A Single-center, Open-label, Randomized, Controlled, Crossover Study to Investigate the Nicotine Pharmacokinetic Profile of the Carbon Heated Tobacco Product 1.1 Menthol (CHTP 1.1 M) Following Single Use in Smoking, Healthy Subjects Compared to Menthol Conventional Cigarettes
Phase: NA
Conditions: Smoking
Sponsor: Philip Morris Products S.A.

 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the written 
consent of Philip Morris International. 
Clinical Study Protocol P2M-PK-04-JP 
 
Study title: 
A single-center, open-label, randomized, controlled, crossover 
study to investigate the nicotine pharmacokinetic profile of the 
Carbon Heated Tobacco Product 1.1 Menthol (CHTP 1.1 M) 
following single use in smoking, healthy subjects compared to 
menthol conventional cigarettes 
Short name: 
Nicotine pharmacokinetic profile of the CHTP 1.1 M 
Registration number: 
Not assigned 
Product name: 
Carbon Heated Tobacco Product 1.1 Menthol (CHTP 1.1 M) 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Version number: 
Version 2.0 
Date: 
18 May 2015 
Authors: 
, PhD, Clinical Scientist  
, MEng MSc, Biostatistician 
, MD, Medical Safety Officer 
 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 2 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Amendment 1 
SUMMARY OF CHANGES 
The following administrative changes are issued as non-substantial amendments of the clinical 
study protocol P2M-PK-04-JP: 
 Replacement of the current Medical Safety Officer 
, MD, PhD: The 
Medical Safety Officer duties have been assumed ad interim by 
, 
MD until 31 May 2015. As of the 1st June 2015, the responsible Medical Safety Officer 
will be 
, MD, PhD, MFPM. These administrative changes 
are reflected on the front page, in section 8.3 
“Reporting and Follow-Up of Serious 
Adverse Events”, in section 13.1.2 “Sponsor” and in section 13.1.3 “Other 
Responsibilities”. 
 The contact details of the local contract research organization 
 have changed 
due to relocation. These administrative changes are reflected in section 13.1.3 “Other 
Responsibilities”. 
 Replacement of the current Biostatistician 
, PhD: The Biostatistician 
duties have been assumed by 
, MEng, MSc. These 
administrative changes are reflected on the front page and in section 13.1.2. Sponsor. 
 Replacement of the current Clinical Scientist 
, PhD: The Clinical 
Scientist duties have been assumed by 
 
, PhD. These 
administrative changes are reflected on the front page and in section 13.1.2. Sponsor.  
 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 3 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Product Name: 
Carbon Heated Tobacco Product 1.1 Menthol (CHTP 1.1 M) 
Study Title: 
A single-center, open-label, randomized, controlled, crossover study to investigate the 
nicotine pharmacokinetic profile of the Carbon Heated Tobacco Product 1.1 Menthol (CHTP 
1.1 M) following single use in smoking, healthy subjects compared to menthol conventional  
cigarettes 
Study Number: 
P2M-PK-04-JP 
Short Study Title: 
Nicotine pharmacokinetic profile of the CHTP 1.1 M 
Objectives and Endpoints: 
Primary Objective and Endpoints: 
To evaluate the rate and amount of nicotine absorbed (as assessed by maximum plasma 
concentration [Cmax] and area under the concentration-time curve [AUC] from start of 
product use to time of last quantifiable concentration [AUC(0-last)]) from the CHTP 1.1 
M relative to menthol conventional cigarettes (mCC) following single use of the CHTP 
1.1 M and mCC. 
Endpoints: 
• Cmax 
• AUC(0-last) 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 4 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Secondary Objectives and Endpoints: 
1. To evaluate the difference on plasma nicotine pharmacokinetic (PK) absorption 
parameters (AUC from start of product use extrapolated to infinity [AUC(0-∞)], up to 
12 hours [AUC(0-12)],  and partial AUC(0-t’), where t’ is the subject-specific time of 
maximum plasma nicotine concentration following single use of the mCC 
[AUC(0-t’)]) between the CHTP 1.1 M and mCC. 
Endpoints: 
• AUC(0-∞) 
• AUC(0-12) 
• Partial AUC(0-t’) 
2. To evaluate the time to the maximum concentration (tmax) of plasma nicotine for the 
CHTP 1.1 M as compared to mCC. 
Endpoint: 
• tmax 
3. To describe the terminal half-life (t1/2) of plasma nicotine for the CHTP 1.1 M and 
mCC. 
Endpoint: 
• t1/2 
4. To describe the differences on urge-to-smoke over time between the CHTP 1.1 M 
and mCC. 
Endpoint: 
• Urge-to-smoke questionnaire (questionnaire of smoking urges brief [QSU-
brief]) total score, factor 1 and factor 2 
5. To describe product evaluation of the CHTP 1.1 M and mCC. 
Endpoint: 
• Product 
evaluation 
questionnaire 
(modified 
cigarette 
evaluation 
questionnaire [MCEQ]) subscales scores 
6. To describe the levels of carbon monoxide (CO) exposure for the CHTP 1.1 M as 
compared to mCC. 
Endpoint: 
• CO exposure biomarkers: levels of exhaled CO and carboxyhemoglobin 
(COHb) in blood 
7. To monitor the safety during the study. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 5 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Endpoints: 
• Incidence of adverse events (AEs)/serious adverse events (SAEs) 
• Respiratory symptoms: cough assessment by visual analogue and Likert 
scales and one open question 
• Vital signs 
• Spirometry 
• Electrocardiogram (ECG) 
• Clinical chemistry, hematology, and urine analysis safety panel 
• Physical examination 
• Concomitant medication  
• Incidence of CHTP 1.1 M malfunctions and misuse, 
 
 
Additional study assessments (for baseline characteristics): 
• Serology for human immunodeficiency virus 1/2 and hepatitis B and C 
• Urine pregnancy test (female subjects of childbearing potential only), urine cotinine test, 
urine drug screen 
• Alcohol breath test 
• Chest X-ray 
• Nicotine dependence to be assessed with the Fagerström test for nicotine dependence 
revised version 
• Cytochrome 
P450 
2A6 
(CYP2A6) 
activity 
expressed 
as 
trans-3'-
hydroxycotinine/cotinine molar metabolite ratio in plasma 
Study Hypothesis: 
Given that the objective of this study is to determine the point estimate and precision of the 
ratio of the CHTP 1.1 M:mCC for Cmax and AUC(0-last), there is no statistical hypothesis to 
be tested. 
Evaluation Criterion:  
The study will target to describe the 95% confidence intervals (CI) of the CHTP 1.1 M:mCC 
ratio for the primary nicotine PK parameters estimated with a precision of ±30%. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 6 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Study Design: 
This is a randomized, controlled, 2-period, 2-sequence, single-use crossover study. Each 
subject will receive CHTP 1.1 M and mCC (Figure 1): 
 
