A Randomized, Controlled, Open-label, 2-arm Parallel Group, Single Center Study to Demonstrate Reductions in Exposure to Selected Smoke Constituents in Healthy Smokers Switching to the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) Compared to Continuing to Use Conventional Cigarettes During 5 Days in Confinement.
Phase: NA
Conditions: Smoking
Sponsor: Philip Morris Products S.A.



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Clinical Study Protocol 
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without the written consent of Philip Morris Products S.A. 
E-mail 2: 
.pmi.com 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
 
Reason to change: The phone number and the e-mail 
address of the Sponsor’s MSO have changed. 
13.1.2 
Sponsor 
Amended text:  
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5, 
2000 Neuchâtel, 
Switzerland 
Tel: +41 (58) 242 2111 
Fax: +41 (58) 242 2811 
 
 
 
 
   
Medical 
Safety 
Officer 
Phone: +41 
 
E-mail: 
.pmi.com 
 
Old text: 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5, 
2000 Neuchâtel, 
Switzerland 
Tel: +41 (58) 242 2111 
Fax: +41 (58) 242 2811 
 
 , 
Phone: Mobile :   
E-mail: 
.pmi.com 

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Clinical Study Protocol 
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without the written consent of Philip Morris Products S.A. 
 
7.3.4 
Demonstration 
and CHTP 1.0 
Test 
Amended text:  On Day -3 after enrollment, subjects will 
have a product test, using up to 5 sticks of CHTP 1.0.  
Old text:   On Day -3 after enrollment, subjects will have a 
product test, using 3 to 5 sticks of CHTP 1.0.  
Reason to change: The minimum number of three sticks is 
removed as some subjects might refuse to use three sticks at 
minimum. 
9.2.3 
Exposure 
Period – Table 
15 Time 
Schedule – 
Day of 
Discharge 
(Day 6) 
Amended text: Start of Procedure:  Before Discharge 06:29 
AM ± 1 hour. Procedures: Spirometry pre- and post-
bronchodilatator (recording of FEV1, FVC, FEV1/FVC). 
Old text:  Start of Procedure: 06:29 AM ± 1 hour. 
Procedures: Spirometry pre- and post-bronchodilatator 
(recording of FEV1, FVC, FEV1/FVC). 
Reason to change: Due to the feasibility of the conduct, 
spirometry can also be performed before discharge without 
the defined time window of 06:30 AM ± 1 hour, as no 
product will be used on the Discharge Day.  

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SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Name of Product: 
Carbon Heated Tobacco Product 1.0 (CHTP 1.0) 
Study Title: 
A randomized, controlled, open-label, 2-arm parallel group, single center study to 
demonstrate reductions in exposure to selected smoke constituents in healthy smokers 
switching to the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) compared to continuing 
to use conventional cigarettes during 5 days in confinement.  
Study Number: 
P2R-REXC-06-EU, no acronym 
Study Short Title: 
Reduced exposure study using CHTP 1.0 during 5 days in confinement. 
Primary Objective and Endpoints: 
1. To demonstrate the reduction of biomarkers of exposure (BoExp) to selected harmful 
and potentially harmful constituents (HPHCs) in smokers switching from CC to 
CHTP 1.0 as compared to smokers continuing to use CC. 
Endpoints (Day 5): 
 BoExp to HPHCs in urine (expressed as concentration adjusted for creatinine in 24-
hour urine): 
 BoExp to 1,3-butadiene: monohydroxybutenylmercapturic acid (MHBMA). 
 BoExp to acrolein: 3-hydroxypropylmercapturic acid (3-HPMA). 
 BoExp to benzene: S-phenylmercapturic acid (S-PMA). 

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 BoExp to carbon monoxide (CO): 
 Carboxyhemoglobin (COHb) in blood (expressed as % of saturation of 
hemoglobin). 
Secondary Objectives and Endpoints: 
1. To determine the reduction of additional BoExp to HPHCs in smokers switching from 
CC to CHTP 1.0 as compared to smokers continuing to use CC. 
Related Endpoints (Day 5): 
 BoExp to CO: 
 CO in exhaled breath (expressed as ppm). 
 BoExp to HPHCs in urine (expressed as quantity excreted and concentration adjusted 
to creatinine): 
 BoExp to 1,3-butadiene: MHBMA (expressed only as quantity excreted) . 
 BoExp to acrolein: 3-HPMA (expressed only as quantity excreted). 
 BoExp to benzene: S-PMA (expressed only as quantity excreted). 
 BoExp to pyrene: Total 1-hydroxypyrene (Total 1-OHP). 
 BoExp to N-nitrosonornicotine: Total N-nitrosonornicotine (Total NNN). 
 BoExp to 4-aminobiphenyl: 4-aminobiphenyl (4-ABP). 
 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 acrylonitrile: 2-cyanoethylmercapturic acid (CEMA). 
 BoExp to ethylene oxide: 2-hydroxyethylmercapturic acid (HEMA). 
 BoExp to benzo(a)pyrene: 3-hydroxybenzo(a)pyrene. 
 BoExp to crotonaldehyde: 3-hydroxy-1-methylpropyl-mercapturic acid (3-
HMPMA). 
 BoExp to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butadone (NNK): Total 4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). 
2. To describe the levels of selected BoExp over the Exposure Period in smokers switching 
from CC to CHTP 1.0 as compared to smokers continuing to use CC. 

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Related Endpoints (Day 1 to Day 5): 
 BoExp to CO: 
 CO in exhaled breath (expressed as ppm). 
 COHb in blood (expressed as % of saturation of hemoglobin). 
 BoExp to various HPHCs in urine (expressed as quantity excreted and concentration 
adjusted to creatinine): 
 MHBMA 
 3-HPMA 
 S-PMA 
 Total 1-OHP. 
 Total NNN. 
 4-ABP. 
 1-NA. 
 2-NA. 
 o-tol. 
 CEMA. 
 HEMA. 
 3-hydroxybenzo(a)pyrene. 
 3-HMPMA. 
 Total NNAL. 
3. To determine the levels of nicotine on Day 5 in smokers switching from CC to CHTP 1.0 
as compared to smokers continuing to use CC and to describe their levels over the 
Exposure Period. 
Related Endpoint (Day 1 to Day 5): 
 BoExp to nicotine: 
 Nicotine equivalents (NEQ): molar sum of free nicotine, nicotine-glucuronide, 
free cotinine, cotinine-glucuronide, free trans-3’-hydroxycotinine, trans-3’-
hydroxycotinine-glucuronide in 24 hour urine (expressed in quantity excreted 
and concentration adjusted to creatinine). 

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 Nicotine and cotinine in plasma. 
4. To describe the changes in CYP1A2 enzymatic activity in smokers switching from CC 
to CHTP 1.0, and in smokers continuing to use CC. 
Related Endpoint (Day 5): 
 Molar metabolic ratio of paraxanthine/caffeine (CAF) in plasma. 
5. To describe the daily CHTP 1.0/CC consumption over the Exposure Period in smokers 
switching from CC to CHTP 1.0 as compared to smokers continuing to use CC. 
Related Endpoint (Day 1 to Day 5): 
 Number of CHTP 1.0 and CC used each day for each subject. 
6. To monitor the safety profile during the study: 
Related Endpoints: 
 Incidence of adverse events (AEs)/ serious adverse events (SAEs). 
 Incidence of CHTP 1.0 malfunctions and misuse,
 
 
 Respiratory symptoms: cough assessment by visual analogue scale (VAS). Likert 
scales, and one open question. 
 Vital signs. 
 Spirometry. 
 Electrocardiogram (ECG). 
 Clinical chemistry, hematology, and urine analysis safety panel. 
 Physical examination. 
 Concomitant medications. 
Exploratory Objectives and Endpoints:  
1. To describe the following parameters in smokers switching from CC to CHTP 1.0 as 
compared to smokers continuing to use CC. 
Related Endpoints: 
 Excretion of mutagenic material in urine: Ames mutagenicity test (YG1024+S9) 
on Day 5 in 24-hour urine. 
 Subjective effects of smoking: 

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without the written consent of Philip Morris Products S.A. 

Questionnaire of smoking urges (brief version): Day 1 to Day 5.

Minnesota nicotine withdrawal scale, revised version: Day 1 to Day 5.

Cytochrome P450 2A6 (CYP2A6) enzymatic activity: the molar metabolic ratio
of trans-3’-hydroxycotinine/cotinine: Day 6.
2. To evaluate the relationship between the levels of BoExp and NEQ in smokers switching
from CC to CHTP 1.0, and in smokers continuing to use CC.
Related Endpoint (Day 5):

NEQ and BoExp in 24-hour urine.
3. To describe the following parameters over the course of the study in smokers switching
from CC to CHTP 1.0 as compared to smokers continuing to use CC.
Related Endpoints:

Product evaluation: modified cigarette evaluation questionnaire (MCEQ) (Day 1
to Day 5).

Puffing topography (Day -2, Day 1, and Day 4) and the Human Puffing
Topography (HPT) questionnaire.

Plug and diffuser analysis: smoke nicotine in plug and diffuser (Day 4).
Study Hypothesis: 
The hypotheses to be tested are that the geometric means of the BoExp levels for CHTP 1.0 
are lower relative to CC on Day 5. 
Evaluation Criterion: 
The study is designed to be able to detect a reduction of 50% or more in the levels of 
MHBMA, 3-HPMA, S-PMA, and COHb in the CHTP 1.0 arm compared to the CC arm at 
the end of Exposure Period, using a one sided test with 2.5% type I error probability. 
Study Design 
A randomized, controlled, open-label, 2-arm, parallel group, single-center study with a 
stratified randomization by sex and average daily CC consumption over the last 6 weeks 
prior to admission as self-reported (smokers smoking 10 to 19 CC/day and smokers 
smoking > 19 CC/day).  
During the confinement period, adherence to product allocation (exclusive use of CHTP 1.0 
in the CHTP 1.0 arm or CC in the CC arm, respectively) will be ensured by controlled 
distribution of each CHTP 1.0 and CC on request of the subject. 

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without the written consent of Philip Morris Products S.A. 
 The Baseline Period (from Day -2, 06:30 AM until Day 1, 06:29 AM): 
All subjects will continue smoking their single preferred brand of CC ad libitum. Twenty 
four-urine collection for Day -2 will start in the morning of Day -2 ending in the morning 
of Day -1. Twenty four-urine collection for Day -1 will start in the morning of Day -1 
ending in the morning of the Day 1. During Day -1, spirometry and CYP2A6 blood 
sampling have to be done prior to smoking.  
On Day -1, subjects will be randomized to 1 of the 2 study arms in a 1:1 ratio using a 
stratified randomization: 
 CHTP 1.0 arm: ~40 subjects, ad libitum use of CHTP 1.0. 
 CC arm: ~40 subjects, ad libitum use of CC. 
Subjects will be informed of their randomized study arm by the site collaborators on 
Day 1 prior to 06:30 AM (the start of the Exposure Period). 
 The Exposure Period (from Day 1, 06:30 AM until Day 5, 11:00 PM):  
The Exposure Period will consist of 5 days of ad libitum use of the assigned product 
(CHTP 1.0 or CC, exclusively) between 06:30 AM and 11:00 PM.  
Subjects in the CC and CHTP 1.0 arms who are willing to attempt quitting during the 
study will be encouraged to do so and will be referred to a smoking cessation aid service. 
The subjects will not be discontinued from the study, will come to all scheduled visits 
for assessments, and his/her financial compensation will not be affected.  
Use of any tobacco/nicotine containing product other than the assigned product will not 
be allowed throughout the Exposure Period and may, at the discretion of the Investigator, 
result in the subject’s discontinuation from the study. 
Twenty four-hour urine will be collected from Day 1 to Day 5 on site to measure BoExp. 
On Day 1, product use must not start prior to the end of urine collection of Day -1. The 
end of the 24-h urine collection period for Day 5 will end in the morning of Day 6 prior 
to Discharge. 
 The Day of Discharge (Day 6) (from Day 5, 11:01 PM to Discharge): 
Procedures of Discharge including but not limited to laboratory parameters will be 
conducted to discharge the subject from the clinic. Use of CC will be allowed on Day 6 
but only after twenty four-hour urine collection is completed, and spirometry and 
CYP2A6 blood sampling have been performed. 
 The Safety Follow-up Period (from Discharge on Day 6 to Day 13): 
After Discharge, the subject will enter a 7-day Safety Follow up Period during which the 
follow-up of ongoing AEs/SAEs will be done by the study site. All AEs will be followed-

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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. Within 3 days 
after the end of the Safety Follow-up Period the investigator will attempt to contact the 
subjects by phone to check for if all AEs/SAEs potentially occurring during the Safety 
Follow-up period are fully reported. 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 
General Practitioner for follow up on ongoing AEs. 
The end of the study for a subject is defined as Discharge on Day 6 or the date of early 
termination of the subject plus the 7 days for the Safety Follow-up Period plus up to 3 
days to ensure that all AEs/SAEs potentially occurring during the Safety Follow-up 
period are fully reported.  
If the investigator can reach the subject by phone within 3 days after the end of the Safety 
Follow-up Period, 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 by phone 
within 3 days after the end of the Safety Follow-up Period, 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 EOS of the entire study is the end of the Safety Follow-up Period plus up to 3 days 
of the last subject. 
Study Population and Main Criteria for Inclusion/Exclusion: 
Approximately 80 smoking, healthy Caucasian female or male adult subjects meeting the 
following main inclusion criteria: 
 Subject is aged ≥ 21 years. 
 Subject is Caucasian. 
 Subject is healthy, as judged by the Investigator. 
 Subject smokes at least 10 commercially available non-menthol CCs per day (no brand 
restrictions) at least for the last 6 weeks prior to admission, based on self-reporting. 
 Subject has smoked at least for the last 3 years. 
 Subject does not plan to quit smoking in the next 3 months. 
 Subject is ready to comply with the study protocol (e.g., to use CHTP 1.0 for the duration 
of the study). 
Subjects who do not complete the study after randomization will not be replaced. 

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Investigational Products; Dose; and Mode of Administration: 
 Carbon Heated Tobacco Product 1.0 (CHTP 1.0). CHTP 1.0 will be provided by the 
Sponsor. 
 Subject’s own preferred commercially available non-menthol single brand of CC. 
Duration of Study: 
The entire study duration per subject will be 17 to 61 days including a Screening Period of 
up to 42 days prior to Admission on Day -3, a 9-day confinement period (from Day -3 to 
Discharge on Day 6) followed by the 7 days for the Safety Follow-up Period (until Day 13) 
plus up to 3 days. 
Statistical Methods:  
Analysis of BoExp will be conducted on the natural log scale. The transformed Day 5 data 
will be analyzed by means of a generalized linear model using randomized arm as covariate 
adjusting for the following baseline information: sex, average cigarette consumption over 
the previous 4 weeks (value at admission for stratification), and baseline value of the BoExp. 
Estimates of differences between groups will be back-transformed to provide relative effects. 
Assumptions of the analysis of variance (ANOVA) model will be tested. Markedly non-log 
normally distributed BoExp data will be transformed or analyzed by appropriate non-
parametric methods. 
Unless stated otherwise, all statistical tests will be two-sided and conducted at the 5% level, 
and all quoted confidence intervals (CIs) will be two-sided 95% confidence intervals. 
Sample Size: 
A total of 80 subjects (~ 40 in the CHTP 1.0 arm, ~ 40 in the CC arm) will be randomized. 
This sample size is needed to attain 80% power to detect a 50% reduction or more in the 
levels of MHBMA, 3-HPMA, S-PMA, and COHb in the CHTP 1.0 arm compared to the CC 
arm after 5 days of exposure, one sided test with 2.5% type I error probability. 
The overall type I error will be protected by using a closed testing procedure (i.e., testing the 
four above listed endpoints simultaneously). 
 

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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................7 
TABLE OF CONTENTS .........................................................................................................16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................21 
1 
ETHICS AND REGULATIONS .....................................................................................25 
1.1 
Independent Ethics Committee (IEC) Approval ....................................................25 
1.2 
Ethical Conduct of the Study .................................................................................26 
1.3 
Subject Information and Consent...........................................................................26 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................27 
2 
INTRODUCTION ...........................................................................................................28 
2.1 
Background ............................................................................................................28 
2.2 
Purpose of the Study ..............................................................................................29 
2.3 
Anticipated Benefits and Risks ..............................................................................29 
3 
STUDY OBJECTIVES ....................................................................................................31 
3.1 
Primary Objective and Endpoints ..........................................................................31 
3.2 
Secondary Objectives and Endpoints.....................................................................31 
3.3 
Exploratory Objectives and Endpoints ..................................................................34 
4 
INVESTIGATIONAL PLAN ..........................................................................................35 
4.1 
Overall Study Design and Plan ..............................................................................35 
4.2 
Rationale for Study Design ....................................................................................38 
4.3 
Appropriateness of Measurements .........................................................................39 
4.4 
Study Duration .......................................................................................................39 
5 
STUDY POPULATION ..................................................................................................40 
5.1 
Inclusion Criteria ...................................................................................................40 
5.2 
Exclusion Criteria ..................................................................................................41 
5.3 
Discontinuation of Subjects from the Study ..........................................................43 
5.4 
Lost to Follow-up ...................................................................................................44 
5.5 
Violation of Selection Criteria ...............................................................................45 
6 
INVESTIGATIONAL PRODUCTS ...............................................................................46 
6.1 
Description of Investigational Products .................................................................46 
6.2 
Packaging and Labeling .........................................................................................46 
6.3 
Use of Investigational Product(s)...........................................................................47 
6.4 
Method for Assigning Subjects to Study Arms .....................................................48 

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6.5 
Blinding..................................................................................................................48 
6.6 
Investigational Product Accountability and Compliance ......................................49 
6.7 
Restrictions ............................................................................................................50 
6.8 
Concomitant Medication ........................................................................................51 
7 
STUDY PROCEDURES .................................................................................................55 
7.1 
Informed Consent...................................................................................................55 
7.2 
Smoking Cessation Advice and Debriefing ...........................................................55 
7.3 
Clinical Assessments .............................................................................................55 
7.4 
Biomarker Assessment...........................................................................................59 
7.5 
Laboratory Assessments ........................................................................................61 
7.6 
Sample Handling, Storage, and Shipment .............................................................63 
7.7 
Other Study Procedures .........................................................................................66 
7.8 
Questionnaires........................................................................................................68 
8 
ADVERSE EVENTS .......................................................................................................72 
8.1 
Definitions..............................................................................................................72 
8.2 
Assessment of Adverse Events ..............................................................................73 
8.3 
Reporting of Serious Adverse Events ....................................................................75 
8.4 
Reporting of Other Events Critical to Safety Evaluations .....................................76 
8.5 
Reporting and Follow-Up of Pregnancies..............................................................77 
8.6 
Adverse Events Leading to Discontinuation..........................................................78 
8.7 
Investigational Product Malfunction and Misuse ..................................................78 
9 
STUDY ACTIVITIES .....................................................................................................79 
9.1 
Screening Visit .......................................................................................................79 
9.2 
Confinement Period (Day -3 to Day 6) ..................................................................81 
9.3 
Safety Follow-Up Period .......................................................................................97 
9.4 
Early Termination Procedures ...............................................................................98 
10 QUALITY CONTROL AND QUALITY ASSURANCE .............................................100 
10.1 
Monitoring ...........................................................................................................100 
10.2 
Training of Collaborators .....................................................................................100 
10.3 
Audits and Inspections .........................................................................................101 
11 DATA MANAGEMENT ACTIVITIES........................................................................102 
11.1 
Data Capture ........................................................................................................102 
11.2 
Data Handling ......................................................................................................103 
12 PLANNED STATISTICAL METHODS ......................................................................105 

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12.1 
General Considerations ........................................................................................105 
12.2 
Determination of Sample Size and Power Consideration ....................................106 
12.3 
Analysis Populations ............................................................................................108 
12.4 
Primary Endpoints ...............................................................................................108 
12.5 
Secondary Safety Endpoint(s) ..............................................................................110 
12.6 
Exploratory Analysis ...........................................................................................111 
12.7 
Demographics and Baseline Characteristics ........................................................111 
12.8 
Interim Analysis ...................................................................................................111 
13 ADMINISTRATIVE CONSIDERATIONS ..................................................................112 
13.1 
Investigator’s and Study Administrative Structure ..............................................112 
13.2 
Subject Confidentiality ........................................................................................113 
13.3 
Access to Source Documentation ........................................................................114 
13.4 
Record Retention .................................................................................................114 
13.5 
Clinical Study Report ...........................................................................................115 
13.6 
Financial Disclosure.............................................................................................116 
13.7 
Publication and Disclosure Policy .......................................................................116 
13.8 
Insurance ..............................................................................................................116 
14 REFERENCE LIST .......................................................................................................117 
APPENDIX A 
SCHEDULE OF EVENTS ........................................................................120 
APPENDIX B 
PARTICIPATING LABORATORIES ......................................................124 
APPENDIX C 
HPT SODIM® DEVICE ...........................................................................125 
APPENDIX D 
SUMMARY OF BIOMARKERS OF EXPOSURE TO HPHC ................126 
APPENDIX E 
ABNORMAL LABORATORY VALUES................................................128 
 

