistent with applicable regulatory principles of ICH/GCP. 
The Investigator or designee agrees to conduct the clinical study in compliance with the 
protocol agreed with the Sponsor and approved by the IRB/IEC. The Investigator and the 
Sponsor must sign the protocol (and protocol amendments, if applicable) to confirm this 
agreement. A copy of the Declaration of Helsinki [3] is located in the Investigator’s study file. 
1.3 
Subject Information and Consent 
1.3.1 
Informed Consent Form for Study Participation 
Before or atV1, the Investigator or designee will ensure that each subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and benefits of 
the study, and the Investigator or the designee will answer all questions the subject might have 
to his/her full satisfaction. The subject will have sufficient time for consideration of his/her 
participation in the study and will be notified that he/she is free to discontinue his/her 
participation at any time.  
Once the subject has received all the necessary information, and if he/she agrees to participate, 
this will be documented in the ICF which includes both the subject information sheet and 
informed consent by the date and time personally signed and signature of both the subject and 
the person who conducted the inform consent discussion during the visit at V1. No study-
specific procedures will be performed before the ICF has been signed (including date and 
time). 
The signed and personally dated original and completed ICF(s) must be kept by the 
Investigator and filed in the Investigator study 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 discontinues 
from the study, the data collected until the point of discontinuation will be maintained as part 
of the study data and the samples collected prior to discontinuation may be analyzed, unless 
he/she refuses in writing. 

 
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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 Bio-Banking 
Separate ICFs will be signed and personally dated by the subject for the collection of samples 
and their long-term bio-banking storage. The subject’s participation in the study does not 
depend on his/her consent to these separate ICFs. 
 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. No genetic, transcriptomics and/or 
lipidomics testing will be done on these samples. 
 One separate ICF to obtain consent for collection and long-term storage of blood/ plasma 
samples for further transcriptomics and lipidomics analyses.  
Transcriptomics, lipidomics and molecular analyses will provide insight into the biological 
processes that take place following smoking cessation (SC). 
Each subject will be given full and adequate oral and written information about the nature, 
purpose, possible risks and benefits of bio-banking, and the Investigator will answer all 
questions the subject might have to his/her full satisfaction. The subject will be notified that 
he/she is free to withdraw his/her 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 
and time personally signed and signature of both the subject and the personnel who conducted 
the informed consent discussion. The subject’s consent to collection of any samples for long-
term storage in a bio-bank is not a requirement for his/her participation in the study (section 
1.3.1). 
1.3.3 
Amendment to the Informed Consent Form 
If a protocol amendment is required, an amendment may be required to the ICF. If revision of 
the ICF is necessary, the Investigator or designee will, with the support of the Sponsor, ensure 
that the documents have been reviewed and approved by a relevant IRB/IEC before subjects 
are informed and sign and personally date the amended ICF (including date and time). 

 
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1.4 
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator and designee abide by the principles of the ICH guidelines on 
GCP. These guidelines apply specifically to pharmaceutical development, but nevertheless 
provide a robust and ethical framework for conducting a clinical study on smoking cessation. 
The study will also be conducted in accordance with the general ethical principles outlined in 
the Declaration of Helsinki [3]. 
In addition, the Investigator or designee will carry out the clinical study in accordance with 
applicable national and local laws of the pertinent regulatory authorities. 

 
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2 
INTRODUCTION 
2.1 
Background 
Cigarette smoking causes pulmonary diseases, cardiovascular diseases (CVD) and other 
serious diseases in smokers [4]. There is no safe cigarette, and the best way for smokers to 
reduce the adverse health consequences of smoking is to quit. Despite the risks which are 
attributable to smoking, some smokers cannot refrain from smoking or decide to continue 
smoking. For 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 referred by the Food and Drug 
Administration (FDA) as modified risk tobacco products (MRTP) [5].  
The disorders induced by conventional cigarettes (CC) smoking are complex, as there are 
multiple causal chains, and tobacco-related diseases develop over many years. The exposure 
to harmful and potentially harmful constituents (HPHCs) contained in cigarette smoke affects 
multiple organ systems, disease pathways, and mechanisms such as inflammation, oxidative 
stress, platelet activation and lipid metabolism which occur simultaneously. It is well-known 
that there is a dose-response relationship between cigarette smoke exposure and smoking-
related diseases such as chronic obstructive pulmonary disease (COPD), CVD and lung cancer 
[6, 7]. However, there is no single clinical risk endpoint or biomarker that is considered as a 
validated surrogate measure reflecting the biological process, physiological system, and/or a 
mechanism of action that is associated with or known to contribute to smoking-related 
diseases.  
The US Institute of Medicine (IOM) refers to smoking cessation as the “gold standard” for the 
assessment of a reduced risk products (RRP), providing “an aspirational goal for risk and 
exposure.” [6].  
It has been shown that several functional and biological markers (clinical risk endpoints) 
associated with smoking-related adverse health effects are favorably changed after SC in both 
the short and long term [8-10]. These effects are sufficiently sensitive to changes in smoking 
status to suggest that they can be used for the risk assessment of candidate MRTPs. Thus, 
conventional cigarette (CC) smoking and SC are considered natural benchmarks for assessing 
the exposure and risk reduction potential of candidate MRTPs [5, 11]. The observation of 
clinical risk endpoints after switching from CC to a candidate MRTP in comparison to SC 
should be a reasonable indicator for disease risk reduction to the individual smoker. The 
clinical risk endpoints selected for this study are the markers with the strongest scientific 
evidence of favorable changes following SC.  

 
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2.2 
Purpose of the Study 
There is sufficient literature reporting favorable changes in clinical risk endpoints with SC, 
however the observation time period of one year of continuous abstinence is often sparse or 
even not available, and the currently available information is derived from multiple clinical 
studies making it difficult to compare the findings.  
The primary objective of the SCR Study is to establish data on changes on a broad range of 
BoExp and Clinical Risk Endpoints as observed after 12 months of smoking cessation.  
This study will serve two purposes: 1) to be used as a benchmark in the context of candidate 
MRTP assessments (i.e., to allow comparison between the risks and benefits from the use of a 
candidate MRTP compared to SC), and 2) corroborate and supplement the existing data on 
biological and functional health effects of SC.  
The primary objective clearly differentiates the SCR study from other Smoking Cessation 
studies where testing the efficacy of a smoking cessation treatment (i.e. drug or behavioral 
cessation support) is the primary objective. 
2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
Extensive SC support (SC counseling, behavioral support (BS) and training on the use of 
nicotine replacement therapy (NRT) will be provided over the duration of the study. The 
combination of these different methods of smoking cessation support has been shown to 
markedly increase the success rate of quitting smoking. Subjects who participate in this study 
will also benefit from repeated and extensive health check-ups, which may help to uncover 
undiagnosed medical conditions. 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures 
The risk related to study procedures (e.g., blood samples) are deemed to be part of procedures 
routinely performed during normal or extended health examinations by the subject’s health 
care professional.  
Administration of salbutamol/albuterol for the spirometry testing may potentially elevate blood 
pressure, increase the heart rate and cause tremor, inner agitation, palpitation due to sinus 
tachycardia, muscle cramps or headaches. However, these effects are limited after single use 
and only more frequent following repeated use and oral administration. Salbutamol/albuterol 

 
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should not be administered to subjects whose blood pressure and/or heart rate is already 
markedly elevated and whose heart rhythm is already irregular. 
The subject will use NRT, if any, as per the label approved in the subject’s country of residence. 
The risk related to the use of NRT is described in detail in the NRT label leaflet and will be 
explained to the subjects by the Investigator or designee. The possibility of unforeseeable 
events/risks due to study related procedures will be explained at V1. Mitigation of such risks 
will include close monitoring and medical supervision to detect any unforeseeable risk or 
safety signals at the earliest time possible. 

 
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3 
STUDY OBJECTIVES AND ENDPOINTS 
The objectives and endpoints of this study are:  
1. To describe the clinical, biological and functional changes in smokers who are 
continuously abstinent from smoking. 
Clinical risk endpoints associated with CVD at week 13 (V8), week 26 (V11) and week 52 
(V17): 
 White blood cell count (WBC), platelet count, glycosylated hemoglobin (HbA1c), and 
carboxyhemoglobin (COHb) in blood. 
 High and low density lipoprotein cholesterol (HDL-C, and LDL-C), myeloperoxidase 
(MPO), soluble intercellular adhesion molecule-1 (sICAM-1), apolipoprotein A1 and 
B (Apo A1 and Apo B), and high sensitivity C-reactive protein (hs-CRP) in serum. 
 Fibrinogen, and homocysteine in plasma. 
 Albumin, 11-dehydrothromboxane B2 (11-DTX-B2) and 8-epi-prostaglandin-alpha (8-
epi-PGF2) in urine (expressed as concentrations adjusted to creatinine). 
Clinical risk endpoints associated with respiratory diseases: 
 Spirometry (pre and post-bronchodilator): Forced expiratory volume in 1 second 
(FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow (FEF 25-75), 
at week 13 (V8), week 26 (V11) and week 52 (V17). 
 Lung volume: vital capacity (VC), total lung capacity (TLC), functional residual 
capacity (FRC), inspiratory capacity (IC), at selected sites specialized for lung function 
testing at week 13 (V8), week 26 (V11) and week 52 (V17). 
 Cough symptoms (intensity and frequency), amount of sputum production and 
bothersomeness of cough symptom from the cough questionnaire at week 13 (V8), 
week 26 (V11) and week 52 (V17). 
Clinical risk endpoint associated with xenobiotic metabolism at week 13 (V8), week 26 
(V11) and week 52 (V17): 
 Cytochrome P450 2A6 (CYP2A6) activity: Molar metabolic ratio of trans-3-
hydroxycotinine/cotinine in plasma. 

 
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Clinical risk endpoint associated with genotoxicity at week 13 (V8), week 26 (V11), and 
week 52 (V17): 
 Total 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total 
NNAL) in 
urine 
(expressed as concentration adjusted to creatinine). 
2. To describe the changes in BoExp to harmful and potentially harmful constituents 
(HPHCs) in smokers who are continuously abstinent from smoking. 
BoExp to HPHCs at week 13 (V8), week 26 (V11) and week 52 (V17): 
 BoExp to CO: CO in exhaled breath (expressed as ppm).* 
 BoExp to nicotine: cotinine and nicotine in plasma and nicotine equivalents (Neq) in 
urine3* 
 BoExp to 1,3-butadiene : monohydroxybutenylmercapturic acid (MHBMA).* 
 BoExp to acrolein: 3-hydroxypropylmercapturic acid (3-HPMA).* 
 BoExp to acrylonitrile: 2-cyanoethylmercapturic acid (CEMA).* 
 BoExp to benzo(a)pyrene: 3-hydroxybenzo(a)pyrene (B[a]P).* 
 BoExp to pyrene: Total 1-hydroxypyrene (Total 1-OHP).* 
 BoExp to crotonaldehyde: 3-hydroxy-1-methylpropylmercapturic acid (3-HMPMA).* 
 BoExp to N-nitrosonornicotine: total N-nitrosonornicotine (Total NNN).* 
 BoExp to 4-aminobiphenyl: 4-aminobiphenyl (4-ABP). 
 BoExp to benzene: S-phenylmercapturic acid (S-PMA). 
 BoExp to 1-aminonaphthalene: 1-aminonaphthalene (1-NA). 
 BoExp to 2-aminonaphthalene: 2-aminonaphthalene (2-NA). 
 BoExp to o-toluidine: o-toluidine (o-tol). 
 BoExp to ethylene oxide: 2-hydroxyethylmercapturic acid (HEMA). 
 BoExp to toluene: S-benzylmercapturic acid (S-BMA). 
                                                 
3 Nicotine equivalents (Neq) are defined as molar sum of free nicotine, nicotine-glucuronide, free cotinine, 
cotinine-glucuronide, free trans-3’-hydroxycotinine, trans-3’- hydroxycotinine-glucuronide.  

 
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All BoExp measured in urine, will be expressed as concentrations adjusted to creatinine. Only 
BoExp marked with “ * ” will be assessed at week 26 (V11) and week 52 (V17). 
3. To describe the rate of continuous SA at each visit following the actual quit date (AQD) 
of smoking cessation. 
4. To monitor the safety: 
 Adverse events (AEs)/ serious adverse events (SAEs). 
 Body weight. 
 Vital signs. 
 Spirometry 
 Electrocardiogram (ECG). 
 Clinical chemistry, hematology and urine analysis safety panel. 
 Physical examination. 
 Concomitant medications. 
Additional study assessments:  
 Prochaska ‘Stage of Change’ questionnaire. 
 Fagerström test for nicotine dependence (FTND, revised version). 
 Socio-economic status (in the following countries: US, UK, Poland, Germany and 
Japan). 
 Lifestyle assessments. 

 
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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This multi-region, multi-center, ambulatory study will be conducted in the US, Japan and 
Europe. Smokers who are motivated to quit smoking within the next 30 days at the Screening 
Visit will be enrolled to reach approximately 950 subjects continuously abstinent from 
smoking from AQD onwards at week 2 (V5), in order to achieve at least 190 successful quitters 
expected to complete the study. Once approximately 950 subjects will reach V5, screening and 
enrolment will be stopped. Subjects already enrolled in the study at that point in time and that 
are between V2 and V5, will be kept in the study and allowed to progress over Visit 5. On the 
contrary, on-going subjects that have completed screening visit and are before visit 2 will be 
discontinued from the study and classified as screen failures. 
Smokers who are not continuously abstinent from smoking (i.e., free from tobacco product use 
(e.g., CC, pipes, cigars, snus) or any nicotine containing product (including electronic 
cigarettes) other than NRT)) from their AQD onwards will be discontinued from the study (see 
sections 5.3 and 6.2). 
NRT use will be allowed as per label for up to 3 months (+2 weeks) after the start date of NRT 
to support the subject to remain abstinent from smoking. NRT may be started at any time 
between the TQD and 1 week after the AQD. The start day of NRT will be counted as Day 1 
of NRT use.  From that day on, the duration of NRT use must not exceed 3 months + 2 weeks. 
NRT will be reimbursed. 