Figure 1 
Study Flow Chart 
Period 1:  From Day -2 to Day 1. After Day 1 product use, the subject will start his/her 
washout for period 2  
Period 2:  From Day 2 to Day 3. The products should be used at the same time (within 1 
hour) on Day 1 and Day 3  
48 eligible, healthy smoking subjects will be randomized to one of the 2 sequences: 
Sequence 1: CHTP 1.1 M then mCC 
Sequence 2: mCC then CHTP 1.1 M 
Subjects will be discharged from the investigational site in the morning of Day 4 after 
performance of the Discharge assessments. 
From discharge on Day 4 until Day 11: a 7-day safety follow-up will be done for the 
recording of spontaneously reported AEs and SAEs (passive surveillance) and the active 
follow-up by the investigational site of AEs/SAEs ongoing at the time of discharge.  
Study Population and Main Criteria for Inclusion: 
A total of 48 healthy female or male Japanese currently smoking adult subjects following 
the main inclusion criteria: 
 Subject is at a minimum 23 years of age 
 Smoking, healthy subject as judged by the Investigator 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 7 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
 Subject does not plan to quit smoking in the next 3 months 
 The subject is ready to accept interruptions to smoking for up to 6 days 
 The subject is ready to accept using CHTP 1.1 M 
Subjects will be randomized to 1 of 2 sequences. Each sex and each of the smoking level 
(ISO nicotine levels ≤ 0.6 mg and 0.6 to 1 mg) will have a quota applied to ensure they 
represent at least 40% of the total study. 
Subjects who do not complete the study after randomization will not be replaced. 
Investigational Products: 
 CHTP 1.1 M 
 Subject’s own supply of commercially available preferred single brand mCC 
Study Duration: 
The entire study per subject will last from 15 to 42 days, including a screening period of up 
to 28 days (Day -31 to Day -4) prior to Admission, and 7 days of confinement (Day -3 to 
discharge on Day 4). In the morning of Discharge (Day 4) examinations will be conducted. 
After Discharge, subjects will then enter a 7-day safety follow-up (until Day 11) for the 
recording of spontaneously reported AEs/SAEs and the active follow-up of ongoing 
AEs/SAEs by the site. 
Statistical Methods: 
All primary and secondary endpoints will be summarized with descriptive statistics. In 
addition, PK, subjective effects of smoking, and safety variables will be analyzed as follows. 
Pharmacokinetics: 
Only subjects without major protocol deviations that impact the evaluability of the data will 
be included in the PK analysis set. 
Nicotine PK parameters will be derived from plasma nicotine data by non-compartmental 
analysis. 
An analysis of variance (ANOVA) will be conducted on natural logarithmically transformed 
AUC(0-last) and Cmax endpoints. The model will include terms for sequence, subjects within 
sequence, product exposure, and period as fixed effect factors. The results of this analysis 
will be presented in terms of adjusted geometric least square means and 95% confidence 
intervals (CI) for CHTP 1.1 M:mCC ratio. 
AUC(0-∞), AUC(0-12),AUC(0-t’), and t1/2 will be analyzed using the same approach adopted for 
the primary endpoints. The Hodges-Lehmann estimates of median tmax differences between 
the CHTP 1.1 M and mCC will be presented together with the 95% CI. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 8 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Subjective effects of smoking: 
A mixed effects ANOVA using period, sequence, and product exposure as fixed effects and 
subjects within sequence as a random effect will be adopted to analyze the domain scores of 
the product evaluation (MCEQ) questionnaire, for the comparison between CHTP 1.1 M and 
mCC. The same model will be evaluated for the urge-to-smoke (QSU-brief), including the 
assessment time points as repeated measurements. The results will be presented in terms of 
least square means and 95% CI for the CHTP 1.1 M-mCC differences. Questionnaire scores 
will be summarized by product exposure, including the mean percent change from the value 
prior to T0. The maximum percent decrease over time and the time to maximum percent 
decrease over time will be summarized by product exposure and analyzed using the Hodges-
Lehmann method for the QSU-brief total score. 
Safety Analysis:  
The safety population will comprise all subjects who are exposed to the CHTP 1.1 M during 
the study, including the product test at Admission. Adverse event data will serve as the 
primary assessment of safety. Safety data will be listed and tabulated by sequence. 
Sample Size: 
A total of 48 subjects will be randomized. 
48 subjects are needed to estimate the mean Cmax parameter ratio between CHTP 1.1 M and 
mCC with a 80% probability of obtaining a margin of error (95% CI) of at most ±30%, 
assuming that the CHTP 1.1 M have a nicotine PK profile similar to mCC (Cmax ratio equal 
to 1.00) and a 5% dropout rate. 
The sample size of this study is based on our current understanding from the use of the 
Tobacco Heated System 2.2 Menthol (THS 2.2 Menthol), another PMI heated platform 
tobacco product, in the Japanese population where the within-subject coefficient of variation 
for nicotine Cmax and AUC(0-last) was found to be 60% and 50%, respectively. 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 9 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
TABLE OF CONTENTS 
SUMMARY OF CHANGES .....................................................................................................2 
SYNOPSIS .................................................................................................................................3 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................16 
1 
ETHICS AND REGULATIONS .....................................................................................20 
1.1 
Institutional Review Board Approval ....................................................................20 
1.2 
Ethical Conduct of the Study .................................................................................20 
1.3 
Subject Information and Consent...........................................................................21 
1.3.1 Informed Consent Form for Study Participation .......................................21 
1.3.2 Amendment to the Informed Consent Form .............................................21 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................21 
2 
INTRODUCTION ...........................................................................................................23 
2.1 
Background ............................................................................................................23 
2.1.1 Smoking-Related Diseases and Harm Reduction Strategy .......................23 
2.1.2 Description of the Product and Scientific Findings ..................................23 
2.2 
Purpose of the Study ..............................................................................................24 
2.3 
Anticipated Benefits and Risks ..............................................................................24 
2.3.1 Anticipated Benefits ..................................................................................24 
2.3.2 Anticipated Foreseeable Risks due to Study Procedures ..........................24 
2.3.3 Anticipated Foreseeable Risks due to Investigational Product (CHTP 
1.1 M) ........................................................................................................24 
2.3.4 Unforeseeable Risks ..................................................................................25 
3 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................26 
3.1 
Primary Objective and Endpoints ..........................................................................26 
3.2 
Secondary Objectives and Endpoints.....................................................................26 
4 
INVESTIGATIONAL PLAN ..........................................................................................29 
4.1 
Overall Study Design and Plan ..............................................................................29 
4.2 
Rationale for Study Design and Control Group .....................................................30 
4.3 
Study Duration .......................................................................................................31 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 10 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
4.4 
Appropriateness of Measurement ..........................................................................31 
5 
STUDY POPULATION ..................................................................................................32 
5.1 
Inclusion Criteria ...................................................................................................32 
5.2 
Exclusion Criteria ..................................................................................................33 
5.3 
Discontinuation of Subjects from the Study ..........................................................36 
5.4 
Lost to follow up ....................................................................................................37 
5.5 
Violation of Selection Criteria ...............................................................................37 
6 
INVESTIGATIONAL PRODUCTS ...............................................................................38 
6.1 
Description of Investigational Products .................................................................38 
6.2 
Packaging and Labeling .........................................................................................38 
6.3 
Use of Investigational Products .............................................................................39 
6.3.1 Admission (Day -3) ...................................................................................39 
6.3.2 Investigational Period (Day -2 to Day 3) ..................................................39 
6.3.3 Single Use of Products (Day 1 and Day 3) ...............................................39 
6.3.4 Day of Discharge .......................................................................................40 
6.3.5 Safety Period .............................................................................................40 
6.3.6 Stopping Rules for Investigational Product ..............................................40 
6.4 
Method for Assigning Subjects to Sequences ........................................................40 
6.5 
Blinding..................................................................................................................41 
6.6 
Investigational Product Accountability and Compliance ......................................41 
6.6.1 Dispensing Investigational Product ...........................................................41 
6.6.2 Storage and Accountability .......................................................................41 
6.6.3 Investigational Product Retention .............................................................42 
6.6.4 Compliance to Investigational Products ....................................................42 
6.7 
Restrictions ............................................................................................................42 
6.7.1 Smoking Restrictions ................................................................................42 
6.7.2 Dietary Restrictions ...................................................................................42 
6.7.3 Concomitant Medication ...........................................................................43 
6.7.4 Other ..........................................................................................................44 
7 
STUDY PROCEDURES .................................................................................................45 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 11 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
7.1 
Informed Consent Form .........................................................................................45 
7.2 
Smoking Cessation Advice and Debriefing ...........................................................45 
7.3 
Support during Smoking Abstinence/Periods of Reduced Smoking .....................45 
7.4 
Clinical Assessments .............................................................................................46 
7.4.1 Demographic Data ....................................................................................46 
7.4.2 Identification of the Current Cigarette Brand ...........................................46 
7.4.3 Smoking History and Willingness to Quit Smoking .................................46 
7.4.4 Demonstration and CHTP 1.1 M Test .......................................................46 
7.4.5 Medical History, Concomitant Disease, Previous and Ongoing 
Medications ...............................................................................................47 
7.4.6 Physical Examination ................................................................................47 
7.4.7 Body Height and Weight ...........................................................................47 
7.4.8 Vital Signs .................................................................................................47 
7.4.9 Other Clinical Assessments .......................................................................48 
7.4.9.1 
Spirometry .................................................................................48 
7.4.9.2 
Electrocardiogram .....................................................................48 
7.4.9.3 
Chest X-ray ...............................................................................48 
7.5 
Biomarker Assessment...........................................................................................49 
7.5.1 Biomarker of Exposure .............................................................................49 
7.5.1.1 
Biomarker of Exposure to CO and COHb ................................49 
7.5.1.2 
Biomarkers of Exposure to Nicotine .........................................49 
7.5.2 CYP2A6 Activity ......................................................................................50 
7.6 
Laboratory Assessments ........................................................................................50 
7.6.1 Clinical Chemistry, Hematology, and Urine Analysis for Safety Panel ...50 
7.6.2 Serology ....................................................................................................51 
7.6.3 Urine Drug Screen .....................................................................................51 
7.6.4 Urine Cotinine Screening ..........................................................................51 
7.6.5 Alcohol Breath Test ..................................................................................51 
7.6.6 Urine Pregnancy Testing ...........................................................................51 
7.7 
Sample Handling, Storage, and Shipment .............................................................51 
7.7.1 Blood Samples ..........................................................................................51 
7.7.2 Urine Samples ...........................................................................................52 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 12 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
7.8 
Questionnaires........................................................................................................52 
7.8.1 Fagerström Test for Nicotine Dependence (FTND, revised version) .......52 
7.8.2 Assessment of Cough ................................................................................52 
7.8.3 Modified Cigarette Evaluation Questionnaire (MCEQ, modified 
version) ......................................................................................................53 
7.8.4 Questionnaire of Smoking Urges ..............................................................53 
8 
ADVERSE EVENTS .......................................................................................................54 
8.1 
Definitions..............................................................................................................54 
8.1.1 Adverse Events ..........................................................................................54 
8.1.2 Serious Adverse Events .............................................................................54 
8.2 
Assessment of Adverse Events ..............................................................................54 
8.2.1 Collection of Information ..........................................................................54 
8.2.2 Period of Collection ..................................................................................55 
8.2.2.1 
Screening Period .......................................................................55 
8.2.2.2 
Admission until End of Study ...................................................55 
8.2.3 Intensity of Adverse Event ........................................................................56 
8.2.4 Relationship to Investigational Product and Relationship to Study 
Procedures .................................................................................................56 
8.2.5 Expectedness .............................................................................................56 
8.3 
Reporting and Follow-Up of Serious Adverse Events ...........................................57 
8.4 
Reporting of Other Events Critical to Safety Evaluations .....................................58 
8.4.1 Abnormal Results of Laboratory Tests .....................................................58 
8.5 
Reporting and Follow–Up of Pregnancies .............................................................59 
8.6 
Adverse Events Leading to Discontinuation..........................................................60 
8.7 
Investigational Product Malfunction and Misuse ..................................................60 
9 
STUDY ACTIVITIES .....................................................................................................61 
9.1 
Screening Visit (Day -31 to Day -4) ......................................................................61 
9.2 
Admission (Day -3)................................................................................................63 
9.3 
Investigational Period ............................................................................................65 
9.3.1 Days of Smoking Abstinence (Day -2, Day -1 and Day 2) .......................65 
9.3.2 Days of Single Use (Day 1 and Day 3) .....................................................66 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 13 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
9.4 
Discharge ...............................................................................................................68 
9.5 
Safety Follow-up Period ........................................................................................69 
9.6 
Early Termination Procedures ...............................................................................70 
10 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................71 
10.1 Monitoring .............................................................................................................71 
10.2 Training of Collaborators .......................................................................................71 
10.3 Audits and Inspections ...........................................................................................72 
11 DATA MANAGEMENT ACTIVITIES..........................................................................73 
11.1 Data Capture ..........................................................................................................73 
11.1.1 Case Report Forms and Study Records .....................................................73 
11.1.2 Protocol Deviations ...................................................................................73 
11.2 Data Handling ........................................................................................................74 
11.2.1 Data Verification .......................................................................................74 
11.2.2 Coding .......................................................................................................74 
11.2.3 Database Lock ...........................................................................................75 
12 PLANNED STATISTICAL METHODS ........................................................................76 
12.1 General Considerations ..........................................................................................76 
12.1.1 Stratification Criteria .................................................................................76 
12.1.2 Definitions for Statistical Data Analysis ...................................................76 
12.1.3 Descriptive Statistics .................................................................................76 
12.1.4 Handling of Missing Values and of Values outside the Detection 
Limits ........................................................................................................76 
12.1.5 Significance Level for Inferential Analysis ..............................................77 
12.2 Determination of Sample Size and Power Consideration ......................................77 
12.3 Analysis Populations ..............................................................................................77 
12.3.1 PK Populations ..........................................................................................77 
12.3.2 Safety Population ......................................................................................77 
12.4 Demographics and Baseline Characteristics ..........................................................78 
12.5 Primary Endpoints .................................................................................................78 
12.5.1 Primary Endpoints Analysis Variables .....................................................78 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 14 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
12.5.2 Baseline Comparability .............................................................................78 
12.5.3 Descriptive Analysis .................................................................................78 
12.5.4 Confirmatory Analyses .............................................................................79 
12.6 Secondary Endpoints .............................................................................................79 
12.6.1 Secondary Endpoint Analysis Variables ...................................................79 
12.6.2 Baseline Comparability .............................................................................79 
12.6.3 Descriptive Analysis .................................................................................80 
12.6.4 Confirmatory Analyses .............................................................................80 
12.6.5 Safety Endpoints .......................................................................................80 
12.7 Exploratory Analyses .............................................................................................81 
12.8 Interim Analysis .....................................................................................................81 
13 ADMINISTRATIVE CONSIDERATIONS ....................................................................82 
13.1 Investigator’s and Study Administrative Structure ................................................82 
13.1.1 Investigator ................................................................................................82 
13.1.2 Sponsor ......................................................................................................82 
13.1.3 Other Responsibilities ...............................................................................83 
13.2 Subject Confidentiality ..........................................................................................83 
13.3 Access to Source Documentation ..........................................................................84 
13.4 Record Retention ...................................................................................................84 
13.5 Clinical Study Report .............................................................................................86 
13.6 Financial Disclosure...............................................................................................86 
13.7 Publication and Disclosure Policy .........................................................................86 
13.8 Insurance ................................................................................................................86 
14 REFERENCE LIST .........................................................................................................87 
15 APPENDICES .................................................................................................................90 
15.1 Appendix A – Schedule of Events .........................................................................90 
15.2 Appendix B - Participating Laboratories ...............................................................94 
15.3 Appendix C - Investigational Product and Instructions for Use ............................95 
15.4 Appendix D - Abnormal Laboratory Values .........................................................96 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 15 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
LIST OF IN-TEXT TABLES 
Table 1 
Definition of Randomization Sequences ...................................................30 
Table 2 
Single Use of Products (Day 1 and Day 3) ................................................40 
Table 3 
Description of Blinded Study Personnel ....................................................41 
Table 4 
Drugs and Substances Considered Interacting with CYP2A6 ...................43 
Table 5 
Clinical Laboratory Parameters for Safety Panel.......................................50 
Table 6 
Time Schedule – Screening (Day -31 to Day -4) .......................................61 
Table 7 
Time Schedule – Admission (Day -3) .......................................................63 
Table 8 
Time Schedule – Wash-out (Day -2, Day -1) ............................................65 
Table 9 
Time Schedule – Wash-out (Day 2)...........................................................66 
Table 10 
Time Schedule – Single Use (Day 1 and Day 3) .......................................66 
Table 11 
Time Schedule – Day 4 Discharge .............................................................69 
Table 12 
Time Schedule – Early Termination Procedures .......................................70 
Table A1 
Schedule of Events .....................................................................................90 
Table D1 
Abnormal Laboratory Values Rating: Serum Chemistry Parameters ........96 
Table D2 
Abnormal Laboratory Values Rating: Hematology Parameters ................97 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Flow Chart .........................................................................................6 
Figure 2 
Study Flow Chart .......................................................................................29 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 16 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
ADL 
Activities of daily living 
AE 
Adverse event 
ANOVA 
Analysis of variance 
AUC 
Area under the concentration-time curve 
AUC(0-∞) 
Area under the concentration-time curve from time 0 extrapolated 
to infinity 
AUC(0-last) 
Area under the concentration-time curve from T0 to time of last 
quantifiable concentration 
AUC(0-t’) 
Partial AUC, where t’ is the subject-specific time of maximum 
nicotine concentration following the single use of cigarettes 
BMI 
Body mass index 
CC 
Conventional cigarette(s) 
CD 
Compact disc 
CI 
Confidence interval 
Clast 
Last quantifiable concentration 
Cmax 
Maximum concentration 
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 
CYP2A6 
Cytochrome P450 2A6 
ECG 
Electrocardiogram 
EOS 
End of study 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 17 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
FDA 
Food and Drug Administration  
FEV1  
Forced expiratory volume in 1 second 
FTND 
Fagerström test for nicotine dependence (revised version) 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
HPHCs 
Harmful and potentially harmful constituents  
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 
mCC 
Menthol conventional cigarette 
MCEQ 
Modified cigarette evaluation questionnaire  
MedDRA 
Medical dictionary for regulatory activities 
MRTP 
Modified risk tobacco product 
PK 
Pharmacokinetic(s) 
PMI 
Philip Morris International 
QC 
Quality control 
QSU-brief 
Questionnaire of smoking urges 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SHM 
Sample handling manual 
SOP 
Standard operating procedure 
T 
Time point  
T0 
Time point of first product use during study day 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 18 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
t½ 
Half-life 
tmax 
Time to maximum concentration 
 