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LIST OF IN-TEXT TABLES 
Table 1 
Description of Blinded Study Personnel ....................................................48 
Table 2 
Examples of Medications with Effects on CYP1A2 and CYP2A6 
Activity ......................................................................................................51 
Table 3 
Hematology and Clinical Chemistry Parameters (Safety) .........................62 
Table 4 
Human Puffing Topography – Per-Puff Parameters ..................................67 
Table 5 
Human Puffing Topography – Per-CHTP 1.0/Cigarette Parameters .........67 
Table 6 
Time Schedule – Screening Visit (Day -45 to Day -3) ..............................79 
Table 7 
Time Schedule – Admission (Day -3) .......................................................82 
Table 8 
Time Schedule – Day -2 ............................................................................84 
Table 9 
Time Schedule – Day -1 ............................................................................85 
Table 10 
Time Schedule – Day 1 ..............................................................................87 
Table 11 
Time Schedule - Day 2 ..............................................................................89 
Table 12 
Time Schedule - Day 3 ..............................................................................91 
Table 13 
 Time Schedule - Day 4 .............................................................................92 
Table 14 
Time Schedule - Day 5 ..............................................................................94 
Table 15 
Time Schedule - Day of Discharge (Day 6) ...............................................96 
Table 16 
Time Schedule - Early Termination Procedures ........................................98 
Table 17. 
Coefficients of Variation (YVD-CS01-EU study) ...................................107 
Table 18. 
Expected Power (YVD-CS01-EU study assumptions) ............................107 
Table 19. 
Test-Wise Power (YVD-CS01-EU study assumptions) ..........................107 
Table A1 
Study Assessments (Separate Table [Table A2] Shown for 24-hour 
Urine Collections) ....................................................................................120 
Table A2 
Schedule for 24-hour Urine Collection Assessments ..............................123 
 

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LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ..............................................................................................12 
Figure 2 
Study Design ..............................................................................................35 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Events ...................................................................................120 
Appendix B 
Participating Laboratories ........................................................................124 
Appendix C 
HPT Sodim® Device ...............................................................................125 
Appendix D 
Summary of Biomarkers of Exposure to HPHC ......................................126 
Appendix E 
Abnormal Laboratory Values ..................................................................128 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
ADL 
Activities of daily living 
AE 
Adverse event 
ANOVA 
Analysis of variance 
BMI 
Body mass index 
BoExp 
Biomarker of exposure 
CAF 
Caffeine 
CC 
Conventional cigarette(s) 
CD 
Compact disc 
CI 
Confidence interval 
CHTP 
Carbon Heated Tobacco Product 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria for adverse events and common 
toxicity criteria  
CTMS 
Clinical trial management system 
CV (documentation) 
Curriculum vitae 
CV (statistics) 
Coefficient of variation 
CYP1A2 
Cytochrome P450 1A2 
CYP2A6 
Cytochrome P450 2A6 
DMP 
Data management plan 
ECG 
Electrocardiogram 
EOS 
End of study 
FAS 
Full analysis set 
FDA 
Food and Drug Administration  
FEV1  
Forced expiratory volume in 1 second 

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FTND 
Fagerström test for nicotine dependence (revised version) 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
HPHCs 
HPT 
Harmful and potentially harmful constituents 
Human puffing topography  
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IP 
Investigational product 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IV 
Intravenous 
IxRS 
Interactive web/voice response system 
LLN 
Lower limit of the normal range 
LLOQ 
Lower limit of quantification 
MCEQ 
Modified cigarette evaluation questionnaire 
MedDRA 
Medical dictionary for regulatory activities 
MRTP 
Modified risk tobacco product 
PMI 
Philip Morris International 
PX  
Paraxanthine 
QC 
Quality control 
QSU-brief 
Questionnaire of smoking urges 
SA 
Smoking abstinence 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SHM 
Sample handling manual 
SOP 
Standard operating procedure 
SRO 
Subject reported outcome(s) 
T 
Time point  

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T0 
Time point of first product use during study day 
t½ 
Half-life 
 
 
ULN 
Upper limit of the normal range 
ULOQ 
Upper limit of quantification 
VAS 
Visual analogue scale 
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: 
Conventional cigarette 
(CC) 
The term ‘conventional cigarette’ refers to commercially available 
cigarettes (manufactured) and excludes cigars, pipes, bidis, and 
other nicotine-containing products. 
Carbon Heated 
Tobacco Product 1.0 
(CHTP 1.0) 
CHTP 1.0 is a non-menthol tobacco stick which is comparable in 
shape and form, and is used in a similar manner to a conventional 
cigarette.  
End of study (EOS) 
The EOS for a subject is defined as Discharge on Day 6 or the date 
of early termination of the subject plus the 7 days for the Safety 
Follow-up Period plus up to 3 days to ensure that all AEs/SAEs 
potentially occurring during the Safety Follow-up period are fully 
reported. The EOS of the entire study is the end of the Safety 
Follow-up Period plus up to 3 days of the last subject. 
Randomization  
Allocation of the respective product at any time on Day -1 utilizing 
an interactive web and voice response system (IxRS). On Day 1, 
the subjects will be individually informed about the product they 
are randomized to prior to the first product use.  
Screening failure 
All subjects that are not enrolled are considered as screen failures. 
Re-screening of subjects who did not meet any entry criteria will 
not be permitted. 

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1 
ETHICS AND REGULATIONS 
1.1 
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 including questionnaires and instructions to be provided 
to the subjects, Investigator’s Brochure [IB], available safety information, the Investigator’s 
curriculum vitae and/or other evidence of qualifications, and any other documents requested 
by the Independent Ethics Committee [IEC]), will be submitted for review and approval to the 
relevant IEC. The IEC shall be appropriately constituted and perform its functions in 
accordance with the International Conference on Harmonization (ICH) Tripartite Guidance for 
Good Clinical Practice (GCP) [1] and local requirements, as applicable.  
In accordance with GCP, a written confirmation of the IEC approval should be provided to the 
Sponsor. This should identify the study (Investigator’s name, study number, and title) and the 
documents that have been approved by the IEC, with dates and version numbers, as well as the 
date of approval. The composition of the IEC, including the name and occupation of the 
chairperson, should be supplied to the Sponsor together with a GCP compliance statement. 
The written approval from the IEC will be filed in the Investigator file, and a copy will be filed 
in the study master file (SMF) 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 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 IEC, and substantial amendments will only be implemented after approval by the 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 IEC should be informed 
immediately. 
The Investigator is responsible for local reporting (e.g., to the IEC) of serious adverse events 
(SAEs) that occur during the study, according to local regulations. 
Relevant safety information will be submitted to the 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. 

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1.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki [2] 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 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 [2] 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 at V1, 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 by the date, time and signature of both the subject and the 
Investigator who conducted the inform consent discussion during Screening Visit. Any 
procedures specifically described in and related to the study protocol and study conduct, will 
not be performed before the ICF has been signed (including date and time). 
The signed and personally dated original 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 will be analyzed, unless he/she refuses in writing. 
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 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. 

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 One separate ICF to obtain consent for serum/plasma and urine collection and long-term 
storage for subsequent analysis of biomarkers 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.  
1.3.3 
Amendment to the Informed Consent Form 
If a protocol amendment is required, an amendment may be required to the ICF. If a 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 the relevant IEC before 
subjects are informed and sign and personally date the amended ICF (including date and time). 
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 as applicable to the study. These guidelines apply specifically to pharmaceutical 
development, but nevertheless provide a robust and ethical framework for conducting a clinical 
study on candidate reduced risk products. The study will also be conducted in accordance with 
the general ethical principles outlined in the Declaration of Helsinki [2]. 
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 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy 
Cigarette smoking causes pulmonary diseases, cardiovascular diseases (CVD) and other 
serious diseases in smokers [3]. 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 products with the potential to reduce the risks of tobacco-related diseases 
(Reduced Risk Products [RRP]). These products are referred by the Food and Drug 
Administration (FDA) as modified risk tobacco products (MRTP) [4].  
PMI develops candidate RRPs with the objective to substantially reduce the exposure to 
harmful and potentially harmful constituents (HPHCs) while providing an acceptable option 
to smokers as substitutes for CC. In this way, PMI can substantially reduce or eliminate a large 
spectrum of HPHCs. PMI’s product development approaches achieve this, for example, by 
heating tobacco at significantly lower temperatures than CC. PMI believes that such products 
present the best opportunity for reducing harm because they produce vastly lower levels of 
HPHCs and are more likely to be accepted by smokers as substitutes for CC. Important to this 
effort has been the development of a product with the potential to provide nicotine in a way 
that closely parallels CC.  
2.1.2 
Description of the Product and Scientific Findings 
Thousands of smoke constituents are formed when tobacco is burned or combusted. More than 
6,000 of these smoke constituents have been identified [5], and more than 100 of them have 
been categorized as HPHCs [6]. 
The product developed by PMI, and to be assessed in this study, is the Carbon Heated Tobacco 
Product 1.0 (CHTP 1.0). With this product, the heating of the tobacco does not exceed a well-
defined temperature profile, which ensures heating without combustion of the tobacco. 
CHTP 1.0 is a non-menthol tobacco stick which has similar apprearance, and is used in a 
similar manner to a CC. To use CHTP 1.0, the consumer removes the protective cap and uses 
regular matches or lighter to ignite the heat source, except that this process should be done 
while holding CHTP 1.0 in the hand, rather than in the mouth (like for a CC). After a short 
pause to allow the tobacco to become heated, the aerosol generated by the heating process is 
inhaled by placing the filter of  CHTP 1.0 in the mouth (or on the lips) and drawing air through 
CHTP 1.0. During use, the tobacco in CHTP 1.0 is exposed to a well-defined temperature 

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profile which ensures heating without combustion and at the same time provides an acceptable 
consumer experience in a consistent manner. 
Non-clinical assessment of CHTP 1.0 showed that no new or increased toxicological hazard in 
the CHTP aerosol was detected compared with CC smoke. Chemical analysis of the aerosol 
confirmed that none of the measured HPHCs from CHTP 1.0 has increased compared to CC. 
The biological activity of the aerosol was tested in vitro and in vivo. A number of in vitro 
assays were performed to assess the cytotoxicity and genotoxicity of the aerosol. The subacute 
toxicity of the aerosol in vivo was evaluated in a 28-day inhalation study in rats. In vitro and 
in vivo results support the hypothesis that the absence of combustion when heating tobacco 
substantially lowers toxic effects. By heating instead of burning tobacco the aerosol of the 
CHTP becomes less complex, measured HPHCs are either substantially reduced or 
undetectable.  
The non-clinical assessment of CHTP 1.0 is described in the Investigator’s brochure and 
supports the clinical assessment of CHTP 1.0. 
One clinical study (ClinicalTrials.gov Identifier: NCT00812279) has been conducted in Poland 
with CHTP 0.1, an earlier and non-menthol prototype version of CHTP 1.0. After 5 days of 
exposure marked reductions in exposure to HPHCs in the CHTP 0.1 arm and SA (smoking 
abstinence) arm compared to subjects continuing smoking CC were observed, and no safety 
concern was revealed. No clinical studies have been conducted with CHTP 1.0. 
2.2 
Purpose of the Study 
The overall goal of the study is to demonstrate reduction in the levels of biomarkers of exposure 
(BoExp) to selected HPHCs and to obtain safety information in healthy subjects using CHTP 
1.0 as compared to smokers continuing smoking their preferred brand of CC. 
In addition, during this study data will be collected to better understand the effect of using 
CHTP 1.0 on excretion of mutagenic material in urine, subjective effects related to smoking, 
cytochrome P450 2A6 [CYP2A6] and P450 1A2 [CYP1A2] enzymatic activity and product 
evaluation.  
2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
Information on health risks associated with smoking and smoking cessation advice will be 
provided at Screening, Admission, and at Discharge. The advice will follow the 
recommendations 
of 
the World Health Organization 
(WHO) 
“Evidence based 
Recommendations on the Treatment of Tobacco Dependence”[7]. Subjects who are motivated 
to quit smoking during the study will be encouraged to do so, and will be referred to appropriate 

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medical services for necessary support and counselling. Subjects who participate in this study 
will also benefit from repeated and detailed health check-ups. 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures 
 Risks related to blood sampling, e.g., excessive bleeding, fainting, hematoma, paresthesia, 
or infection, and the total amount of blood taken over a period of time. 
 Risks related to chest X-rays, (e.g., a small increase of risk to develop cancer later in life). 
 Risks related to drug applications as part of testing procedures (i.e., spirometry, and short-
acting bronchodilator at the Screening Visit) per study protocol and scientifically accepted 
standards. 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product  
 Change in smoking habits due to study requirements and related concomitant symptoms 
(e.g., craving).  
All risks related to study procedures and the product will be explained in detail to the subjects.  
Risk mitigation will include: 
 Using commonly accepted research and scientific standards (e.g., blood samples not to 
exceed blood donation standards).  
 Management and follow-up of adverse events (AEs)/serious adverse events (SAEs). 
 Medical assessment, management of all study participants with follow-up of those who 
have experienced an AE(s)/SAE(s). 
2.3.4 
Unforeseeable Risks 
The possibility of unforeseeable events/risks will be explained in detail to study participants. 
Unexpected malfunction of CHTP 1.0 may lead to unforeseeable risk. Subjects will be 
informed that CHTP 1.0 is not demonstrated to be less harmful than CC. Mitigation will 
include close monitoring and medical supervision to detect any unforeseeable risk or safety 
signals at the earliest time possible. 

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3 
STUDY OBJECTIVES 
3.1 
Primary Objective and Endpoints 
The primary objective of this study is: 
1. To demonstrate the reduction of biomarkers of exposure (BoExp) to selected HPHCs in 
smokers switching from CC to CHTP 1.0 as compared to smokers continuing to use CC. 
Endpoints (Day 5): 
 BoExp to HPHCs in urine (expressed as concentration adjusted for creatinine in 24-
hour urine): 
 BoExp to 1,3-butadiene: monohydroxybutenylmercapturic acid (MHBMA). 
 BoExp to acrolein: 3-hydroxypropylmercapturic acid (3-HPMA). 
 BoExp to benzene: S-phenylmercapturic acid (S-PMA). 
 BoExp to carbon monoxide (CO): 
 Carboxyhemoglobin (COHb) in blood (expressed as % of saturation of 
hemoglobin). 
3.2 
Secondary Objectives and Endpoints 
The secondary objectives of this study are: 
1. To determine the reduction of additional BoExp to HPHCs in smokers switching from CC 
to CHTP 1.0 as compared to smokers continuing to use CC. 
Related Endpoints (Day 5): 
 BoExp to CO: 
 CO in exhaled breath (expressed as ppm). 
 BoExp to HPHCs in urine (expressed as quantity excreted and concentration adjusted 
to creatinine): 
 BoExp to 1,3-butadiene: MHBMA (expressed only as quantity excreted)  . 
 BoExp to acrolein: 3-HPMA (expressed only as quantity excreted). 
 BoExp to benzene: S-PMA (expressed only as quantity excreted). 
 BoExp to pyrene: total 1-hydroxypyrene (total 1-OHP). 
 BoExp to N-nitrosonornicotine: total N-nitrosonornicotine (total NNN). 

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 BoExp to 4-aminobiphenyl: 4-aminobiphenyl (4-ABP). 
 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 acrylonitrile: 2-cyanoethylmercapturic acid (CEMA). 
 BoExp to ethylene oxide: 2-hydroxyethylmercapturic acid (HEMA). 
 BoExp to benzo(a)pyrene: 3-hydroxybenzo(a)pyrene. 
 BoExp to crotonaldehyde: 3-hydroxy-1-methylpropyl-mercapturic acid (3-
HMPMA). 
 BoExp to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butadone (NNK): total 4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). 
2. To describe the levels of selected BoExp over the Exposure Period in smokers switching 
from CC to CHTP 1.0 as compared to smokers continuing to use CC. 
Related Endpoints (Day 1 to Day 5): 
 BoExp to CO: 
 CO in exhaled breath (expressed as ppm). 
 COHb in blood (expressed as % of saturation of hemoglobin). 
 BoExp to various HPHCs in urine (expressed as quantity excreted and concentration 
adjusted to creatinine): 
 MHBMA 
 3-HPMA 
 S-PMA 
 Total 1-OHP. 
 Total NNN. 
 4-ABP. 
 1-NA. 
 2-NA. 
 o-tol. 
 CEMA. 

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 HEMA. 
 3-hydroxybenzo(a)pyrene. 
 3-HMPMA. 
 Total NNAL. 
3. To determine the levels of nicotine on Day 5 in smokers switching from CC to CHTP 1.0 
as compared to smokers continuing to use CC and to describe their levels over the Exposure 
Period. 
Related Endpoint (Day 1 to Day 5): 
 BoExp to nicotine: 
 Nicotine equivalents (NEQ): molar sum of free nicotine, nicotine-glucuronide, free 
cotinine, 
cotinine-glucuronide, 
free 
trans-3’-hydroxycotinine, 
trans-3’-
hydroxycotinine-glucuronide in 24 hour urine (expressed in quantity excreted and 
concentration adjusted to creatinine). 
 Nicotine and cotinine in plasma. 
4. To describe the changes in CYP1A2 enzymatic activity in smokers switching from CC to 
CHTP 1.0, and in smokers continuing to use CC. 
Related Endpoint (Day 5): 
 Molar metabolic ratio of paraxanthine/caffeine in plasma. 
5. To describe the daily CHTP 1.0/CC consumption over the Exposure Period in smokers 
switching from CC to CHTP 1.0 as compared to smokers continuing to use CC. 
Related Endpoint (Day 1 to Day 5): 
 Number of CHTP 1.0 and CC used each day for each subject. 
6. To monitor the safety profile during the study: 
Related Endpoints: 
 Incidence of adverse events (AEs)/ serious adverse events (SAEs) 
 Incidence of  CHTP 1.0 malfunctions and misuse 
 
 
 Respiratory symptoms: cough assessment by visual analogue scale (VAS). Likert 
scales, and one open question. 
 Vital signs. 

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 Spirometry. 
 Electrocardiogram (ECG). 
 Clinical chemistry, hematology, and urine analysis safety panel. 
 Physical examination. 
 Concomitant medications. 
3.3 
Exploratory Objectives and Endpoints 
The exploratory objectives of this study are: 
1. To describe the following parameters in smokers switching from CC to CHTP 1.0 as 
compared to smokers continuing to use CC. 
Related Endpoints: 
 Excretion of mutagenic material in urine: Ames mutagenicity test (YG1024+S9) on 
Day 5 in 24-hour urine. 
 Subjective effects of smoking: 
 Questionnaire of smoking urges (brief version): Day 1 to Day 5. 
 Minnesota nicotine withdrawal scale, revised version: Day 1 to Day 5. 
 Cytochrome P450 2A6 (CYP2A6) enzymatic activity: the molar metabolic ratio of 
trans-3’-hydroxycotinine/cotinine: Day 6. 
2. To evaluate the relationship between the levels of BoExp in urine and NEQ in smokers 
switching from CC to CHTP 1.0, and in smokers continuing smoking CC. 
Related Endpoint (Day 5): 
 NEQ and BoExp in 24-hour urine. 
3. To describe the following parameters over the course of the study in smokers switching 
from CC to CHTP 1.0 as compared to smokers continuing smoking CC. 
Related Endpoints: 
 Product evaluation: modified cigarette evaluation questionnaire (MCEQ) (Day 1 to 
Day 5). 
 Puffing topography (Day -2, Day 1, and Day 4) and Human Puffing Topography 
(HPT) questionnaire. 
 Plug and diffuser analysis: smoke nicotine in plug and diffuser (Day 4). 

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Visit. At Screening, spirometry needs to be done at least 1 hour after having stopped 
smoking. Use of any tobacco/nicotine containing product other than CC will not be allowed 
after the Screening Visit. Subject will be instructed not to smoke in the morning prior to 
the admission to the site on the Admission Day. 
 Admission Day (from Admission on Day -3 until 06:29 AM of Day -2): 
Subjects will be in a confinement setting for 9 days from Day -3 onwards. On Day -3 
(Admission), after all inclusion/exclusion criteria are checked, eligible subjects will be 
enrolled and then perform a product test, using up to 5 sticks of CHTP 1.0. After the product 
test, subjects not ready to use the CHTP 1.0 will be discontinued. All subjects that are not 
enrolled are considered as screen failures. Smoking will be allowed until 11.00 PM at 
Admission.  
 Baseline Period (from Day -2, 06:30 AM until Day 1, 06:29 AM): 
All subjects will continue smoking their single preferred brand of CC ad libitum. Twenty 
four-urine will be collected starting in the morning of the Day -2 finishing in the morning 
of the Day -1, and starting in the morning of the Day -1 finishing in the morning of Day 1. 
During Day -1, spirometry and CYP2A6 blood sampling have to be done prior to smoking.  
On Day -1, subjects will be randomized to 1 of the 2 study arms in a 1:1 ratio using a 
stratified randomization: 
 CHTP 1.0 arm: ~ 40 subjects, ad libitum use of CHTP 1.0. 
 CC arm: ~ 40 subjects, ad libitum use of CC. 
Subjects will be informed of their randomized study arm by the site collaborators on Day 1 
prior to 06:30 AM (the start of the Exposure Period). Subjects who do not complete the 
study after randomization will not be replaced. 
 Exposure Period (from Day 1, 06:30 AM until Day 5, 11:00 PM): 
The exposure period will consist of 5 days of exlusive ad libitum use of the assigned 
product (CHTP 1.0 or CC) between 06:30 AM and 11:00 PM.  
Subjects in the CC and CHTP 1.0 arms who are willing to attempt quitting smoking during 
the study will be encouraged to do so and will be referred to appropriate medical service. 
Use of any tobacco/nicotine containing product other than the assigned product will not be 
allowed throughout the Exposure Period and may, at the discretion of the Investigator, 
result in the subject’s discontinuation from the study. 
Twenty four-hour urine will be collected from Day 1 to Day 5 on site to measure BoExp. 
On Day 1, product use must not start prior to the end of urine collection of Day -1. The end 

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of the 24-h urine collection period for Day 5 will end in the morning of Day 6 prior to 
Discharge. 
 Day of Discharge (Day 6) (from Day 5, 11:01 PM to Discharge): 
Procedures of Discharge including but not limited to laboratory parameters will be 
conducted to discharge the subject from the clinic after 9 days in a confined setting. Use of 
CC will be allowed on Day 6 but only after 24-h urine collection is completed, and 
spirometry and CYP2A6 blood sampling have been performed. 
 Safety Follow-up Period (from Discharge on Day 6 to Day 13): 
After Discharge, the subject will enter a 7-day Safety Follow up Period during which the 
follow-up of ongoing AEs/SAEs will be done by the study 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. Within 3 days after 
the end of the Safety Follow-up Period the investigator will attempt to contact the subjects 
by phone to check for if all AEs/SAEs potentially occurring during the Safety Follow-up 
Period are fully reported.   
The end of the study for a subject is defined as Discharge on Day 6 or the date of early 
termination of the subject plus the 7 days for the Safety Follow-up Period plus up to 3 days 
to ensure that all AEs/SAEs potentially occurring during the Safety Follow-up period are 
fully reported.  
If the investigator can reach the subject by phone within 3 days after the end of the Safety 
Follow-up Period, 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 by phone 
within 3 days after the end of the Safety Follow-up Period, 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 EOS of the entire study is the end of the Safety Follow-up Period plus up to 3 days of 
the last subject. 
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 General Practitioner for follow up on 
ongoing AEs. 
 