 
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Abbreviations: CC = Conventional cigarettes; NRT = Nicotine replacement therapy; SA = Smoking abstinence; V = Visit; W 
= week 
Figure 2 
Study Design 
Screening Period 
The Screening Period will take place 1 to 42 days prior to enrolment at V2 (Baseline). 
Eligibility of the subjects to participate in the study will be assessed during the Screening Visit 
(V1). Subjects who are still eligible at the end of V1 will be provided with urine containers 
and instructions for the 24-hour urine home collection. Eligible subjects will be contacted prior 
to V2 to confirm their eligibility and to take an appointment for V2.  
Baseline Visit - V2 (from check-in to check-out from the site) 

 
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Twenty-four-hour urine collection will start in the morning of the day prior to V2 and end 24 
hours later in the morning of V2. Enrolment of the subject will take place after the subject’s 
check-in on site with the cooled urine container(s) filled with his/her 24-hour urine and re-
check of inclusion criteria n°4 and n°6. All other procedures and data collection will be 
completed following the enrolment of the subject. All subjects will continue smoking their 
preferred brand of CC. 
Before check-out, subjects will be asked to define their target quit date (TQD), the date from 
which the subject will stop smoking. The TQD must be within 14 days after V2. 
From Check-out of V2 to Actual Quit Date 
This period aims to identify subjects who are more motivated and more likely to quit as well 
as to remain continuously abstinent from smoking for the whole duration of the study. The 
period starts from check-out of V2 and ends with the actual quit date (AQD) (Day 1) including 
the TQD, V3 and the Grace Period. This period might last up to 28 days for each subject. 
The subject will be asked to come to the clinic for V3 within 24 to 48 hours after their defined 
TQD. The goal of this visit will be to ensure that the subject has actually quit smoking and to 
provide him/her with the necessary support. From V3 onwards, SC counseling and BS will be 
provided to the subject according to the SC support plan. Additional SC support will be offered 
at any time when requested by the subject. 
A Grace Period of a maximum of 14 days will be allowed after the TQD, during which 
occasional slips (defined as occasional use of nicotine and/or tobacco-containing products day) 
of smoking will be accepted. From the AQD onwards, strict abstinence from any tobacco- or 
nicotine-containing product (including electronic cigarettes) other than NRT is required. 
Subjects will be asked to record their AQD and to communicate this date to the site in order to 
schedule following visits. The latest possible day for the AQD to occur is defined as the last 
day of the Grace Period (i.e., TQD + 14 days). 
The Smoking Abstinence Period (from the AQD up to the check-out of V17 [week 52]) 
From the AQD, subjects will be asked to come on site for at week 1 (V4), at week 2 (V5) and 
then on a monthly basis at week 4 (V6 ), at week 9 (V7), at week 13 (V8), at week 17 (V9), at 
week 22 (V10), at week 26 (V11), at week 30 (V12), at week 35 (V13), at week 39 (V14), at 
week 43 (V15), at week 48 (V16) , and at week 52 (V17). Visits will be scheduled based on 
the AQD. A time window of ± 8 days is allowed for the visits, with the exception of V4 (± 3 
days) and V5 (± 3 days). 
The V8 , V11 , and V17 will correspond to full assessment visits at site(s) where 24-hour urine 
and blood sampling will be collected for analysis of BoExp and clinical risk endpoints. The 

 
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collection of the 24-hour urine will start at home in the morning the day before the visit and 
will end 24 hours later in the morning of the day of the visit to the clinic. 
The Safety Follow-Up Period and Phone Contact (28 days after the check-out of V17 [V18 
(±3 days); week 56]) 
A subject who has completed V17, or a subject who has been discontinued from the study 
prematurely (early termination), will enter a 28-days Safety Follow-Up Period during which 
spontaneously reported new AEs/SAEs will be recorded, and the active follow-up of ongoing 
AEs/SAEs will be done by the site. All AEs will be followed-up until resolved, stabilized (i.e., 
no worsening of the event), or a plausible explanation for the event has been found until the 
end of the Safety Follow-Up Period.  
At the end of the Safety Follow-Up Period in Week 56 (V18 (±3 days)), the investigator will 
attempt to contact only the subject who has previously completed V17 by phone to check if all 
AEs/SAEs potentially occurring during the Safety Follow-Up period are fully reported and for 
self-reporting by the subject on continuous smoking abstinence. At the end of the Safety 
Follow-Up Period, all ongoing AEs will be documented as “ongoing” and will not be followed-
up by the Investigator. At the discretion of the Investigator, the subject will be referred to 
his/her General Practitioner for follow up on ongoing AEs. 
If the investigator can reach the subject who has previously completed V17 by phone at the 
end of the Safety Follow-Up Period in Week 56, the date of this phone call with the subject 
will be recorded as the date of the end of the study of the subject.  
If the investigator cannot reach the subject who has previously completed V17 by phone at the 
end of the Safety Follow-Up Period in Week 56 after a reasonable number of attempts, the date 
of the last contact (e.g., last visit of the subject, last phone call with the subject) will be recorded 
as the date of the end of the study of the subject. 
The individual end of the study for a subject who has previously completed V17 is defined as 
V18. 
The individual end of the study for a subject who has been discontinued from the study 
prematurely (early termination) is defined as the date of the early termination of the subject 
plus 28 days of the Safety Follow-Up Period.  
The EOS of the entire study is the end of the Safety Follow-Up Period of the last subject. 

 
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4.2 
Rationale for Study Design  
This clinical study aims at understanding the clinical, biological and functional changes after 
one year of smoking cessation in healthy subjects. Healthy subjects will be included in this 
study, since the impact of potential diseases on the study endpoints is difficult to evaluate. 
The minimum age of 30 years old in the inclusion criteria was selected based on the legal age 
of smoking in some of the chosen countries (20 years old) and to account for the 10 years of 
smoking history.  
This study is of non-investigational nature and will be used to establish a benchmark to 
compare the risks and benefits for a smoker switching from a CC to a candidate MRTP 
compared to smoking cessation. No control arms are required.  
Since literature [12] indicates that > 40% of subjects who remain tobacco free at 2 weeks 
continue to remain tobacco free for > 6 months, whereas > 80% of those who relapse in the 
first 2 weeks are smoking at 6 months, a period starting from check-out of V2 and ending with 
the V5 including the TQD, V3, the Grace Period and AQD has been implemented in the study 
design to evaluate smoking abstinence status and to select the subjects who are more likely to 
remain smoking abstinent for the whole duration of the study. Subjects discontinued from the 
study between AQD and V5 will be replaced in order to achieve approximately 950 subjects 
who are continuously abstinent from smoking at V5. From V5 onwards, subjects will not be 
replaced. 
To help smokers quitting tobacco, subjects will be provided with SC support and NRT (if 
requested by the subject). NRT are recommended as SC aids in Europe [13], Japan [14] and 
US [15], in addition to SC support. Other drugs to aid SC have been approved in several 
countries (e.g., bupropion and varenicline). However, since information on their effect on the 
selected clinical risk endpoints is sparse, their use will not be allowed in this study. 
Twenty-four hour-urine that will be collected in this study is the standard method to measure 
the levels of excretion of BoExp.  
As part of the characterization of the study population it is important to measure variables that 
have been shown to be related to nicotine dependence and product reinforcing value. Based on 
prior tobacco research these factors include age, gender, ethnicity, educational and socio-
economic status (SES), tobacco use history, expectations of the effects of the products tested, 
nicotine exposure, health and mental health status and use of psychoactive substances. In order 
to capture such data and allow comparing populations across studies, subjects will be asked 
questions about their socio-economic status.  

 
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4.3 
Appropriateness of Measurements 
The clinical risk endpoints to be assessed are selected based on a) their association with 
smoking-related diseases b) their association with smoking status, c) their reversibility upon 
SC/abstinence, and d) their suitability to be measured with valid and robust methods in clinical 
studies, e) timeframe of reversibility of measure in the perspective of the study duration. These 
clinical risk endpoints are associated with cardiovascular and respiratory diseases, genotoxicity 
and xenobiotic metabolism as presented in Appendix 4. 
The BoExp (list in Appendix 5) measured in this study were selected based on the following 
criteria: 1) HPHCs to be assessed in this study are derived from the list of HPHCs 
recommended for lowering in cigarette smoke as defined by the World Health Organization 
(WHO [16] and the draft guidance on Reporting Harmful and Potentially Harmful Constituents 
in Tobacco Products and Tobacco Smoke [17]; 2) the HPHC should be specific to the source 
of exposure with other sources being minor or non-existent; 3) the BoExp to an HPHC should 
be easily detectable using reliable, reproducible, precise analytical methods; 4) the HPHC 
should reflect a specific toxic exposure or be a reliable surrogate of exposure to HPHCs; 5) 
The list of HPHCs should include HPHCs from both gas and particulate phase; 6) The list of 
HPHCs should include a broad variety of chemical classes and organ toxicity classes 
(carcinogen, cardiovascular toxicant, respiratory toxicant, reproductive and development 
toxicant, addiction potential) and 7) represent HPHCs formed at different temperature levels. 
All questionnaires utilized for this study, except the cough-VAS and the socio-economic 
questionnaire, are available as validated questionnaires. 
4.4 
Study Duration 
The maximum total duration of the study for a subject will be 66 weeks. A Screening Period 
of up to 42 days will be followed by V2, plus a period of a maximum of 28 days until the AQD 
including the TQD visit and the Grace Period, followed by a 52-week smoking abstinence 
period in an ambulatory setting and a 28-days Safety Follow-Up Period ending after a phone 
contact with successful quitters in Week 56 (V18 (±3 days)). The EOS of the entire study will 
be defined as the end of the Safety Follow-Up Period of the last subject. 

 
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5 
STUDY POPULATION 
5.1 
Selection of Study Population 
Smoking adults (female or male), healthy subjects with no restriction on race and ethnicities, 
who have smoked at least 10 CC per day on average for the last 12 months and who have been 
smoking for at least the last 10 years will be enrolled in this study.  
The study will be a multi-center study, with approximately 50 sites located in Europe, Japan 
and US.  
5.1.1 
Inclusion Criteria 
Each subject enrolled at Baseline Visit (V2) must meet the following criteria: 
Inclusion Criteria 
Screening 
(V1) 
Baseline 
(V2) 
1. Subject has signed the ICF and is able to understand the 
information provided in the ICF. 
X 
 
2. Subject is aged from 30 to 65 years old (inclusive). 
X 
 
3. Smoking, healthy subject as judged by the Investigator based on 
all available assessments from the Screening Period (e.g., safety 
laboratory, spirometry, vital signs, physical examination, ECG, 
concomitant medications and medical history). 
X 
 
4. Subject smokes at least 10 commercially available CCs per day 
on average (no brand restrictions), for the last 12 months, based 
on self-reporting. Furthermore, the subject has been smoking for 
at least the last 10 years prior to screening. The smoking status 
will be verified based on a urinary cotinine test (cotinine ≥ 200 
ng/mL). 
X 
X 
5. The subject is willing to quit smoking within the next 30 days, as 
assessed by the Prochaska’s ‘Stage of Change’ questionnaire. 
X 
 
6. The subject is ready to comply with the study protocol (e.g., 
readiness to accept continuous smoking abstinence for 52 
weeks). 
X 
X 
5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the study: 

 
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Exclusion Criteria 
Screening 
(V1) 
Baseline 
(V2) 
1. As per the Investigator (or designee) judgment, the subject 
cannot participate in the study for any reason (e.g., 
medical, psychiatric and/or social reason). 
X 
 
2. The subject is legally incompetent, physically or mentally 
incapable of giving consent (e.g., emergency situation, 
under 
guardianship, 
in 
a 
social 
or 
psychiatric 
establishment, prisoner or involuntarily incarcerated). 
X 
 
3. Clinically 
relevant 
gastrointestinal, 
renal, 
hepatic, 
neurological, 
hematological, 
endocrine, 
oncological, 
urological, pulmonary, immunological, psychiatric or 
cardiovascular disorders or any other conditions that in the 
opinion of the investigators would jeopardize the safety of 
the participant or affect the validity of the study results. 
X 
 
4. Abnormal findings on physical examination, in the medical 
history, or in clinical laboratory results deemed clinically 
relevant by investigators (as per the common terminology 
criteria for adverse events [CTCAE]). 
X 
 
5. Acute illness (e.g., upper-respiratory-tract infection, viral 
infection etc.) requiring treatment within 42 days prior to 
enrolment in the study. 
 
 
X 
 
6. Use of any prescribed or over-the-counter systemic 
medication listed in Table 1* (except for vitamins) within the 
last 42 days prior to enrolment in the study (except for 
hormonal 
contraceptives 
and 
hormone-replacement 
therapy). 
 
 
X 
7. The subject has (FEV1/FVC) < 0.7 and FEV1 < 80% 
predicted value at post-bronchodilator spirometry. 
X 
 
8. The subject has (FEV1/FVC) < 0.75 (post-bronchodilator) 
and reversibility in FEV1 (that is both > 12% and > 200 mL 
from pre- to post-bronchodilator values). 
X 
 
9. The subject has a body mass index (BMI) < 18.5 or ≥ 35 
kg/m2. 
X 
 
10. As per the Investigator’s or designee’s judgment, the 
subject has medical conditions which require or will require 
in the course of the study, a medical intervention (e.g., start 
X 
 

 
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Exclusion Criteria 
Screening 
(V1) 
Baseline 
(V2) 
of treatment, surgery, hospitalization) which may interfere 
with the study participation and/or study results. 
11. The subject has a positive alcohol test and/or he/she has a 
history of alcohol abuse that could interfere with his/her 
participation in the study. 
X 
 
12. The subject has a positive urine drug test. 
X 
 
13. The subject has positive serology test for human 
immunodeficiency virus (HIV)1/2, Hepatitis B or Hepatitis 
C. 
X 
 
14. The subject has donated or received whole blood or blood 
products within 3 months prior to V1. 
X 
 
15. The subject has been previously screened for this study.  
X 
 
16. The subject is a current or former employee of the tobacco 
industry or their first-degree relatives (parent, sibling, 
child). 
X 
 
17. The subject is an employee of the investigational site or 
any other parties involved in the study or their first-degree 
relatives (parent, sibling and child). 
X 
 
18. The subject has participated in a clinical study within 3 
months prior to V1. 
X 
 
19. For women only: subject is pregnant (does have positive 
pregnancy test) or is breast feeding. 
X 
 
X 
* Concomitant Medication with potential impact on Clinical Risk Endpoints (section 6.4). Subjects using salbutamol for post-bronchodilator 
spirometry testing at screening will not be excluded from the study. 
5.2 
Recruitment Strategies and Retention 
Stratified sampling will be used to ensure adequate representation of subjects by sex (i.e., to 
have at least 40% of each sex at enrolment (see enrolment plan in a separate document)). 
Enrolment and attrition rates will be monitored during the study. In particular, the enrolment 
strategy and sample size may be adapted, depending on the actual attrition rate observed during 
the study conduct. If a higher than expected attrition rate is observed, the sample size may be 
increased to ensure adequate statistical power. If a lower than expected attrition rate is 

 
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observed, all subjects continuously abstinent from smoking, as assessed by the four criteria 
described in section 6.2, will be retained in the study. 
Smoking cessation support will be provided to the subject to prevent him/her from smoking 
during the study (section 1.1). 
5.3 
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 (e.g., subject who are not continuously 
abstinent from smoking after AQD, section 6.2). A subject can only be discontinued from the 
study after enrolment. 
Subjects will be informed that they are free to withdraw from the study at any time. Subjects 
should be questioned for the reason of premature withdrawal from the main study, although 
they are not obliged to disclose it.  
If the subject withdraws his/her consent for the main study (main ICF), the Investigator or 
designee needs to document if: 
 If applicable, the subject still consents for long-term bio-banking. 
 Whether the subject requested withdrawal of Health Insurance Portability and 
Accountability Act (HIPAA) authorization (for the US sites only). 
 The subject agrees to undertake the early termination procedures (section 9.6) 
This information needs to be fully documented in the source document and CRF.  
When a subject is discontinued from the study, he/she will be asked to perform the examination 
procedures planned in section 9.6 as soon as possible after the time of discontinuation unless 
the subject refuses to perform the assessments in writing.  
Subjects discontinued from the study cannot re-enter the study. 
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 Investigator or designee no longer justifies the subject’s 
participation in this study. 
 Pregnancy test is positive (section 8.5 for further details on the management of 
pregnancies).  