 
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 
λz 
Terminal elimination rate constant 
Explanation of Terms 
The following special terms are used in this protocol: 
End of Study 
End of Study (EOS) is defined as the discharge on Day 4 or the date 
of early termination of the last subject plus a 7-day Safety Follow-
up Period. 
Enrolment 
Enrolment is the period starting at the time of the first product test 
use at Admission until EOS. 
First product use time 
point 
Start of the product use of the CHTP 1.1 M or mCC corresponding 
to the first puffing of the CHTP 1.1 M or mCC.  
mCC 
The term ‘menthol conventional cigarette’ refers to manufactured 
and commercially available menthol cigarettes and excludes hand-
rolled cigarettes, cigars, pipes, bidis, and other nicotine-containing 
products. 
Carbon Heated Tobacco 
Product 1.1 Menthol 
(CHTP 1.1 M)  
CHTP 1.1 M is a tobacco stick which is comparable in shape and 
form, and is used in a similar manner to a menthol conventional 
cigarette. To use the CHTP 1.1 M, the consumer removes the 
protective cap and uses a conventional lighting method to ignite the 
heat source. 
 
, the aerosol generated by the heating process is inhaled by 
placing the lips on the filter and drawing air through the CHTP 1.1 
M. 
Randomization 
Assignment to the respective product at any time on Day -1 utilizing 
an interactive web/voice response system (IxRS). On Day 1, the 
subjects will be individually informed about the product they are 
randomized to just before the first product use. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 19 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Screen failure 
Subject who signs informed consent form but does not meet the 
entry criteria prior to enrolment at Admission (Day -3) or met all 
entry criteria, but was not enrolled due to completion of enrolment 
(i.e., supernumerary subject). Re-screening of subjects who did not 
meet any entry criteria will not be permitted.  