 
 

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4.2 
Rationale for Study Design  
This clinical study aims to demonstrate the reduction of BoExp to selected HPHCs in smokers 
switching from CC to CHTP 1.0, a candidate RRP. The comparator in this study will be 
smokers who continue to use CC. 
The Exposure Period in confinement will provide information on exposure reductions 
achieveable in a well-controlled environment with full control on daily CHTP 1.0 / CC 
consumption. The choice of HPHCs to be assessed in this study is derived from the WHO [8] 
and the draft guidance on “Reporting Harmful and Potentially Harmful Constituents in 
Tobacco Products and Tobacco Smoke” [9]. 
In the WHO list, 9 HPHCs (acrolein, CO, 1-3 butadiene, benzene, NNN, NNK, acetaldehyde, 
benzo[a]pyrene, and formaldehyde) with evidence of carcinogenicity, respiratory, and cardiac 
toxicity were recommended to be measured as priority in the smoke chemistry for mandated 
lowering [8]. Exposure to 4 HPHCs (acrolein, CO, 1,3-butadiene, and benzene) among these 
9 priority HPHCs will be assessed by measuring their respective BoExp as primary endpoints 
after 5 days of exclusive use of CHTP 1.0 and CC. The following characteristics apply to these 
selected BoExp: 
 They are several-fold higher in smokers than in smokers abstinent from smoking [10]. 
 They exhibit, on average, an elimination half-life (t1/2)of ≤ 24-hours. Therefore, the 5 days 
of exposure are sufficient to reach the steady state with CHTP 1.0. 
 They were decreased in smokers who switched to an earlier prototype of CHTP 1.0 for 5 
days, similarly to that observed in smokers who stopped smoking (data on file from a 
previous study with the ClinicalTrials.gov Identifier: NCT00812279). 
In addition to the 9 HPHCs recommended to be measured by WHO list, the FDA has required 
additional 9 HPHCs for reporting to FDA (in total 18 HPHCs in cigarette smoke) [9]. From 
the WHO and FDA list, exposure to additional 9 HPHCs ( acrylonitrile, 4-ABP, 1-NA, 2-NA, 
benzo[a]pyrene, crotonaldehyde, NNK, NNN, and toluene) will be assessed by measuring the 
respective BoExp as secondary endpoints after 5 days of exclusive use of CHTP 1.0 and CC. 
Cytochrome P450 1A2 activity, which is well known to be increased by smoking and to be 
decreased upon smoking abstinence (SA), will be measured in this study to evaluate the effect 
of CHTP 1.0 use on the activity of this enzyme [11]. Cytochrome P450 2A6 activity, the 
enzyme involved in nicotine metabolism, will be assessed in this study to evaluate if the use 
of CHTP 1.0 impacts the activity of this enzyme. 
Twenty-four hour-urine that will be collected in this study is the standard method to measure 
the levels of excretion of BoExp.  
All subjects will be asked to buy their own CC according to their anticipated needs for the 
study in order to minimize any changes in their smoking behavior. 

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4.3 
Appropriateness of Measurements 
The BoExp measured in this study were selected based on the following criteria:  
 HPHCs to be assessed in this study are derived from the list of HPHCs recommended for 
lowering in cigarette smoke as defined by the WHO [8] and the draft guidance on 
”Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and 
Tobacco Smoke” [9];  
 The HPHC should be specific to the source of exposure with other sources being minor or 
non-existent;  
 The BoExp to an HPHC should be easily detectable using reliable, reproducible, precise 
analytical methods;  
 The HPHC should reflect a specific toxic exposure or be a reliable surrogate of exposure 
to HPHCs;  
 The list of HPHCs should include HPHCs from both gas and particulate phase;  
 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 
 BoExp represent HPHCs formed at different temperature levels. 
All questionnaires utilized for this study, except the cough-VAS and HST questionnaires, are 
available as validated questionnaires. 
4.4 
Study Duration 
The entire study duration per subject will be 17 to 61 days including a Screening Period of up 
to 42 days prior to Admission on Day -3, a 9-day confinement period (from Day -3 to Discharge 
on Day 6) followed by the 7 days for the Safety Follow-up Period (until Day 13) plus up to 3 
days. 
 

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5 
STUDY POPULATION 
In total, approximately 80 smoking healthy Caucasian female or male subjects who has smoked 
at least 10 non-menthol CC per day for the last 6 weeks prior to Admission will be included in 
this study. Each sex and each of the smoking strata should have a quota applied to ensure they 
represent at least 40% of the study population. 
The maximum number of CC is not limited. Subjects must have a smoking history of at least 
3 years of smoking prior to the Screening Visit. There will be no brand restrictions. Subjects 
can smoke different non-menthol brands until Admission to the clinic. 
From Admission to the clinic onwards, however, they must restrict themselves to one 
preferred, non-menthol CC brand.  
5.1 
Inclusion Criteria 
Subjects who meet all the following inclusion criteria can be enrolled into the study: 
Inclusion Criteria 
Rationale 
Screening  Admission 
(Day -3) 
1. Subject has signed the ICF and is able to 
understand the information provided in the ICF. 
Administrative 
X 
 
2. Subject is aged ≥ 21 years. 
Safety 
X 
 
3. Subject is of Caucasian origin. 
Effect 
X 
 
4. Currently smoking, healthy subject as judged by 
the 
Investigator 
or 
designee 
based 
on 
assessments from the Screening Period (e.g., 
safety laboratory, spirometry, vital signs, physical 
examination, ECG, medical history, and X-ray). 
Safety 
X 
X 
5. Subject smokes at least 10 commercially 
available non-menthol CCs per day (no brand 
restrictions) with a maximum yield of 1 mg nicotine 
ISO/CC, as labelled on the cigarette package, at 
least for the last 6 weeks prior to Admission, 
based on self-reporting.  
Effect 
 
X 
6. The subject has been smoking at least for the last 
3 years. The smoking status will be verified based 
on a urinary cotinine test (cotinine ≥ 200 ng/mL). 
Effect 
X 
 
7. The subject does not plan to quit smoking in the 
next 3 months. 
Safety 
X 
 

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Inclusion Criteria 
Rationale 
Screening  Admission 
(Day -3) 
8. The subject is ready to comply with the study 
protocol (e.g., to use CHTP 1.0). 
Effect 
X 
X 
5.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the study: 
Exclusion Criteria 
Rationale 
Screening  
Admission 
(Day -3) 
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). 
Safety 
X 
X 
2. The subject is legally incompetent, physically 
or mentally incapable of giving consent (e.g., 
emergency situation, under guardianship, in a 
social or sanitary establishment, prisoner or 
involuntarily incarcerated). 
Administrative 
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. 
Safety 
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]). 
Safety 
X 
X 
5. The subject has (FEV1/FVC) < 0.7 and FEV1 < 
80% 
of 
the 
predicted 
value 
at 
post-
bronchodilator spirometry. 
Safety 
X 
 
6. The subject has asthma condition (FEV1/FVC 
< 0.75 and reversibility in FEV1 > 12% (or > 200 
mL)) from pre- to post-bronchodilator values). 
Safety 
X 
 
7. The subject has a body mass index (BMI) < 
18.5 or ≥ 32 kg/m2. 
Safety 
X 
 

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Exclusion Criteria 
Rationale 
Screening  
Admission 
(Day -3) 
8. 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 of 
treatment, surgery, hospitalization) which may 
interfere with the study participation and/or 
study results. 
Effect 
X 
X 
9. The subject has used nicotine-containing 
products other than commercially available CC 
(either tobacco-based products or nicotine 
replacement therapies), as well as electronic 
cigarettes and similar devices after the 
Screening Visit, i.e. within 6 weeks prior to 
admission. 
Effect 
 
X 
10. The 
subject 
has 
received 
medication 
(prescription or over-the-counter) in Table 2 
(except for vitamins) within 14 days or within 5 
half-lives of the drug (whichever is longer) 
prior to Admission (Day -3) which has an 
impact on CYP1A2 or CYP2A6 activity. 
Effect 
 
X 
11. The subject has a positive alcohol test and/or 
the subject has a history of alcohol abuse that 
could interfere with the subject ’s participation 
in the study. 
Administrative 
X 
X 
13. The subject has a positive urine drug test. 
Administrative 
X 
X 
14.The subject has positive serology test for 
human 
immunodeficiency 
virus 
(HIV)1/2, 
hepatitis B or hepatitis C. 
Safety  
X 
 
15.The subject has donated or received whole 
blood or blood products within 3 months prior 
to Admission. 
Safety 
 
X 
16. The subject is a current or former employee of 
the tobacco industry or their first-degree 
relatives (parent, sibling, child). 
Administrative 
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). 
Administrative 
X 
 

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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. 
Exclusion Criteria 
Rationale 
Screening  
Admission 
(Day -3) 
18. The subject has participated in a clinical study 
within 3 months prior to the Screening Visit. 
Safety 
X 
 
19. The subject has been previously screened in 
this study. 
Administrative 
X 
 
20. For women only:  
Subject is pregnant (does have positive 
pregnancy tests at the Screening and at 
Admission) or is breast feeding. 
Safety 
X 
X 
21. For women only: 
Subject does not agree to use an acceptable 
method of effective contraception.* 
Safety 
X 
X 
* Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with spermicidal 
foam/gel/film/suppository vasectomized partner(s), or true abstinence (periodic abstinence and withdrawal are not effective 
methods) from Screening until the end of the Safety Follow-up Period plus up to 3 days. . Hysterectomy, tubal ligation, 
bilateral oophorectomy or post-menopausal status are reasons for not needing to use birth control. Post-menopausal status is 
defined as women who have not experienced menses for greater than 12 months. If a woman claims she’s post-menopausal, 
but has had her menses within 12 months, a follicle stimulating hormone test must be performed and must be within acceptable 
limits. 
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 discontinued from the study by the decision of the Investigator.  
Subjects will be informed that they are free to withdraw from the study (upon decision of the 
subject) at any time. Subjects should be questioned for the reason of withdrawal from the study, 
although they are not obliged to disclose it.  
If the subject withdraws from the study he/she will be asked to confirm at least the following 
points and this information will be fully documented by Investigator or designee: 
 The subject agrees to undertake the early termination procedures for safety assessments as 
defined in section 9.4. 
 If applicable, the subject still consents for long-term biobanking (2 ICFs). 
 The subject agrees that the samples collected up to the time of withdrawal will be analyzed 
and data collected up to the time of withdrawal will be used in the analysis and report. If 
the subject refuses he/she needs to document his disagreement in writing. 
Subjects who terminate the study after Enrolment and prior to their individual regular discharge 
on the Day of Discharge (Day 6) will be asked to undertake all early termination procedures 

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listed in section 9.4, unless the subject refuses to perform the assessments. After the date of 
termination, the subject will enter into the 7-days for the Safety Follow-up Period. 
Subjects who terminate the study after Enrolment and after their individual regular discharge 
on the Day of Discharge (Day 6), however, prior to their individual EOS and during the 7-day 
Safety Follow-up Period, will not be asked to undertake early termination procedures. 
Subjects must be discontinued from the study for any of the following reasons: 
 Withdrawal of informed consent. 
 Any AE or condition (including clinically significant changes in a laboratory parameter) 
which at the discretion of the Investigator no longer justifies the subject’s participation in 
this study.  
 Positive pregnancy testing (section 8.5). 
 The Sponsor or Investigator terminates the study or the study terminates at a particular site. 
If the Sponsor or the Investigator decides to prematurely terminate the study, the subject 
will be promptly informed. The Investigator or designee should report the fact and the 
reason in writing to the IEC. 
 Discontinuation is considered to be in the best interest of the subject or the other subjects 
as judged by the Investigator. 
 Subjects using any nicotine/tobacco product different from the assigned product. 
Subjects may be discontinued from the study for the following reason: 
 Non-compliance to the study procedures based on the judgment of the Investigator. 
Until randomization, subjects can be replaced, however subjects that discontinue the study 
after randomization will not be replaced and will not be allowed to re-enter the study. 
5.4 
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 
and corresponds to the date of the end of study of the subject. 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.  
If the site has lost track of the subject but the subject has reached the maximum number of 
study days (Day 13), then the PI(s) or designee(s) will declare the subject lost to follow-up at 
this date.

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5.5 
Violation of Selection Criteria 
Any subjects who do not meet the entry criteria after signing the ICF and prior to Enrolment 
at Day -3 will be considered as screen failures and will be replaced by other subjects. Re-
screening of subjects will not be permitted. 

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6 
INVESTIGATIONAL PRODUCTS 
6.1 
Description of Investigational Products 
 CHTP 1.0 
CHTP 1.0 is a non-menthol tobacco stick which is comparable in shape and form, and is used 
in a similar manner to CC. To use CHTP 1.0, the consumer removes the protective cap and 
uses a conventional lighting method to ignite the heat source. After a short pause to allow the 
tobacco to become heated, the aerosol is generated by drawing air through CHTP 1.0. During 
use, the tobacco in CHTP 1.0 is heated and does not exceed a well-defined temperature profile 
which ensures heating without combustion of the tobacco and at the same time provides an 
acceptable consumer experience in a consistent manner. 
CHTP 1.0 will be provided by the Sponsor and its distribution will be limited to an 
appropriately trained study site collaborator. Additional information are provided in section 
2.1.2. 
The overall objective of CHTP 1.0 is to provide an acceptable experience in which the HPHC 
level in the aerosol is substantially reduced in comparison with CCs. 
 CC  
Commercially available non-menthol CC (no brand restrictions) with a maximum yield of 1 mg 
nicotine ISO/CC, as labelled on the cigarette package, will be used as a reference product to 
CHTP 1.0. CC will not be provided by the Sponsor.  
All eligible subjects will be asked to purchase their own preferred single-brand of non-menthol 
CC prior to Admission. As randomization takes place at any time on Day -1, every study 
subject needs to buy his/her anticipated amount of single-brand CC for a total of 9 days plus 2 
extra packs.  
6.2 
Packaging and Labeling 
At Admission, all study subjects will provide the anticipated amount of CC in sealed packs to 
the site collaborators. The CC packs provided by the subjects should not be opened and the 
cellophane should be intact. 
Each pack of CC provided by the subject will be labeled to identify which subject the CCs 
belong to (labels should be affixed to the cellophane of the lower part of the pack). 
For CHTP 1.0, the packs will be labelled with the necessary information including, but not 
limited to, product code and expiry date. 

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6.3 
Use of Investigational Product(s) 
Subjects will never be requested or forced to smoke or to use the CHTP 1.0 and will be free to 
stop smoking at any time during the study. The study is designed as an ad libitum use study.  
During the Screening Period, subjects will be allowed to smoke according to their smoking 
habits except during the procedures of the Screening Visit (section 9.1) Subject will be 
instructed not to smoke in the morning prior to Admission on Day -3. 
6.3.1 
Admission Day (Day -3 to Day -2) 
Smoking ad libitum will be allowed throughout the day. All subjects will be allowed to 
continue smoking ad libitum their single preferred brand of usual CC.  
After Enrolment, all subjects will undergo a CHTP 1.0 product test. If subject is not willing to 
use CHTP 1.0 after the product test, he/she will be discontinued from  Enrolment and undergo 
early termination procedures, followed by a 7-day Safety Follow-up Period. 
6.3.2 
Baseline Period (Day -2 to Day 1) 
During the Baseline Period, all subjects will be allowed to continue smoking ad libitum their 
single preferred brand of non-menthol CC. 
6.3.3 
Exposure Period (Day 1 to Day 5)  
Subjects will not be allowed to smoke any CC or use any nicotine/tobacco-containing products 
other than their assigned product. 
 CHTP 1.0 arm 
Subjects randomized to the CHTP 1.0 arm will use exclusively CHTP 1.0 from Day 1, 06:30 
AM onwards until Day 5, 11:00 PM. 
 CC arm 
Subjects randomized to the CC arm will continue smoking their CC from Day 1, 06:30 AM 
onwards until Day 5, 11:00 PM. 
6.3.4 
Day of Discharge (Day 6) 
Use of CC will be allowed on Day 6 but only after twenty four-hour urine collection of Day 5 
is completed, and spirometry and CYP2A6 blood sampling have been performed. 

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6.3.5 
Safety Follow-up Period  
During the Safety Follow-up Period (after discharge at Day 6 until Day 13), all subjects are 
free to smoke their own CC ad libitum. 
6.3.6 
Stopping Rules for Investigational Product 
For safety purposes, smoking should be temporarily stopped in the event of any signs 
suggesting nicotine overexposure, (e.g., gastrointestinal disturbance [nausea, vomiting, 
diarrhea, stomach or abdominal pain], cold sweats, headache, dizziness, and breathing 
problems) or any reasons at the discretion of the Investigator or designee. 
6.4 
Method for Assigning Subjects to Study Arms 
When all the eligibility criteria have been met, randomization will be done through the 
interactive web and voice response system (IxRS) on Day -1 at any time during the day. 
Subjects will be informed of their randomized study arm in the morning of Day 1, prior to 
06:30 AM (the start of the Exposure Period) . Subjects will be randomized to one of the 2 study 
arms: CHTP 1.0:CC in a 1:1 ratio.  
Stratified randomization will be conducted by sex and by average daily CC consumption over 
the last 6 weeks prior to Admission as self-reported (smokers smoking 10 to 19 CC/day and 
smokers smoking > 19 CC/day). In each arm, each sex and each of the smoking strata should 
have a quota applied to ensure they represent at least 40% of the population. 
6.5 
Blinding 
This is an open-label study; therefore the subjects and Investigators or designees will be 
unblinded to the subject’s arm. However, there will be a limited degree of blinding in the data 
review and data analysis process. In particular, PMI and contract research organization (CRO) 
personnel will be blinded to the randomized arm as summarized in Table 1: 
Table 1 
Description of Blinded Study Personnel 
Blinded Study Personnel 
End of Blinding Period 
PMI and CRO Study Statisticians 
After the SAP finalization or the database locka whichever 
comes last.  
PMI Data Manager 
After the finalization of PMI blind database reviewb. 
PMI Clinical Scientist 
After the finalization of PMI blind database reviewb. Can be 
actively un-blinded when appropriate. 
a 
Data will be accessible blinded to randomization arm and to product use by means of a dummy randomization or masking.  
b 
As part of the PMI quality control (QC) activity, data listings will be reviewed by the CRO and PMI before database 
lock, with no access to the randomization information. Full details will be available in the data review plan. 

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Any PMI and CRO personnel who are not listed in the above table will be unblinded by default. 
6.6 
Investigational Product Accountability and Compliance 
6.6.1 
Dispensing Investigational Product 
From Day -3 onwards to Day 5, the Investigational Product (IP) CC, and from Day 1 onwards 
to Day 5, the IP CHTP, will be dispensed to the subjects stick by stick. One will be allowed at 
a time and documented in an appropriate log.  
On each day of the confinement period, the time of dispense and return for each product 
(CC/CHTP 1.0) use has to be documented from Day -3 for CC and from Day 1 for CHTP 1.0 
onwards.  
CHTP 1.0 will not be promoted for commercial distribution or test market. 
6.6.2 
Storage and Accountability  
CHTP 1.0 and CC will be stored in a secured storage site with access limited to authorized 
personnel only. The study collaborator designated by the Principal Investigator will be 
responsible for the storage and accountability of the IPs in accordance to sponsor’s 
requirements. CHTP 1.0 must be stored under controlled conditions (temperature and 
humidity), whereas CCs can be stored in normal conditions (at ambient temperature with no 
temperature or humidity control). 
Subjects will return each used CHTPs 1.0 or butt of each used CC immediately after use to the 
site collaborators for accountability. The time of return of the products will be documented in 
an appropriate log. At the end of the study, unused CCs given to the site collaborators at 
Admission will be given back to the subjects. 
6.6.3 
Investigational Product Retention 
Used and unused CHTP 1.0 will be destroyed or returned to the Sponsor upon study completion 
as per instructions which will be provided by the Sponsor in due time. 
Irrespective of the study arm, atDischarge from the site, the site staff will return to the subjects 
any remaining CCs given by them on the Day of Admission. 
6.6.4 
Compliance to Investigational and Reference Products 
Compliance for all study arms will be ensured by strict distribution of the products (stick by 
stick) and collection of the CC butts and CHTP 1.0 after each use. Distribution and return of 
these products will be documented in appropriate logs. 