 
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 The Sponsor, the Investigator or designee terminates the study. If the Sponsor, the 
Investigator or designee decides to prematurely terminate the study, the subject will be 
promptly informed. The Investigator or designee should report the fact and the reason of 
termination in writing to the IRB or IEC. 
 Discontinuation is considered to be in the best interest for the subject himself/herself or for 
other subjects participating to the study, as judged by the investigator or designee. 
 Non-compliance with continuous smoking abstinence (see section 6.2), as assessed by the 
following four criteria: 
1. Self-reporting by the subject of use of any of the following product from 
AQD onwards: 
 Tobacco product, such as CC, snus, cigars. 
 Nicotine-containing products, other than NRT.  
 NRT continued after the allowed timeframe, i.e. 3 months (+2 weeks) 
after the start date of NRT. 
 Electronic cigarettes (with or without nicotine). 
2. Smoking abstinence verification by exhaled CO breath test at each visit from 
V4 onwards (CO breath test is > 10 ppm) 
3. Smoking abstinence verification by urine cotinine test in spot urine at site at 
each visit from V10 onwards (urine cotinine test is ≥ 100 ng/ml). 
4. Smoking abstinence verification by analysis of the free cotinine concentration 
(part of the nicotine equivalents) in 24-hour-urine collected at Visit 11 (urine 
cotinine concentration is ≥ 50 ng/mL). 
If any one of these four criteria is met, the subject must be discontinued.  
  
Subjects may be discontinued from the study for any of the following reasons on the judgment 
of the Investigator or designee: 
 Non-compliance to the study procedures other than compliance to continuous smoking 
abstinence. 
 Use of medication supportive to smoking cessation, other than NRT, from the TQD 
onwards. 
Subjects discontinued from enrolment to V5 will be replaced in order to achieve approximately 
950 subjects who are continuously abstinent from smoking at V5. From V5 onwards, subjects 

 
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will not be replaced. All subject discontinuations have to be documented properly in the source 
document and in the CRF. 
5.4 
Assessments at Visit 17 to be performed if Total NNAL is above 
the cut-off at Visit 11 
Analysis of Total NNAL will be performed by a central laboratory to determine which 
assessments will be performed at Visit 17. The concentration of Total NNAL will be 
determined in 24-hour urine collected at Visit 11 (cut-off < 75.9 pg/mL) [18]. If the 
concentration of Total NNAL is ≥ 75.9 pg/mL, the subject will remain in and continue with 
the study, unless the subject is discontinued for other reasons. However, for this subject, only 
the following assessments at Visit 17 will be performed: 
 Smoking cessation support 
 Prior/Concomitant medication 
 Pregnancy test (all female subjects) 
 Vital signs 
 CO Breath test 
 Cotinine test in spot urine (cut-off < 100 ng/mL) 
 AE/SAE recording. 
5.5 
Lost to Follow-up 
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. The date of 
the last contact (e.g. last visit, last phone call) should also be recorded in the source document. 
When the PI(s) or designee(s) declare(s) a subject is lost to follow-up, the lost to follow-up 
date will be recorded and will correspond to the date of the end of study of the subject.  
If the site has lost track of the subject but the subject has reached the maximum number of 
study days (465 days), then the PI(s) or designee(s) will declare the subject lost to follow-up 
at this date.

 
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5.6 
Violation of Selection Criteria 
Subjects who, after signing the ICF at screening, do not meet the entry criteria at Screening or 
at V2 or do not come to V2 with their 24h urine container filled will be considered as screen 
failures. Re-screening will not be permitted.  
If a violation of selection criteria is detected, subjects might be discontinued from the study 
based on a case-by-case decision of the PI. 

 
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6 
RESTRICTIONS AND SUPPORT DURING THE STUDY 
6.1 
Smoking Cessation Support 
Information on the risk of smoking and SC advice will be provided to the subject. The approach 
to SC support including SC counseling and behavioral support in this study will be explained 
and the benefits and risks of using NRT discussed with the subject. The Investigator or 
designee will provide information on the different NRTs available and the Investigator or 
designee and the subject will agree on which NRT will be used as supportive medication. The 
subject may choose to not use NRT and to rely on smoking cessation counseling and behavioral 
support only. 
Once the NRT is selected, the subject will be advised on how to use the NRT as per approved 
country label and for up to 3 months (+2 weeks) after the start date of NRT. NRT may be 
started at any time between the TQD and 1 week after the AQD.   
If the NRT selected (e.g., gum, lozenge, patch, nasal spray, depending on the availability in 
the country of study) is not available over the counter, the Investigator or designee will 
prescribe the selected NRT as per local country regulations. The combined use of NRT (e.g., 
patch and gum together) or the switch from one NRT to another one will be allowed in this 
study as per country label (e.g., NRT combined use for EU allowed, but not in JP) and for up 
to 3 months (+2 weeks) after the start date of NRT. No medication supportive for SC other 
than NRT (e.g., bupropion or varenicline) will be allowed. 
A SC specialist (e.g., psychologist) may be contacted and will be available upon the subject’s 
request, or if considered necessary, upon the request of the Investigator or designee. 
Smoking cessation support, including SC counseling and behavioral support, will be provided 
at each visit and in-between visits throughout the study from the TQD onwards as defined in 
the SC support plan (separate document) and whenever requested by the subject. 
6.2 
Compliance 
Compliance with continuous smoking abstinence is defined by the four following criteria: 
1. No self-reporting by the subject of use of any of the following product from AQD onwards: 
- 
Tobacco product, such as CC, snus, cigars. 
- 
Nicotine-containing products, other than NRT.  
- 
NRT continued after the allowed timeframe, i.e. TQD + 3 months (+2 weeks). 
- 
Electronic cigarettes (with or without nicotine). 

 
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2. CO breath test ≤ 10 ppm [19], as verified at each visit from V4 onwards. 
3. Urine cotinine test < 100 ng/mL in spot urine at site, as verified at each visit from V10 
onwards [19].  
4. Free cotinine concentration < 50 ng/mL in 24-hour-urine collected at Visit 11 [19]. 
If any of these four criteria is not met, the subject must be discontinued (see section 5.3). 
6.3 
Restrictions 
6.3.1 
Smoking Restrictions 
Subjects will be allowed to use their own brand of CC until their AQD. Occasional slips of 
using CC during the Grace Period between TQD and AQD is allowed as described in section 
4.1. The use of NRT between the TQD and AQD while no full smoking abstinence is achieved 
will depend on the NRT country label. From their AQD, use of any tobacco, nicotine 
containing product other than NRT, as well as e-cigarettes will not be allowed in this study. 
At Screening Visit (V1) and V2 pre- and post-bronchodilator spirometry will be done after at 
least 1 hour of not smoking (section 7.4.7.1). 
6.3.2 
Dietary Restrictions 
Subjects have to fast for 10 hours prior to blood draws for: 
 Hematology and clinical chemistry safety laboratory except at the Screening Visit (V1). 
 Clinical risk endpoints. 
 Serum/plasma/blood bio-banking. 
Subjects do not have to fast prior to the timepoints for the urine analysis of the safety panel. 
6.4 
Concomitant Medication 
For the definition of prior and concomitant (ongoing medications), please see section 7.4.3. 
Medication will be allowed during the study and will carefully be monitored by the Investigator 
or designee. The Investigator or designee is responsible for the medical care including 
medication of the subjects during their participation in the study. Any decisions regarding the 
prescription of medication will be made in the best interest of the subject. Any use of 
concomitant medication, including NRT, must be fully documented in the source document 
and recorded into the CRF. For NRT, the Investigator or designee will instruct the subject to 

 
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use the NRT as per country label for up to 3 months (+2 weeks) after TQD. The use of 
medication supportive for smoking abstinence other than NRT will not be allowed. 
Any concomitant medication which has a potential impact on the study endpoints, including 
non-steroidal anti-inflammatory drugs (NSAIDs) including over-the-counter products should 
be avoided and carefully considered.  
Table 1 provides an overview of selected medication and their potential impact on clinical risk 
endpoints.  
To provide additional information and guidance to the Investigator or designee, Appendix 2 
provides an overview of drug half-lives for drugs considered to have an impact on some of the 
study endpoints listed below in Table 1.  
In case drugs/short-and long-term vitamins listed in Table 1 are taken by the subject from the 
enrolment onwards, they will be recorded as concomitant medications (except when 
salbutamol is used for post-bronchodilator spirometry testing), but this will not be a reason to 
discontinue the subject from the study.  
Table 1 
Concomitant Medication and Impact on Clinical Risk Endpoints 
Concomitant Medication 
HDL-C 
WBC 
FEV1 
11-DTX-
B2 
8-epi 
PGF2α 
Vitamins B: 
- 
Thiaminchlorid (Vitamin B1) 
- 
Nicotinic acid (Vitamin B3) 
- 
Pyridoxin (Vitamin B6) 
- 
Cyanocobalamin (Vitamin B12) 
● 
 
 
 
 
Ascorbic acid (vitamin C) 
● 
 
 
 
 
Tocopherol (vitamin E) 
 
 
 
 
● 
Non-steroidal anti-inflammatory drugs 
(NSAID) 
 
● 
 
● 
 
Antivirals/antibiotics 
 
● 
 
 
 
Short acting β agonists, long acting β 
agonists (e.g., salbutamol)* 
 
 
● 
 
 
Aminophylline/theophylline 
 
 
● 
 
 
Systemic broncholytic drugs (e.g., 
terbutalinsulfat) 
 
 
● 
 
 

 
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Concomitant Medication 
HDL-C 
WBC 
FEV1 
11-DTX-
B2 
8-epi 
PGF2α 
Tiotropium, anticholinergic 
bronchodilator 
 
 
● 
 
 
Inhaled Glucocorticosteroids 
 
 
● 
 
 
Antiplatelet agents (e.g., 
phenprocoumon, apixaban, warfarin) 
 
 
 
 
● 
Antidiabetic drugs (thiazolidinediones 
(Pioglitazone, Rosiglitazone)) 
● 
 
 
● 
 
Beta-blockers (e.g., atenolol, metoprolol) 
 
 
● 
 
 
Angiotensin converting enzyme (ACE) 
inhibitors (e.g., captopril, enalapril, 
lisinopril, and ramipril). 
 
 
 
● 
 
Statins / other cholesterol-lowering 
drugs (e.g., fluvastatin, simvastatin, 
ezetimibe) 
● 
 
 
● 
 
Antidepressant (e.g., bupropion)  
 
● 
 
 
 
Estrogen 
 
 
 
● 
 
* Except when salbutamol is used for post-bronchodilator spirometry testing. 

 
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7 
STUDY PROCEDURES 
Personnel performing study assessments must have appropriate and documented training. An 
overview of all study assessments is shown in the schedule of events (Appendix 1). Site 
personnel will adhere to the site’s standard operating procedures (SOPs) for all activities. 
Appropriate medical advice will be provided to the subject in case of any medical findings 
requiring health care. 
7.1 
Informed Consent and Guidance 
Prior to any study assessments being performed, the subject will be asked to provide his/her 
written consent to participate to the study (ICF) (section 1.3). All assessments must start after 
the time of ICF signature by the subject for study participation. 
In addition to the ICF for study participation, the subject will be asked to provide his/her 
separate consent for sample bio-banking (section 1.3.2): 
 ICF for the additional bio-banking of serum/plasma/urine samples for further 
measurements of clinical risk endpoints and BoExp. 
 ICF for the additional bio-banking of blood and plasma samples for further transcriptomics 
and lipidomics analysis. 
The subject’s participation in the study does not depend on his/her consent for bio-banking and 
will be separated from the consent for study participation. The different consents will be 
captured in the CRF. 
7.2 
Information on the Risk of Smoking and Smoking Cessation 
Advice 
Each subject will be given information on the risks of smoking and SC advice at V1, V2 and 
in case of discontinuation. Information will be given on an individual basis during a face-to-
face meeting between the subject and the Investigator or designee, and may additionally be 
given in a group session. Details of the interviews will be recorded in the source document.  
7.3 
Smoking Cessation Support 
Smoking cessation support, including SC counseling and behavioral support, will be provided 
at each visit and between visits throughout the study and whenever requested by the subject 
(section 6.1). General recommendations on SC support are provided in the SC support plan 
(separate document).  

 
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7.4 
Clinical Assessments 
Any clinically relevant medical condition detected at V1 has to be documented as a 
concomitant disease. This also applies to clinically relevant findings in laboratory values, vital 
signs, spirometry and ECGs detected at V1. Any untoward medical occurrence in a subject 
detected during the study which was not present at V1 must be documented as an AE. 
Worsening of a pre-existing condition from V1 onwards will also be documented as an AE.  
The results of the clinical assessments described in this section will be recorded in the CRF. 
7.4.1 
Demographic Data 
Demographic data (sex, age, race and/or ethnicity) will be recorded.  
See Appendix 1 for the timepoints of assessment. 
7.4.2 
Questions on Smoking History/Habits and Intention to Quit Smoking.  
Subjects will be asked the following questions about their smoking history and habits: 
5. Have you smoked for at least the past 10 years? (yes/no) 
6. How many years have you smoked? (numeric response, 2 digits) 
7. On average, how many cigarettes per day have you smoked over the last year? (numeric 
response, 2 digits) 
8. On average, how many cigarettes per day have you smoked since you started smoking? 
(numeric response, 2 digits) 
9. On average, how would you describe your e-cigarette use over the last year? (check 
one) 
a. Daily.  
i. 
How much use per day? (numeric response, 2 digits)  
b. Weekly. 
i. 
How much use per week? (numeric response, 2 digits)  
c. Sporadically. (less than once per week) 
d. Tried e-cigarettes. (between 1 – 10 uses ) 
e. Never tried e-cigarettes. 
This self-reported CC daily consumption at V1 and V2 will be used to assess eligibility.  