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 20 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
1 
ETHICS AND REGULATIONS 
1.1 
Institutional Review Board Approval 
Prior to the start of the study, the clinical study protocol, together with its associated documents 
(informed consent form [ICF] which includes both subject information sheet and informed 
consent, subject recruitment procedures [e.g., advertisements], written information to be 
provided to the subjects, Investigator’s Brochure [IB], available safety information, the 
Investigator’s curriculum vitae and/or other evidence of qualifications, the list of any other 
documents requested by the Institutional Review Board [IRB]), will be submitted for review 
and approval to the relevant IRB. The IRB shall be appropriately constituted and perform its 
functions in accordance with the International Conference on Harmonization (ICH) Tripartite 
Guidance for Good Clinical Practice (GCP [1]), Ministerial Ordinance on GCP for drugs, and 
local legal and regulatory requirements, as applicable. 
In accordance with GCP, a written confirmation of the IRB 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 IRB, with dates and version numbers, as well as the 
date of approval. The composition of the IRB, including the name and occupation of the 
chairperson, should be supplied to the Sponsor together with a GCP compliance statement. 
The written approval from the IRB will be filed in the Investigator’s file, and another original 
copy will be filed in the study master file (SMF) at the Sponsor or designated organization. 
The study must not start before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IRB. 
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the Investigator. All amendments will be submitted 
to the IRB, and substantial amendments will only be implemented after approval by the IRB. 
These requirements for approval should in no way prevent any action from being taken by the 
Investigator 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, and is implemented for 
safety reasons, the Sponsor and the IRB should be informed immediately. 
Relevant safety information will be submitted to the IRB during the course of the study in 
accordance with national regulations and requirements. 
1.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki 2013 [2] and are consistent with ICH/GCP [1], Ethical Guidelines for 
Clinical Studies (Ministry of Health, Labour and Welfare, 2003 [as last amended on July 31, 
2008]) [3], Ministerial Ordinance on Good Clinical Practice for Drugs (as last amended by the 
Ordinance of Ministry of Health, Labour and Welfare) [4], and applicable regulatory principles 
and requirements. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 21 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
The Investigator agrees to conduct the clinical study in compliance with the protocol agreed 
with the Sponsor and approved by the IRB. 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 2013 [2] should be located in the Investigator’s study file. 
1.3 
Subject Information and Consent 
1.3.1 
Informed Consent Form for Study Participation 
At the Screening Visit, the Investigator will ensure 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 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 
in the study, the subject and the person who conducted the inform consent discussion will both 
sign, date and time the ICF. The ICF includes both the subject information sheet and informed 
consent. No study-specific procedures will be performed before the ICF has been signed 
(including date and time).  
The original, dated, and signed ICF(s) is kept in the Investigator study file at the site, and a 
copy must be given to the subject. 
The subject will be informed that if he/she withdraws from the study, the data collected until 
the point of withdrawal will be maintained as part of the study data and the samples collected 
prior to withdrawal will be analyzed, unless the subject disagrees 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 
Amendment to the Informed Consent Form  
If a protocol amendment is required, or if any new information regarding the risk profile of the 
investigational product (IP) becomes available, or for any other reason deemed necessary, an 
amendment to the ICF may be required. 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 a relevant IRB before subjects are required to re-sign the ICF 
(including date and time). If new and important safety information is received, subjects who 
already completed or are discontinued from the study will be informed by letters, emails or 
phone calls. 
1.4 
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 22 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
representative, and the Investigator abide by the principles of the ICH guidelines on GCP [1]. 
These guidelines apply specifically to pharmaceutical development but nevertheless provide a 
robust and ethical framework for conducting clinical studies of tobacco 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 will carry out the clinical study in accordance with applicable 
national and local laws of the pertinent regulatory authorities. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 23 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
2 
INTRODUCTION 
2.1 
Background 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy 
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. To those smokers who 
are not able or not willing to quit, Philip Morris International (PMI) is developing alternative 
approaches by developing products with the potential to reduce the risks of tobacco-related 
diseases. These products are now referred to by the US Food and Drug Administration (FDA) 
as Modified Risk Tobacco Products (MRTPs) [5]. 
PMI develops candidate MRTPs with the objective to substantially reduce the exposure to 
harmful and potentially harmful constituents (HPHCs) while providing an acceptable option 
to smokers as substitutes for 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 [6], and more than 100 of them have 
been categorized as HPHCs [7]. 
The product developed by PMI, and to be assessed in this study, is the Carbon Heated Tobacco 
Product 1.1 Menthol (CHTP 1.1 M). CHTP 1.1 M avoids combustion and is heating tobacco 
to significantly lower temperatures than CC. 
CHTP 1.1 M is a tobacco stick which looks the same as, and is used in a similar manner to a 
mCC. To use the CHTP 1.1 M, the consumer removes the protective cap and uses a 
conventional lighting method to ignite the heat source. 
 
, the aerosol generated by the heating process is inhaled by placing the lips 
on the filter and drawing air through the CHTP 1.1 M. During use, the tobacco in the CHTP 
1.1 M is exposed to a well-defined temperature profile which ensures heating without 
combustion and at the same time provides an acceptable consumer experience in a consistent 
manner. 
The non-clinical assessment of CHTP 1.1 M is described in the investigator’s brochure and 
supports the clinical assessment of CHTP 1.1 M. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 24 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
One clinical study has been conducted with CHTP 0.1, an earlier and non-menthol 
development version of the CHTP 1.1 M, in Europe. The study showed marked reductions in 
exposure to HPHCs compared to subjects continuing smoking CC in controlled conditions and 
no safety concerns. No clinical studies have been conducted with the CHTP 1.1 M. 
2.2 
Purpose of the Study 
The purpose of this clinical study is to evaluate the profile of nicotine uptake (rate and extent 
of nicotine absorbed) after single use of the CHTP 1.1 M compared to mCC in healthy smokers. 
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, at Admission, and at Discharge. The advice will follow the 
recommendations of the World Health Organization (WHO) [8] “Evidence based 
Recommendations on the Treatment of Tobacco Dependence”. Subjects who are motivated to 
quit smoking during the study will be given the opportunity to continue their smoking cessation 
attempt and will be referred to appropriate stop smoking services for continuing support and 
counselling at a higher level. 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 with short-
acting bronchodilator at Screening) per study protocol and scientifically accepted 
standards. 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product (CHTP 
1.1 M) 
• 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. 
Support for smoking abstinence will be provided. Further 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). 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 25 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
• 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 detailed to study participants. 
Unexpected malfunction of the CHTP 1.1 M may lead to unforeseeable risk. Subjects will be 
informed that the CHTP 1.1 M is not demonstrated to be less harmful than mCC. Mitigation 
will include close monitoring and medical supervision to detect any unforeseeable risk or 
safety signals at the earliest time possible. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 26 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective and Endpoints 
To evaluate the rate and amount of nicotine absorbed (as assessed by maximum plasma 
concentration [Cmax] and area under the concentration-time curve [AUC] from start of 
product use to time of last quantifiable concentration [AUC(0-last)]) from the CHTP 1.1 M 
relative to menthol conventional cigarettes (mCC) following single use of the CHTP 1.1 
M and mCC. 
Endpoints: 
• Cmax 
• AUC(0-last) 
3.2 
Secondary Objectives and Endpoints 
1. To evaluate the difference on plasma nicotine pharmacokinetic (PK) absorption 
parameters (AUC from start of product use extrapolated to infinity [AUC(0-∞)], up to 
12 hours [AUC(0-12)],  and partial AUC(0-t’), where t’ is the subject-specific time of 
maximum plasma nicotine concentration following single use of the mCC [AUC(0-t’)]) 
between the CHTP 1.1 M and mCC. 
Endpoints: 
• AUC(0-∞) 
• AUC(0-12) 
• Partial AUC(0-t’) 
2. To evaluate the time to the maximum concentration (tmax) of plasma nicotine for the 
CHTP 1.1 M as compared to mCC. 
Endpoint: 
• tmax 
3. To describe the terminal half-life (t1/2) of plasma nicotine for the CHTP 1.1 M and mCC. 
Endpoint: 
• t1/2 
4. To describe the differences on urge-to-smoke over time between the CHTP 1.1 M and 
mCC. 
Endpoint: 
• Urge-to-smoke questionnaire (questionnaire of smoking urges brief [QSU-
brief]) total score, factor 1 and factor 2 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 27 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
5. To describe product evaluation of the CHTP 1.1 M and mCC. 
Endpoint: 
• Product evaluation questionnaire (modified cigarette evaluation questionnaire 
[MCEQ]) subscales scores 
6. To describe the levels of carbon monoxide (CO) exposure for the CHTP 1.1 M as 
compared to mCC. 
Endpoint: 
• CO exposure biomarkers: levels of exhaled CO and carboxyhemoglobin (COHb) 
in blood 
7. To monitor the safety during the study. 
Endpoints: 
• Incidence of adverse events (AEs)/serious adverse events (SAEs) 
• Respiratory symptoms: cough assessment by visual analogue and Likert scales 
and one open question 
• Vital signs 
• Spirometry 
• Electrocardiogram (ECG) 
• Clinical chemistry, hematology, and urine analysis safety panel 
• Physical examination 
• Concomitant medication.  
• Incidence of CHTP 1.1 M malfunctions and misuse, 
 
 
Additional study assessments (for Baseline characteristics): 
• Serology for human immunodeficiency virus 1/2 and hepatitis B and C 
• Urine pregnancy test (female subjects of childbearing potential only), urine cotinine test, 
urine drug screen 
• Alcohol breath test 
• Chest X-ray 
• Nicotine dependence to be assessed with the Fagerström test for nicotine dependence 
revised version 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 28 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
• 
Cytochrome P450 2A6 (CYP2A6) activity expressed as trans-3'-hydroxycotinine/cotinine 
molar metabolite ratio in plasma 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 29 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a randomized, controlled, 2-period, 2-sequence, single-use crossover study. Each 
subject will receive CHTP 1.1 M and mCC (Figure 2). 
The end of the whole study is defined as the date that the last subject completes his/her 7-day 
safety follow-up period.  
Subjects that terminate the study after Enrolment and prior to completion of the study will be 
asked to undertake early termination procedures (section 9.6).  
1) Screening and Admission (from the ICF signature to the enrolment at Admission):  
A Screening Visit will be conducted within 4 weeks (Day -31 to Day -4) prior to Admission to 
the investigational site (Day -3). A demonstration of the CHTP 1.1 M will be done by the site 
collaborators during the Screening Visit. Screening procedures do not necessarily have to be 
conducted on the same day. On Day -3 (Admission), after all inclusion/exclusion criteria are 
checked, all eligible subjects will be enrolled and perform a product test using 3 to 5 CHTPs 
1.1 M. After product test, subjects not ready to use the CHTP 1.1 M will be discontinued.  All 
subjects that are not enrolled are considered as screen failures. Subject will be instructed not 
to smoke in the morning prior to Admission. After Admission, smoking will not be allowed 
until blood drawing for the assessment of CYP2A6 activity and spirometry have been 
performed (section 9.2). After these assessment procedures, smoking will be allowed until 
11.00 PM at Admission. 
 