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6.7 
Restrictions 
6.7.1 
 Smoking Restrictions 
At the Screening Visit pre- and post-bronchodilator spirometry will be done at least 1 hour 
after having stopped smoking. Subjects will be instructed not to smoke in the morning of 
Day -1 and the Day of Discharge (Day 6) until twenty four-hour urine collection of Day 5 is 
completed, blood drawing for CYP2A6 activity assessment and spirometry will have been 
performed.  
During the confinement period, smoking will generally only be allowed during the designated 
smoking times, from 06:30 AM to 11:00 PM.  
Subjects will not have free access to their CC or CHTP 1.0 which will be dispensed by the site 
collaborators individually as described in section 6.6.1.  
To avoid cross smoke contamination between the two study arms, subjects must use their 
assigned product (CHTP 1.0 or CC) in separate smoking rooms.  
Using CHTP 1.0 or smoking CC will not be allowed during study procedures.  
6.7.2 
Dietary Restrictions 
A standard diet will be designed by a dietician for the whole confinement period. For each 
meal, the caloric and fat content should be controlled in order to avoid a “high-fat” diet. A 
“high-fat” diet is defined as a diet which contains “approximately 50 percent of total caloric 
content of the meal [from fat] and is high in calories (approximately 800 to 1000 calories)” 
[12]. 
In order to avoid any effect on assessment of biomarkers of exposure, grilled or pan-fried meat, 
pre-cooked meats (e.g. tuna, ham, corned beef, and smoked meats), bacon and sausage will not 
be permitted. In addition, alcohol, broccoli, brussels sprouts, cauliflower, grapefruit and 
xanthine-containing foods and beverages (coffee, tea, chocolate, cocoa, mate, guarana, etc.) 
will not be allowed except when you are asked to drink a cup of coffee for one of the assessment 
(you will be instructed accordingly by your site staff).  
Subjects are not allowed to bring their own food (including sweets or chewing gum, etc.) or 
beverages to the investigational site. Meals will be served according to the agreed schedules. 
Additional light snacks, fruits (with the exception of grapefruits), and raw vegetables can be 
distributed to the subjects without restrictions at any time during confinement as long as they 
comply with the dietician’s standard diet. Consumption of non-carbonated water is allowed, 
however, should be carefully monitored. Consumption of quinine-containing drinks (e.g., tonic 
water) is not allowed during the study. The same menu and meal schedule will be administered 
uniformly for all subjects in all study arms.  

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In addition, for the purpose of the Ames test planned on Day -1 and Day 5, the menus served 
on Day -2 and Day 4 will be identical. 
Fasting state has to be observed for at least 10 hours prior to blood drawings for the safety 
laboratory on Day -1, on Day 6, for blood/plasma samples for further transcriptomics and 
lipidomics analyses on Day -1 and Day 6. 
6.8 
Concomitant Medication 
For the purpose of this study, no concomitant medication should be taken by the subjects from 
Screening to Discharge without prior informing the Investigator or designee. Any medication 
with an impact on the CYP1A2 and CYP2A6 metabolism (as prescription and over-the-counter 
products) as presented below in Table 2 must be avoided. 
Prior to database lock, concomitant medication will be assessed according to their potential 
impact on CYP1A2 and CYP2A6 activity and potential impact on the study results. 
Concomitant medication and prior medications will first be assessed at Screening Visit. To be 
eligible for the study, any medication with impact on CYP1A2 and CYP2A6 metabolism must 
be discontinued at least 14 days or for at least 5 half-lives (whichever is longer) prior to 
admission to the site. They must not be used during the entire study until Discharge. It is at the 
discretion of the Investigator or designee to assess if the termination of such medication at 
Screening is medically justified and safe for the subject. 
Estrogens for contraception and for hormone replacement therapy, even though known to be 
CYP1A2 inhibitors, will be allowed in this study. The use of estrogens must be documented 
on the eCRF.  
The following drugs and substances are examples considered as having an impact on CYP1A2 
and CYP2A6 activity (Table 2). Prior to database lock, the concomitant medication will be 
assessed according to the potential impact on CYP1A2 and CYP2A6 activity and the potential 
impact on study results. 
 
 
Table 2 
Examples of Medications with Effects on CYP1A2 and CYP2A6 
Activity 
CYP1A2 Inhibitors [13] 
Pharmacologic Category 
Amlodipine 
Antihypertensive; calcium channel blocker  
Cimetidine 
Histamine H2 antagonist 
Ciprofloxacin 
Antibiotic, fluoroquinolone 

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Fluvoxamine 
Antidepressant, selective serotonin reuptake inhibitor 
Fospropofol 
General anesthetic 
Gemfibrozil 
Antilipemic agent, fibric acid 
Ketoconazole 
Antifungal agent, topical 
Diclofenac 
NSAID 
Methoxsalen 
Psoralen 
Mexiletine 
Antiarrhythmic agent 
Miconazole 
Antifungal agent, topical 
CYP1A2 Inhibitors [13] 
Pharmacologic Category 
Nifedipine 
Antihypertensive, calcium channel blocker 
Norfloxacin 
Antibiotic, fluoroquinolone 
Propofol 
Systemic general anesthetic 
Primaquine 
Aminoquinoline (antimalarial) 
Ofloxacin 
Antibiotic, fluoroquinolone 
Thiabendazole 
Antihelmintic agent 
Tranylcypromine 
Antidepressant, monoamine oxidase inhibitor 
Zileuton 
5-lipoxygenase inhibitor 
CYP1A2 Inducers [13] 
Drug Class 
Carbamazepine 
Anticonvulsant 
Phenobarbital 
Anticonvulsant, barbiturate 
Primidone 
Anticonvulsant, barbiturate  
Rifampin 
Antibiotic, antitubercular agent 
CYP1A2 Substrates [13] 
Drug Class 
Acenocoumarol 
Anticoagulant 
Alosetron 
Antiemetic, selective 5-HT3 receptor antagonist 
Aminophylline 
Phosphodiesterase enzyme inhibitor, nonselective  
Betaxolol 
Antihypertensive, beta-blocker 
Caffeine 
Central nervous system stimulant, phosphodiesterase 
enzyme inhibitor 
Clomipramine 
Antidepressant, tricyclic  
Clozapine 
Antipsychotic agent 
Cyclobenzaprine 
Skeletal muscle relaxant 
Dacarbazine 
Antineoplastic agent, alkylating agent 

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Duloxetine 
Antidepressant, serotonin/norepinephrine reuptake inhibitor 
Estradiol 
Estrogen derivate 
Estrogens, conjugated A/synthetic 
Estrogen derivate  
Estrogen, conjugated equine 
Estrogen derivate  
Estrogen, esterified 
Estrogen derivate  
Estropipate 
Estrogen derivate  
Flutamide 
Antineoplastic agent, antiandrogen 
Fluvoxamine 
Antidepressant, selective serotonin reuptake inhibitor  
CYP1A2 Substrates [13] 
Drug Class 
Guanabenz 
Antihypertensive, central Alpha-2 adrenergic agonist  
Mexiletine 
Antiarrhythmic agent, class Ib 
Mirtazapine 
Antidepressant, alpha-2 antagonist 
Olanzapine 
Antimanic agent, antipsychotic agent 
Pimozide 
Antipsychotic agent 
Propranolol 
Antihypertensive, beta-blocker  
Ramelteon 
Hypnotic 
Rasagiline 
Anti-Parkinson's agent, MAO type B inhibitor 
Riluzole 
Glutamate inhibitor 
Ropinirole 
Anti-Parkinson's agent, dopamine agonist 
Ropivacaine 
Local anaesthetic 
Tacrine 
Anti-Alzheimer agent, cholinesterase inhibitor 
Theophylline 
Phosphodiesterase enzyme inhibitor, nonselective 
Thiothixene 
Antipsychotic agent 
Tizanidine 
Alpha-2 adrenergic agonist 
Trifluoperazine 
Antipsychotic agent 
CYP2A6 Inhibitors [13] 
Drug Class 
Amiodarone 
Antiarrhythmic agent, class III 
Desipramine 
Antidepressant, tricyclic 
Isoniazid 
Antitubercular agent 
Ketoconazole 
Antifungal agent, topical 
Letrozole 
Antineoplastic agent, aromatase inhibitor 
Methoxsalen 
Psoralen 

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Miconazole 
Antifungal agent, topical 
Tranylcypromine 
Antidepressant, monoamine oxidase inhibitor 
CYP2A6 Inducers [13] 
Drug Class 
Amobarbital 
Barbiturate 
Pentobarbital 
Anticonvulsant, barbiturate 
Phenobarbital 
Anticonvulsant, barbiturate  
Rifampin 
Antibiotic, antitubercular agent 
Secobarbital 
Barbiturate 
CYP2A6 Substrates [13] 
Drug Class 
Dexmedetomidine 
Alpha-2 adrenergic agonist, sedative 
Ifosfamide 
Antineoplastic agent, alkylating agent 
The Investigator is responsible for the medical care of the subjects during their participation in 
this study. 
If the use of a concomitant medication cannot be avoided for the subject’s safety, it has to be 
fully documented (section 7.3.5). Concomitant medications should be followed up with the 
CRO Medical Monitor on an ongoing basis.  
 

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7 
STUDY PROCEDURES 
Personnel performing or recording study assessments must have appropriate and fully 
documented training. Quality control (QC) measures have to be in place. An overview of all 
study assessments is shown in the schedule of events (Appendix A). Considering that not all 
subjects can have a procedure at the same time point, adequate time windows will be given for 
each study procedure and each time point in section 9. Site personnel will adhere to the site’s 
standard operating procedures (SOPs) for all activities or otherwise specified by the protocol. 
Appropriate medical advice will be provided to the subject in case of any medical findings 
requiring health care. 
7.1 
Informed Consent 
Prior any study assessments is 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). 
The subject’s participation in the study does not depend on his/her consent for sample bio-
banking and will be separated from the consent for study participation. The different consents 
will be captured in the CRF. 
7.2 
Smoking Cessation Advice and Debriefing 
Each subject will be given advice on the risks of smoking, with smoking cessation (SC) advice, 
three times during the study: at the Screening Visit, at Admission on Day -3, and at Discharge 
on Day 6. The form of a brief interview will be used according to current WHO 
recommendations [7]. Details of the interview will be recorded in the source document file. 
Information on the risk of smoking/smoking cessation advice will be given to the subjects on 
an individual basis during a face-to-face meeting between the subject and the Investigator and 
may additionally be given in a group session. 
In addition to the information of the risk of smoking/SC advice, a debriefing of subjects will 
be done together with information on the risk of smoking and SC advice to address any 
intended or unintended beliefs participants have about CHTP 1.0. The goal of the debriefing 
is to ensure that subjects exit the study with an accurate understanding of product risks 
including an understanding that CHTP 1.0 has not been demonstrated to be less harmful than 
CC.  
7.3 
Clinical Assessments 
The results of the clinical assessments described in this section will be recorded in the CRF. 

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7.3.1 
Demographic Data 
Demographic data (gender, age, race and/or ethnicity) will be recorded.  
See Appendix A for the timepoints of assessment. 
7.3.2 
Identification of the Current Cigarette Brand 
Identification of the current non-menthol CC brand smoked by the subject will be done at the 
Screening Visit and at Admission. Subjects will be asked to bring their own supply of current 
CC brand to the site and will have to hand their CC supply for the confinement period to the 
site collaborators. The site staff will document the brand name and yields in the source 
documentation.  
7.3.3 
Questions on Smoking History/Habits and Intention to Quit Smoking.  
Subjects will be asked by the site collaborators the following questions about their smoking 
history and habits: 
1. Have you smoked for at least the past 3 years? (yes/no) 
2. How many years have you smoked? (numeric response, 2 digits) 
3. On average, how many cigarettes per day have you smoked over the last 6 weeks? 
(numeric response, 2 digits) 
4. On average, how many cigarettes per day have you smoked since you started smoking? 
(numeric response, 2 digits) 
5. Have you used nicotine-containing products other than commercially available non-
menthol CC within 6 weeks prior to admission?  For example, any tobacco-based 
products or NRT, electronic cigarettes, or similar devices. (NOTE: This question is to 
be asked on the Admission Day only.)  
6. 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. 

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7. Are you planning to quit smoking during the next 3 months? (yes/no) 
This self-reported CC daily consumption will be used to assess eligibility at the Screening Visit 
or on the Admission Day. 
See Appendix A for the timepoints of assessment. 
7.3.4 
Demonstration and CHTP 1.0 Test 
All subjects will have a demonstration of CHTP 1.0 at the Screening Visit. On Day -3 after 
enrollment, subjects will have a product test, using up to 5 sticks of CHTP 1.0. Only subjects 
willing and ready to use CHTP 1.0 will continue in the study. 
7.3.5 
Medical History, Concomitant Disease, Previous and Ongoing Medications 
Relevant medical history and any concomitant disease will be documented at the Screening 
Visit. Medical history is defined as any condition that started and ended prior to the Screening 
Visit. A concomitant disease is defined as any condition that started after ICF signature or was 
started prior to the Screening Visit and is still ongoing at the Screening Visit. 
Prior medication taken within 4 weeks prior to Screening Visit and any concomitant 
medication needs to be documented. Any medication which was started prior to the Screening 
Visit and is still being taken by the subject will be considered as concomitant medication. 
Medication initiated after Screening is also referred to as concomitant medication. This applies 
to both prescription and over-the-counter products. 
Records should include the drug name (preferably both generic and trade name), route of 
administration (e.g., oral, intravenous), total daily dose/unit (expressed in metric units, for 
example, mg, mL, or IU), indication, and the start and, if applicable, the stop date (day, month, 
and year). Therapy changes (including changes of regimen) during the study have to be 
documented. If a concomitant medication is still being taken by the subject at the end of the 
study, this will be recorded in the CRF. 
7.3.6 
Physical Examination 
A physical examination will be conducted at the Screening Visit, at Admission and at 
Discharge. 
See Appendix A for the timepoints of assessment. 
7.3.7 
Body Height and Weight 
Body weight will be recorded at the Screening Visit, at Admission and at Discharge. Body 
height will be measured at the Screening Visit only. The BMI will be calculated from the body 
weight and height using the following formula: 

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BMI = weight in kilograms
height in meters2
= 𝑘𝑔
𝑚2 
See Appendix A for the timepoints of assessment. 
7.3.8 
Vital Signs 
Systolic and diastolic blood pressure, pulse rate and respiratory rate will be measured in the 
morning at applicable visits. All measurements will be made after the subject has rested for at 
least 5 minutes in a supine position.  
For every measurement of vital signs, it has to be ensured and documented that the duration 
between the end of last smoking and the measurement should be at least 15 minutes. 
See Appendix A for the timepoints of assessment. 
7.3.9 
Other Clinical Assessments 
7.3.9.1 
Spirometry 
All personnel performing lung function testing must have the appropriate training according 
to local requirements with the record of the training. Quality control measures should be 
available and be properly documented. In a sitting position, the subject will be at rest for at 
least 15 minutes prior to lung function testing, i.e. pre and post-bronchodilator application. All 
lung function maneuvers will be recorded with the subject in a sitting position throughout the 
study. 
The spirometry test will be performed in accordance with the 2005 guideline of the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) Joint Task Force on the 
standardization of spirometry [14]. 
The spirometry tests will include the recording of FEV1, FVC and FEV1/FVC ratio. 
All spirometry testing must be performed at least 1 hour after having stopped smoking (if 
applicable).  
See section 6.7.1 for the smoking restrictions associated spirometry. 
Pre and post- bronchodilator spirometry tests will be performed. The ratio of FEV1/FVC will 
be calculated from the highest acceptable FEV1 and the highest acceptable FVC, respectively. 
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. 

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The results from FEV1 and the ratio FEV1 to FVC at the Screening Visit will be used for 
eligibility criteria to assess spirometry and asthma conditions. 
For all the other visits, pre- bronchodilator spirometry will be used to describe the changes in 
pre-spirometry measurements over the duration of the study. Values for FEV1 and FVC will 
be recorded. The ratio FEV1/FVC will be calculated from the highest acceptable FEV1 and the 
highest acceptable FVC respectively.  
See Appendix A for the timepoints of assessment. 
7.3.9.2 
 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 10 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 A for the timepoints of assessment. 
7.3.9.3 
Chest X-ray 
A chest X-ray (anterior-posterior and left lateral views) will be assessed during the Screening 
Period to exclude subjects with relevant pulmonary diseases. Subjects will be referred to a 
radiology facility (within or outside the investigational site) for this procedure. No new 
examination is required if the subject can present a chest X-ray with anterior-posterior and left 
lateral views at the Screening Visit which is not older than 6 months. 
7.4 
Biomarker Assessment 
All bioanalytical assays and laboratory assessments (section 7.5) will be carried out using 
validated methods. The bioanalytical methods used will be documented in the bioanalytical 
reports. A list of laboratories is provided in Appendix B. 
Precautions should be taken during blood sampling and processing to prevent the 
contamination of samples with environmental nicotine or CO. 

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7.4.1 
Biomarker of Exposure 
7.4.1.1 
Biomarker of Exposure to CO and COHb 
COHb measured in blood and exhaled CO will be investigated as a measure of exposure to 
CO.  
 CO breath test: 
CO in exhaled breath will be measured using the Smokerlyzer® (e.g., Micro 4 
Smokerlyzer® device or similar).  
A CO breath test will be conducted once per day, preferably in the evening around 8:00 
PM. The CO breath test should be conducted in timely conjunction with the blood sampling 
for COHb.  
See Appendix A for the timepoints of assessment. 
 COHb test: 
Tests for COHb measurement will be performed at a designated laboratory. One blood 
sample will be taken in the evening around 8:00 PM. The COHb sampling should be 
conducted in timely conjunction with the CO breath test. 
See Appendix A for the timepoints of assessment. 
7.4.1.2 
Plasma Nicotine and Cotinine 
Nicotine and cotinine concentrations will be measured in plasma to evaluate the exposure to 
nicotine. 
One blood sample in subjects in the CHTP 1.0 and CC arm will be taken in the evening around 
8:00 PM. 
See Appendix A for the timepoints of assessment. 
7.4.1.3 
Biomarkers of Exposure to HPHCs 
The following BoExp to HPHCs will be measured in 24-hour urine collection samples as per 
the schedule of events (Appendix A): 
 Primary endpoints: MHBMA, 3-HPMA, S-PMA. 
 Secondary endpoints: total 1-OHP, total NNN, 4-ABP, 1-NA, 2-NA, o-tol, CEMA, 
HEMA, 3-hydroxybenzo(a)pyrene, 3-HMPMA, total NNAL, NEQ. 