 
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Intention to quit smoking within the next 30 days will be assessed at V1 by the means of the 
Prochaska’s questionnaire (section 7.7.1.1).  
See Appendix 1 for the timepoints of assessment. 
7.4.3 
Medical History and Prior and Concomitant Medications 
Relevant medical history and any concomitant disease will be documented at V1. Medical 
history is defined as any condition that started and ended prior to V1. A concomitant disease 
is defined as any condition that started prior to and is still ongoing at V1, or is detected at V1. 
Medications will be allowed and carefully monitored during the study by the Investigator or 
designee. The Investigator or designee is responsible for the medical care including medication 
of the subjects during their participation in the study. Any decisions regarding the prescribed 
medications will be made in the best interest of the subject. Any use of concomitant medication 
must be fully documented in the source document and transcribed into the CRF. 
All medication taken 4 weeks prior to V1 (prior medications) and all concomitant medication 
taken during the study will be documented in the source documentation and recorded in the 
CRF. Medication which was started prior to V1 and which is still being taken by the subject 
during the study as well as medication that is initiated after V1 will be considered as a 
concomitant medication. This applies to both prescription and over-the-counter products (e.g., 
vitamins). NRT will be recorded as a concomitant medication. 
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 start and if applicable, the stop date (day, month and year). Any 
therapy changes (including changes of regimen) during the study have to be documented. Any 
concomitant medication that is still being taken by the subject at the EOS will be recorded in 
the CRF. 
7.4.4 
Physical Examination 
A complete physical examination, including auscultation and palpation will be performed.  
See Appendix 1 for the timepoints of assessment. 
7.4.5 
Body Height, Weight and Waist Circumference  
Body weight, height and waist circumference will be measured. The same scale should be used 
for all assessments. 

 
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Appropriate medical advice will be provided to the subject in case any medical findings 
requiring health care are identified. 
Body mass index (BMI) will be calculated from the body weight and height using the following 
formula: 
BMI =  
weight in kilograms 
————————     ( kg/m² ) 
height in meters² 
At V1, BMI will be calculated from the height and weight recorded at V1. At the following 
visits, BMI will be calculated from the height at V1 and body weight recorded at each 
respective visit. 
See Appendix 1 for the timepoints of assessment. 
7.4.6 
Vital Signs 
Systolic and diastolic blood pressure, pulse rate and respiratory rate will be measured. All 
measurements will be made after the subject has rested for at least 5 minutes in a supine 
position.  
See Appendix 1 for the timepoints of assessment. 
7.4.7 
Other Clinical Assessments 
7.4.7.1 
Lung Function Testing 
See Appendix 1 for the timepoints of assessment. 
All personnel performing lung function testing must have the appropriate training. Quality 
control measures should be available and be properly documented. The subject will be at rest 
for at least 15 minutes prior to lung function testing. All lung function maneuvers will be 
recorded with the subject in a sitting position throughout the study. 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 or designee.  
Spirometry testing  
The spirometry test will be performed on a computerized spirometry system, such as 
Vitalograph® Compact 6600 (Vitalograph; Ennis, Ireland) or similar, in accordance with the 
2005 guideline of the American Thoracic Society (ATS)/European Respiratory Society (ERS) 

 
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Joint Task Force on the standardization of spirometry. Spirometry testing will be managed by 
a central provider, including the provision of equipment and site manual. The Pulmonary 
Function Testing (PFT) manual will include information on equipment, procedures, subject 
instructions and precautions. 
The spirometry tests will include the recording of FEV1, FVC, FEV1/FVC ratio and FEF 25-
75. All spirometry tests will be performed as described in the Investigator PFT site manual 
[20]. 
All spirometry testing must be performed at least 1 hour after smoking (if applicable).  
Pre- and post-bronchodilator spirometry testing 
Pre and post- bronchodilator spirometry assessments will be performed. Each assessment 
requires at least three valid spirometry tests. The ratio of FEV1/FVC will be calculated from 
the highest acceptable FEV1 and the highest acceptable FVC, respectively.  
The results from FEV1 and the ratio FEV1 to FVC at V1 will be used for eligibility criteria to 
assess spirometry and asthma conditions. 
For all the other visits, 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. 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. In 
case, the tests do not meet the acceptability criteria the subject will need to come back within 
a 5-day window to repeat the tests. More details will be provided in the Pulmonary Function 
Testing (PFT) manual. 
All post-bronchodilator spirometry testing will be performed 15-30 minutes post 
administration of around 400 µg of salbutamol/albuterol (usually equivalent to 4 puffs 
assuming 100 g/puff). The time of salbutamol/albuterol inhalation and time of spirometry 
assessment will be recorded in the source document. 
See Appendix 1 for the timepoints of assessment. 
Lung volume measurements using multiple breath helium dilution technique  
All lung volumes measurements will be done pre-bronchodilator. 
Lung volume measurements will be conducted as part of the lung function tests in selected and 
specialized centers and the following values will be recorded: VC, FRC, IC and TLC. If 
required, a second trial can be performed. Between trials, 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 at FRC plus IC. VC will be the highest from FRC-He if more than one attempt is 

 
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performed. Residual volume will be calculated as TLC minus VC. VC is the highest from FRC-
He wash in. 
The helium dilution technique will be used in accordance with the recommendations of the 
American Thoracic Society/European Respiratory Society (ATS/ERS) Joint Task Force on the 
standardization of the measurement of lung volumes [21]. This technique is a closed-circuit 
system where a spirometer is filled with a mixture of helium 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. 
See Appendix 1 for the timepoints of assessment. 
7.4.7.2 
 Electrocardiogram 
Electrocardiogram (ECG) recording will be performed as per the site’s local practice. A 
standard 12-lead ECG will be recorded after the subject has rested for at least 5 minutes in a 
supine position.  
The following parameters will be documented: heart rate, PR interval, QRS interval, QT 
interval, and QT interval corrected by the ECG machine according to Bazett’s formula and 
Federici’s formula. Every ECG has to be assessed as normal, abnormal – clinically not 
relevant, or abnormal – clinically relevant. A diagnosis has to be provided on the eCRF for all 
ECGs assessed as abnormal – clinically relevant. All ECG print-outs will be interpreted by a 
qualified physician. Any print-outs of ECGs on thermo-sensitive paper must be photocopied 
and stapled together for inclusion in the source documents and signed by Principal Investigator 
or designee. 
See Appendix 1 for the timepoints of assessment. 
7.5 
Laboratory Assessments 
7.5.1 
Assessments in Blood 
7.5.1.1 
Hematology and Clinical Chemistry 
The following parameters will be measured: 

 
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Table 2 
Hematology and Clinical Chemistry Parameters (Safety) 
Hematology 
Clinical Chemistry 
 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 
 Fasting glucose 
 Gamma-glutamyl transferase (GGT) 
 Lactate dehydrogenase (LDH) 
 Potassium  
 Sodium 
 Total and direct bilirubin 
 Total cholesterol 
 Triglycerides 
See Appendix 1 for the timepoints of assessment. 
7.5.1.2 
Serology 
A test for hepatitis B surface antigen, hepatitis C virus and human immunodeficiency virus 
(anti-HIV1/2) will be done at V1. 
7.5.2 
Assessments in Urine 
7.5.2.1 
Urine Analysis 
The following parameters will be analyzed semi-quantitatively in urine: 
 pH 
 Bilirubin 

 
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 Glucose 
 Nitrite 
 Red blood cell traces 
 Protein 
 Specific gravity 
See Appendix 1 for the timepoints of assessment. 
7.5.2.2 
Urine Drug Screen 
The urine will be screened for the following drugs or class or drugs: amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine and opiates. 
See Appendix 1 for the timepoints of assessment. 
7.5.2.3 
Urine Cotinine Tests 
In this study, urine cotinine will be analyzed in three different ways. Two different tests will 
be used at site and a third analysis will be carried out by a central laboratory. 
A urine cotinine test will be performed to confirm the subject’s smoking status as smoker at 
Screening and Baseline Visits. The test must detect cotinine with a cotinine threshold of ≥ 200 
ng/mL. 
Another urine cotinine test in spot urine at site will be used to verify continuous smoking 
abstinence at each visit from V10 onwards. The cut-off value defined for this smoking 
abstinence verification is < 100 ng/mL.  
Repeat testing for the urine cotinine test in spot urine at site is permitted in case of unclear 
results. 
Subjects who have completed the study before the effective date of the current study protocol 
(Final Version 7.0) without having ever been tested for cotinine in urine by the urine cotinine 
test (cut-off < 100 ng/ml) in spot urine at site will not be recorded as subjects with a protocol 
deviation hereof.   
Subjects who have already performed one or several Visits from Visit 10 onwards before the 
effective date of the current study protocol (Final Version 7.0) without having been tested for 
cotinine in urine by the urine cotinine test (cut-off < 100 ng/ml) in spot urine at site will not be 
recorded as subjects with a protocol deviation hereof. 

 
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The urine cotinine test used at Screening and at Baseline and the one used at each visit from 
V10 onwards are two different tests and cannot be exchanged. 
See Appendix 1 for the timepoints of assessment. 
A third analysis of cotinine in urine will be performed by a central laboratory as a criterion for 
discontinuation (see section 5.3 and 6.2), i.e. free cotinine concentration (part of the nicotine 
equivalents) will be determined in 24-hour urine collected at Visit 11. If the concentration of 
free cotinine is ≥ 50 ng/mL, the subject will be discontinued at the time the results are made 
available. 
7.5.2.4 
Urine Pregnancy Testing 
All female subjects will perform pregnancy tests. Female subjects with a positive pregnancy 
test at V1 or V2 will not be enrolled and will be considered as screen failures. In case of any 
positive urine pregnancy test, the Investigator or designee will inform the 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. 
See Appendix 1 for the timepoints of assessment. 
7.5.3 
Assessments in Exhaled Breath 
7.5.3.1 
Exhaled CO Breath Test 
Exhaled CO breath test will serve as a verification of compliance to SA during the study 
conduct. The cut-off value defined for this smoking abstinence verification is ≤ 10 ppm. During 
the visits on site, it will be measured with a Micro 4 Smokerlyzer® device or similar.  
The CO breath test should be conducted in timely conjunction with the blood sampling for 
COHb when appropriate. 
Repeat testing for the CO breath test is not permitted.  
See Appendix 1 for the timepoints of assessment. 
7.5.3.2 
Alcohol Test 
Subjects will have a urine or breath alcohol test at V1.  

 
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7.6 
Biomarkers of Assessments 
7.6.1 
Biomarkers of Exposure to HPHCs 
For normalization of BoExp to HPHCs, creatinine will also be measured in the 24-hour urine 
samples. 
See Appendix 1 for the timepoints of assessment. 
The list of BoExp is provided in Appendix 5. 
7.6.1.1 
Clinical Risk Endpoints 
The list of the clinical risk endpoints to be measured in the study is provided in Appendix 4. 
For normalization of clinical risk endpoints measured in urine, creatinine will also be measured 
in the 24-hour urine samples. 
The COHb test should be conducted in timely conjunction with the CO breath (section 7.5.3.1). 
The samples will be collected irrespective of the time. 
See Appendix 1 for the timepoints of assessment. 
7.6.1.2 
CYP2A6 activity test 
CYP2A6 activity will be measured in plasma using the molar metabolic ratio of trans-3’-
hydroxycotinine to cotinine [22]. CYP2A6 activity drives the metabolism of nicotine to 
cotinine and subsequent metabolites. 
See Appendix 1 for the timepoints of assessment. 
7.6.2 
Sample Handling, Storage, and Shipment 
All blood and urine samples will be tested at a central laboratory. The urine pregnancy tests 
and cotinine dipstick tests will be done by personnel at the study sites. 
Detailed procedures for collection and handling of samples are described in a separate 
Investigator Laboratory Manual (ILM). Safety laboratory samples will be destroyed as per the 
laboratory’s standard procedures. All primary and back-up samples for the assessments of 
clinical risk endpoints and BoExp (except bio-banking samples) of discontinued subjects will 
be destroyed after all bioanalytical reports have been finalized or the database has been locked, 
whichever comes last. Personnel at the facility/-ies where samples are stored will be informed 
in writing by the Sponsor when destruction of the samples will be allowed. 

 
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The bioanalytical lab(s) will be listed in the ILM. 
7.6.3 
Blood Samples 
Blood samples will be collected by qualified and trained site personnel. Subjects should be in 
a seated position during blood collection. The maximal total volume of blood drawn for each 
subject will be around 375 mL, which includes about 65 mL for safety and repeated analysis, 
about 50 mL for long-term storage of the bio-banking samples for further analysis of BoExp 
and clinical risk endpoints (only if additional consent is given) and 40 mL for long-term storage 
bio-banking samples for further analysis of transcriptomics and lipidomics (only if additional 
consent is given) (section 7.6.5). 
The blood sampling for transcriptomics & lipidomics, and the data related to these samples 
will be anonymized. Anonymized data and samples are initially single or double coded where 
the link between the subjects’ identifiers and the unique code(s) is subsequently deleted.  
7.6.4 
Urine Samples 
7.6.4.1 
Spot Urine Samples  
Spot urine samples will be used for the urine drug screen, urine cotinine tests, urine pregnancy 
test and safety urine analysis.  
7.6.4.2 
24-hour Urine Collection  
Twenty four-hour urine fraction will be collected.  
The day before the visit, subjects will start collection of 24-hour urine at home. Subjects will 
discard their first void in the morning. The collection period will start immediately after. After 
24-hour ± 1 hour of urine collection, in the morning of the visit, subjects will empty their 
bladder again 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 must be passed into the toilet. The start and the end time of urine collection 
will be recorded by the subject in a form 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-TBX-B2, albumin and sample 
for bio-banking (if consent received), aliquots from the 24-hour urine collection will be taken. 
In the table of assessments, for the 24-hour urine collection, the dot corresponds to the day on 
which the 24-hour urine collection period ends. 

 
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See Appendix 1 for the timepoints of assessment. 
7.6.5 
Bio-banking for Long Term Storage of Blood and Urine 
If a subject gives consent for sample bio-banking for further analysis of BoExp and clinical 
risk endpoints, additional samples of urine (from the 24-hour urine collection) and 
serum/plasma (50 mL of blood in total) will be collected as follows: 
 From the 24-hour urine collections 5 aliquots of 10 mL urine for each visit. 
 Serum/plasma: at each visit 2 tubes with about 5 mL of blood each will be filled and 
centrifuged: from one tube, two aliquots of 1 mL plasma and from the second tube 2 
aliquots of 1 mL of serum will be collected and stored. 
If a subject gives consent for sample bio-banking of whole blood/plasma for further 
transcriptomics & plasma for lipidomics analysis, an additional 9 mL of blood will be collected 
for each assessment: 5 mL for transcriptomics will be aliquoted in 2 tubes (2.5 mL of 
blood/tube); for lipidomics, the 4 mL of blood will be centrifuged and the plasma aliquoted in 
2 tubes of 500 l each.  
The samples intended for sample bio-banking will be kept frozen, separated from the other 
samples collected, and will be shipped to a central storage facility according to the ILM. After 
the final CSR is signed, samples of plasma/serum/blood will be stored for a maximal period of 
5 years and samples of urine will be stored for a maximal period of 2 years. The blood/plasma 
bio-banking for transcriptomics and lipidomics will be stored for a maximum period of 5 years. 
If a subject withdraws his/her consent for sample bio-banking the facility at which the samples 
are stored will follow their procedures for destruction of banked samples as stated in section 
1.3.2. 
See Appendix 1 for the timepoints of assessment. 
7.7 
Other Study Procedures 
7.7.1 
Questionnaires 
The subject questionnaires and the cough-VAS used in this study will be entered by the subject 
directly in a subject reported outcomes (SRO) device or on paper copy. All subject reported 
outcome data as well as instructions will be provided in the subject’s local language. The 
questionnaires and the cough-VAS will be reviewed for completeness by the study site staff 
and subjects will be requested to complete any missing information. 