Figure 2 
Study Flow Chart 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 30 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
2) The Investigational Period (from Day -2 to Discharge):  
The Investigational period will consist of 2 periods (Period 1, Period 2) with each period 
consisting of approximately 48 to 57 hours smoking abstinence and 1 day of single product 
use. 
Period 1:  From Day -2 to Day 1. After Day 1 product use, the subject will start his/her 
washout for period 2 
Period 2:  From Day 2 to Day 3. The products should be used at the same time (within 1 hour) 
on Day 1 and Day 3  
48 eligible, healthy smoking subjects will be randomized to one of 2 sequences: 
Table 1 
Definition of Randomization Sequences 
Sequence 
Sample Size 
1.  CHTP 1.1 M then mCC  
24 
2. mCC then  CHTP 1.1 M 
24 
Each sex and smoking strata (International Organization for Standardization [ISO] nicotine 
levels ≤ 0.6 mg vs. 0.6 to 1.0 mg) will have a quota applied to ensure they represent at least 
40% of the study population for each Sequence (Sequence 1 and Sequence 2). 
 
Subjects will be discharged from the investigational site in the morning of Day 4 after 
performance of Discharge assessments. 
3) The Safety Follow-up Period (from Discharge until Day 11): 
A 7-day safety follow-up will be done for the recording of spontaneously reported AEs and 
SAEs (passive surveillance) and the active follow-up by the investigational site of AEs/SAEs 
ongoing at Discharge. Any AE will in general be followed-up until resolved, stabilized (i.e., 
no worsening of the event), or until a plausible explanation for the event has been found.  
The end of study for the subject is defined as the Discharge on Day 4 or the date of early 
termination of the subject plus a 7-day safety follow-up period. For further information on 
safety follow-up requirements refer to section 8.2. 
4.2 
Rationale for Study Design and Control Group 
The minimum age of 23 years old in the inclusion criteria was selected based on: 
• The legal age of smoking in Japan is 20 years 
• To account for the 3 years of smoking history 
In this study, mCCs (up to 1.0 mg nicotine ISO yield/mCC) will be used as a reference product. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 31 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
The nicotine wash-out period was set to a minimum of approximately 48 hours (more than 5 
times the half-life elimination of nicotine) as the half-life elimination (t1/2) of nicotine in blood 
observed was about 4 hours in a previous study with the Tobacco Heating System 2.2 Menthol 
[9]. In a cross-over study, the washout period should be of the same duration for the two 
periods. Due to logistical reasons (smoking is difficult to be controlled by the site staff 
overnight), the wash-out prior to the first period will be slightly longer (approximately 57 
hours) than the second period (approximately 48 hours). 
The use of estrogen contraceptive is known to accelerate nicotine clearance by 20% - 30% in 
women as compared to women who do not take such [10]. Therefore, for the purpose of this 
study, it is not allowed to use hormonal contraception containing estrogens. This also applies 
to hormone replacement therapy. 
The activity of CYP2A6 will be measured at baseline as nicotine metabolism by CYP2A6 
varies between individuals of the same ethnicity/race and across ethnicity/race due to genetic 
variations. These genetic differences could be associated with reduced/increased nicotine 
metabolism [11]. 
4.3 
Study Duration  
The entire study per subject will last from 15 to 42 days, including a Screening period of up to 
28 days (Day -31 to Day -4) prior to Admission, and 7 days of confinement (Day -3 to time 
discharge on Day 4). In the morning of Discharge (Day 4), examinations will be conducted. 
After Discharge, subjects will then enter a 7-day safety follow-up (until Day 11) for the 
recording of spontaneously reported AEs/SAEs and the active follow-up of ongoing AEs/SAEs 
by the site. 
4.4 
Appropriateness of Measurement 
All laboratory measures utilized for this study are validated and are appropriate for the study 
assessments.  
All questionnaires used in this study, except cough questionnaires, are available as validated 
questionnaires.  

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 32 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
5 
STUDY POPULATION 
Forty-eight female or male Japanese currently smoking healthy adult subjects who smoke at 
least 10 mCC per day will be randomized into this study. The number of mCC consumption is 
not limited. Subjects must have a smoking history of at least 3 years of consecutive smoking 
prior to Screening. The smoking status of the subjects will be verified based on a urine cotinine 
test (cotinine ≥ 200 ng/mL).  
Subject who signs informed consent form but does not meet the entry criteria prior to enrolment 
at Admission or met all entry criteria, but was not enrolled due to completion of enrolment 
(i.e., supernumerary subject) will be considered as screen failure. 
 
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 at a minimum 23 years of age 
(inclusive).  
Safety 
X 
 
3. Subject is Japanese. 
Administrative 
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 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 33 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Inclusion Criteria 
Rationale 
Screening 
Admission 
(Day -3) 
5. Subject 
smokes 
at 
least 
10 
commercially available mCCs per day 
(no brand restriction) with a maximum 
yield of 1 mg nicotine ISO/mCC, as 
labelled on the cigarette package, for 
the last 4 weeks, based on self-
reporting. Furthermore, the subject has 
been smoking for at least the last 3 
consecutive years. The smoking status 
will be verified based on a urinary 
cotinine test (cotinine ≥ 200 ng/mL). 
Effect 
X 
X 
6. The subject does not plan to quit 
smoking in the next 3 months. 
Safety 
X 
 
7. The subject is ready to accept 
interruptions of smoking for up to 6 
days. 
Safety 
X 
X 
8. The subject is ready to accept using the 
CHTP 1.1 M. 
Effect 
 
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’s judgment, the 
subject cannot participate in the study 
for 
any 
reason 
(e.g., 
medical, 
psychiatric, and/or social reason). 
Safety  
X 
X 
2. A subject who is legally incompetent, 
or physically or mentally incapable of 
giving 
consent 
(e.g., 
emergency 
situation, 
under 
guardianship, 
prisoners, 
or 
subjects 
who 
are 
involuntarily incarcerated). 
Administrative 
X 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 34 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Exclusion Criteria 
Rationale 
Screening 
Admission 
(Day -3) 
3. The subject has a clinically relevant 
disease which requires medication 
(including 
but 
not 
limited 
to 
gastrointestinal, 
renal, 
hepatic, 
neurological, hematological, endocrine, 
oncological, 
urological, 
immunological, 
pulmonary, 
and 
cardiovascular disease or any other 
medical condition (including safety 
laboratory as per CTCAE), which as per 
the judgment of the Investigator would 
jeopardize the safety of the subject). 
Safety 
X 
X 
4. The subject has FEV1/FVC < 0.7 and 
FEV1 < 80% predicted value at post-
bronchodilator spirometry [12]. 
Safety 
X 
 
5. 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 
 
6. The subject has a body mass index 
(BMI) < 18.5 or ≥ 32.0 kg/m2. 
Safety 
X 
X 
7. As per the Investigator’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 
8. The 
subject 
has 
used 
nicotine-
containing 
products 
other 
than 
commercially available mCC (either 
tobacco-based products or nicotine 
replacement therapies), as well as 
electronic 
cigarettes 
and 
similar 
devices, within 4 weeks prior to 
Screening. 
Effect 
X 
X 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 35 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Exclusion Criteria 
Rationale 
Screening 
Admission 
(Day -3) 
9. The subject has received medication 
(prescription 
or 
over-the-counter) 
within 14 days or within 5 half-lives of 
the drug prior to Admission (whichever 
is longer) which has an impact on 
CYP2A6 activity. 
Effect 
 
X 
10. 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 study. 
Administrative 
X 
X 
11. The subject has a positive urine drug 
test. 
Administrative 
X 
X 
12. The subject has a positive serology test 
for HIV 1/2, hepatitis B, or hepatitis C.  
Safety 
X 
 
13. Donation or receipt of whole blood or 
blood products within 3 months prior to 
Admission. 
Safety 
X 
X 
14. The subject is a current or former 
employee of the tobacco industry or of 
their first-degree relatives (parent, 
sibling, child). 
Administrative 
X 
 
15. The subject is an employee of the 
investigational site or any other parties 
involved in the study or of their first-
degree relatives (parent, sibling, child). 
Administrative 
X 
 
16. The subject has participated in a clinical 
study within 3 months prior to the 
Screening Visit. 
Safety 
X 
 
17. The subject has been previously 
screened in this study and failed to meet 
the eligibility criteria. 
Administrative 
X 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 36 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Exclusion Criteria 
Rationale 
Screening 
Admission 
(Day -3) 
18. For women of childbearing potential 
only*: 
Subject is pregnant (does not have 
negative pregnancy tests at Screening 
and 
at 
Admission 
if 
not 
post-
menauposal) or is breast feeding. 
Safety 
X 
X 
19. For women of childbearing potential 
only*: 
Subject does not agree to use an 
acceptable 
method 
of 
effective 
contraception.** 
Safety 
X 
X 
* Women who are not of childbearing potential meet at least one of the following criteria: 
Have undergone hysterectomy or bilateral tubal ligation, 
Have medically confirmed ovarian failure, or  
Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no 
alternative pathological or physiological cause). 
** Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with spermicidal 
foam/gel/film/suppository, hormonal contraception containing progesterone only, 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. 
Hormonal contraception with estrogen containing products is NOT allowed in this study. 
5.3 
Discontinuation of Subjects from the Study 
Discontinued subjects will include both, subjects who withdraw from the study (subject’s 
decision) or subjects who are removed from the study. A subject can only be discontinued from 
the study after enrolment. 
Subjects will be informed that they are free to withdraw from the study (upon decision of the 
subject) at any time. Subjects should be questioned for the reason for withdrawal from the 
study, although they are not obliged to disclose it. If the subject withdraws from the study 
he/she will be asked to confirm at least the following points and this information will be fully 
documented by Investigator: 
• The subject agrees to undertake the early termination procedures (section 9.6) for safety 
assessments. 
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, unless the subject disagrees in 
writing. 
When a subject is discontinued from the study, all early termination procedures listed in section 
9.6 are performed unless the subject refuses to perform the assessments. After the date of 
termination, the subject will enter into the 7-day safety follow-up period. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 37 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
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 head of the medical institution should report the fact and 
the reason in writing to the IRB. 
• Discontinuation is considered to be in the best interest of the subject or the other subjects 
as judged by the Investigator. 
• Subjects using any nicotine/tobacco product different from the assigned product will be 
withdrawn from the study. 
• Subjects who do not meet inclusion #8 or any other eligibility criteria. 
• Subject is not willing to use CHTP 1.1M after product test at Admission. 
 