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BoExp to HPHCs in urine will be expressed as quantity excreted, and their concentrations will 
be adjusted to creatinine. For normalization of BoExp to HPHCs, creatinine will also be 
measured in the 24-hour urine samples. 
7.4.2 
CYP1A2 Activity Test 
CYP1A2 activity will be assessed in plasma by measuring paraxanthine (PX) and caffeine 
(CAF) concentrations and calculating the PX/CAF molar metabolic ratio. Samples to measure 
PX and CAF will be drawn approximately 6 hours (±15 minutes) after the intake of a cup of 
coffee made from 4.2 g (±10%) regular instant coffee (Nescafé Gold Instant; Nestlé; 
Deutschland; CAF content: 72 mg/2 g) with 150 ml ±10 ml water. The CAF content will be 
approximately 150 mg CAF (11).  
The exact time of intake of the cup of coffee in the morning and of the time of blood sampling 
6 hours [±15 minutes] later must be recorded. 
See Appendix A for the timepoints of assessment. 
7.4.3 
CYP2A6 Activity Test 
CYP2A6 activity will be measured in plasma using the molar metabolic ratio of trans-3’-
hydroxycotinine to cotinine. CYP2A6 activity drives the metabolism of nicotine to cotinine 
and subsequent metabolites. CYP2A6 blood sampling has to be done prior to smoking. 
See Appendix A for the timepoints of assessment. 
7.4.4 
Ames Mutagenicity Test 
Urine mutagenicity, a biomarker for measuring mutagen load, will be measured in 24-hour 
urine. 
The urinary determination of each sample will be done in one bacterial strain (S. typhimurium 
strain YG1024) using S9 metabolic activation and 4 doses for each of the urine extracts.  
See Appendix A 1 for the timepoints of assessment. 
7.5 
Laboratory Assessments 
A list of laboratories is provided in Appendix B. 
7.5.1 
Clinical Chemistry, Hematology, and Urine Analysis for Safety Panel 
Hematology, clinical chemistry, and urine analysis for the safety panel will be measured at 
Screening, on Day -1 and at Discharge on Day 6 (Day of Discharge). Tests will be conducted 
at a local laboratory or the site. Blood will be taken after no less than the 10 hours of fasting 

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except at the Screening Visit (section 6.7.2). The urine test/urine analysis safety panel will be 
performed at a local laboratory. Parameters to be measured are listed in Table 3. 
Table 3 
Hematology and Clinical Chemistry Parameters (Safety) 
Hematology 
Clinical Chemistry 
Urine Analysis 
- Hematocrit 
- Hemoglobin 
- Mean corpuscular 
hemoglobin  
- Mean corpuscular 
hemoglobin concentration  
- Mean corpuscular volume  
- Platelet count 
- Red blood cell count  
- White blood cell (WBC) 
count 
- Differential WBC count:  
 
Neutrophils 
 
Basophils  
 
Eosinophils  
 
Lymphocytes 
 
Monocytes 
- Albumin 
- Total protein 
- Alkaline phosphatase 
- Alanine aminotransferase  
- Aspartate aminotransferase  
- Blood urea nitrogen 
- Creatinine 
- Gamma-glutamyl transferase  
- Fasting glucose 
- Lactate dehydrogenase  
- Potassium  
- Sodium 
- Total bilirubin 
- Direct bilirubin 
- Total cholesterol 
- Triglycerides 
- pH 
- Bilirubin 
- Glucose 
- Nitrite 
- Red blood cell traces 
- Protein 
- Specific gravity 
- Urine sediment 
See Appendix A for the timepoints of assessment. 
7.5.2 
Serology 
A test for hepatitis B surface antigen, hepatitis C virus and human immunodeficiency virus 
(anti-HIV1/2 and p24 antigen) will be done. In case of positive results, the subject will be 
referred to appropriate medical care. 
See Appendix A for the timepoints of assessment. 
7.5.3 
Urine Drug Screening 
The urine will be screened for the following drugs or class or drugs: amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine and opiates. 
See Appendix A for the timepoints of assessment. 

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7.5.4 
Urine Cotinine Screening 
A urine dip-stick or casette cotinine test will be performed to confirm the subject’s smoking 
status. The test must detect cotinine with a cotinine threshold of ≥ 200 ng/mL, (e.g., One-Step 
Cotinine Test 008A086, Ultimed, Belgium). 
See Appendix A for the timepoints of assessment. 
7.5.5 
Alcohol Breath Test 
Subjects will undertake a breath alcohol test using an alcometer device (e.g., Alcotest 7410 
Plus, Dräger). 
See Appendix A for the timepoints of assessment. 
7.5.6 
Urine Pregnancy Test 
All female subjects will have pregnancy testing at the Screening Visit, at Admission to the 
clinic and at Discharge. Female subjects with a positive pregnancy test at the Screening Visit 
or at Admission 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. 
The post-menopause is formally defined as the time after which a woman has experienced 12 
consecutive months of amenorrhea (lack of menstruation) without a period. If a woman claims 
she is post-menopausal, but has had her menses within 12 months, a follicle stimulating 
hormone test must be performed and must be within acceptable limits of the post-menopausal 
status. When the post-menopausal status of a female is confirmed, the pregnancy test scheduled 
during the study will not be done. 
In the event of an unclear urine pregnancy test, absence of pregnancy should be confirmed by 
a serum follicle stimulating hormone level >20 IU/l. 
All pregnancies detected during the study must be reported and handled as described in section 
8.5. 
See Appendix A for the timepoints of assessment. 
7.6 
Sample Handling, Storage, and Shipment 
All blood samples are to be tested at a central laboratory with the exception of the safety 
laboratory panel which will be tested at a local laboratory (see Appendix B). The urine dip-
stick for the safety laboratory, urine pregnancy tests, urine drug screening, and urine cotinine 
tests will be done by personnel at the study sites. 

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Detailed procedures for collection and handling of samples are described in a separate sample 
handling manual (SHM). Safety laboratory samples will be destroyed as per the laboratory’s 
standard procedures. All primary and back-up samples for the assessments of BoExp (except 
bio-banking samples) of discontinued subjects will be destroyed after the bioanalytical report 
has 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. 
The bioanalytical lab(s) will be listed in the SHM. 
7.6.1 
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 180 mL, which includes about 20 mL for safety and repeated analysis, 
about 20 mL for long-term storage of the bio-banking samples for further analysis of 
biomarkers (only if additional consent is given) and 20 mL for long-term storage bio-banking 
samples for further analysis of transcriptomics and lipidomics (only if additional consent is 
given) (section 7.6.3). 
The blood sampling for transcriptomics and 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. 
7.6.2 
Urine Samples 
Spot urine samples will be used for the urine drug screening, urine cotinine test, urine 
pregnancy test and safety urine analysis. 
Twenty four-hour urine will be collected from Day -2 to Day 6 on site to measure BoExp. On 
Day 1, product use must not start prior to the end of urine collection of Day -1.  
Twenty four-hour urine sample collection for Day -2 will start approx. at 06:30 AM on Day -2 
after the first morning void which should be discarded and will end after 24 hours ±1 hour on 
Day -1 
From Day -1 on, the 24-hour urine collection for the respective day will immediately start after 
the end of 24-hour urine collection of the previous day (after 24 hours ± 1 hour) (Appendix A). 
After nearly 24-hours of urine collection, 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, with the exception of about 
10 mL for the spot urine tests (described above). The spot urine sample of the amount of 10 
mL for the urine pregnancy test and safety urine analysis will be taken from the final portion 
of the 24-hour urine sample before putting this final portion into the sampling container. The 
amount of 10 mL for the spot urine tests should not be subtracted from the 24-hour urine 

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sample. 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 collaborators. The volume of 
24-hour urine will be measured by the site collaborators upon collection of urine containers 
from the subjects. 
For assessment of urine BoExp, creatinine for normalization of urine BoExp, sample bio-
banking and urine mutagenicity, aliquots from the 24-hour urine collection will be taken. In 
the schedule of events for the 24-hour urine collection (see Appendix A) the dot corresponds 
to the day on which the 24-hour urine collection period starts. For example, NEQ measured at 
Day 5 in the 24-hour urine collection starts on Day 5 and ends in the morning of Day 6 prior 
to Discharge. 
For the Discharge on Day 6, subjects will empty their bladder shortly before 06:29 AM. This 
will be the last urine portion for the 24-hour urine for the Day 5 dot mark in the schedule of 
events. The spot urine sample of the amount of 10 mL for the urine pregnancy test and safety 
urine analysis will be taken from the final portion of the 24-hour urine sample before putting 
this final portion into the sampling container. The amount of 10 mL for the spot urine tests 
should not be subtracted from the 24-hour urine sample. For assessment of urine BoExp, 
creatinine, and samples for bio-banking (if consent received, 5 tubes of urine will be taken for 
bio-banking), aliquots from the 24-hour urine collection will be taken. In the schedule for 24-
hour urine collection assessments, the dot corresponds to the day on which the 24-hour urine 
collection period ends. 
See Appendix A for the timepoints of assessment. 
7.6.3 
Bio-Banking for Long-Term Storage of Blood and Urine 
If a subject gives consent for sample bio-banking for long-term storage, additional samples of 
urine (from the 24-hour urine collection) and serum/plasma (20 mL of blood in total) will be 
collected as follows: 
 Samples from the 24-hour urine will be collected from the urine collections that started on 
Day -1 and on Day 5, respectively.  
 Serum/plasma will be collected on Day -1 and Day 6.  
These samples are intended for possible later analysis of additional biomarkers. No genetic or 
transcriptogenomics testing will be performed on these samples. 
If a subject gives consent for sample bio-banking of whole blood/plasma for further 
transcriptomics and plasma for lipidomics analysis, an additional 10 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 4 tubes of 500 l each.  

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The samples intended for sample bio-banking will be kept frozen and shipped to a central 
storage facility. 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 
7.6.3. 
See Appendix A for the timepoints of assessment. 
7.7 
Other Study Procedures 
7.7.1 
Human Puffing Topography Assessment 
Human puffing topography involves the measurement of each smoker’s unique way of 
smoking CCs or using CHTP 1.0 using the HPT SODIM® device. The HPT SODIM® device, 
model SPA/M (SODIM® Instrumentation, Fleury les Aubrais, France) is a device which is 
used to measure puffing topography (see Appendix C). It consists of a special sample holder 
(containing a constriction in the middle) which is placed between the subject’s mouth and the 
filter of the CC or CHTP 1.0 being smoked/used. The sample holder is connected by 2 narrow 
tubes to a portable data logger/recording system (see Appendix C for a description of the 
device). Any malfunction of the HPT SODIM® portable device will be documented in 
appropriate log. 
At Day -2, the HPT SODIM® device has to be used for all CC smoked for all subjects. On 
Day 1 and Day 4 of the confinement period, the HPT SODIM® device has to be used for every 
product use for all subjects in the CC and CHTP 1.0 arms. 
Smoking topography with the HPT SODIM® device will not be recorded for subjects smoking 
CC that are incompatible with the HPT SODIM® device (e.g., slim CC). 
For each subject, one HPT Device (configured for CC use) will be assigned at Day -2 which 
will be used by that subject on all HPT assessments days during baseline. Then, at Day 1, 
subjects randomized to the CC arm will still use the same HPT Device that was used during 
baseline whereas new HPT Devices (configured for CHTP 1.0 use) will be assigned for 
subjects randomized in the CHTP 1.0 arm.  
The Sponsor will provide training on the use of the HPT SODIM® device to the site 
collaborators. The site collaborators will, in turn, provide training to the subjects. All HPT 
SODIM® devices will be returned to the Sponsor after completion of the study. 

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7.7.2 
 Human Puffing Topography Parameters 
The HPT SODIM® device measures and records the flow and other per-puff parameters listed 
in Table 4 below. From the per-puff parameters (Table 4), the per-cigarette parameters shown 
in Table 5 will be derived (representing average values or totals per cigarette). 
Prior to calculation of the per-CHTP 1.0/CC parameters, the Sponsor’s HPT group will validate 
the data and discard any invalid data. Only valid data for the per-CHTP/cigarette parameters 
will be part of the study database and will be analyzed. 
Table 4 
Human Puffing Topography – Per-Puff Parameters 
Description 
Variable 
Unit 
Puff number 
Ni 
 
Puff volume 
Vi 
ml 
Puff duration 
Di 
s 
Average flow [Vi/Di] 
Qmi 
ml/s 
Peak flow 
Qci 
ml/s 
Inter puff interval 
Ii 
s 
Sum of Ii and Di 
DFi 
s 
Work [INT Pmi*FinalFlow*dt] 
Wi 
mJ 
Average pressure drop 
Pmi 
mmWG 
Peak pressure drop 
Pci 
mmWG 
Average resistance [Pmi/Qmi] 
Rmi 
mmWG/ml/s 
Peak resistance [Pci/Qci] 
Rci 
mmWG/ml/s 
Table 5 
Human Puffing Topography – Per-CHTP 1.0/Cigarette Parameters 
Description 
Variable 
Formula 
Unit 
Total number of puffs 
NPC 
Σ Ni 
 
Total puff volume 
TVOL 
Σ Vi 
ml 
Average puff volume 
AvgVi 
Σ Vi / NPC, i=1 ... NPC 
ml 
Average puff duration 
AvgDi 
Σ Di / NPC, i=1 ... NPC 
s 
Total puff duration 
TDi 
Σ Di 
s 
Average flow 
AvgQmi 
Σ Qmi / NPC, i=1 … NPC 
ml/s 
Peak flow 
AvgQci 
Σ Qci / NPC, i=1 … NPC 
ml/s 

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Description 
Variable 
Formula 
Unit 
Total inter puff interval 
TIi 
Σ Ii 
s 
Average inter puff interval 
AvgIi 
Σ Qci / NPC, i=1 … NPC 
s 
Total smoking duration 
TDFi 
Σ DFi 
s 
Total work 
TWi 
Σ Wi 
mJ 
Average work 
AvgWi 
Σ Wi / NPC, i=1 … NPC 
mJ 
Average pressure drop 
AvgPmi 
Σ Pmi / NPC, i=1 … NPC 
mmWg 
Average peak pressure drop 
AvgPci 
Σ Pci / NPC, i=1 … NPC 
mmWg 
Puffing intensity 
SMINT 
TVOL/TDFi 
ml/s 
Puffing time index 
PTI 
(100*TDi)/TDFi 
% 
Puff frequency 
PFeq 
NPC/(TDFi/60) 
Min-1 
7.7.3 
CHTP Plug and Diffuser Analysis 
All CHTPs 1.0 used on Day 4 will be collected and sent to an external laboratory for analysis 
of smoke nicotine in the plug and diffuser. 
7.7.4 
Handling and Collection of CHTPs 1.0 after use on Day 4 
 Right after the end of using a CHTP 1.0 on Day 4, the used CHTP 1.0 will be inserted into 
the glass tube provided with the heat source oriented to the bottom of the glass tube. The 
extinguisher must not be used beforehand.  
 The glass tube is then placed in the glass tube holder to let CHTP 1.0 used cooling down. 
 Within 12 hours after the CHTP 1.0 collection, the combi filter will be manually separated 
from the rest of CHTP 1.0 by applying an appropriate bending force (between the diffuser 
and the polymer-film filter [PLA] section).  
 Close the tube with a yellow cap and store the tubes at 4 ± 3°C until shipment. 
Further details will be provided in the site manual. 
7.8 
Questionnaires 
The subject questionnaires and the cough-VAS used in this study will be answered and 
assessed by the subject directly 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 viewed for completeness by the site collaborators 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 
site collaborators, using open, non-directive questions (section 8). 
See Appendix A for the timepoints of assessment. 
The questionnaires should be done at the same time for each visit. 
7.8.1 
Fagerström Test for Nicotine Dependence (Revised Version) 
Potential nicotine dependence will be assessed via a subject self-reported questionnaire using 
the Fagerström test for nicotine dependence (FTND) in its revised version [17]. 
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 A for the timepoints of assessment. 
7.8.2 
Assessment of Cough-VAS 
Subjects will be asked to self-report and 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. 

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Finally, subjects will be asked to share any other important observations with the site 
collaborators about their coughing. 
See Appendix A for the timepoints of assessment. 
7.8.3 
Modified Cigarette Evaluation Questionnaire (MCEQ, Modified Version) 
Product evaluation will be assessed using the subject self-reported MCEQ [18]. The MCEQ 
assesses the degree to which subjects experience the reinforcing effects of smoking, by 
measuring: 
 Smoking satisfaction (satisfying, tastes good, enjoy smoking). 
 Psychological rewards (calms down, more awake, less irritable, helps concentrate, reduces 
hunger). 
 Aversion (dizziness, nauseous). 
 Enjoyment of respiratory tract sensations (single-item assessment). 
 Craving reduction (single-item assessment). 
See Appendix A for the timepoints of assessment. 
7.8.4 
Human Puffing Topography Questionnaire (HPT Questionnaire) 
A specific subject self-reported questionnaire, used for exploratory purposes, has been 
developed by PMI to evaluate the impact of the utilization of the HPT SODIM® device on 
smoker’s puffing experience in terms of ritual disruption. This is a questionnaire with 5 items 
to be rated on a 5-point scale and open questions. Subjects will be asked by the Investigator or 
designee to complete the HPT questionnaire at:  
 On Day -2, HPT and HPT questionnaire will be done in all subjects using CC compatible 
with the HST SODIM® 
 On Day 1 and Day 4 in the confinement period, HPT and HPT questionnaire will be done 
in all subjects in the CHTP 1.0 and CC arms. Puffing topography with the HPT SODIM® 
device will not be done in subjects using CC that are incompatible with the HPT SODIM® 
device (e.g., slim CC). 
See Appendix A for the timepoints of assessment. 
7.8.5 
Questionnaire of Smoking Urges 
To assess the urge-to-smoke, all subjects will be asked to complete a 10-item brief version of 
the QSU [19]. The QSU-brief is a subject self-reported questionnaire with 10 items to be rated 

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on a 7-point scale, ranging from 1 (strongly disagree) to 7 (strongly agree). Higher scores in 
this questionnaire indicate a higher urge-to-smoke.  
The findings in this brief version were consistent with the expressions of craving found in the 
32-item version of the QSU [20]. The findings supported a multi dimensional 
conceptualization of craving to smoke and demonstrated the utility of a brief multi-dimensional 
measure of craving [19]. 
See Appendix A for the timepoints of assessment. 
7.8.6 
Minnesota Nicotine Withdrawal Scale (Revised Version) 
The MNWS revised version is a valid and reliable subject self-reported scale that has been 
used previously to examine signs and symptoms of withdrawal from cigarette smoking [21, 
22]. It consists of 2 scales: a ”self-report scale’ and an ‘observer scale.” 
For the purpose of this study, only the self-reporting scale will be used and filled-in by the 
subject. Furthermore, the subject’s weight will not be recorded for the purpose of the MNWS. 
At the end of the assessment of the questionnaire, the subject’s pulse rate will be recorded. 
Subjects will be asked to rate the items for the previous 24 hours on a scale ranging from 0 to 
4 (where 0 = none, 1 = slight, 2 = mild, 3 = moderate, 4 = severe). 
See Appendix A for the timepoints of assessment. 
 

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8 
ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
According to ICH Topic E2A (Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting [23]), an AE is defined as any untoward medical occurrence in a 
subject administered an IP or reference product, which does not necessarily have a causal 
relationship with the IP or reference product. An AE can therefore be any unfavorable and 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an IP or reference product, whether or not it is 
considered related to the IP or reference product. 
The FDA MRTP guideline specifies the following definition for adverse events for tobacco 
products [4]. 
An AE is any health-related event associated with the use of a tobacco product in humans, 
which is adverse or unfavorable, whether or not it is considered related to the tobacco product. 
An AE can arise from any use of the product (including use in combination with other products 
and overdose). 
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. 

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8.2 
Assessment of Adverse Events 
The Investigator or designee is responsible for obtaining, assessing and documenting all AEs 
during the study. 
8.2.1 
Collection of Information 
Adverse event information will be collected from the time of signature of the ICF onwards 
until EOS either by the Investigator or designee via spontaneous reporting or by the use of 
consistent, open, non-directive questions from site collaborators (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 ‘anemia’ rather than 
‘decreased hemoglobin’). 
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 8.3). 
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 site collaborators as described below.  
Medical history is defined as any condition that started and ended prior to the Screening Visit. 
A concomitant disease is defined as any condition that started after ICF signature or was started 
prior to the Screening Visit and is still ongoing at the Screening Visit. Relevant medical history 
and any concomitant disease will be documented at the Screening Visit. 
8.2.2.1 
Screening Period 
Any AEs which occur during the Screening Period will be captured by the site collaborators 
and assessed by the Investigator or designee in order to establish relationship or relatedness in 

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respect to study procedures. All collected AEs will be reported in the CSR and will be in 
accordance with the respective regulatory guidelines.  
8.2.2.2 
Admission until End of the Study  
From Admission onwards until Discharge, all AEs will be actively collected by the site 
collaborators. 
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. 
During the Safety Follow-up Period AEs and/or SAEs will be recorded after reporting by the 
subject. SAEs will be reported by the Investigator as described in this document and the safety 
management plan (SMP). Any ongoing AEs during the Safety Follow-up Period will be 
followed up by the site. All AEs will be followed-up until they have been resolved, stabilized 
(i.e., no worsening of condition), or an acceptable explanation has been found until the end of 
the Safety Follow-up Period. Within 3 days after the end of the Safety Follow-up Period the 
investigator will attempt to contact the subjects by phone to check for if all AEs/SAEs 
potentially occurring during the Safety Follow-up period are fully reported. 
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 General Practitioner for follow-up on ongoing AEs. 
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 Investigational Product and Relationship to Study 
Procedures 
It is difficult to establish a firm method to distinguish an adverse reaction (that is AE that is 
causally related to the IP) from a clinical AE that is temporally associated to the use of an IP. 
In general, all AEs and/or SAEs will be assessed by the Investigator as either ‘related’ or ‘not 
related’ to IP or reference product as described below. In addition to the assessment of the 

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relationship of the clinical event to the IP, the Investigator shall document a potential 
relationship of the clinical event to any particular study procedure.  
Not related: The temporal relationship of the clinical event to IP or reference product 
administration makes a causal relationship unlikely, or concomitant medication, therapeutic 
interventions, or underlying conditions provide a sufficient explanation for the observed event. 
Related: The temporal relationship of the clinical event to study IP or reference product 
administration makes a causal relationship possible, and concomitant medication, therapeutic 
interventions, or underlying conditions do not provide a sufficient explanation for the observed 
event. 
8.2.5 
Expectedness 
Any AE assessed as related to the IP CHTP 1.0 will be assessed for its expectedness. An AE 
will be regarded as ‘unexpected’ if its nature or severity is not consistent with information 
already known about the IP, and is not listed in the current IB. The IB provides further detail 
on signs or symptoms that might be expected with the use of the IP, including information 
relating to malfunction or misuse. 
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 the IP, or to any study procedures, or any SAE related to the product and 
spontaneously reported after the Safety Follow-up must be reported by the Investigator or other 
site collaborators within 24 hours after first awareness by any party involved in the study 
to 
 and to the Sponsor. 
An SAE report form must be faxed or e-mailed as an attachment to: 
Safety: 
Fax number: 
+41 
 
E-mail: 
 
Address: 
 
 
 
 

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Sponsor Contact: 
 
 
     
Phone: 
+41 
 
E-mail 1: 
pmi.com  
E-mail 2: 
.pmi.com 
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 
 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 
 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 the CRF, in addition to the SAE report 
form. 
8.4 
Reporting of Other Events Critical to Safety Evaluations 
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the 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. 