 
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Symptoms or worsening of symptoms documented on any of the questionnaires or on the VAS 
do not need to be documented as additional AEs because the questionnaires and the cough-
VAS will be analyzed as part of the final report. However, it is at the discretion of the 
Investigator or designee 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 the 
study site staff, using open, non-directive questions (section 8.2). 
See Appendix 1 for the timepoints of assessment. 
7.7.1.1 
Prochaska ‘Stage of Change’ Questionnaire: Intention to Quit Smoking 
The Prochaska’s ‘Stage of Change’ questionnaire will be used to assess the smokers’ mental 
state for the intention to quit (Appendix 2 for staging algorithm; [23, 24].There are 5 stages of 
change: 1. Precontemplation, 2. Contemplation. 3. Preparation. 4. Action. 5. Maintenance. In 
the Precontemplation stage, the individual does not recognize smoking as a problem.  
In the Contemplation stage, the individual is gathering information about smoking, such as 
contacting a health care provider or a tobacco quit line for information on the effects of 
smoking or smoking cessation consequences. During this stage, the stress and inconvenience 
of quitting smoking is greater than the immediate and possible long-term health effects of 
continuing smoking. In the Preparation stage, intention and behavior begin to come together 
and the subject is preparing to enter into action in the next 30 days. It is necessary for the 
subject to recognize the benefits of not smoking, before a subject can enter the Action stage 
and as a result, changes his/her smoking behavior. After six months of not smoking, the 
individual reaches the Maintenance stage when different skills may be needed to prevent 
relapse from smoking.  
All subjects who are planning to quit smoking within the next 30 days will be eligible for the 
study regardless of having one day of quit attempt over the past year. 
See Appendix 1 for the timepoints of assessment. 
7.7.1.2 
Fagerström Test for Nicotine Dependence (revised version) 
Potential nicotine dependence will be assessed via a questionnaire using the Fagerström test 
for nicotine dependence (FTND) in its revised version [25]. 
The questionnaire consists of six questions which will be answered by the subject 
himself/herself. The scores obtained on the test allow the classification of nicotine dependence 
in three different levels: mild (0-3 points), moderate (4-6 points), and severe (7-10 points). 
See Appendix 1 for the timepoints of assessment. 

 
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without the written consent of Philip Morris Products S.A. 
7.7.1.3 
Assessment of Cough-VAS 
Subjects will be asked to assess the respiratory symptom ‘cough’ on a VAS, on three Likert 
scales, and with an open question. Assessment of cough will be conducted irrespective of the 
time. 
Subjects will be asked if they have experienced a regular need to cough, e.g., whether they 
have coughed several times in the previous 24 hours prior to assessment. If the answer is ‘yes’, 
subjects will be asked to complete a VAS, 3 Likert scales and to answer the open question. 
On the VAS, subjects will assess how bothersome their cough was during the previous 24 
hours. The VAS ranges from ‘not bothering me at all’ to ‘extremely bothersome.’ 
Furthermore, subjects will assess the intensity and frequency of cough and the amount of 
sputum production during the previous 24 hours on Likert scales. 
The intensity of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 1 = 
very mild – 2 = mild – 3 = moderate – 4 = severe – 5 = very severe. 
The frequency of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = rarely – 2 = sometimes – 3 = fairly often – 4 = often – 5 = almost always. 
The amount of sputum production will be assessed on a 4-point Likert scale ranging from 0 to 
3, with 0 = no sputum – 1 = a moderate amount of sputum – 2 = a larger amount of sputum – 
3 = a very large amount of sputum. 
Finally, subjects will be asked to share any other important observations with the staff about 
their coughing. 
See Appendix 1 for the timepoints of assessment. 
7.7.1.4 
Socio-Economic Status 
The SES information will be collected in the following countries: US, UK, Poland, Germany 
and Japan. 
As part of the characterization of the study population it is important to measure variables that 
have been shown to be related to nicotine dependence and tobacco product reinforcing value. 
Based on prior tobacco research these factors include age, gender, ethnicity, tobacco use 
history, educational as well as socio-economic status. 
SES information is recorded in similar manner in the clinical program, in behavioral research 
and will be eventually assessed in post-marketing studies. In order to evaluate factors affecting 
the success for a 12-month SC, the socio-economic status constitutes an important 
demographic parameter. Socio-economic status data will be reported across the randomized 

 
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clinical studies and will be collected in observational pre- and post-marketing studies. At V1 
the subjects will be informed in details about the exams and evaluations planned during the 
study, and similarly notified about the SES assessments which will be done at V2. After having 
provided informed consent at V1, the subjects will be enrolled in the study. 
Subjects will be asked a series of questions related to their education, occupational status, size 
and annual income of their household. These data will be used to create a measure for SES that 
categorizes subjects into low, moderate and high SES [26]. If the subject does not want to 
answer the questionnaire, he/she will not be withdrawn from the study. 
See Appendix 1 for the timepoints of assessment. 
7.7.1.5 
Lifestyle Assessment 
Subjects will be asked questions to capture baseline covariates such as diet, alcohol intake, 
sleep deficit, exercise and exposure to passive smoking. 
See Appendix 1 for the timepoints of assessment. 

 
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8 
ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
Since no investigational products will be used in this study, any health-related event occurring 
during the study will be reported. 
For the purpose of this study an AE is defined as any untoward medical occurrence that may 
present itself during the conduct of a study and which may or may not have a causal 
relationship with the study procedures. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom or disease. 
8.1.2 
Serious Adverse Events 
A SAE is defined as, but is 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, an 
SAE 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 an SAE; however they will be recorded as AE 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 Investigator or designee is responsible for obtaining, assessing and documenting all AEs 
during the study.  

 
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8.2.1 
Collection of Information 
Adverse event information will be collected from the time of signature of the ICF onwards 
until EOS either by the Investigator or designee 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 since you were last asked?”). 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 seriousness criteria must be recorded both on the AE report form of the 
CRF and on a separate SAE report form (section 8.2.3). 
8.2.2 
Period of Collection 
From the time of signature of the ICF onwards until EOS, all AEs (includes SAEs) will be 
collected by the study site staff as described below.  
8.2.2.1 
Screening Period  
All existing health conditions identified during the Screening Period will be recorded as 
concomitant disease and the subject’s eligibility for Baseline to the study will be reviewed. 
Any AEs which occur during the Screening Period will be captured by the study site staff and 
assessed by the Investigator or designee in order to establish relationship or relatedness in 
respect to study procedures. All collected AEs will be reported in the CSR and will be in 
accordance with the respective regulatory guidelines.  

 
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8.2.2.2 
From Enrolment until the End of the Study  
Any new, clinically relevant, abnormal finding detected during the study or worsening of a 
pre-existing condition/concomitant disease will be documented as an AE and/or SAE. 
All ongoing AEs at the EOS will not be followed-up by the Investigator or designee. At the 
discretion of the Investigator, the subject will be referred to his/her General Practitioner for 
follow up on ongoing AEs (section 8.3). 
8.2.3 
Intensity of Adverse Event 
For each AE, the intensity will be evaluated by the Investigator or designee 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. 
Change in severity (intensity) needs to be documented. 
8.2.4 
Relationship to Study Procedures 
In general, all AEs and/or SAEs will be assessed by the Investigator or designee as either 
‘related’ or ‘not.  
Not related: The temporal relationship of the clinical event to study procedures 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 procedures makes a causal 
relationship possible, and concomitant medication, therapeutic interventions, or underlying 
conditions do not provide a sufficient explanation for the observed event. 
8.3 
Reporting of Serious Adverse Events 
Any SAEs reported or observed during the study after signature of the ICF until EOS, whether 
or not attributable to any medication or to any study procedures must be reported by the 
Investigator or other study site staff within 24 hours after first awareness by any party 
involved in the study to United BioSource Corporation (UBC) Safety and to the Sponsor. 
An SAE report form must be faxed or e-mailed as an attachment to: 

 
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UBC Safety: 
Fax number: 
 
E-mail: 
 
Address: 
United BioSource Corporation 
 
 
. 
Sponsor Contact: 
, MD, 
Medical Safety Officer 
Phone: 
 
E-mail 1: 
 
E-mail 2: 
 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube 
Quai Jeanrenaud 5 
2000 Neuchâtel, Switzerland 
The Investigator or designee is responsible for local reporting (e.g., to the IRB/IEC) of SAEs 
that occur during the study, according to local regulations.  
Any SAE will be reported to the competent authorities by the Sponsor as per local 
requirements.  
Any additional/follow-up information that becomes available after the initial SAE report form 
has been completed will be forwarded to UBC Safety 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 for form completion and only modified or new information 
needs to be specified. Information provided in the follow-up SAE report form supersedes any 
information that was initially reported. 
All SAEs will be followed up by the Investigator or designee and/or UBC Safety until their 
resolution or until the Investigator or designee considers the event to be stabilized (i.e., no 
worsening of condition), or until an acceptable explanation has been found (e.g., a chronic 
condition). 
The SAE report form to be used in this study is provided as a separate document and included 
in the study master file. All SAEs will be recorded, in addition to the SAE report form. 

 
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8.4 
Reporting of Other Events Critical to Safety Evaluations 
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator or designee and assessed for clinical relevance. If an abnormal 
laboratory result is detected after Screening and considered clinically relevant (see below), this 
should be recorded as an AE. 
The grading scheme shown in Appendix 6 [27] will be used by the Investigator or designee to 
assess abnormal laboratory AEs as follows: 
 All Grade 1 abnormal laboratory values will be evaluated by the Investigator or designee 
with respect to baseline value 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 a subject has Grade 2 and higher abnormal laboratory values at V1 it is at the discretion 
of the Investigator or designee to enroll the subject or not. This decision must be 
documented in the source document and captured in the CRF. A grade 2 and higher 
laboratory abnormal value at V1 must be recorded as concomitant disease. 
 If there is any worsening in grade from Grade 2 and above during the study the Investigator 
or designee must report this worsening as an AE. 
 Where there is no grading available, the abnormal laboratory value will be evaluated by 
the Investigator or designee and assessed for clinical relevance. If considered to be 
clinically relevant, the Investigator will report it as an AE. 
 Any other abnormal clinical laboratory result (including those that are not part of the core 
safety assessments) can, at the discretion of the Investigator or designee, be reviewed and 
assessed. Even if they do not meet the criteria of the CTCAE grading scheme (please see 
above), the Investigator or designee 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., intensity, seriousness, outcome) will be assessed as for other AEs. 

 
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8.5 
Reporting and Follow-Up of Pregnancies 
All subjects who are diagnosed as pregnant after enrolment (V2) will be discontinued from the 
study. Smoking cessation counseling will be provided to those subjects who are still abstinent 
from smoking and will be referred to the respective health care facility/health care provider for 
further support. In case a subject has relapsed to smoking and is diagnosed as pregnant, advice 
on the risk of smoking and smoking cessation advice will be provided and subjects will be 
referred to the respective health care facility/health care provider for further support. 
Pregnancy Forms will be filled but no follow-up on pregnancy outcome will be performed.  
The Investigator or designee is responsible for informing the IRB/IEC of any pregnancy that 
occurs during the study and its outcome, according to local regulations. 
8.6 
Adverse Events Leading to Discontinuation 
Subjects who are discontinued from the study because of an AE, will undergo the early 
termination procedures as described in section 9.67 as soon as possible. The Investigator or 
designee and/or UBC Safety 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. 

 
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9 
STUDY ACTIVITIES 
A detailed schedule of assessments can be found in Appendix 1.  
In general, if no start time for the procedures is provided, the procedure can be performed at 
any time during the day, but should be done at the similar or comparable time for each visit. 
For the details on the procedures, see the related sections. 
9.1 
Screening Visit (V1) 
The Screening (V1) will be performed within 6 weeks (1 to 42 days) prior to V2. First, the ICF 
along with study information should be given to the subject. When/if the ICF is signed, dated 
and timed, the other screening procedures can be performed in the order deemed most practical. 
While it is recommended to complete as many screening procedures as possible in one day, it 
is permissible to complete those over more than one day. Smoking is allowed during screening.  
Table 3 shows the procedures for V1. The sequence of assessments/events is given just for 
illustrative purposes. It will be at the discretion of the site after signature of the ICF. 
Table 3 
Time Schedule – Screening Visit (V1) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Screening 
 
Before any study 
procedure  
 
Informed consent for study 
participation and additional 
consents for bio-banking (if 
applicable) 
Lung volumes will be part of 
the main ICF in selected 
centers only. 
During the visit 
√ 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
 
During the visit 
During the visit  
√ 
Serology (HIV, hepatitis B and C) 
Information on the risk of smoking 
and SC advice 
 
During the visit  
 
Demographic data collected 
 
During the visit  
 
Medical history/concomitant 
disease, prior and concomitant 
medication 
 

 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Screening 
 
During the visit 
 
Questions on smoking 
history/habits  
Readiness to comply with study 
procedure including to remain 
continuously abstinent from 
smoking for 52 weeks  
 
During the visit  
 
Prochaska questionnaire (Intent to 
quit) 
 
During the visit  
 
Lifestyle questions  
 
At any time  
 
ECG 
At least 5 minutes in supine 
position prior to recording.  
During the visit  
 
Vital signs (blood pressure, pulse 
rate, respiratory rate) 
At least 5 minutes in supine 
position  
During the visit  
 
Urine analysis 
 
During the visit  
 
Urine pregnancy test (all females) 
 
During the visit  
 
Physical examination, height and 
weight. 
 
During the visit  
 
Urine drug screen 
 
During the visit  
 
Urine cotinine test 
Cut-off ≥ 200 ng/ml 
During the visit  
 
Alcohol urine or breath test  
 
During the visit  
 
Spirometry pre- and post-
bronchodilatator (recording of 
FEV1, FVC, FEV1/FVC and FEF 
25-75 only) 
Has to be done at least 1 
hour after smoking 
At rest for at least 15 
minutes prior to pulmonary 
function testing. 
In sitting position. 
All post-bronchodilator 
spirometry testing will be 
performed 15-30 minutes 
post administration of 
salbutamol 

 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Screening 
 
During the visit  
 
AE/SAE recording 
If the Screening Visit is 
performed on two separate 
days, the AE/SAE questions 
will be asked again 
During the visit  
 
Inclusion/exclusion criteria  
 
At discharge 
 
Instructions and distribution of 
urine containers 
A paper form will be 
distributed to the subject for 
recording the start and the 
end time of urine collection. 
Abbreviations: AE = Adverse event; BoExp: Biomarkers of exposure; BMI = Body mass index; ECG = Electrocardiogram; 
FEF = Forced expiratory flow; FEV1= Force expiratory volume in 1 second; FVC = Forced vital capacity; HIV = Human 
immunodeficiency virus; SAE = Serious adverse event. 
9.2 
 Baseline Visit (V2)  
Table 4 shows the assessments that will be performed on the day of V2. Assessments must be 
done after enrolment, unless specified. 
Table 4 
Time Schedule – Baseline Day (V2) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
 
During the visit 
 
End of 24-hour urine sample 
collection V2 container 
Prior to enrolment, staff 
should check that the 
subject brought his/her 
urine containers filled with 
urine 
The start of urine collection 
is at subject’s home the day 
before V2 and the end is in 
the morning of V2. 
The urine is collected for 24 
hours ±1 hour. 