Subjects may be discontinued from the study for the following reason: 
• Non-compliance to the study procedures based on the judgment of the Investigator. 
• Sufficient number of subjects are already randomized to the study sequences1. 
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 
The end of the study date for a subject lost to follow-up will be defined as the date when the 
Investigator decides that the subject is lost to follow-up, not to exceed the maximum duration 
of the study. A 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.  
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 who did not meet all eligibility criteria will not be permitted. 
                                                 
1 Surnumerous (« back-up ») subjects should be discontinued from enrollement prior to randomization only. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 38 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
6 
INVESTIGATIONAL PRODUCTS 
6.1 
Description of Investigational Products 
CHTP 1.1 M 
CHTP 1.1 M is a tobacco stick which is comparable in shape and form, and is used in a similar 
manner to mCC. To use the CHTP 1.1 M, the consumer removes the protective cap and uses a 
conventional lighting method to ignite the Heat Source.
 
, the aerosol is generated by drawing air through the CHTP 1.1 M. During 
use, the tobacco in the CHTP 1.1 M 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. 
The CHTP 1.1 M will be provided by the Sponsor and its distribution will be limited to a 
qualified and appropriately trained study site collaborator. Additional information are provided 
in section 2.1.2. 
The overall objective of the design CHTP 1.1 M is to provide an acceptable experience in 
which the HPHC level in the aerosol is substantially reduced in comparison with mCCs. 
mCC 
In the study sequences 1 and 2, the reference product to CHTP 1.1 M is commercially available 
single brand mCC. mCC will not be provided by the Sponsor. All eligible subjects will be 
asked to purchase their own preferred single-brand of mCC prior to Admission. Every study 
subject needs to buy his/her anticipated amount of single-brand mCC for a total of 2 days plus 
2 extra packs.  
6.2 
Packaging and Labeling 
At Admission, all study subjects will provide the anticipated amount of mCC in sealed packs 
to the site collaborators. The mCC packs provided by the subject should not be opened and the 
cellophane should be intact.  
Each pack of mCC provided by the subject will be labeled to identify to which subject the 
mCC belong to (labels should be affixed to the cellophane of the lower part of the pack).  
Packs of mCC will be labeled to identify necessary information to match the subject with 
his/her suppliers. 
For the CHTP 1.1 M, the packs will be printed with the necessary information including, but 
not limited to, product code and expiry date. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 39 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
6.3 
Use of Investigational Products 
Subjects will never be requested or forced to smoke and will be free to stop smoking at any 
time of the 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). 
6.3.1 
Admission (Day -3) 
Subject will be instructed not to smoke in the morning prior to Admission on Day -3. After 
Admission, smoking will not be allowed until blood drawing for the assessment of CYP2A6 
activity and spirometry have been conducted. After these assessment procedures, smoking will 
be allowed until 11.00 PM of the Admission Day. All subjects (except women with a positive 
pregnancy test at Screening or Admission) will undergo a CHTP 1.1 M test. 
6.3.2 
Investigational Period (Day -2 to Day 3) 
During the first wash-out, each subject will maintain smoking abstinence from Day -3 11:00 
PM to the time of single use of his/her allocated product at Day 1. At Day 1, after the single 
use of the product, subjects will maintain smoking abstinence for the rest of the day. During 
Day 2, subjects will maintain smoking abstinence until the time of single use of his/her 
allocated product at Day 3. Subjects will not be allowed to smoke or use any other 
nicotine/tobacco-containing products other than the products they are allocated to. 
Time point 0 (T0) will be defined as start of the single product use on the single use days or as 
start of the first product use on each study day. The start time of product use for mCC and 
CHTP 1.1 M corresponds to the first puff of the mCC or CHTP 1.1 M. 
 
 
As randomization will take place at any time on Day -1, the subjects will be individually 
informed about the sequence they are randomized to just before the first product use on Day 1.  
6.3.3 
Single Use of Products (Day 1 and Day 3) 
On Day 1 and Day 3, subjects will use the product they are randomized to only once in the 
morning between 6:00 AM and 9:00 AM, and will abstain from the product or other 
nicotine/tobacco-containing items for the rest of the day. The start of the first product use must 
be in the window of 6:00 AM to 9:00 AM and should be at the same time (within 1 hour) for 
both days. 
At Day 1, subjects randomized to sequence 1 will use one CHTP 1.1 M, subjects randomized 
to sequence 2 will smoke one mCC as shown in Table 2: 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 40 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Table 2 
Single Use of Products (Day 1 and Day 3) 
 
Sequence 1 
Sequence 2 
Day 1 
CHTP 1.1 M 
mCC 
Day 3 
mCC 
CHTP 1.1 M 
6.3.4 
Day of Discharge 
On the Day of Discharge (Day 4), smoking will be only allowed after all laboratory procedures 
and the spirometry have been performed. All examinations at Discharge will be conducted on 
Day 4 prior to Discharge. 
6.3.5 
Safety Period 
During the Safety Follow-up Period, subjects are free to smoke according to their usual 
smoking habits. 
6.3.6 
Stopping Rules for Investigational Product 
For safety purposes, using CHTP 1.1 M or smoking mCC 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. If the study product is 
discontinued, the reasons for discontinuation will be documented in the source documents and 
subjects will undertake early termination procedures (section 9.6). 
6.4 
Method for Assigning Subjects to Sequences 
Randomization to product exposure sequence will be done through IxRS. 
Each sex and each of the smoking level (ISO nicotine levels ≤ 0.6 mg and 0.6 to 1 mg) will 
have a quota applied to ensure they represent at least 40% of the total study. 
In particular, the maximum number of subjects having the same sex or nicotine level value will 
be limited to 28. 
The randomization of the planned sample size of 48 subjects will be ensured by applying quota 
to the number of subjects per each sequence (24 subjects). 
Subjects will be randomly assigned to one of the two product exposure sequences by means of 
a permuted-block schema. Block size and other randomization details will be available in the 
randomization plan. 
The randomization plan will be generated by an independent statistician and none of the CRO 
and sponsor staff, Investigators, and study subjects will have any access to the randomization 
schema prior to randomization. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 41 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
6.5 
Blinding 
This is an open-label study; therefore the subjects and Investigators will be unblinded to the 
subject’s sequence. However, there will be a limited degree of blinding in the data review and 
data analysis process. In particular, PMI and CRO personnel will be blinded to the randomized 
sequence as summarized in Table 3: 
Table 3 
Description of Blinded Study Personnel 
Blinded Study 
Personnel 
 
End of Blinding Period 
PMI and CRO 
study statisticians 
 
After the SAP finalization or database lock1, 
whichever comes last 
 
 
 