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The grading scheme shown in Appendix E 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 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. 
8.5 
Reporting and Follow-Up of Pregnancies 
For pregnancies detected between the time point of signature of the ICF to the enrolment of 
the subject, the subject will be considered as a screen failure and removed from the study. No 
pregnancy form will be filled, however the diagnosed pregnancy must be captured in the screen 
failure CRF. 
Any pregnancy that occurred after first exposure to the IP and is potentially associated with 
exposure to the IP, including pregnancies spontaneously reported to the Investigator or 
designee after the EOS must be reported by the Investigator and followed-up until the 
pregnancy outcome is reached.  
Potential association with exposure to the IP is defined as the conception date being calculated 
to have been before the date of the last IP exposure. 

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The Investigator will complete a pregnancy form (provided as a separate document) for all 
pregnancies diagnosed (including positive urine pregnancy tests). 
The procedure to report a pregnancy and provide any additional/follow-up information to 
 
 and the Sponsor must be followed in the same manner and within the same timelines as 
described for a SAE (section 8.3). In addition, each pregnancy has to be reported as a non 
serious AE. No invasive procedures, including drawing of blood, must be done in such subjects 
after the discovery of pregnancy.  
 will follow up pregnancies only if they were detected after first product use (i.e., 
after CHTP 1.0 test at Admission). If pregnancies are to be followed-up, they will be followed-
up until an outcome is reached (e.g., normal delivery, spontaneous abortion, or voluntary 
termination). Any pregnancy complication, adverse pregnancy outcome, or maternal 
complications will be recorded. 
The Principal Investigator or designee is responsible for informing the IRB of any pregnancy 
that occurs during the study and its outcome, according to local regulations. 
8.6 
Adverse Events Leading to Discontinuation 
Subjects who are discontinued from the study because of an AE, will undergo the early 
termination procedures as described in section 9.4 as soon as possible. The Investigator or 
designee and/or 
 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. 
8.7 
Investigational Product Malfunction and Misuse 
Any occurrences of CHTP 1.0 malfunction (
 
) or misuse (use not in 
accordance with its label and instruction) by a subject, will be documented by the Investigator 
or his/her designated collaborator using a product issue log provided by the sponsor.  
Investigational product misuse may result in use-related hazards. 
Furthermore, any misuse or malfunction of CHTP 1.0 that lead to an AE/SAE will follow the 
same processes as described above for the reporting of an AE/SAE. 

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9 
STUDY ACTIVITIES 
A detailed schedule of assessments can be found in Appendix A. 
The time points shown are to be considered the time of assessment for the first subject. As not 
all subjects can be treated at the same time, a short time window will be implemented for 
subsequent subjects. Measurements not conducted at the exact time point, but conducted within 
the given time window (if applicable) do not constitute a protocol deviation but an accepted 
variability for the given time point.  
In general, if no start time for the procedure is provided, then the procedure can be performed 
at any time during the day. 
9.1 
Screening Visit  
The Screening Visit will be performed within 6 weeks (1 to 42 days) prior to Admission. 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. The point of time of each screening procedure must be recorded in the source 
document. 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 
the Screening Visit.  
Table 6 shows the procedures for the Screening Visit. The sequence of assessments/events is 
given just for illustrative purposes and will be at the discretion of the site after signature of the 
ICF. 
Table 6 
Time Schedule – Screening Visit (Day -45 to Day -3) 
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) 
 
During the visit 
√ 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
 

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Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of 
Procedure 
 
Screening 
 
During the visit 
During the visit  
√ 
Serology (HIV, hepatitis B and 
C) 
Information on the risks of 
smoking, smoking cessation 
advice and debriefing.  
 
During the visit  
 
Demographic data collected 
 
During the visit 
 
Questions about smoking 
history/habits and Intention to 
quit smoking 
 
During the visit  
 
Medical history/concomitant 
disease, prior and concomitant 
medication 
 
During the visit 
 
Identification of currently used 
CC brand 
 
During the visit 
 
FTND questionnaire 
 
During the visit 
 
ECG 
At least 10 minutes in 
supine position prior to 
recording 
During the visit 
 
Chest X-ray 
If not performed 6 months 
prior to Screening 
During the visit  
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in 
supine position 
During the visit  
 
Safety urine analysis 
 
During the visit  
 
Urine pregnancy test (females 
only) 
 
During the visit  
 
Physical examination, height 
and weight 
 
During the visit  
 
Urine drug screening 
 
During the visit  
 
Urine cotinine screening 
 
During the visit  
 
Alcohol breath test  
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of 
Procedure 
 
Screening 
 
During the visit  
 
Spirometry pre- and post-
bronchodilatator (recording of 
FEV1, FVC, FEV1/FVC) 
Has to be done at least 1 
hour after having stopped 
smoking 
At rest in sitting position 
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 
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  
 
During the visit  
 
CHTP 1.0 product 
demonstration  
 
Abbreviations: AE = Adverse event; CC = Conventional cigarette; CHTP 1.0 = Carbon Heated Tobacco Product 1.0; 
ECG = Electrocardiogram; FEV1= Force expiratory volume in 1 second; FVC = Forced vital capacity; FTND = Fagerström 
test for nicotine dependence; HIV = Human immunodeficiency virus; SAE = Serious adverse event. 
9.2 
Confinement Period (Day -3 to Day 6)  
9.2.1 
Admission (Day -3) 
The procedures of Day -3 can be performed in order deemed most practical. Table 7 shows the 
assessments that will be performed on the day of Admission (Day -3).  

Philip Morris Products SA 
Clinical Study Protocol 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Table 7 
Time Schedule – Admission (Day -3) 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of Procedure 
 
Admission (Day -3) 
 
During the visit  
 
Urine drug screening  
Prior to Enrolment  
During the visit 
 
Urine cotinine screening 
Prior to Enrolment 
During the visit 
 
Urine pregrancy test (female only) 
Prior to Enrolment 
During the visit 
 
Alcohol breath test 
Prior to Enrolment 
During the visit 
 
Information on the risks of 
smoking, smoking cessation 
advice and debriefing. 
Prior to Enrolment 
During the visit 
 
Prior/concomitant medication 
Prior to Enrolment 
During the visit 
 
Questions about smoking 
history/habits and intention to quit 
smoking 
Prior to Enrolment 
During the visit 
 
Identification of currently used CC 
brand 
Prior to Enrolment 
During the visit 
 
Vital signs (blood pressure, pulse 
rate, respiratory rate) 
At least 5 minutes in 
supine position  
Prior to Enrolment 
During the visit 
 
Physical examination, body 
weight, and calculated BMI 
Prior to Enrolment 
During the visit 
 
Inclusion/exclusion criteria 
All eligibility criteria must 
be checked. 
During the visit 
 
Enrolment 
 
 
 
Product test for CHTP 1.0 (Use of 
up to 5 sticks of CHTP 1.0) 
After enrolment. 
Subjects who are 
unwilling to use the 
product for 5 days will 
be discontinued from 
the study 
CHTP 1.0 used will be 
collected for 
accountability. 
 
 
AE/SAE recording 
At any time of the day 
 
 
Concomitant medications 
At any time of the day 
 
 
Collection of used CC butts 
For accountability 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXC-06-EU  
Final 4.0/24 June 2015 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of Procedure 
 
Admission (Day -3) 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; CC = Conventional cigarette(s); CHTP 1.0 = Carbon Heated 
Tobacco Product 1.0; SAE = Serious adverse event. 
9.2.2 
Baseline Period (Day -2 and Day -1) 
Table 8 and Table 9 show the assessments that will be performed on Day -2 and Day -1, 
respectively. 
The collection of 24-hour urine sample for Day -2 will start in the morning of Day -2 and will 
end in the morning of Day -1.  
The collection of 24-hour urine sample for Day -1 will start in the morning of Day -1 and will 
end in the morning of Day 1.  

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Clinical Study Protocol 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Table 8 
Time Schedule – Day -2 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of 
Procedure 
 
Baseline Period (Day -2) 
 
6:30 AM 
 
Start of smoking CC 
 
 
 
AE/SAE recording 
At any time of the day 
 
 
Concomitant medications 
At any time of the day 
 
 
Start of 24-hour urine sample 
collection for Day -2.  
The start of urine 
collection should start 
after the first morning 
void which should be 
discarded, and the end 
is in the morning of the 
following day. 
06:30 AM - 09:30 AM 
 
Start of HPT assessment 
The HPT SODIM® 
device has to be used 
for all smoking events 
when compatible CCs 
are smoked. 
Prior to 11:30 AM  
 
Vital signs (blood pressure, pulse 
rate, respiratory rate) 
At least 5 minutes in 
supine position 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
 
CO breath test  
Has to be done in 
conjunction with COHb 
blood sampling. 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
COHb in blood 
Has to be done in 
conjunction with CO 
breath test. 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be 
measured in the same 
assay as nicotine. No 
additional blood 
samples required. 
8:00 PM - 11:00 PM 
 
Craving questionnaire (QSU brief) 
 
8:00 PM - 11:00 PM 
 
Product evaluation questionnaire 
(MCEQ) 
 
8:00 PM - 11:00 PM 
 
HPT questionnaire  
 
11:00 PM 
 
End of smoking period 
 
6:30 AM - 11:15 PM 
 
Collection of used CC butts  
For accountability  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXC-06-EU  
Final 4.0/24 June 2015 
Page 85 of 131 
 
 
 
 
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. 
Abbreviations: AE = Adverse event; CC = Conventional cigarette(s); CO = Carbon monoxide; COHb = Carboxyhemoglobin; 
QSU–brief = Questionnaire of smoking urges (brief version); MCEQ = Modified cigarette evaluation questionnaire; 
SAE = Serious adverse event. 
Table 9 
Time Schedule – Day -1 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Baseline Period (Day -1) 
 
6:30 AM 
 
Start of smoking 
 
 
 
AE/SAE recording 
At any time of the day 
 
 
Concomitant medications 
At any time of the day 
 
 
End of 24-hour urine sample 
collection for Day -2 
The urine is collected for 24 
hours ±1 hour. The end  of 
the 24-hour urine collection 
should be prior to smoking 
the first CC. 
 
 
Start of 24-hour urine sample 
collection for Day -1.  
The start of 24-hour urine 
collection of Day -1 should 
be subsequent to the end of 
24-hour urine collection of 
Day -2  
 
 
Urine sample to be taken 
from the 24-hour urine of Day 
-2. 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 
Prior to 11:30 AM 
√ 
CYP2A6 activity in plasma 
Has to be done early in the 
morning prior smoking 
Prior to 11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position 
Prior to 11:30 AM 
 
MNWS questionnaire 
Has to be done prior to 
smoking 
Prior to 11:30 AM 
 
Assessment of cough (VAS) 
Has to be done prior to 
smoking 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXC-06-EU  
Final 4.0/24 June 2015 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Baseline Period (Day -1) 
 
Prior to 11:30 AM 
 
Spirometry pre- and post-
bronchodilatator (recording of 
FEV1, FVC, FEV1/FVC) 
Has to be done before 
smoking 
At rest in sitting position 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 
Prior to 11:30 AM 
√ 
Bio-banking for biomarkers 
and transcriptomics and 
lipidomics 
If additional consent is 
signed.  
After at least 10 hours of 
fasting 
Prior to 11:30 AM 
√ 
Clinical laboratory 
parameters (hematology, 
clinical chemistry) 
After at least 10 hours of 
fasting 
Prior to 11:30 AM  
 
Safety urine analysis  
 
Prior to 11:30 AM 
 
Intake of a cup of coffee 
made from 4.2 g (±10%) 
regular instant coffee; CAF 
content: 72 mg/2 g) with 150 
ml ±10 ml water.  
The time of intake of the cup 
of coffee must be recorded 
04:00 PM - 06:00 PM 
√ 
CYP1A2 activity in plasma 
6 hours ±15 minutes after 
intake of the the cup of 
coffee . 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
 
CO breath test  
Has to be done in 
conjunction with COHb 
blood sampling. 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
COHb in blood 
Has to be done in 
conjunction with CO breath 
test. 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXC-06-EU  
Final 4.0/24 June 2015 
Page 87 of 131 
 
 
 
 
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. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Baseline Period (Day -1) 
 
8:00 PM-11:00 PM 
 
Craving questionnaire (QSU 
brief) 
 
8:00 PM-11:00 PM 
 
Product evaluation 
questionnaire (MCEQ) 
 
11:00 PM 
 
End of smoking period 
 
6:30 AM-11:15 PM 
 
Collection of used CC butts  
For accountability  
 
 
Randomization 
Day -1 
Abbreviations: AE = Adverse event; BoExp = Biomarker (s) of exposure; CC = Conventional cigarette(s); CHTP 1.0 = 
Carbon Heated Tobacco Product 1.0; CO = Carbon monoxide; COHb = Carboxyhemoglobin; CYP1A2 = Cytochrome 
P450 1A2; CYP2A6 = Cytochrome P450 2A6; MCEQ = Modified cigarette evaluation questionnaire; MNWS = Minnesota 
nicotine withdrawal scale (revised version); QSU–brief = Questionnaire of smoking urges (brief version); SAE = Serious 
adverse event 
9.2.3 
Exposure Period (Days 1 to 5) 
Table 10 shows the assessments that will be performed on Day 1.  
The collection of 24-hour urine of Day -1 starting on Day -1 will end on Day 1.  
The collection of 24-hour urine sample for Day 1 will start on Day 1 and will end on Day 2. 
Table 10 
Time Schedule – Day 1 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 1 
 
6:30 AM 
 
Start of use of IPs 
 
 
 
AE/SAE recording 
At any time of the day 
 
 
Concomitant medications 
At any time of the day 
 
 
End of 24-hour urine sample 
collection for Day -1 
The urine is collected for 24 
hours ±1 hour. The end of 
the 24-hour urine collection 
should be prior to first use of  
IPs. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXC-06-EU  
Final 4.0/24 June 2015 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 1 
 
 
 
Start of 24-hour urine 
sample collection for Day 1.  
The start of 24-hour urine 
collection of Day 1 should be 
subsequent to the end of 24-
hour urine collection of 
Day -1.  
 
 
Urine sample to be taken 
from the 24-hour urine of 
Day -1 
Aliquots from 24-hour urine 
will be collected according to 
Table A2.  
Bio-banking for biomarkers 
(if additional consent is 
obtained) 
06:30 AM - 09:30 AM 
 
Start of HPT assessment 
In both study arms CHTP 1.0 
and CC, the HPT SODIM® 
device has to be used for all 
smoking events when 
compatible CCs are smoked 
Prior to 11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position 
Prior to 11:30 AM 
 
MNWS questionnaire 
Has to be done prior to use 
of IPs 
Prior to 11:30 AM 
 
Assessment of cough (VAS) 
Has to be done prior to use 
of IPs 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
 
CO breath test  
Has to be done in 
conjunction with COHb 
blood sampling 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
COHb in blood 
Has to be done in 
conjunction with CO breath 
test 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required 
8:00 PM - 11:00 PM 
 
Craving questionnaire (QSU 
brief) 
 
8:00 PM - 11:00 PM 
 
Product evaluation 
questionnaire (MCEQ) 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P2R-REXC-06-EU  
Final 4.0/24 June 2015 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 1 
 
8:00 PM - 11:00 PM 
 
HPT questionnaire  
 
11:00 PM 
 
End of use of IPs 
 
6:30 AM - 11:15 PM 
 
Collection of used CC butts 
For accountability 
6:30 AM - 11:15 PM 
 
Collection of used CHTP 1.0 
For accountability  
Abbreviations: AE = Adverse event; BoExp = Biomarker (s) of exposure; CC = Conventional cigarette(s); CHTP 1.0 = 
Carbon Heated Tobacco Product 1.0; CO = Carbon monoxide; COHb = Carboxyhemoglobin; CYP1A2 = Cytochrome 
P450 1A2; CYP2A6 = Cytochrome P450 2A6; HPT = Human puffing topography; MCEQ = Modified cigarette evaluation 
questionnaire; MNWS = Minnesota nicotine withdrawal scale (revised version); QSU–brief = Questionnaire of smoking 
urges (brief version); SAE = Serious adverse event 
Table 11 shows the assessments that will be performed on Day 2. 
The collection of 24-hour urine of Day 1 starting on Day 1 will end on Day 2. 
The collection of 24-hour urine sample for Day 2 will start on Day 2 and will end on Day 3. 
Table 11 
Time Schedule - Day 2 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 2 
 
6:30 AM  
 
Start of use of IPs 
 
 
 
AE/SAE recording 
At any time of the day 
 
 
 
 
 
 
Concomitant medications 
At any time of the day 
 
 
End of 24-hour urine sample 
collection for Day 1 
The urine is collected for 24 
hours ±1 hour. The end  of 
the 24-hour urine collection 
should be prior to first use of 
IPs.  
 
 
Start of 24-hour urine sample 
collection for Day 2.  
The start of 24-hour urine 
collection of Day 2 should 
be subsequent to the end of 
24-hour urine collection of 
Day 1  

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Clinical Study Protocol 
Confidential 
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Final 4.0/24 June 2015 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 2 
 
 
 
Urine sample to be taken 
from the 24-hour urine of Day 
1 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 
Prior to 11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position 
Prior to 11:30 AM 
 
MNWS questionnaire 
Has to be done prior to use 
of IPs 
Prior to 11:30 AM 
 
Assessment of cough (VAS) 
Has to be done prior to use 
of IPs 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
 
CO breath test 
Has to be done in 
conjunction with COHb 
blood sampling 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
COHb in blood 
Has to be done in 
conjunction with CO breath 
test 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required 
8:00 PM - 11:00 PM 
 
Craving questionnaire (QSU 
brief) 
 
8:00 PM - 11:00 PM 
 
Product evaluation 
questionnaire (MCEQ) 
 
11:00 PM 
 
End of use of IPs  
 
6:30 AM - 11:15 PM 
 
Collection of used CC butts 
For accountability 
6:30 AM - 11:15 PM 
 
Collection of used CHTP 1.0 
For accountability  
Abbreviations: AE = Adverse event; BoExp = Biomarker (s) of exposure; CC = Conventional cigarette(s); CHTP 1.0 = 
Carbon Heated Tobacco Product 1.0; CO = Carbon monoxide; COHb = Carboxyhemoglobin; MCEQ = Modified cigarette 
evaluation questionnaire; MNWS = Minnesota nicotine withdrawal scale (revised version); QSU–brief = Questionnaire of 
smoking urges (brief version); SAE = Serious adverse event 
Table 12 shows the assessments that will be performed on Day 3. 
The collection of 24-hour urine of Day 2 starting on Day 2 will end on Day 3. 
The collection of 24-hour urine sample for Day 3 will start on Day 3 and will end on Day 4. 

Philip Morris Products SA 
Clinical Study Protocol 
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P2R-REXC-06-EU  
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Table 12 
Time Schedule - Day 3 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 3 
 
6:30 AM 
 
Start of use of IPs 
 
 
 
AE/SAE recording 
At any time of the day 
 
 
Concomitant medications 
At any time of the day 
 
 
End of 24-hour urine sample 
collection for Day 2 
The urine is collected for 24 
hours ±1 hour. The end  of 
the 24-hour urine collection 
should be prior to first use of 
IPs.  
 
 
Start of 24-hour urine sample 
collection of Day 3.  
The start of 24-hour urine 
collection of Day 2 should 
be subsequent to the end of 
24-hour urine collection of 
Day 2  
 
 
Urine sample to be taken 
from the 24-hour urine of Day 
2 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 
Prior to 11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position 
Prior to 11:30 AM 
 
MNWS questionnaire 
Has to be done prior to use  
of IPs. 
Prior to 11:30 AM 
 
Assessment of cough (VAS) 
Has to be done prior to use 
of IPs. 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
 
CO breath test  
Has to be done in 
conjunction with COHb 
blood sampling 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
COHb in blood 
Has to be done in 
conjunction with CO breath 
test 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required 
8:00 PM - 11:00 PM 
 
Craving questionnaire (QSU 
brief) 
 

Philip Morris Products SA 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 3 
 
8:00 PM - 11:00 PM 
 
Product evaluation 
questionnaire (MCEQ) 
 
11:00 PM 
 
End of use of IPs 
 
6:30 AM - 11:15 PM 
 
Collection of used CC butts 
For accountability 
6:30 AM - 11:15 PM 
 
Collection of used CHTP 1.0 
For accountability  
Abbreviations: AE = Adverse event; BoExp = Biomarker (s) of exposure; CC = Conventional cigarette(s); CHTP 1.0 = 
Carbon Heated Tobacco Product 1.0; CO = Carbon monoxide; COHb = Carboxyhemoglobin; MCEQ = Modified cigarette 
evaluation questionnaire; MNWS = Minnesota nicotine withdrawal scale (revised version); QSU–brief = Questionnaire of 
smoking urges (brief version); SAE = Serious adverse event 
Table 13 shows the assessments that will be performed on Day 4. 
The collection of 24-hour urine of Day 3 starting on Day 3 will end on Day 4. 
The collection of 24-hour urine sample for Day 4 will start on Day 4 and will end on Day 5. 
Table 13 
 
Time Schedule - Day 4 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 4 
 
6:30 AM 
 
Start of use of IPs 
 
 
 
AE/SAE recording 
At any time of the day 
 
 
Concomitant medications 
At any time of the day 
 
 
End of 24-hour urine sample 
collection for Day 3 
The urine is collected for 24 
hours ±1 hour. The end  of 
the 24-hour urine collection 
should be prior to first use of 
IPs.  
 