 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
 
During the visit  
 
Questions about smoking 
history/habits 
Prior to enrolment  
During the visit  
 
Inclusion criteria n°4 and 6 
Prior to enrolment 
During the visit 
 
Exclusion criteria n° 5 and 6 
Prior to enrolment 
During the visit  
 
Urine cotinine test 
Prior to enrolment 
Cut-off ≥ 200 ng/ml 
During the visit 
 
Urine pregnancy test (all females) 
Prior to enrolment 
During the visit 
 
Enrolment 
After all inclusion and 
exclusion criteria have been 
satisfactorily met and 
subject has provided filled 
urine containers 
 
 
Urine sampling to be taken from 
the 24-hour urine V2 container 
Samples will be collected 
for some clinical risk 
endpoints and the full list of 
BoExp. 
 
 
 
Must be done after 
enrolment 
During the visit 
 
Urine analysis 
Must be done after 
enrolment 
During the visit 
√ 
Clinical laboratory parameters 
(hematology, clinical chemistry)  
After at least 10 hours of 
fasting 
Must be done after 
enrolment 
During the visit 
√ 
CVD Clinical risk endpoints  
After at least 10 hours of 
fasting 
Must be done after 
enrolment 
During the visit 
√ 
Serum/plasma for bio-banking for 
BoExp/clinical risk endpoints and 
blood/plasma transcriptomics & 
lipidomics 
If additional consent is 
signed 
After at least 10 hours of 
fasting 

 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
 
Must be done after 
enrolment 
During the visit 
√ 
Nicotine in plasma 
Must be done after 
enrolment 
During the visit 
√ 
CYP2A6 activity (including 
cotinine) in plasma 
Must be done after 
enrolment 
During the visit 
√ 
COHb in blood 
Has to be done in 
conjunction with CO breath 
test.  
Irrespective of CC use. 
Must be done after 
enrolment 
During the visit 
 
CO breath test 
Irrespective of CC use. Has 
to be done in conjunction 
with COHb blood sampling. 
During the visit 
 
AE/SAE recording, concomitant 
medications 
At any time of the day 
During the visit 
 
Vital signs (blood pressure, pulse 
rate, respiratory rate) 
At least 5 minutes in supine 
position  
Must be done after 
enrolment 
During the visit 
 
Physical examination, weight and 
waist circumference  
Must be done after 
enrolment 
Prior to smoking 
 
Lung function: spirometry pre-
bronchodilator, then lung volumes 
(in selected centers only) followed 
by spirometry post-bronchodilator 
Has to be done at least 
after 1 hour without 
smoking 
Subject at rest for at least 
15 minutes prior to lung 
function testing. 
In sitting position. 
All post-bronchodilator 
spirometry testing will be 
performed 15-30 minutes 

 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
 
post administration of 
salbutamol 
Needs to be done in the 
morning prior to 12:00 PM 
but after enrolment 
During the visit 
 
Cough-VAS and SES 
questionnaires 
Must be done after 
enrolment 
During the visit 
 
Lifestyle questions 
Must be done after 
enrolment 
During the visit 
 
FTND questionnaire 
Must be done after 
enrolment 
Before check-out 
 
Information on the risk of smoking 
and SC advice. 
Must be done after 
enrolment 
During the visit 
 
Smoking cessation support 
At this visit, the Investigator 
or his/her designee will 
provide recommendation to 
the subject for NRT, if NRT 
use is needed. 
Must be done after 
enrolment 
Before check-out 
 
Define individual TQD 
Must be done after 
enrolment 
Abbreviations: AE = Adverse event; BoExp = Biomarkers of exposure; CVD: Cardiovascular diseases; CO: Carbon 
monoxide; COHb = Carboxyhemoglobin; CYP = Cytochrome P450; FTND = Fagerström test for nicotine dependence; 
NRT = Nicotine replacement therapy; SES= Socio-economic situation; SAE = Serious adverse event; VAS = Visual analog 
scale. 
9.3 
Visit 3 (V3) 
The subject will be asked to come to the clinic within 24 to 48 hours after the TQD defined at 
V2. Table 5 shows the assessments that will be performed on V3. 

 
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Table 5 
Time Schedule – Target Quit Date (V3) 
Time 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
During the visit 
AE/SAE recording 
 
During the visit 
SC support 
At this visit, the Investigator 
or his/her designee will 
provide recommendation to 
the subject for NRT, if NRT 
use is needed. 
During the visit 
Concomitant medications and record preferred 
NRT (if applicable) 
 
Abbreviations: AE = Adverse event; SAE = Serious adverse event; NRT = Nicotine replacement therapy. 
9.4 
Actual Quit Date  
No visit on site will take place at the AQD. However, the AQD will serve as a starting point 
(date) to establish dates of all subsequent visits. 
9.5 
Smoking Abstinence Period (V4 to V17) 
Table 6 describes the assessments on V4, V5, V6, V7, V9, V10, V12, V13, V14, V15 and V16 
and Table 7 the assessments of V8, V11 and V17. A time window of ± 8 days is allowed for 
these visits, with the exception of V4 and V5: ± 3 days. The collection of 24-hour urine will 
start at home. The period from check-out of V2 to AQD has been established in order to 
identify subjects more likely to remain continuously abstinent from smoking for the whole 
duration of the study. 
Table 6 
Time Schedule – Visits V4, V5, V6, V7, V9, V10, V12, V13, V14, V15 
and V16  
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
 
During the visit 
 
AE/SAE recording 
 

 
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During the visit 
 
Urine pregnancy test (all 
females). 
  
During the visit  
 
Urine cotinine test 
From Visit 10 onwards. The 
cut-off value defined for this 
verification of continuous 
abstinence from smoking is < 
100 ng/mL. 
During the visit 
 
SC support and self-reporting by 
the subject on continuous 
smoking abstinence. 
 
During the visit 
 
CO breath test 
 
During the visit 
 
Vital signs (blood pressure, pulse 
rate, respiratory rate). 
At least 5 minutes in supine 
position  
During the visit 
 
Concomitant medication 
 
Abbreviations: AE = Adverse event; CO = Carbon monoxide; SAE = Serious adverse event. 
Table 7 
Time Schedule – Visits V8, V11, and V17 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
 
During the visit  
 
Urine cotinine test 
From Visit 10 onwards. 
The cut-off value defined 
for this verification of 
continuous abstinence 
from smoking is < 100 
ng/mL. 
During the visit 
 
End of 24-hour urine sample 
collection 
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. 
During the visit 
 
Urine sampling to be taken from the 
24-hour urine visit container 
At V8, samples are 
collected for some clinical 

 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
 
risk endpoints and the full 
list of BoExp. 
At V11 and V17, samples 
are collected for some 
clinical risk endpoints and 
the reduced list of BoExp. 
During the visit 
 
Urine sample to be taken for bio-
banking of BoExp and CVD clinical 
risk endpoints  
If additional consent is 
signed (for bio-banking). 
During the visit 
√ 
CVD Clinical risk endpoints  
After at least 10 hours of 
fasting 
During the visit 
√ 
Bio-banking for BoExp/clinical risk 
endpoints and transcriptomics & 
lipidomics 
If additional consent is 
signed.  
After at least 10 hours of 
fasting 
During the visit 
√ 
Clinical laboratory parameters 
(hematology and clinical chemistry) 
After at least 10 hours of 
fasting 
During the visit 
√ 
CYP2A6 activity (including cotinine) 
in plasma 
 
During the visit 
√ 
Nicotine in plasma 
 
During the visit 
√ 
COHb in blood 
Has to be done in 
conjunction with CO 
breath test. 
During the visit 
 
CO breath test 
Has to be done in 
conjunction with COHb 
blood sampling. 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Urine pregnancy test (all females). 
 
During the visit 
 
ECG 
V11 and V17 only. At 
least 5 minutes in supine 
position prior to recording. 

 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
 
During the visit 
 
SC support and self-reporting by 
the subject on continuous smoking 
abstinence. 
 
During the visit 
 
Physical examination, weight and 
waist circumference. 
 
During the visit 
 
Urine analysis.  
 
In the morning 
 
Lung function: spirometry pre-
bronchodilator, then lung volumes 
(in selected centers only) followed 
by spirometry post-bronchodilator 
Subject at rest for at least 
15 minutes prior to lung 
function testing. 
In sitting position. 
All post-bronchodilator 
spirometry testing will be 
performed 15-30 minutes 
post administration of 
salbutamol 
Needs to be done in the 
morning prior to 12:00 
PM. 
During the visit 
 
Vital signs (blood pressure, pulse 
rate, respiratory rate) 
At least 5 minutes in 
supine position  
During the visit 
 
Cough-VAS questionnaire and 
lifestyle questions 
 
During the visit 
 
Concomitant medication 
 
Abbreviations: AE = Adverse event; BoExp = Biomarkers of exposure; CO = Carbon monoxide; COHb = 
Carboxyhemoglobin; CVD = Cardiovascular disease; CYP= Cytochrome P450; ECG = Electrocardiogram; SAE = Serious 
adverse event; VAS = Visual analog scale. 
  
9.6 
Safety Follow-Up Period and Phone Contact (V18) 
 
A subject who has completed V17, or a subject who has been discontinued from the study 
prematurely (early termination), will enter a 28-days Safety Follow-Up Period during which 
spontaneously reported new AEs/SAEs will be recorded, and the active follow-up of ongoing 
AEs/SAEs will be done by the site. All AEs will be followed-up until resolved, stabilized (i.e., 

 
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no worsening of the event), or a plausible explanation for the event has been found until the 
end of the Safety Follow-Up Period.  
At the end of the Safety Follow-Up Period in Week 56 (V18 (±3 days)), the investigator will 
attempt to contact only the subject who has previously completed V17 by phone to check if all 
AEs/SAEs potentially occurring during the Safety Follow-Up period are fully reported and for 
self-reporting by the subject on continuous smoking abstinence. At the end of the Safety 
Follow-Up Period, all ongoing AEs will be documented as “ongoing” and will not be followed-
up by the Investigator. At the discretion of the Investigator, the subject will be referred to 
his/her General Practitioner for follow up on ongoing AEs. 
If the investigator can reach the subject who has previously completed V17 by phone at the 
end of the Safety Follow-Up Period in Week 56, the date of this phone call with the subject 
will be recorded as the date of the end of the study of the subject.  
If the investigator cannot reach the subject who has previously completed V17 by phone at the 
end of the Safety Follow-Up Period in Week 56 after a reasonable number of attempts, the date 
of the last contact (e.g., last visit of the subject, last phone call with the subject) will be recorded 
as the date of the end of the study of the subject. 
Table 8 
Time Schedule – Visit V18  
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
 
 
 
 
 
During the phone 
contact 
 
Self-reporting by the subject on 
continuous smoking abstinence 
 
During the phone 
contact 
 
AE/SAE recording 
 
 
9.7 
Early Termination Procedures 
If a subject is discontinued from the study prematurely, he/she will be advised to perform the 
following assessments listed in Table 9 below. 

 
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Table 9 
Time Schedule – Early Termination Procedures  
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Urine pregnancy test (all females) 
  
During the visit 
 
Urine analysis  
 
During the visit 
√ 
Clinical laboratory parameters 
(hematology and clinical 
chemistry) 
 
During the visit 
 
Information on the risk of smoking 
and SC advice 
 
During the visit 
 
ECG 
At least 5 minutes in supine 
position prior to recording. 
During the visit 
 
Physical examination 
 
In the morning 
 
Lung function: spirometry pre-
bronchodilator, then lung volumes 
(in selected centers only) followed 
by spirometry post-bronchodilator 
Subject at rest for at least 15 
minutes prior to lung function 
testing. 
In sitting position. 
All post-bronchodilator 
spirometry testing will be 
performed 15-30 minutes 
post administration of 
salbutamol 
Needs to be done in the 
morning prior to 12:00 PM. 
During the visit 
 
Vital signs (blood pressure, pulse 
rate, respiratory rate) 
At least 5 minutes in supine 
position  
Abbreviations: AE = Adverse event; SAE = Serious adverse event. 
 

 
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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
The contract research organization (CRO) Clinical Research Associate (“Monitor”) will be 
responsible for the monitoring of the study. Monitoring will be performed according to the 
CRO’s SOPs and as per the agreed monitoring plan with the Sponsor. 
The Investigator or designee 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 satisfactorily met. 
The Investigator or designee shall access medical records for the Monitor in order that entries 
in the CRFs may be verified. The Investigator or designee, as part of his/her responsibilities, 
is expected to ensure that the study adheres to GCP requirements. 
An Investigator’s meeting will be held prior to the site initiation visit. During this meeting, the 
general training of the study procedures and specific training on selected procedures will be 
done and documented. 
Subsequent to the Investigator’s meeting, and before the first subject is screened and included 
in the study, a site initiation visit will be conducted by the Monitor and, if necessary, with the 
Sponsor or its authorized representative. The purpose of the site initiation visit 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 Investigator and study personnel will cooperate with the Monitor, provide all appropriate 
documentation and will be available to discuss the study. 
The Monitor and the Sponsor’s personnel will be available between visits, should the 
Investigator or other staff at the sites need information and/or advice. 
Site visits will be made at regular intervals during the study. The frequency of the monitoring 
visits will be defined in the monitoring plan agreed with the Sponsor. 
The Investigator, or a designated member of the Investigator’s staff, must be available during 
the monitoring visit to review the data and resolve any queries and to allow direct access to the 
subject’s records for source data verification. 

 
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10.2 Training of Staff 
A formal meeting (Investigator’s meeting) will be conducted prior to site initiation. During 
this meeting, the Sponsor or its authorized representative will discuss the requirements of the 
clinical study protocol and related documents and will also provide training to the relevant 
systems and other study-specific procedures. The activities of this meeting will be described 
in the monitoring plan. 
Further to the Investigator meeting, the Investigator or designee 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. The Investigator or designee will maintain a record of all individuals involved in the 
study. 
10.3 Audits and Inspections 
Good Clinical Practice regulations require 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/IEC may 
perform audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted and data were recorded, 
analyzed and accurately reported according to the protocol, ICH/GCP guidelines and any 
applicable regulatory requirements. The Investigator or designee will contact the Sponsor or 
the authorized representative immediately if contacted by a regulatory agency about an 
inspection at their site. 
The Investigator and study staff are responsible for maintaining a comprehensive and accurate 
filing system of all study-related documentation that will be suitable for inspection at any time 
by the Sponsor, its authorized representative and/or regulatory agencies. By signing this 
protocol, the Investigator or designee understands and agrees to provide access to the necessary 
documentation and files. 