PMI clinical 
scientist 
 
After the finalization of PMI blind database review2. 
Can be actively un-blinded when appropriate. 
1 Data will be accessible blinded to randomization sequence and to product use by means of a dummy randomization or 
masking.  
2 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. 
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 
At Admission, on Day 1 and Day 3, the CHTP 1.1 M and mCC will be dispensed by the study 
site collaborator. Each dispense of the product to the subject will be recorded. In addition, the 
start times of using any product must be recorded for Day -3, Day 1 and Day 3.  
The CHTP 1.1 M will not be promoted for commercial distribution or test market. 
6.6.2 
Storage and Accountability 
The CHTP 1.1 M and mCC will be stored in a secured site storage place with limited access to 
the authorized personnel only. The study collaborator (the IP product storage manager) 
designated by the Head of the investigational site will be responsible for the storage and 
accountability of the IPs in accordance to sponsor’s requirements. 
Subjects will return each butt of any used CHTPs 1.1 M or mCC 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 mCCs given to the site collaborators at 
Admission will be given back to the subjects. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 42 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
6.6.3 
Investigational Product Retention 
Unused CHTP 1.1 M will be destroyed or returned to the Sponsor upon study completion.  
6.6.4 
Compliance to Investigational Products 
Compliance for all sequences will be ensured by strict distribution of the products (product by 
product) and collection of used CHTP 1.1 M and the mCC butts after use will be documented 
in appropriate logs. 
The CO breath test will be considered as one of the measures of compliance during the wash-
out days in all subjects.  
6.7 
Restrictions 
6.7.1 
Smoking Restrictions 
At the Screening Visit pre- and post-bronchodilator spirometry will be done at least 1 hour of 
not smoking.  
Subjects will be instructed to abstain from smoking in the morning of the Admission (Day -3) 
until blood drawing for CYP2A6 activity assessment and spirometry will have been performed. 
Subjects will not have free access to their mCC which will be dispensed by the site 
collaborators individually as described in Section 6.6.1. 
On Day 1 and Day 3, to avoid nicotine cross contamination, CHTP 1.1 M users and mCC 
smokers will use and smoke in dedicated separate rooms: one room for CHTP 1.1 M and one 
room for mCC. Every subject must use or smoke alone with an interval between subjects 
allowing ventilation of the room. 
Using CHTP 1.1 M or smoking mCC is not allowed during study procedures except during 
blood sampling for nicotine PK on Day 1 and Day 3. Furthermore, smoking is not allowed at 
Discharge until the spirometry and all the laboratory procedures have been conducted. 
During the days of wash-out or single product use, no NRT, nicotine-containing products or 
other products supportive to smoking abstinence are allowed to be used or will be provided to 
the subjects. 
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)” 
[13].  
Subjects are not allowed to bring their own food or beverages to the investigational site. Meals 
will be served according to the schedules provided in section 9. Additional light snacks, fruits 
(with the exception of grapefruits), and raw vegetables can be distributed to the subjects 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 43 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
without restrictions at any time during confinement as long as they comply with the dietician’s 
standard diet. Consumption of water is allowed as desired. Consumption of quinine-containing 
drinks (e.g., tonic water) is not allowed. The same menu and meal schedule will be 
administered uniformly for all subjects in all sequences.  
Fasting state has to be observed for at least 10 hours prior to blood drawings for the safety 
laboratory at Admission and at Discharge. 
6.7.3 
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 CYP2A6 metabolism (as prescription and over-the-counter products) as 
presented below in Table 4 must be avoided. 
In this study, it is not allowed to use hormonal contraception containing estrogens. This also 
applies to hormone replacement therapy. Hormonal contraception with products containing 
progesterone only is allowed during this study. Subjects using estrogens during the study will 
be withdrawn.  
The following drugs and substances are examples considered as having an impact on CYP2A6 
activity ([14], Table 4). Prior to database closure, the concomitant medication will be assessed 
according to the potential impact on CYP2A6 activity and the potential impact on study results.  
Table 4 
Drugs and Substances Considered Interacting with CYP2A6 
Inhibitor 
Drug Class 
Amiodarone 
Antiarrhythmic agent 
Desipramine 
Antidepressant 
Isoniazid 
Antitubercular agent  
Ketoconazole 
Antifungal agent  
Letrozole 
Antineoplastic agent 
Methoxsalen 
Systemic psoralen  
Miconazole 
Antifungal agent  
Tranylcypromine 
Antidepressant 
Inducer 
Drug Class 
Amobarbital 
Barbiturate 
Pentobarbital 
Anticonvulsant, Barbiturate 
Phenobarbital 
Anticonvulsant, Barbiturate 
Rifampin 
Antibiotic, antitubercular agent 
Secobarbital 
Barbiturate 
Substrate 
Drug Class 
Dexmedetomidine 
α2-Adrenergic agonist, sedative 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 44 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Ifosfamide 
Antineoplastic agent, alkylating agent 
Data source: [14]. This list is not exhaustive. 
The Investigator is responsible for the medical care of the subjects during their participation in 
this study. Any decision regarding the prescription of medication or over the counter 
medication will be taken in the best interest of the subject.  
If the use of a concomitant medication cannot be avoided for the subject’s safety, it has to be 
fully documented (section 7.4.5). Concomitant medications should be followed up with the 
CRO Medical Monitor on an ongoing basis.  
Concomitant medication will be assessed at the Screening Visit. To be eligible for the study, 
any medication with impact on CYP2A6 metabolism must be discontinued at least 14 days 
prior to Admission to the clinic or for at least the duration that would be equal to five half-lives 
of the given substance (whichever is longer). They must not be used during the entire study 
until Discharge. It is at the discretion of the Investigator to assess if a termination of such 
medication at Screening is medically justified and safe for the subject. 
6.7.4 
Other 
From Admission to Discharge, practice of intensive exercise and physical work-out will be 
prohibited as it may impact the nicotine absorption profile. 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 45 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
7 
STUDY PROCEDURES 
Personnel performing or recording study measurements must have the appropriate and fully 
documented training. Quality control (QC) measures have to be in place. All study procedures 
are provided as an overview in the schedule of events (section 15.1, Appendix A – Schedule 
of Events).  
In this section, only the expected/planned time points for the various measurements are given. 
Considering that not all subjects can have a procedure at the same time point, adequate time 
windows are 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 relevant to the 
quality of the study. Appropriate medical advice will be provided to the subject in case of any 
medical findings requiring health care. 
7.1 
Informed Consent Form 
Each subject must give his/her informed consent prior to participating in the study. During the 
consent process, the Investigator obtaining consent must inform each subject of the nature, 
risks and benefits of, and alternatives to study participation. In addition, each subject must 
review the ICF and must have sufficient time to understand and have adequate opportunity to 
ask questions. The ICF must be signed and dated (date and time) prior to undertaking any 
study-specific procedures. Once the ICF is signed the subject is part of the study and will not 
be allowed to re-enter in case of a screening failure due to an eligibility criteria not met or an 
early discontinuation. A copy of the signed ICF must be given to the subject.  
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, and at Discharge. The form 
of a brief interview will be used according to current WHO recommendations [8]. 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 at each smoking cessation advice session to address any intended or unintended beliefs 
participants have about CHTP 1.1 M. 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 1.1 M has not been demonstrated to be less harmful than mCC. 
7.3 
Support during Smoking Abstinence/Periods of Reduced Smoking 
All subjects will be closely monitored by the site collaborators. This includes monitoring of 
clinical tests e.g., vital signs, physical examination, and body weight. It also refers to close 
monitoring of the subject’s behavior, AEs, and his/her mood. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 46 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
7.4 
Clinical Assessments 
Any clinically significant finding detected during the Screening Visit has to be documented as 
a concomitant disease. This also applies to clinically significant findings in laboratory values, 
vital signs, and ECGs, detected during the Screening Visit. Any untoward medical occurrence 
in a subject detected during the study which was not present at the Screening Visit must be 
documented as an AE. Worsening of a pre-existing condition from the Screening Visit onwards 
will also be documented as an AE. If a clinically significant finding is detected during the 
screening period, the Investigator needs to check if exclusion criterion number 3 is still 
fulfilled.  
7.4.1 
Demographic Data 
Demographic data (gender, date of birth/age) will be recorded at the Screening Visit. 
7.4.2 
Identification of the Current Cigarette Brand 
Identification of the current mCC 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 mCC brand 
to the site and will have to hand their mCC supply for the confinement period to the site 
collaborators, who will take a photograph of the front and of the side of the cigarette pack 
supplied by the subject to document brand name and yields. Photos will be considered as source 
documentation. A copy of the photos will be provided to the Sponsor electronically as DVD 
or CD. 
7.4.3 
Smoking History and Willingness to Quit Smoking 
Subjects will be questioned for their smoking history at Screening. This will include questions 
to evaluate whether the subject was a smoker for at least the last three consecutive years and 
to determine the number of mCC smoked during the previous 4 weeks. The subject will also 
be asked if he/she is planning to quit smoking during the next 3 months. In addition, the subject 
will be asked if he/she has used nicotine-containing products other than commercially available 
mCC (either tobacco-based products or NRT), electronic cigarettes, or similar devices, within 
4 weeks prior to assessment. 
Furthermore, subjects will be asked at Screening and Admission if they are ready for up to 6 
days of smoking interruption. Only subjects prepared and able to comply with this requirement 
will be considered for participation in the study. 
7.4.4 
Demonstration and CHTP 1.1 M Test 
All subjects will have a demonstration of the CHTP 1.1 M at the Screening Visit. Only subjects 
willing and ready to use the CHTP 1.1 M will be enrolled in the study. On Day -3, after 
enrolment, subjects will have a product test, using 3 to 5 CHTP 1.1 M.  

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 47 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
7.4.5 
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 Screening. 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 the Screening Visit 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. 
7.4.6 
Physical Examination 
A physical examination will be conducted at the Screening Visit, at Admission and at 
Discharge. 
7.4.7 
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, rounded to the first decimal place:  
BMI = weight in kilograms
height in meters2
= 𝑘𝑔
𝑚2 
7.4.8 
Vital Signs 
Systolic and diastolic blood pressure, pulse rate, and respiratory rate will be measured at the 
Screening Visit, at Admission, at every day in confinement, and at Discharge. All parameters 
will be recorded in supine position after the subject has rested for at least 5 minutes. 
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.  

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 48 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
7.4.9 
Other Clinical Assessments 
7.4.9.1 
Spirometry 
Spirometry with and without a short-acting bronchodilator (i.e., pre- and post-
bronchodilatator) will be done at the Screening Visit to evaluate inclusion/exclusion criteria. 
At Screening, spirometry pre- will be done first, followed by spirometry post-bronchodilator. 
Spirometry pre- and post- bronchodilator at Screening will be used for eligibility. Furthermore, 
spirometry pre-bronchodilator will be performed at Admission prior to product test as well as 
at Discharge. See section 6.7.1 for the smoking restrictions associated spirometry. 
Spirometry will follow the 2005 testing and quality recommendations by the American 
Thoracic Society/European Respiratory Society Joint Task Force on the standardization of 
spirometry along with the electronic data submission and documentation processes [15]. 
Spirometry predicted values will be standardized to the Japanese Respiratory Predicted set 
[16]. 
All personnel performing lung function testing should have the appropriate training and QC 
measures should be put into place and be properly documented and filed at the pulmonary 
function laboratory (including the records of the calibration, if applicable). The FEV1, FVC, 
and FEV1/FVC will be recorded. 
7.4.9.2 
Electrocardiogram 
An ECG will be recorded at Screening and on the following study days: Day 1 and Day 3 
(single use days). The ECG testing will be performed as per the site local practice. A standard 
12-lead ECG will be recorded after the subject has rested for at least 10 minutes in supine 
position. 
The following parameters will be documented: heart rate, PR interval, QRS interval, QT 
interval, and QTc interval corrected by the ECG device according to Bazett’s formula. Every 
ECG has to be assessed as normal, abnormal – clinically not significant, or abnormal – 
clinically significant. A diagnosis has to be provided in the CRF for all ECGs assessed as 
abnormal – clinically significant. ECG print-outs will be interpreted by a qualified physician. 
Any print-outs of ECGs on thermo-sensitive paper must be photocopied, initialed, dated, and 
stapled together for inclusion in the source data file. 
7.4.9.3 
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.  