 
Start of 24-hour urine sample 
collection of Day 4.  
The start of 24-hour urine 
collection of Day 2 should 
be subsequent to the end of 
24-hour urine collection of 
Day 3  

Philip Morris Products SA 
Clinical Study Protocol 
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P2R-REXC-06-EU  
Final 4.0/24 June 2015 
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Confidentiality Statement 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 4 
 
 
 
Urine sample to be taken 
from the 24-hour urine of Day 
3. 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 
06:30 AM - 09:30 AM 
 
Start of HPT assessment 
In both study arms CHTP 
1.0 and CC, the HPT 
SODIM® device has to be 
used for all smoking events 
when compatible CCs are 
smoked 
Prior to 11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position 
Prior to 11:30 AM 
 
MNWS questionnaire 
Has to be done prior to use 
of IPs. 
Prior to 11:30 AM 
 
Assessment of cough (VAS) 
Has to be done prior touse 
of IPs. 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
 
CO breath test 
Has to be done in 
conjunction with COHb 
blood sampling 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
COHb in blood 
Has to be done in 
conjunction with CO breath 
test 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required 
8:00 PM - 11:00 PM 
 
Craving questionnaire (QSU 
brief) 
 
8:00 PM - 11:00 PM 
 
Product evaluation 
questionnaire (MCEQ) 
 
8:00 PM - 11:00 PM 
 
HPT questionnaire  
 
11:00 PM 
 
End of use of IPs. 
 
6:30 AM - 11:15 PM 
 
Collection of used CC butts 
For accountability 
6:30 AM - 11:15 PM 
 
Collection of used CHTP 1.0 
For accountability and plug 
and diffuser analysis 

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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 4 
 
Abbreviations: AE = Adverse event; BoExp = Biomarker (s) of exposure; CC = Conventional cigarette(s); CHTP 1.0 = 
Carbon Heated Tobacco Product 1.0; CO = Carbon monoxide; COHb = Carboxyhemoglobin; MCEQ = Modified cigarette 
evaluation questionnaire; MNWS = Minnesota nicotine withdrawal scale (revised version); QSU–brief = Questionnaire of 
smoking urges (brief version); SAE = Serious adverse event 
Table 14 shows the assessments that will be performed on Day 5.  
The collection of 24-hour urine of Day 4 starting on Day 4 will end on Day 5.  
The collection of 24-hour urine sample for Day 5 will start on Day 5 and will end on Day 6. 
Table 14 
Time Schedule - Day 5 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 5 
 
6:30 AM 
 
Start of use of IPs 
 
 
 
AE/SAE recording 
At any time of the day 
 
 
Concomitant medications 
At any time of the day 
 
 
End of 24-hour urine sample 
collection for Day 4 
The urine is collected for 24 
hours ±1 hour. The end  of 
the 24-hour urine collection 
should be prior to first use of 
IPs.  
 
 
 
BoExp (for primary and 
secondary endpoints, NEQ) 
and creatinine in 24-hour 
urine 
 
 
Start of 24-hour urine sample 
collection of Day 5.  
The start of 24-hour urine 
collection of Day 5 should 
be subsequent to the end of 
24-hour urine collection of 
Day 4  
 
 
Urine sample to be taken 
from the 24-hour urine of Day 
4 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 

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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 5 
 
Prior to 11:30 AM 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position 
Prior to 11:30 AM 
 
MNWS questionnaire 
Has to be done prior to use 
of IPs 
Prior to 11:30 AM 
 
Assessment of cough (VAS) 
Has to be done prior to use 
of IPs 
Prior to 11:30 AM 
 
Intake of a cup of coffee 
made from 4.2 g (±10%) 
regular instant coffee; CAF 
content: 72 mg/2 g) with 150 
ml ±10 ml water. 
The time of intake of the cup 
of coffee must be recorded  
04:00 PM - 06:00 PM 
√ 
CYP1A2 activity in plasma 
6 hours ±15 minutes after 
intake of the cup of coffee  
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour ) 
 
CO breath test  
Has to be done in 
conjunction with COHb 
blood sampling 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
COHb in blood 
Has to be done in 
conjunction with CO breath 
test 
In the evening prior 
to 9:00 PM (approx. 
8:00 PM ± 1 hour) 
√ 
Plasma nicotine and cotinine 
sample 
Cotinine will be measured in 
the same assay as nicotine. 
No additional blood samples 
required 
8:00 PM - 11:00 PM 
 
Craving questionnaire (QSU 
brief) 
 
8:00 PM - 11:00 PM 
 
Product evaluation 
questionnaire (MCEQ) 
 
11:00 PM 
 
End of use of IPs 
 
6:30 AM - 11:15 PM 
 
Collection of used CC butts 
For accountability 
6:30 AM - 11:15 PM 
 
Collection of used CHTP 1.0 
For accountability  
Abbreviations: AE = Adverse event; BoExp = Biomarker (s) of exposure; CC = Conventional cigarette(s); CHTP 1.0 = 
Carbon Heated Tobacco Product 1.0; CO = Carbon monoxide; COHb = Carboxyhemoglobin; MCEQ = Modified cigarette 
evaluation questionnaire; MNWS = Minnesota nicotine withdrawal scale (revised version); QSU–brief = Questionnaire of 
smoking urges (brief version); SAE = Serious adverse event 

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Table 15 shows the assessments that will be performed on Day 6, prior to Discharge from the 
study unit. 
The collection of 24-hour urine of Day 5 starting on Day 5 will end on Day 6. 
Table 15 
Time Schedule - Day of Discharge (Day 6) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 6 
 
 
 
AE/SAE recording 
At any time of the day 
 
 
Concomitant medications 
At any time of the day 
 
 
End of 24-hour urine sample 
collection for Day 5 
The urine is collected for 24 
hours ±1 hour.  
 
 
Urine sample to be taken 
from the 24-hour urine of 
Day 5 
Aliquots from 24-hour urine 
will be collected according to 
Table A2. 
Bio-banking for biomarkers 
(if additional consent is 
obtained) 
06:29 AM ±30 min 
√ 
Clinical laboratory 
parameters (hematology, 
clinical chemistry) 
After at least 10 hours of 
fasting 
06:29 AM ±30 min 
√ 
CYP2A6 activity in plasma 
Has to be done before 
smoking 
Before Discharge  
 
Spirometry pre- and post-
bronchodilatator (recording 
of FEV1, FVC, FEV1/FVC) 
Has to be done before 
smoking 
At rest in sitting position 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 
06:29 AM ± 1 hour  
 
MNWS questionnaire 
 
06:29 AM ± 1 hour 
 
Assessment of cough (VAS) 
 

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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 6 
 
Prior to 11:30 AM 
√ 
Bio-banking for biomarkers, 
transcriptomics and 
lipidomics 
If additional consent is 
signed 
After at least 10 hours of 
fasting 
Before Discharge 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position 
Before Discharge 
 
Physical examination, body 
weight, and calculated BMI 
 
Before Discharge 
 
Safety urine analysis 
 
Before Discharge 
 
Urine pregnancy test 
(females only) 
 
Before Discharge  
 
ECG 
At least 10 minutes in supine 
position prior to recording 
Before Discharge 
 
Information on the risks of 
smoking, smoking cessation 
advice and debriefing. 
 
 
 
Discharge 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; BoExp = Biomarker (s) of exposure; CC = Conventional 
cigarette(s); CYP2A6 = Cytochrome P450 2A6; FEV1 = Forced expiratory volume in 1 second; FVC = Forced vital 
capacity; MNWS = Minnesota nicotine withdrawal scale (revised version); SAE = Serious adverse event 
9.3 
Safety Follow-Up Period    
All subjects participating in the product test on Day -3 will enter the 7 days for the Safety 
Follow-up Period.  
After Discharge on Day 6 (or if prematurely discontinued from the study), the subject will 
enter a 7-day Safety Follow up Period during which the follow-up of ongoing AEs/SAEs will 
be done by the study 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. Within 3 days after the end of the Safety Follow-up Period the 
investigator will attempt to contact the subjects by phone to check for if all AEs/SAEs 
potentially occurring during the Safety Follow-up period are fully reported. 
 

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Any AEs or SAEs that are ongoing at the end of the 7 days of the Safety Follow-up Period will 
be managed as described in section 8.2.2.2. 
9.4 
Early Termination Procedures 
Early termination procedures will be as follows, if the subject agrees: 
Table 16 
Time Schedule - Early Termination Procedures 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Early Termination 
 
 
 
AE/SAE recording 
At any time of the day 
 
 
Concomitant medications 
At any time of the day 
 
√ 
Clinical laboratory 
parameters (hematology, 
clinical chemistry) 
After at least 10 hours of 
fasting 
  
 
Spirometry pre- and post-
bronchodilatator (recording 
of FEV1, FVC, FEV1/FVC) 
Has to be done 1 hour of not 
smoking 
At rest in sitting position 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 
 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 minutes in supine 
position 
 
 
ECG 
At least 10 minutes in supine 
position prior to recording 
 
 
Physical examination, body 
weight, and calculated BMI 
 
 
 
Safety urine analysis 
 
 
 
Urine pregnancy test 
(females only) 
 

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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Early Termination 
 
 
 
Information on the risks of 
smoking, smoking cessation 
advice and debriefing. 
 
 
 
Discharge 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; FEV1 = Forced expiratory volume in 1 second; FVC = 
Forced vital capacity;  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 collaborators 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 collaborators, 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. 
10.2 Training of Collaborators 
A formal meeting (Investigator’s meeting) will be conducted prior to site initiation. During 
this meeting, the Sponsor or its authorized representative will discuss the requirements of the 
clinical study protocol and related documents and will also provide training to the relevant 

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systems and other study-specific procedures. The activities of this meeting will be described 
in the monitoring plan. 
Further to the Investigator meeting, the Investigator or designee will ensure that appropriate 
training relevant to the study is provided to all collaborators involved in the study, and that any 
new information relevant to the performance of this study is forwarded in a timely manner to 
the site collaborators. 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 site collaborators are responsible for maintaining a comprehensive and 
accurate filing system of all study-related documentation that will be suitable for inspection at 
any time by the Sponsor, its authorized representative and/or regulatory agencies. 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 
review and will be recorded and tracked in the CTMS or other approved format. 
Telecommunications and other verbal communications regarding deviations will be considered 

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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. 
11.2.1 
Data Verification 
The data will be verified as defined in the DMP and data verification plan. Discrepancy will 
be generated electronically, and issued as queries to the site, as necessary. 
Data queries will be raised for discrepant or missing data. All changes to data will be captured 
in the database with a comprehensive audit trail. 
11.2.2 
Coding 
Adverse events, medical/surgical history, and prior/concomitant medication will be classified 
according to the terminology of the latest version of the following dictionaries, at time of 
coding the first entry: 

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Adverse events, concomitant 
disease, medical history: 
Medical Dictionary for Regulatory Activities (MedDRA®) 
Medications: 
WHO Drug Dictionary Enhanced and Anatomical 
Therapeutic and Chemical classification system 
CHTP 1.0 issues and/or 
malfunction: 
C54451/Medical Device Problem Codes FDA CDRH [24] 
11.2.3 
 Database Lock 
When all outstanding data management issues have been resolved and quality review and 
cleaning activities are complete, the database or selected data is/are declared soft-locked. 
Access to change data in the soft-locked database or to change selected data at this time is 
limited. 
After data review by the Sponsor, resolution of all raised queries and QC of the changed data, 
the database or selected data thereof will be declared locked upon Sponsor approval, as 
applicable. 
Any changes to the database after that time can only be made by written agreement between 
the Sponsor and the data management and statistical team at the CRO. Any of those changes 
must be documented in the database log file. 
After study completion, the study database will be transferred to the Sponsor in the format 
specified in the DMP and defined in the data transfer agreement. The clinical database will be 
provided in the “Clinical Data Interchange Standards Consortium Study Data Tabulation 
Model Data Structure Specifications”. 

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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 primary study endpoints, the following stratification criteria will be 
used: 
1. Gender (male; female). 
2. Average daily CC consumption over the 6 weeks prior to admission as reported on the 
Admission Day (smokers smoking 10 to 19 CC/day and smokers smoking > 19 CC/day). 
12.1.2 
Definitions for Statistical Data Analysis 
Baseline: 
Unless specified, baseline is defined as the last available time point prior to Day 1, 06:30 AM. 
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by product arm 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. 
For BoExp, the geometric mean and coefficient of variation (CV) will be presented in addition 
to the mean and SD. 
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. 

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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 
Unless stated otherwise, all statistical tests will be two-sided and conducted at the 5% level, 
and all quoted confidence intervals (CIs) will be two-sided 95% CIs.  
The primary endpoints will be tested using a multiple testing procedure to preserve the overall 
alpha level by simultaneously testing the endpoints using a closed procedure with each test 
performed at an alpha level of 5%. This implies that statistical significance is required for all 
primary endpoints in order to be able to make confirmatory claims about any of the endpoints. 
Full details of this approach will be provided in the SAP.  
12.2 Determination of Sample Size and Power Consideration 
The following discussion addresses the ability to detect a reduction of 50% or more in the 
levels of MHBMA, 3-HPMA, S-PMA, and COHb in CHTP 1.0 arm compared to the CC arm 
after 5 days of exposure, one sided test with 2.5% type I error probability. 
Table 17 describes the expected coefficients of variation (CV) and mean ratios (MR) between 
CHTP 1.0 and the two control arms based on data from a controlled, randomized, open-label, 
3-arm parallel single-center confinement study that investigated exposure to selected smoke 
constituents in smokers switching from CC to smoking article cigarettes for 5 days, the YVD-
CS01-EU study   (ClinicalTrials.gov: ID: NCT00812279) sponsored by PMI. 

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Table 17. 
Coefficients of Variation (YVD-CS01-EU study) 
 
CHTP 1.0/CC 
MR (CV) 
COHb 
0.40 (0.32) 
3-HPMA 
0.30 (0.50) 
MHBMA 
0.15 (0.70) 
S-PMA 
0.20 (0.70) 
Abbreviations: 3-HPMA = 3-hydroxypropylmercapturic acid; CC = Conventional cigarettes; COHb = Carboxyhemoglobin; 
CV = Coefficients of variation; MHBMA = Monohydroxybutenyl mercapyuric acid; MR = Mean ratios; S-PMA = S-
phenylmercapturic acid; CHTP 1.0 = Carbon Heated Tobacco Product 1.0 
The power to detect a reduction was computed. 
Table 18 describes the expected power to detect a reduction of 50% or more in the levels of 
MHBMA, 3-HPMA, S-PMA, and COHb in CHTP 1.0 arm compared to the CC arm after 5 
days of exposure, with a one sided test with 2.5% type I error probability using the assumptions 
from YVD-CS01-EU, and 80 randomized subjects in a 1:1 ratio (40 in CHTP 1.0 arm and 40 
in CC arm). 
Table 18. 
Expected Power (YVD-CS01-EU study assumptions) 
 
Reduction 
Assumptions 
50% 
51% 
52% 
53% 
54% 
55% 
YVD-CS01-EU 
88% 
82% 
73% 
62% 
49% 
35% 
The test-wise powers to detect a reduction of 50% or more in the levels of MHBMA, 3-HPMA, 
S-PMA, and COHb in CHTP 1.0 arm compared to the CC arm after 5 days of exposure, with 
a one sided test with 2.5% type I error probability using the assumptions from YVD-CS01-
EU, and 80 randomized subjects in a 1:1 ratio (40 in CHTP 1.0 arm and 40 in CC arm) are 
described in Error! Reference source not found.  
Table 19. 
Test-Wise Power (YVD-CS01-EU study assumptions) 
Parameter 
Test-wise power 
COHb 
88% 
3-HPMA 
>99% 
MHBMA 
>99% 
S-PMA 
>99% 

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Given the above calculation, the sample size was considered sufficient to have more than 80% 
power to detect a reduction of 50% or more in the levels of MHBMA, 3-HPMA, S-PMA, and 
COHb in CHTP 1.0 arm compared to the CC arm after 5 days of exposure, using a one sided 
test with 2.5% type I error probability. 
12.3 Analysis Populations 
The main population for non-safety analysis will be the full analysis set (FAS) population. The 
per-protocol (PP) population will be used only for the analysis of the primary endpoint to 
examine the robustness of the primary analyses. 
Safety will be analyzed using the safety population. 
12.3.1 
Full Analysis Set 
The FAS consists of all the randomized subjects who had at least one post-randomization 
product use experience, if randomized to CHTP 1.0 or CC, and have at least one valid 
nonsafety assessment (CHTP 1.0, CC). 
12.3.2 
Per Protocol Population 
The PP population is a subset of FAS and includes all randomized subjects who fulfill key 
compliance criteria of the protocol, and have no major protocol deviation (to be further 
described in the SAP). 
12.3.3 
Safety Population 
The safety population consists of all the subjects who had at least one exposure to CHTP 1.0 
(product test at Admission Day). Subjects in the safety population will be analyzed according 
to actual exposure. 
12.4 Primary Endpoints 
12.4.1 
Primary Endpoints Analysis Variables 
The primary endpoints are: 
 MHBMA (concentration adjusted for creatinine in 24-hour urine) on Day 5 
 3-HPMA (concentration adjusted for creatinine in 24-hour urine) on Day 5 
 S-PMA (concentration adjusted for creatinine in 24-hour urine) on Day 5 
 COHb on Day 5 

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See section 3.1. 
Evaluation criterion: 
The study is designed to be able to detect a reduction of 50% or more in the levels of MHBMA, 
3-HPMA, S-PMA, and COHb in the CHTP 1.0 arm compared to the CC arm at the end of the 
Exposure Period, using a one-sided test with 2.5% type I error probability. 
12.4.2 
Baseline Comparability 
Not applicable.  
12.4.3 
Descriptive Summary 
Primary endpoints will be summarized as described in section 12.1.3 on the FAS. 
Should more than 20% of the subjects be excluded from the FAS population, the above 
descriptive analysis will be repeated on the PP population.  
12.4.4 
Confirmatory Analyses 
The hypothesis to be tested for each of the biomarkers of exposure of the primary and 
secondary objectivesis that the geometric mean level on Day 5 of the biomarker for CHTP 1.0 
is lower relative to CC. 
Analysis of BoExp will be conducted on the natural log scale. In order to test the following 
hypothesis:  
 Null hypothesis (H0): m1 ≥ m2  
 Alternative hypothesis (H1): m1 < m2  
Where m1 and m2 are the geometric means of the biomarker levels on Day 5 for CHTP 1.0 
and CC respectively.  
The transformed data will be analyzed by means of a generalized linear model using product 
arm as covariate adjusting for the following baseline information: gender, average cigarette 
consumption over the previous 4 weeks, and baseline value of endpoint. Estimates of 
differences between groups will be back-transformed to provide relative effects.  
Assumptions of the analysis of variance model will be tested. Markedly non-lognormally 
distributed BoExp data will be transformed or analyzed by appropriate non-parametric 
methods.  
Should more than 20% of the subjects be excluded from the FAS, would the above 
confirmatory analysis will be repeated on the PP population. 

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12.5 Secondary Safety Endpoint(s) 
See section 3.2. 
More details on derivation rules will be given in the SAP. 
12.5.1 
Secondary Endpoint Analysis Variables 
See section 3.2. 
More details on derivation rules will be given in the SAP. 
12.5.2 
Baseline Comparability 
Not applicable. 
12.5.3 
Descriptive Analysis 
In general, secondary endpoints will be summarized as described in section 12.1.3 on the FAS. 
12.5.4 
Safety Analysis 
In general, all safety data will be listed and tabulated on the safety population by product arm, 
using the approach described in section 12.1.3. Safety variables collected during Exposure 
Period will also be reported by product exposure. 
Adverse event data will serve as the primary assessment of safety. Other safety variables 
monitored in this study include: respiratory symptoms (cough assessment VAS and Likert 
scales); vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate); 
spirometry; 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 system organ 
class and preferred term. Summaries will also be presented for AEs leading to withdrawal, AEs 
leading to death, AEs by relatedness to product exposure, AEs by severity, and laboratory AEs. 
Tabulations will be performed for both the number of subjects experiencing an event and the 
number of events. 
The number and percentage of subjects with clinical findings will be tabulated by sequence for 
laboratory parameters. 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). Descriptive statistics will be summarized by visit and change from 
Baseline for laboratory parameters, ECG, respiratory symptoms, and vital signs. 

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12.6 Exploratory Analysis 
12.6.1 
Exploratory Endpoint Analysis Variables 
See section 3.3. 
12.6.2 
Baseline Comparability 
Not applicable. 
12.6.3 
Descriptive Analysis 
In general, exploratory endpoints will be summarized as described in section 12.1.3 on the 
FAS. 
12.7 Demographics and Baseline Characteristics 
Demographic and other Baseline characteristics will be reported for safety population. 
Summary statistics will be provided by exposure group and stratified by sex and by cigarette 
consumption. Formal statistical analysis will not be performed on Baseline demographic data. 
12.8 Interim Analysis 
There are no planned interim analyses. 