 
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11 DATA MANAGEMENT ACTIVITIES 
All data management activities will be described in details in the Data Management Plan 
(DMP) and documents specified therein. The electronic systems used, CRF and SRO, to collect 
subject data will be FDA 21 CFR Part 11 compliant. 
11.1 Data Capture 
11.1.1 
Case Report Forms and Study Records 
With the exception of the SRO data, all results from the clinical assessments will be recorded 
in the source data file by the Investigator or his authorized designee(s), and then captured in 
the CRFs at the study site. 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 transferring the data to the CRF according to the CRF Completion Guidelines. 
The Investigator or designee has the ultimate responsibility for the collection and reporting of 
all data related to the clinical study and ensuring that the data are accurate, authentic/original, 
legible, timely (contemporaneous), enduring and available when required. The CRF must be 
signed by the Investigator or designee to attest that the data contained in the CRF are true and 
accurate. Any corrections made to source documents and/or CRFs must be recorded, without 
obscuring the original values, and must be accompanied by the date of change, reason for 
change and identification of the person making the change. The CRF data will be verified 
against the source documents at the study site by the Monitor. Instances of missing or unclear 
data will be discussed with the Investigator or designee for resolution. All SRO questionnaires 
will be provided to the subject in his/her local language. 
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 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 study endpoints. 
All protocol deviations will be entered into the clinical trial management system (CTMS) or 
other approved format. 
Information from the source documents will represent the primary source of protocol 
deviations. Information following site monitoring and other manual reviews will be 
documented in the site visit reports, follow-up letters, audit documentation, or other manual 

 
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review and will be recorded and tracked in the CTMS or other approved format. 
Telecommunications and other verbal communications regarding deviations will be considered 
and handled as important communication, documented and tracked as Protocol Deviations, as 
necessary. 
Individual entries for protocol deviations that are recorded in the CTMS, or other approved 
format, following site monitoring and other manual reviews will be reviewed against the 
individual data points in the CRF database but will not be formally reconciled with the CRF 
database (e.g., their description or occurrence date). The overall procedure for managing 
protocol deviations is described in the SOPs and/or agreed upon procedure of the CRO data 
management team. All deviations will be reviewed periodically, as determined at study start, 
to identify trends to improve monitoring and/or potential impact on the statistical analysis. 
11.2 Data Handling 
All study data will be managed by the data management team at the CRO. The overall 
procedures for quality assurance of clinical study data are described in the SOPs of the CRO 
data management team. The data management team at 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 enrolled including screening failures and AE during the study (from the 
time of informed consent to the end of the study of the subject) will be captured in the source 
documents and all AEs will be entered in the study database (CRF). 
All data collected during the study are declared property of the Sponsor, irrespective of the 
location of the database and the data management CRO. 
Additional details are covered in the DMP. 

 
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12 PLANNED STATISTICAL METHODS 
12.1 General Considerations 
Full details of the statistical analysis will be given in a SAP. Any changes to the planned 
statistical methods will be documented in the clinical study report. The statistical evaluation 
will be performed using SAS®, version 9.2 or later.  
The data from this study could be used for the purpose of providing data for the design and 
interpretation of assessment studies of PMI candidate modified risk tobacco products. 
12.1.1 
Stratification Criteria 
For the analysis of the study endpoints, the following stratification criteria will be used: 
1. Sex (male; female) 
2. Region (US, EU, JP) 
12.1.2 
Definitions for Statistical Data Analysis 
Baseline: 
Unless specified, baseline is defined as the last available time point prior to TQD. 
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by region, study center, and subject, unless 
otherwise specified. 
In general, summary statistics will be stratified by region and sex at Baseline. 
Descriptive statistics (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 (CV) for data analyzed in the log scale; frequency counts and percentages for 
categorical data) will be presented overall and at each time point, where applicable. 
Apart from FEV1, WBC, HbA1c, LDL-C, Apo A1, Apo B and HDL-C, for other clinical risk 
endpoints and BoExp, the geometric mean and CV will be presented in addition to the 
(arithmetic) mean and SD. Absolute and percent change from Baseline will be summarized for 
endpoints analyzed in the real and logarithmic scale, respectively. 
Descriptive statistics of endpoint parameters will be presented at each assessment time point. 

 
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12.1.4 
Handling of Missing Values and of Values outside the Detection Limits 
Descriptive summaries will be provided for the evaluable data with no imputation. 
Missing values for the endpoints analyzed via the mixed model method will not be directly 
imputed as they are handled within the analysis itself.  
Values below the lower limit of quantification (LLOQ) will be imputed using 0.5 x LLOQ. 
For values above the upper limit of quantification (ULOQ), the ULOQ will be used for 
calculation and reporting in summary tables. The number of values below LLOQ or above 
ULOQ will be presented in each summary table. 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 (if no value below LLOQ is present) and maximum (if 
no value above ULOQ are present) of the observed values. 
For questionnaire data, total scores and domain or subscale scores may use a certain degree of 
imputation by averaging across individual item scores. 
Further details will be provided in the SAP. 
12.1.5 
Significance Level for Inferential Analysis 
This study has no formal pre-specified hypotheses associated with the study objectives. 
However, 95% CI will accompany all effect estimates.  
12.2 Determination of Sample Size and Power Consideration 
Enrolment is planned for approximately 950 adults with at least 2 weeks of abstinence after 
the AQD. Unsuccessful quitters will be discontinued from the study. Subjects who 
discontinued the study after V5 will not be replaced. 
Since no formal hypotheses have been formulated for the objectives, sample size calculations 
are based on precision of effect estimates for FEV1. Other endpoints are assumed to exhibit a 
larger effect size than FEV1 and thus would result in smaller sample size estimates. The sample 
size of this study is based on our current understanding of the effect and variability of SC from 
the results of the Lung Health Study [1] in the subject intending to quit smoking at Baseline, 
since no data on the attrition rate at 12 months after 2 weeks of smoking cessation are available. 
In particular, approximately 190 subjects are needed to estimate the mean increase from 
Baseline of 1.98 [% pred.] [1] in FEV14 at V17, with a 90% probability of obtaining a margin 
                                                 
4 Sample size calculations are driven by FEV1. Other endpoints are assumed to exhibit a larger effect size than 
FEV1 and thus would result in smaller sample size estimates. 

 
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of error (95% CI) of at most ±1 [% pred.]. The anticipated SD of the change from Baseline of 
6.4 [% pred.] was estimated using the results of the Lung Health Study [1] and includes an 
inflation of 10% in order to account for additional sources of variability, including the multi-
national nature of the study. As the analysis will only be conducted in successful quitters, this 
sample size was increased to 950, to account for a predicted continuous abstinence rate of 20% 
expected at week 52 for continuous quitters after 2 weeks from AQD. This is based on an 
assumed increase of 5% from the 15% abstinence rate at week 52 expected for subjects at 
enrolment [2]. Sample size calculations are conducted using SAS® version 9.2 for the 95% CI 
of the mean differences between paired observations (proc power onesamplemeans) [28]. The 
SAS® implementation of the method published by Beal [29] is adopted to estimate the 
probability of obtaining at most the target 95% CI of ± 1 [% pred.].  
The overall enrolment and attrition rate will be monitored during the recruitment phase of the 
study and sample size may be adapted to ensure at least 190 successful quitters complete V17.  
12.3 Analysis Populations 
Descriptive summaries will be produced and analyses will be conducted in enrolled subjects 
who continuously abstained from smoking (quitters) for at least 13 weeks (V8), with no major 
protocol deviations which impact data evaluability (to be defined in the SAP). In enrolled 
subjects failing to continuously abstain from smoking after V8, only endpoint data assessed 
prior to the date of relapse will be included in the analysis.  
Descriptive summaries and analysis will also be conducted in the subgroup of subjects who 
completed the 1-year continuous SC (completers). 
12.4 Demographics and Baseline Characteristics 
Demographic and other Baseline characteristics will be summarized as reported in section 
12.1.3 for the groups of quitters retained in the study at V8, V11, and V17. There will be no 
formal comparison of Baseline data, that is, no statistical hypothesis testing will be performed. 
12.5 Study Endpoint(s) 
12.5.1 
Study Endpoint Analysis Variables 
See section 3 “Study Objectives and Endpoints”. 

 
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12.5.2 
Baseline Comparability 
Study endpoints at baseline will be summarized as reported in section 12.1.3 for the quitters in 
the analysis population and in the subgroup of completers. There will be no formal comparison 
of endpoint values at Baseline, that is, no statistical hypothesis testing will be performed. 
12.5.3 
Descriptive Summary 
Study endpoints across time will be summarized by study visit as reported in section 12.1.3 for 
the analysis population and in the subgroup of completers. Summary statistics of endpoints 
will also include the mean change from Baseline, together with 95% CI. A similar approach 
will be used to analyze the relative change from Baseline for those BoExp having at least 50% 
of the measured values above the limit of quantification (LOQ).  
12.5.4 
Exploratory Analysis: Random Coefficient Modeling 
For clinical risk endpoints associated with CVD, respiratory diseases, airway inflammation, 
genotoxicity and xenobiotics, the pattern and form of the endpoint change over time will be 
modeled using random measurement effects models in the analysis population and in the 
subgroup of completers. Sex, cigarette consumption at Baseline, age, region, and other 
Baseline variables will be considered for inclusion in the model. A backward elimination 
procedure will be used to identify independent predictors of risk markers (to be defined in the 
SAP). Goodness of fit will be evaluated by the analysis of residuals (model diagnostics) and 
by comparing the values predicted versus the observed parameter changes (calibration). Least 
square estimates of the effect of variables included in the model will be reported together with 
the 95% CI. 
12.5.5 
Confirmatory Analyses 
No confirmatory analysis is foreseen in this study although data will be used to evaluate the 
effect of SC for benchmarking purposes in the context of PMI products assessment programs. 
The details of the methods used to evaluate the reference effect of SC for specific endpoints 
and population characteristics will be provided in separate analysis plans, and results will be 
reported separately. 
12.6 Safety Endpoint(s) 
In general, all safety data will be listed by region for the overall screened population, and 
tabulated by region for the enrolled population using the approach described in section 12.1.3. 

 
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Safety summaries will also be produced for overall, and by region from V2 to V18 for the 
enrolled population. 
Adverse event data will serve as the primary assessment of safety. Other safety variables 
monitored in this study include: vital signs (systolic and diastolic blood pressure, pulse rate, 
respiratory rate), 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 Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. 
Summaries will also be presented for AEs leading to withdrawal, AEs leading to death, AEs 
by severity, and laboratory AEs. Tabulations will be performed for both the number of subjects 
experiencing an event and the number of events. 
Descriptive statistics will be summarized for laboratory parameters, ECG, respiratory 
symptoms, and vital signs. The number and percentage of subjects with clinical findings will 
be summarized and shift tables showing change from Baseline of clinical findings will be 
provided for: ECGs, physical examinations and laboratory parameters (both shifts in normal 
ranges and toxicity grades).  
12.7 Interim Analysis 
No formal interim analysis of the data is foreseen. Data monitoring will be performed 
according to CRO's SOPs and as per the agreed monitoring plan with PMI.  
Interim data sets will be extracted for the purpose of providing data for the design and 
interpretation of assessment studies of PMI candidate MRTPs. For this purpose, the analysis 
methods are detailed in a separate SAP. 

 
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13 ADMINISTRATIVE CONSIDERATIONS 
13.1 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 name of the subjects participating in this study will be kept confidential. 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 age, 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 & lipidomics, and the data related to these samples will 
be anonymized. Anonymized data and samples are initially single or double coded where the 
link between the subjects’ identifiers and the unique code(s) is subsequently deleted. This is 
applicable for the blood bio-banking for transcriptomics & lipidomics only. 
Any documents that allow full identification of the subject (e.g., the subject’s signed ICF) must 
be maintained in confidence by the Investigator. If any document relating to this study shows 
a subject’s name or any other details relating to an identifiable person (e.g., address, social 
security number, medical chart number, etc.), the name or other identifiable details must be 
obscured before a copy of that document is supplied to the Sponsor or the Sponsor’s authorized 
representative. 
13.2 Access to Source Documentation 
Subjects will be informed that, during the course of the clinical study, the Sponsor, any 
authorized representatives of the Sponsor, IRB/IEC or regulatory authorities may inspect their 
medical records to verify the information collected and ensure that all personal information 
made available for inspection is handled in the strictest confidence and in accordance with 
national and local data protection and privacy legislation. 
The Investigator and all study site staff involved with the study must permit direct access to 
source data/documents for study related monitoring, audits, IRB/IEC review and regulatory 
inspection(s). 

 
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13.3 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 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 [30]. 
Essential documents must be retained by the Investigator for a minimum of: 
 At least 15 years after completion or discontinuation of the study. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. 
Examples of essential records/documents include, but are not limited to: 
 Signed informed consent documents for all subjects and master ICF. 
 Subject identification code list, screening log and enrolment log (if applicable). 
 Record of all communications between the Investigator and the IRB/IEC, composition 
of the IRB/IEC. 
 Record of all communications/contact between the Investigator, the Sponsor, and its 
authorized representatives. 
 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). 
 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. 

 
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 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. 
 Information regarding subjects’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the Investigator/study site as to when these 
documents no longer need to be retained. 
The Investigator/study site must take measures to prevent accidental or premature destruction 
of these documents. 
If an Investigator or designee wishes to assign the study records to another party or move them 
to another location, the Sponsor must be notified in advance. 
The Investigator or designee must obtain written approval from the Sponsor before destruction 
of any records. Normally, these records will be held in the Investigator’s archives. If an 
Investigator or designee is unable to meet this obligation, they must ask the Sponsor for 
permission to make alternative arrangements. Details of these arrangements must be 
documented. 
The Sponsor or Sponsor’s authorized representative will maintain documentation relating to 
the study for 15 years after the CSR has been finalized. 
13.4 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. 
The CSR will be written based on standards of the ICH Guideline for the Structure and Content 
of Clinical Study Reports. In certain circumstances, an abbreviated CSR may be acceptable. 
Submission of the CSR to the IRB/IEC will be complied with as requested by local 
requirements. 
The results of the additional variables will be presented in the study CSR.. 
13.5 Financial Disclosure 
Investigators and designees are required to provide financial disclosure information to the 
Sponsor. In addition, the Investigators and designees must provide the Sponsor with a 

 
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commitment to promptly update this information if any relevant changes occur during the 
course of the investigation and for one year following the completion of the study. 
13.6 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/IEC, or duly authorized representatives of regulatory agencies for this 
purpose under the condition that confidentiality is maintained. The contents of this document 
may not be used in any other clinical study, 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). 

 
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without the written consent of Philip Morris Products S.A. 
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23. DiClemente CC, Prochaska JO, Fairhurst S, Velicer WF, Rossi JS, Velasquez M. The 
process of smoking cessation: an analysis of precontemplation, contemplation, and preparation 
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smokers by stage in three representative samples. Prev Med. 1995;24:401-11. 
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Dependence as a predictor of smoking abstinence: a pooled analysis of varenicline clinical trial 
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26. King BA, Hyland AJ, Borland R, McNeill A, Cummings KM. Socioeconomic variation in 
the prevalence, introduction, retention, and removal of smoke-free policies among smokers: 
findings from the International Tobacco Control (ITC) Four Country Survey. 2011. 
27. 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). 
28. Senn S. Cross-over trials in clinical research: John Wiley & Sons; 2002. 
29. Beal SL. Sample size determination for confidence intervals on the population mean and 
on the difference between two population means. Biometrics. 1989;45:969-77. 
30. ICH E6 (R1). Guideline for good clinical practice. 1996; Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R
1_Guideline.pdf (Accessed on 14 August 2014). 