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13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Investigator’s and Study Administrative Structure 
13.1.1 
Investigator 
Investigator: 
 
BioVirtus Research Site Sp. z o.o. 
 
 
 
Tel: +48 
 
Fax.: +48 
 
 
 
13.1.2 
Sponsor 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5, 
2000 Neuchâtel, 
Switzerland 
Tel: +41 (58) 242 2111 
Fax: +41 (58) 242 2811 
 
Clinical Scientist 
Phone: +41 
 
Mobile: +41 
 
E-mail: 
@pmi.com 
 
 
Biostatistician 
Phone: +41 
 
Mobile: +41
 
E-mail: 
@pmi.com 
 
 
Medical Safety Officer 
Phone: +41 
 
E-mail:
.pmi.com 
 
Clinical Study Manager 
Phone: +41 
 
Mobile : +41 
 
E-mail:
@pmi.com 

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Clinical Study Manager 
Phone: +41 
 
Mobile: +41 
  
E-mail: 
@pmi.com 
13.1.3 
Other Responsibilities 
Any SAEs or pregnancies will be handled by: 
 
 
 
 
 
Fax: 
 
+41 
 
E-mail: 
.com  
Details of the laboratories conducting the clinical safety laboratory services and 
biopharmaceutical analyses are shown in Appendix B. 
13.2 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects' state of 
health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subject in writing and signed by the subject, in compliance with all local and 
national data protection and privacy legislation. 
The 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 and 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 and 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 

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obscured before a copy of that document is supplied to the Sponsor or the Sponsor’s authorized 
representative. 
13.3 Access to Source 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 site collaborators involved with the study must permit direct access to 
source data/documents for study related monitoring, audits, IRB/IEC review and regulatory 
inspection(s). 
13.4 Record Retention 
All records of data, source data and source documents (original records or certified copies), in 
any form (including, but not limited to, written, electronic, magnetic, optical records and scans 
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 [1]. 
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 Enrollment log (if applicable). 
 Record of all communications between the Investigator and the IRB/IEC, composition 
of the IRB/IEC. 
 Record of all communications/contact between the Investigator, the Sponsor, and its 
authorized representatives. 

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 List of sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curricula vitae, and their signatures. 
 Investigator logs. 
 CRFs, study specific questionnaires (and associated data/scoring). 
 AE reports and details of follow-up investigations, details of concomitant medication. 
 All other source documents (e.g., ECGs, consultation reports, physical examination, 
laboratory records) or any electronically captured study source data. 
 Clinical laboratory reports, laboratory normal ranges. 
 Original medical/hospital records, if applicable (the medical files of study subjects 
must be retained in accordance with local legislation and in accordance with the 
maximum period of time permitted by the hospital or study site). 
 Record of any body fluids or tissue samples collected and retained. 
 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. 
13.5 Clinical Study Report 
The Sponsor must ensure that a CSR for this study is prepared regardless of whether the study 
is completed or prematurely terminated. 
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. 

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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. 
13.6 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 
commitment to promptly update this information if any relevant changes occur during the 
course of the investigation and for one year following the completion of the study. 
13.7 Publication and Disclosure Policy 
This document contains 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). 
13.8 Insurance 
The Sponsor is responsible for AEs and health damage of the subjects that are associated with 
the CHTP 1.0 product or with study procedures which are used during the study, except for 
AEs and health damage of the subjects caused by a negligent or an intentional misconduct 
and/or significant deviation to the protocol of the Investigator or the clinical study site or the 
subjects. The Sponsor has taken out insurance to cover any bodily injury and property damage 
caused by the operations carried out by the insured. 

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14 REFERENCE LIST 
[1] ICH E6 (R1). Guideline for Good Clinical Practice. 1996; Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E
6_R1_Guideline.pdf (Accessed on 14 August 2014). 
[2] World Medical Association (WMA). WMA Declaration of Helsinki - Ethical principles 
for medical research involving human subjects. 2013. 
[3] U.S. Department of Health and Human Services. How tobacco smoke causes disease: the 
biology and behavioral basis for smoking-attributable disease: a report of the Surgeon 
General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease 
Control and Prevention, National Center for Chronic Disease Prevention and Health 
Promotion, Office on Smoking and Health. 2010. 
[4] FDA (Food and Drug Administration). Guidance for industry - Modified risk tobacco 
product applications - Draft Guidance. 2012. 
[5] Rodgman A, Perfetti TA. The chemical components of tobacco and tobacco smoke. 2nd 
ed. Taylor & Francis Inc (United States), editor: CRC Press; 2013  
[6] FDA (Food and Drug Administration). Harmful and potentially harmful constituents in 
tobacco products and tobacco smoke; request for comments. Fed Regist. 
2011;76(156):50226-30. 
[7] Raw M, Anderson P, Batra A, Dubois G, Harrington P, Hirsch A, et al. WHO Europe 
evidence based recommendations on the treatment of tobacco dependence. Tob Control. 
2002;11(1):44-6. 
[8] WHO Study Group, Ashley DL, Burns D, Djordjevic M, Dybing E, Gray N, et al. The 
scientific basis of tobacco product regulation: second report of a WHO study group. World 
Health Organ Tech Rep Ser. 2008(951):1-277, 1 p following  
[9] FDA (Food and Drug Administration). Guidance for industry - Reporting harmful and 
potentially harmful constituents in tobacco products and tobacco smoke under Section 
904(a)(3) of the Federal Food, Drug, and Cosmetic Act. 2012. 
[10] Lindner D, Smith S, Leroy CM, Tricker AR. Comparison of exposure to selected cigarette 
smoke constituents in adult smokers and nonsmokers in a European, multicenter, 
observational study. Cancer Epidemiol Biomarkers Prev. 2011;20(7):1524-36. 
[11] Faber MS, Fuhr U. Time response of cytochrome P450 1A2 activity on cessation of heavy 
smoking. Clin Pharmacol Ther. 2004;76(2):178-84. 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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without the written consent of Philip Morris Products S.A. 
[12] FDA (Food and Drug Administration). Food-effect bioavailability and fed bioequivalence 
studies. 2002. 
[13] American Pharmacists Association. Cytochrome P450 enzymes: substrates, inhibitors, and 
inducers.  Drug information handbook. 23rd ed2014. p. 2316-24. 
[14] Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. 
[17] Fagerstrom K, Russ C, Yu CR, Yunis C, Foulds J. The Fagerstrom Test for Nicotine 
Dependence as a predictor of smoking abstinence: a pooled analysis of varenicline clinical 
trial data. Nicotine Tob Res. 2012;14(12):1467-73. 
[18] Cappelleri JC, Bushmakin AG, Baker CL, Merikle E, Olufade AO, Gilbert DG. 
Confirmatory factor analyses and reliability of the modified cigarette evaluation 
questionnaire. Addict Behav. 2007;32:912–23. 
[19] Cox LS, Tiffany ST, Christen AG. Evaluation of the brief questionnaire of smoking urges 
(QSU-brief) in laboratory and clinical settings. Nicotine Tob Res. 2001;3:7-16. 
[20] Tiffany ST, Drobes DJ. The development and initial validation of a questionnaire on 
smoking urges. Br J Addict. 1991;86:1467-76. 
[21] Hughes JR, Hatsukami D. Signs and symptoms of tobacco withdrawal. Arch Gen 
Psychiatry. 1986;43(3):289-94. 
[22] Hughes JR, Hatsukami D. Background on the Minnesota Withdrawal Scale-Revised 
(MNWS-R). 
2008;Available 
from: 
http://www.uvm.edu/~hbpl/?Page=minnesota/default.html (Accessed on 23 July 2014). 
[23] ICH E2A. Clinical safety data management: definitions and standards for expedited 
reporting. 
1994; 
Available 
from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/
Step4/E2A_Guideline.pdf (Accessed on 17 July 2014). 
[24] FDA (Food and Drug Administration). Implementation Specifications, reporting medical 
device 
problems 
(C54451/Medical_Device_Problem_Codes_FDA_CDRH). 
2012; 
Available 
from: 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequire
ments/ReportingAdverseEvents/EventProblemCodes/ucm134761.htm (Accessed on 01 
December 2014). 

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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. 
[25] U.S. Department of Health and Human Services. Common terminology criteria for adverse 
events. 2010; Available from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-
06-14_QuickReference_8.5x11.pdf (Accessed on 23 April 2014)(CTCAE v4.03). 

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APPENDIX A 
SCHEDULE OF EVENTS 
Table A1 
Study Assessments (Separate Table [Table A2] Shown for 24-hour Urine Collections) 
 
Screening 
Confinement Period 
Safety 
Follow-Up 
Study Day 
Day -45 to 
Day -4 
Day -3 
Day -2 
Day -1 
Day 1 Day 2 Day 3 Day 4 Day 5 
Day 6 
(Day of 
Discharge) 
Day 6 to 
Day 13 
One informed consent for study 
participation/ICF for bio-banking 
● 
 
 
 
 
 
 
 
 
 
 
Two informed consent forms for 
long-term bio-banking 
● 
 
 
 
 
 
 
 
 
 
 
Admission/discharge 
 
● 
 
 
 
 
 
 
 
● 
 
Advice on the risk of 
smoking/smoking cessation 
advice/debrief 
● 
● 
 
 
 
 
 
 
 
● 
 
Inclusion/exclusion criteria 
● 
● 
 
 
 
 
 
 
 
 
 
Enrolment 
 
● 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
● 
 
 
 
 
 
 
 
Demographics, medical history, 
concomitant diseases 
● 
 
 
 
 
 
 
 
 
 
 
Vital signs a 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Physical examination b 
● 
● 
 
 
 
 
 
 
 
● 
 
Spirometry c 
● 
 
 
● 
 
 
 
 
 
● 
 
Prior/concomitant medication 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
B/U: Hematology, clinical 
chemistry, urine analysis  
● 
 
 
● 
 
 
 
 
 
● 
 

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Screening 
Confinement Period 
Safety 
Follow-Up 
Study Day 
Day -45 to 
Day -4 
Day -3 
Day -2 
Day -1 
Day 1 Day 2 Day 3 Day 4 Day 5 
Day 6 
(Day of 
Discharge) 
Day 6 to 
Day 13 
Electrocardiogram 
● 
 
 
 
 
 
 
 
 
● 
 
Chest X-ray d 
● 
 
 
 
 
 
 
 
 
 
 
B: HIV, hepatitis B and C 
● 
 
 
 
 
 
 
 
 
 
 
U: Urine drug screening, urine 
cotinine screening test 
● 
● 
 
 
 
 
 
 
 
 
 
U: Pregnancy test 
● 
● 
 
 
 
 
 
 
 
● 
 
Alcohol breath test 
● 
● 
 
 
 
 
 
 
 
 
 
FTND 
● 
 
 
 
 
 
 
 
 
 
 
Identification of the current 
cigarette brand  
● 
● 
 
 
 
 
 
 
 
 
 
Questions about smoking 
history/habits and intention to quit 
smoking 
● 
● 
 
 
 
 
 
 
 
 
 
CHTP 1.0 demonstration 
● 
 
 
 
 
 
 
 
 
 
 
CHTP 1.0 product test e 
 
● 
 
 
 
 
 
 
 
 
 
CO breath test f 
 
 
● 
● 
● 
● 
● 
● 
● 
 
 
B: BoExp in blood: COHb g 
 
 
● 
● 
● 
● 
● 
● 
●  
 
 
B: BoExp in plasma: nicotine, 
cotinine h 
 
 
● 
● 
● 
● 
● 
● 
● 
 
 
B: CYP1A2 activity 
 
 
 
● 
 
 
 
 
● 
 
 
B: CYP2A6 activity c 
 
 
 
● 
 
 
 
 
 
● 
 
QSU-brief questionnaire i 
 
 
● 
● 
● 
● 
● 
● 
● 
 
 

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Screening 
Confinement Period 
Safety 
Follow-Up 
Study Day 
Day -45 to 
Day -4 
Day -3 
Day -2 
Day -1 
Day 1 Day 2 Day 3 Day 4 Day 5 
Day 6 
(Day of 
Discharge) 
Day 6 to 
Day 13 
MNWS (revised version) k 
 
 
 
● 
● 
● 
● 
● 
● 
● 
 
MCEQ (modified version; CHTP 
1.0 and CC arms) k 
 
 
● 
● 
● 
● 
● 
● 
● 
 
 
Assessment of cough 
 
 
 
● 
● 
● 
● 
● 
● 
● 
 
AE/SAE recording 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Collection of CC butts for 
accountability 
 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
Collection of used CHTP 1.0 sticks 
for accountability 
 
● 
 
 
● 
● 
● 
● 
● 
 
 
Collection of used CHTP 1.0 sticks 
for plug and diffuser analysis 
 
 
 
 
 
 
 
● 
 
 
 
HPT questionnaire (CHTP 1.0 and 
CC arms) l 
 
 
● 
 
● 
 
 
● 
 
 
 
 HPT 
 
 
● 
 
● 
 
 
● 
 
 
 
B: Bio-banking m 
 
 
 
● 
 
 
 
 
 
● 
 
Abbreviations: AE = Adverse event; B = Blood sample required; BoExp = Biomarker (s) of exposure; BMI = Body mass index; CC = Conventional cigarette(s); CHTP 1.0 = Carbon 
Heated Tobacco Product 1.0; CO = Carbon monoxide; COHb = Carboxyhemoglobin; CYP1A2 = Cytochrome P450 1A2; CYP2A6 = Cytochrome P450 2A6; FTND = Fagerström 
test for nicotine dependence; HIV = Human immunodeficiency virus; HPT: Human puffing topography; MCEQ = Modified cigarette evaluation questionnaire; MNWS = Minnesota 
nicotine withdrawal scale (revised version); QSU–brief = Questionnaire of smoking urges (brief version); SAE = Serious adverse event; U = Urine sample required 
a. 
Systolic and diastolic blood pressure, pulse rate, and respiratory rate. 
b. 
Physical examination and height (only at Screening), body weight and calculated BMI. 
c. 
At Screening, spirometry needs to be done prior at least 1 hour after having stopped smoking. On Day -1 and Day 6, spirometry, and CYP2A6 blood sampling has to be done 
prior to smoking. 
d. 
Pre-study chest X-ray (with anterior-posterior and left lateral views) may be used, if performed within 6 months prior to Screening. 

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e. 
On Day -3, CHTP 1.0 product test to be conducted after enrolment. After the product test, subjects not ready to use the CHTP 1.0 for 5 days will be discontinued.  
f. 
CO breath test; Day -2 to Day 5: the test will be conducted once per day, preferably in the evening around 08:00 PM ± 1hour in conjunction with COHb tests, where applicable.  
g. 
COHb; Assessments should be done in conjunction with CO breath tests, where applicable. Day -2 to Day 5: one blood sample in the evening around 08:00 PM ± 1 hour. 
h. 
Nicotine/cotinine; Day -2 to Day 5 (both CHTP 1.0 and CC arms): one blood sample around 08:00 ± 1 hour. 
i. 
QSU-brief: daily, from Day -2 to Day 5. 
j. 
MNWS daily from Day -1 to Day 6. 
k. 
MCEQ: daily from Day -2 to Day 5. 
l. 
On Day -2, HPT and HPT questionnaire will be done in all subjects using CC compatible with the HPT SODIM® device. On Day 1 of the confinement period, HPT and HPT 
questionnaire will be done for every product use in all subjects in the CHTP 1.0 and CC arms. On Day 4 of the confinement period, HPT and HPT questionnaire will be done 
in all subjects using CC compatible with the HPT SODIM® device. Puffing topography with the HPT SODIM® device will not be done in subjects using CC that are incompatible 
with the HPT SODIM® device (e.g., slim CC). 
m. Blood/plasma samples for further transcriptomics and lipidomics analyses will only be taken if additional consent for bio-banking is given by the subject. 
Table A2 
Schedule for 24-hour Urine Collection Assessments 
 
Baseline Period 
Confinement Exposure Period 
Study Day 
Day -2 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5  
Collection Period 
Day -2 to 
Day -1 
Day -1 to 
Day 1 
Day 1 to 
Day 2 
Day 2 to 
Day 3 
Day 3 to 
Day 4 
Day 4 to 
Day 5 
Day 5 to 
Day 6 
BoExp in urine  
● 
● 
● 
● 
● 
● 
● 
Creatinine 
● 
● 
● 
● 
● 
● 
● 
Ames mutagenicity test 
 
● 
 
 
 
 
● 
Bio-banking a  
 
● 
 
 
 
 
● 
a. 
Samples (5 tubes of 24-hour urine) will only be taken if additional consent for bio-banking is given by the subject.  
 
 

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APPENDIX B 
PARTICIPATING LABORATORIES 
 
 

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APPENDIX C 
HPT SODIM® DEVICE 
 
 

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APPENDIX D 
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 
Monohydroxybuten
ylmercapturic 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-
Cyanoethylmercapt
uric acid (CEMA) 
Urine 
17 h 
● 
Benzene [gas] 
FDA-18, FDA-
93, HC PMI-
58, WHO-18 
S-
Phenylmercapturic 
acid (S-PMA) 
Urine 
9 to 15 h 
 
Benzo[a]pyrene 
[particulate] 
FDA-18, FDA-
93, HC PMI-
58, WHO-18 
3-
Hydroxybenzo[a]py
rene B[a]P 
Urine 
3 to 4 h 
● 
Carbon monoxide 
[gas] 
FDA-18 FDA-
93 HC PMI-58 
WHO-18  
CO 
Breath 
/  
● 
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 
 

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HPHC [smoke phase] 
HPHC List 
Biomarker 
Matrix 
t1/2 
Reduced 
List of 
BoExp 
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 
 
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 E 
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 [25] 
(mmol/L) 
< LLN - 130 
- 
< 130 - 120 
< 120 
Sodium – 
Hypernatremia [25] 
(mmol/L) 
> ULN - 150 
> 150 - 155 
> 155 – 160 
hospitalization 
indicated 
> 160 
Potassium – 
Hyperkalemia [25] 
(mmol/L) 
> ULN - 5.5 
> 5.5 - 6.0 
> 6.0 - 7.0 
hospitalization 
indicated 
> 7.0 
Potassium – 
Hypokalemia [25] 
(mmol/L) 
< LLN - 3.0 
< LLN - 3.0; 
symptomatic; 
intervention 
indicated 
< 3.0 - 2.5 
hospitalization 
indicated 
< 2.5 
Glucose – 
Hypoglycemia [25] 
(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 [25] 
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 [25] 
> 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 [25] 
(g/dL) 
(g/L) 
< LLN – 3 
< LLN - 30 
< 3 – 2 
< 30 - 20 
< 2 
< 20 
- 
Alkaline phosphatase 
increased [25] 
> ULN – 2.5 x 
ULN 
> 2.5 – 5.0 x ULN 
> 5.0 – 20.0 x 
ULN 
> 20.0 x ULN 
ALT/AST increased [25] 
> ULN – 3.0 x 
ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x 
ULN 
> 20.0 x ULN 

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Serum Chemistry * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-Threatening 
(Grade 4) 
Gamma-glutamyl 
transferase (GGT) 
increased [25] 
> ULN – 2.5 x 
ULN 
> 2.5 – 5.0 x ULN 
> 5.0 – 20.0 x 
ULN 
> 20.0 x ULN 
Blood bilirubin 
increased [25] 
(total and direct) 
> ULN – 1.5 x 
ULN 
> 1.5 – 3.0 x ULN 
> 3.0 – 10.0 x 
ULN 
> 10.0 x ULN 
Cholesterol high [25] 
(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 [25] 
(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. 
* Those parameters that are not listed do not have grading categories in the CTCAE will be reviewed by the Principal 
Investigator and only reported as an AE if considered to be clinically relevant. 

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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 
consequences; 
urgent 
intervention 
indicated 
Hemoglobin increase [25] 
(g/dL) 
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 [25] 
(cell/mm3) 
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 [25] 
(cell/mm3) 
- 
> 4,000 – 20,000 
> 20,000 
- 
Lymphocytes decrease [25] 
(cell/mm3) 
10-9/l 
< LLN – 800 
< LLN – 0.8 
< 800 - 500 
< 0.8 – 0.5 
< 500 - 200 
< 0.5 – 0.2 
< 200 
< 0.2 
Neutrophils decrease [25] 
(cell/mm3) 
10-9/l 
< LLN – 1500 
< LLN – 1.5 
< 1500 - 1000 
< 1.5 – 1.0 
< 1000 - 500 
< 1.0 – 0.5 
< 500 
< 0.5 
Platelets decrease [25] 
(cell/mm3) 
10-9/l 
< LLN – 75,000 
< LLN – 75.0 
< 75,000 – 50,000 
< 75.0 – 50.0 
< 50,000 – 25,000 
< 50.0 – 25.0 
< 25,000 
< 25.0 
Abbreviations: LLN = Lower limit of the normal range; ULN = Upper limit of the normal range; WBC = White blood cell. 
* Those parameters that are not listed do not have grading categories in the CTCAE will be reviewed by the Principal 
Investigator and only reported as an AE if considered to be clinically relevant. 

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ABNORMAL LABORATORY VALUES RATING: URINALYSIS PARAMETERS 
Urine * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-Threatening 
(Grade 4) 
Protein [25] 
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. 
* Those parameters that are not listed do not have grading categories in the CTCAE will be reviewed by the Principal 
Investigator and only reported as an AE if considered to be clinically relevant.