 
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c. 
Subjects will record their AQD which has to be within 14 days after the TQD. Of note, the AQD is not a visit 
d. 
Smoking cessation support including smoking cessation counseling and behavioral support throughout the study according to the smoking cessation support plan. Additional 
SC support will be offered at any time when requested by the subject 
e. 
The list of clinical chemistry, hematology and urine analysis parameters are detailed Table 2. 
f. 
Systolic and diastolic blood pressure, pulse and respiratory rate. 
g. 
CO breath test will be done with a smokerlyser or similar 
h. 
The lung function tests must be performed in the following sequence when appropriate: 
 Spirometry without salbutamol 
 Lung volume (VC, TLC, and IC)* 
 Spirometry with salbutamol 
* Lung volumes will be assessed in selected center(s) specialized in lung function testing 
i. 
Full and reduced lists of urinary BoExp are provided in Appendix 5. Free cotinine concentration (part of the nicotine equivalents) will be determined in 24-hour urine 
collected at Visit 11 (cut-off ≥ 50 ng/mL) as a criterion for discontinuation at the time the results are made available. 
j. 
List of clinical risk endpoints assessed in the different matrices is provided in Appendix 4 
k. 
A country specific socio-economic situation questionnaire will be completed in the following countries: US, UK, Poland, Germany and Japan 
l. 
Only in subjects who signed an additional ICF 
m. For the visits, a time window of ± 8 days is allowed from the AQD, with the exception of V4 and V5 (± 3 days) 
n. 
Self-reporting by the subject on continuous smoking abstinence at Visit 18 (Week 56) is performed via phone contact if the subject has previously completed V17. 
 

 
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Appendix 2 
Medications with 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 
Pyridoxin (vitamin 
B6) 
2 - 5 
10 - 25 
HDL-C 
Cyanocobalamin 
(vitamin B12) 
approx. 24 - 48 
120 - 240  
(≈ 5 - 10 days) 
HDL-C 
Thiamine chlorid 
(vitamin B1) 
4 - 6 
20 - 30 
HDL-C 
Nicotinic acid 
(vitamin B3) 
approx. 24 
120 (≈ 5 days) 
HDL-C 
Ascorbicacid (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 
Anticholinergica/Antimuscarinica 
Ipratropiumbromide 
3.6 
18 
FEV1 
Tiotropium 
120 - 144 
(≈ 5 - 6 days) 
600 - 720 
(≈ 25 - 30 days) 
FEV1 
Aclidiniumbromid 
2 - 3 
10 - 15 
 
Short-acting β-agonists, orally taken 
Terbutalinsulfat 
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 

 
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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 
Salbutamolsulfat 
Plasma t1/2: 2.7 - 5 
Plasma t1/2: 13.5 - 25 
FEV1 
Fenoterol 
approx. 3 
approx. 15 
FEV1 
Inhaled long-acting β-agonists 
Formoterolfumarat 
approx. 5 
approx. 25 
FEV1 
Indacaterolmaleat 
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 
Fluticasonpropionate 
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 
Aminophyllin, 
Theophyllin 
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 
Repaglinid 
4 - 6 
20 - 30 
(up to 1.25 days) 
11-DTX-B2 
Glibenclamid 
8 - 10 
40 - 50 
(≈ 1.7 - 2.1 days) 
11-DTX-B2 
Glimepirid 
5 - 8 
20 - 40 
(up to 1.7 days) 
11-DTX-B2 
Gliclazid 
12 - 20 
60 - 100 
(≈ 2.5 - 4.2 days) 
11-DTX-B2 
Pioglitazon 
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 
Etoricoxib  
22 
110 (≈ 4.6 days) 
WBC, 11-DTX-B2 
Diclofenac 
approx. 2 
approx. 10 
WBC, 11-DTX-B2 
Indometacin 
2; terminal phase: 
4 - 11 
10; terminal phase: 
20-55 (up to 2.3 days) 
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 
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 
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 

 
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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 
Serotonin–norepinephrine reuptake inhibitors (SNRIs)  
Venlafaxine 
5 ± 2 
25 ± 10 
(  1.0 ± 0.4 days) 
WBC 
Tricyclic antidepressants 
Tricyclic 
clomipramine 
20 - 26 
100 - 130 
( 4.2 - 5.4 days) 
WBC 
Non-specified antidepressant drug class 
Nefazodone 
11 - 24 
55 - 120 
( 2.3 - 5 days) 
WBC 
Lipid Lowering Drugs 
Fibrate 
Bezafibrat  
1 - 2 
5 - 10 
HDL-C, Total 
Cholesterol, 
Triglycerides  
Fenofibrat 
Plasma t1/2 
approx. 20 
approx. 100 
(≈ 4.2 days) 
HDL-C, Total 
Cholesterol, 
Triglycerides 
Gemfibrozil 
1.3 - 1.5 
6.5 - 7.5 
HDL-C, 
Apolipoproteins 
Bile acid sequestrants 
Colestyramin 
no absorption into 
blood stream 
n.a. 
HDL-C 
Statines 
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 

 
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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 
Fluvastatin 
2.3 ± 0.9 
11.5 ± 4.5 
HDL-C, 11-DTX-
B2 
Other cholesterol-
lowering drugs 
 
 
 
Ezetimibe 
22 
110 (≈ 4.58 days) 
HDL-C, 11-DTX-
B2, 
Apolipoproteins, 
Total Cholesterol, 
Triglycerides 
* n.a. = not applicable 

 
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Appendix 3 
Prochaska “Stage of Change” Questionnaire 
The Prochaska questionnaire is structured as follows: 
 
CURRENTLY SMOKING
Yes
No
quit in last 6 months
(Action)
quit more than 6 months
(Maintenance)
Seriously considering quitting 
next 6 months
Yes
No
(Precontemplation)
Planning to quit next 30 days
Yes
No
(Contemplation)
24 hour quit attempt past year
Yes
(Preparation)
No
(Contemplation)
 

 
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Appendix 4 
Summary of Clinical Risk Endpoints  
Clinical Risk Endpoints 
Measurement of 
Biofluid / 
Function 
Respiratory 
Forced expiratory volume in 1 second (FEV1) 
Spirometry 
 
Lung 
Forced vital capacity (FVC) 
Spirometry 
Forced expiratory flow 25-75 (FEF 25-75) 
Spirometry 
Total lung volumes, inspiratory capacity and 
functional residual capacity# 
Lung volume 
Frequency / intensity of cough symptoms 
Lung response 
(respiratory symptoms) 
Cardiovascular 
High density lipoprotein cholesterol (HDL-C) 
Lipid metabolism 
Serum 
Low density lipoprotein cholesterol (LDL-C) 
Lipid metabolism 
Serum 
White blood cell count (WBC)* 
Inflammation 
Blood 
High sensitivity C-reactive protein (hs-CRP) 
Inflammation 
Serum 
Platelet count* 
Inflammation 
Blood 
Fibrinogen 
Inflammation 
Plasma 
Soluble intercellular adhesion molecule-1 (sICAM-1) 
Endothelial dysfunction 
Serum 
11-dehydrothromboxane B2 (11-DTX-B2) 
Platelet activation 
Urine 
Albumin 
Endothelial dysfunction 
Urine 
Homocysteine 
Endothelial dysfunction 
Plasma 
8-epi-prostaglandin F2α (8-epi-PGF2α) 
Oxidative stress 
Urine 
Myeloperoxidase (MPO) 
Oxidative stress 
Serum 
Apolipoprotein A1 (Apo A1) 
Lipid metabolism 
Serum 
Apolipoprotein B (Apo B) 
Lipid metabolism 
Serum 
Carboxyhemoglobin (COHb) 
Transport of oxygen by 
hemoglobin 
Blood 
Glycosylated hemoglobin (HbA1c) 
Insulin resistance 
Blood 

 
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Clinical Risk Endpoints 
Measurement of 
Biofluid / 
Function 
Xenobiotics 
Cytochrome 2A6 (CYP2A6) activity 
Nicotine metabolism 
Plasma 
Genotoxicity 
Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
(Total NNAL) 
Exposure to 
carcinogenic HPHC 
(NNK) 
Urine 
* Measured as part of the safety laboratory parameters. 
# Measured in selected centers. 

 
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Appendix 5 
Summary of Biomarkers of Exposure to HPHC 
HPHC 
 [smoke phase] 
HPHC list 
Biomarker 
Matrix 
t1/2 
Reduced 
List of 
BoExp 
1,3-Butadiene 
[gas] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
Monohydroxybutenylme
rcapturic acid (MHBMA) 
Urine 
4 to 16 h 
● 
1-
Aminonaphthalene 
[particulate]  
FDA-18, 
FDA-93, HC 
PMI-58 
1-Aminonaphthalene 
(1-NA) 
Urine 
Not 
described 
 
2-
Aminonaphthalene 
[particulate] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
2-Aminonaphthalene 
(2-NA) 
Urine 
9 h 
 
4-Aminobiphenyl 
[particulate] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
4-Aminobiphenyl (4-
ABP) 
Urine 
26 h 
 
Acrolein [gas] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
3-Hydroxypropyl-
mercapturic acid (3-
HPMA) 
Urine 
10 h 
● 
Acrylonitrile [gas] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
2-
Cyanoethylmercapturic 
acid (CEMA) 
Urine 
17 h 
● 
Benzene [gas] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
S-Phenyl-mercapturic 
acid (S-PMA) 
Urine 
9 to 15 h 
 
Benzo[a]pyrene 
[particulate] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
3-
Hydroxybenzo[a]pyrene 
B[a]P 
Urine 
3 to 4 h 
● 
Carbon monoxide 
[gas] 
FDA-18 
FDA-93 HC 
CO 
Breath 
/  
● 

 
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HPHC 
 [smoke phase] 
HPHC list 
Biomarker 
Matrix 
t1/2 
Reduced 
List of 
BoExp 
PMI-58 
WHO-18  
Pyrene 
FDA-18 
FDA-93 HC 
PMI-58 
WHO-18 
Total 1-hydroxypyene 
(total 1-OHP)  
Urine 
6 to 35 h 
● 
Crotonaldehyde 
[gas] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
3-Hydroxy-1-
methylpropyl-
mercapturic acid (3-
HMPMA) 
Urine 
2 days 
● 
Ethylene oxide 
[gas] 
FDA-93, 
PMI-58 
2-Hydroxyethyl-
mercapturic acid 
(HEMA) 
Urine 
5 h 
 
NNN [particulate] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
Total N-
nitrosonornicotine 
(Total NNN) 
Urine 
15 h 
● 
o-Toluidine [gas] 
FDA-93, 
PMI-58 
o-Toluidine (o-TOL) 
Urine 
10 to 16 h 
 
Toluene [gas] 
FDA-18, 
FDA-93, HC 
PMI-58, 
WHO-18 
S-benzyl-mercapturic 
acid (S-BMA) 
Urine 
9 h 
 
Nicotine 
[particulate] 
FDA-18, 
FDA-93, HC 
PMI-58 
Nicotine (NIC-P) 
Plasma 
1 to 2 h 
● 
 
 
Cotinine (COT-P) 
3-OH Cotinine 
(3-OHCOTP) 
Plasma  
16 to 18 h 
- 
● 
 
 
Nicotine equivalents 
(Neq) 
Urine 
16 h 
(estimated) 
● 
 

 
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Appendix 6 
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 increased (1) 
>1 – 1.5 x 
Baseline; 
>ULN – 1.5 
x ULN 
>1.5 – 3.0 x 
Baseline; 
>1.5 – 3.0 x 
ULN 
>3.0 x Baseline; 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Albumin - Hypoalbuminemia (1) 
(g/dL) 
<LLN – 3; 
<3 – 2; 
<2; 
- 

 
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(g/L) 
<LLN - 30 
<30 - 20 
<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 increased (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 
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 – 1000; 
>5.70 – 11.40 
>1000; 
>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 Sources: 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, FDA, 
Center for Biologics Evaluation and Research - Guidance for Industry. 
* Those parameters that are not listed and do not have grading categories in the CTCAE will be reviewed by the Investigator 
or designne, and will only be reported as an AE if considered to be clinically relevant. 
 

 
Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
SA-SCR-01  
Final Version 8.0/18 May 2017 
Page 131 of 133 
 
 
 
 
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. 
ABNORMAL LABORATORY VALUES RATING: HEMATOLOGY PARAMETERS 
Hematology* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-threatening 
 (Grade 4) 
Anemia 
(Hemoglobin)  
(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 threateming 
conseuqences; 
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 – 3000; 
<LLN – 3.0 
 
<3000 - 2000; 
<3.0 – 2.0  
 
<2000 - 1000; 
<2.0 – 1.0  
 
<1000; 
<1.0  
Lymphocytes 
Increase - (cell/mm3) 
(1) 
- 
>4,000 – 20,000 
>20,000 
- 
Lymphocytes 
Decrease –  
(cell/mm3) (1) 
 
<LLN – 800; 
<LLN – 0.8 x 10-9/l 
<800 - 500; 
<0.8 – 0.5 x  
10-9/l 
<500 - 200; 
<0.5 – 0.2 x  
10-9/l 
<200; 
<0.2 x 10-9/l 
Neutrophils Decrease 
- (cell/mm3) (1) 
<LLN – 1500; 
<LLN – 1.5 x 10-9/l 
<1500 - 1000; 
<1.5 – 1.0 x  
10-9/l 
<1000 - 500; 
<1.0 – 0.5 x  
10-9/l 
<500; 
<0.5 x 10-9/l 
Platelets Decrease - 
(cell/mm3) (1) 
<LLN – 75,000; 
<LLN – 75.0 x 10-9/l 
<75,000 – 
50,000; 
<75.0 – 50.0 x 
10-9/l 
<50,000 – 
25,000; 
<50.0 – 25.0 x 
10-9/l 
<25,000; 
<25.0 x 10-9/l 
Abbreviations: LLN = lower limit of the normal range; ULN = upper limit of the normal range; WBC = white blood cell. 
Data Source: 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 

 
Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
SA-SCR-01  
Final Version 8.0/18 May 2017 
Page 132 of 133 
 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
* Those parameters that are not listed and do not have grading categories in the CTCAE will be reviewed by the Investigator 
or designee, and will only be reported as an AE if considered to be clinically relevant. 
 

 
Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
SA-SCR-01  
Final Version 8.0/18 May 2017 
Page 133 of 133 
 
 
 
 
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. 
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. 
* Those parameters that are not listed and do not have grading categories in the CTCAE will be reviewed by the Investigator 
or designee, and will only be reported as an AE if considered to be clinically relevant.