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 49 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
7.5 
Biomarker Assessment 
All bioanalytical assays and laboratory assessments (section 7.6) will be carried out using 
validated methods. The bioanalytical methods used will be documented in the bioanalytical 
plans and the results reported in the bioanalytical reports. A list of laboratories is provided in 
section 15.2. 
Precautions should be taken during blood sampling and processing to prevent the 
contamination of samples with environmental nicotine or CO. 
7.5.1 
Biomarker of Exposure 
7.5.1.1 
Biomarker of Exposure to CO and COHb 
COHb measured in blood and exhaled CO will be investigated as a measure of exposure to 
CO. The CO breath test should be conducted in timely conjunction with the blood sampling 
for COHb where applicable. 
CO Breath Test 
CO in exhaled breath will be measured using the Smokerlyzer® device such as Micro+™ 
Smokerlyzer® device or similar.  
A CO breath test will be conducted once at Day -3 and Day 4.  
On Day -2, Day -1, Day 1, Day 2, and Day 3, four CO breath tests will be done per day. On 
Day 1 and Day 3, the first test per day will be performed within 15 minutes prior to T0. The 
three other tests will be conducted as described in section 9.  
COHb Test 
Tests for COHb measurement will be performed at a local laboratory. Blood samples will be 
taken as follows at Day 1 and Day 3: a total of five blood samples will be taken. The first 
sample will be taken within 15 minutes prior to using the first product (T0). Thereafter the 
sampling times in relation to T0 are at 15 minutes, 60 minutes, 4 hours, and 12 hours post-T0. 
7.5.1.2 
Biomarkers of Exposure to Nicotine 
Blood samples to measure nicotine in plasma will be taken as follows: 
Single-Use Day 1 and Day 3 for mCC and CHTP 1.1 M: 
A total of 16 blood samples will be taken for a 24-hour profile. The first blood sample will be 
taken within 15 minutes prior to the single use (Day 1 and Day 3, T0). Times of sampling are 
thereafter in relation to T0: T1 after 2 minutes, T2 after 4 minutes, T3 after 6 minutes, T4 after 
8 minutes, T5 after 10 minutes, T6 after 15 minutes, T7 after 30 minutes, T8 after 45 minutes, 
T9 after 60 minutes, T10 after 2 hours, T11 after 4 hours, T12 after 6 hours, T13 after 9 hours, T14 
after 12 hours, and T15 after 24 hours (this sample will be drawn during the day following 
product use, i.e., wash-out). 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 50 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
7.5.2 
CYP2A6 Activity 
CYP2A6 activity will be measured in plasma on Day -3. CYP2A6 activity drives the 
metabolism of nicotine to cotinine and subsequent metabolites. In this study the CYP2A6 
activity will be measured using the metabolic molar ratio of trans-3’-hydroxycotinine/cotinine.  
7.6 
Laboratory Assessments 
A list of laboratories is provided in section 15.2. 
7.6.1 
Clinical Chemistry, Hematology, and Urine Analysis for Safety Panel  
Hematology, clinical chemistry, and urine analysis for the safety panel will be measured at 
Screening, at Admission and at 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 at Admission and Discharge 
(section 6.7.2). Samples at screening will be taken in a non-fasting status. The urine test will 
be performed semi-quantitatively as urine dip-stick test at a local laboratory or the site. 
Parameters to be measured are listed in Table 5.  
Table 5 
Clinical Laboratory Parameters for Safety Panel 
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  
- Glucose 
- Lactate dehydrogenase  
- Potassium  
- Sodium 
- Total bilirubin 
- Direct bilirubin 
- Total cholesterol 
- Triglycerides 
- pH 
- Bilirubin 
- Glucose 
- Nitrite 
- Red blood cell traces 
- Protein 
- Specific gravity 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 51 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
7.6.2 
Serology 
A test for hepatitis B surface antigen, hepatitis C virus, and HIV (anti-HIV 1/2 and p24 antigen) 
will be done at the Screening Visit. In case of positive results, the subject will be referred to 
appropriate medical care. 
7.6.3 
Urine Drug Screen 
A urine drug screen will be performed at the site at the Screening Visit and on the Day of 
Admission. The urine will be screened for amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, and opiates.  
7.6.4 
Urine Cotinine Screening  
A urine dip-stick cotinine test will be performed at the Screening Visit and at Admission to the 
clinic in order to confirm the subject’s smoking status. The test must detect cotinine with a 
cotinine of ≥ 200 ng/mL, (e.g., One-Step Cotinine Test 008A086, Ultimed, Belgium). 
7.6.5 
Alcohol Breath Test 
Subjects will undertake a breath alcohol test at the Screening Visit and at Admission to the 
clinic using an alcometer device. 
7.6.6 
Urine Pregnancy Testing 
All female subjects of childbearing potential will have pregnancy testing at the Screening Visit, 
at Admission to the clinic, and at Discharge. In any case of a positive pregnancy test, the 
Investigator will inform the subject about the risks associated with smoking during pregnancy. 
All pregnancies detected during the study must be reported and handled as described in section 
8.5. 
7.7 
Sample Handling, Storage, and Shipment 
Participating laboratories for blood samples testing will be decided prior to the Investigator 
meeting and site initiation. Safety laboratory samples will be tested at a local laboratory or site 
(section 15.2).  
Detailed procedures for handling of samples are described in the separate sample handling 
manual (SHM). Safety laboratory samples will be destroyed as by the laboratories standard 
procedures. All other samples will be destroyed post database lock or post finalization of the 
bioanalytical reports depending which one is coming the latest. The facility/-ies at which the 
samples are stored will be informed in writing by the Sponsor when destruction of the samples 
shall be performed. 
7.7.1 
Blood Samples  
Blood samples will be drawn by qualified and trained site personnel. Subjects should be in a 
seated position during blood collection. In total, around 210 mL will be drawn for this study 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 52 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
including planned assessments, safety, and repeated analysis for safety. This is comparable to 
a standard blood draw for donation. The required aliquots and volumes for assessments of 
blood/plasma parameters and tests are summarized in the SHM.  
7.7.2 
Urine Samples 
Spot urine samples will be taken for urine drug screen, cotinine screen, pregnancy tests, and 
safety urinalysis. 
7.8 
Questionnaires 
The subject questionnaires and the visual analogue scale (VAS) will be entered by the subject 
directly in the electronic patient reported outcomes device or in paper copy. The questionnaires 
will be reviewed for completeness by the study site collaborators and subjects will be requested 
to complete any missing information. 
7.8.1 
Fagerström Test for Nicotine Dependence (FTND, revised version) 
Potential nicotine dependence will be assessed at Screening using the FTND in its revised 
version [17] as updated in 2012 [18]. 
The questionnaire consists of six questions which have to be answered by the subject 
himself/herself. The scores obtained on the test permit the classification of nicotine dependence 
into three levels: Mild (0 to 3 points); Moderate (4 to 6 points); Severe (7-10 points) [18]. 
7.8.2 
Assessment of Cough  
Subjects will be asked if they have experienced a regular need to cough, e.g., coughing several 
times in the last 24 hours prior to assessment. If the answer is ‘yes’, they will be asked to 
complete a VAS, three Likert scales, and an open question also assessing the previous 24 hours.  
The VAS will assess how bothersome cough is to the subject ranging from ‘not bothering me 
at all’ to ‘extremely bothersome’.  
Furthermore, subjects will be asked to assess the intensity and frequency of cough and the 
amount of sputum production on Likert scales:  
• The intensity of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = very mild – 2 = mild – 3 = moderate – 4 = severe – 5 = very severe 
• The frequency of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = rarely – 2 = sometimes – 3 = fairly often – 4 = often – 5 = almost always 
• The amount of sputum production will be assessed on a 4-point Likert scale ranging from 
0 to 3, with 0 = no sputum – 1 = a moderate amount of sputum – 2 = a larger amount of 
sputum – 3 = a very large amount of sputum 
Finally, subjects will be asked with an open question if there are any other important 
observations that they would like to share with the collaborators about their coughing. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 53 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Assessments will be done on a daily basis on Day -2 and from Day 1 to Day 4. On Day 2 and 
Day 4, questionnaire must be asked 24 hours after T0 of Day 1 and 24 hours after T0 of Day 3. 
7.8.3 
Modified Cigarette Evaluation Questionnaire (MCEQ, modified 
version)  
Product evaluation will be assessed using the MCEQ [19]. 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). 
This questionnaire will only be completed by the subjects, who use the CHTP 1.1 M or smoke 
mCCs during the study. The MCEQ will be completed by subjects themselves on Day 1 and 
Day 3.  
7.8.4 
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 [20]. The QSU-brief is a self-reported questionnaire with 10 items to be rated on a 7-
point scale, ranging from 1 (strongly disagree) to 7 (strongly agree). Higher scores in this 
questionnaire indicate a higher urge-to-smoke.  
The findings in this brief version were consistent with the expressions of craving found in the 
32-item version of the QSU [21]. The findings supported a multi-dimensional 
conceptualization of craving to smoke and demonstrated the utility of a brief multi-dimensional 
measure of craving [20]. 
The QSU-brief will be completed by the subject himself/herself at single use study days in all 
subjects. 
The first assessment will be made within 15 min prior to T0, 9 assessments thereafter in relation 
to T0: 15 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 4 hours, 6 hours, 9 hours, and 
12 hours after T0. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 54 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
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 [22]), 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. 
8.1.2 
Serious Adverse Events 
An SAE is defined as, but not limited to, any untoward medical occurrence that: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity, 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, a 
SAE they may jeopardize the subject or the subject may require medical or surgical 
intervention to prevent one of the outcomes listed in the above definitions. 
Any pre-planned hospitalizations that are known at the time of signing the ICF/subject 
information sheet will not be recorded as SAEs, however they will be recorded as AE only. 
Any AE that occurs during this pre-planned hospitalization will be considered according to the 
above definitions. 
8.2 
Assessment of Adverse Events 
The Investigator 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 the EOS either by the Investigator via spontaneous reporting or by the use of consistent, 
open, non-directive questions from study site collaborators (e.g., “Have you had any health 
problems since the previous visit/How have you been feeling since you were last asked?”). At 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 55 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
the discretion of the Investigator or designee, the collection of AE information may also be 
triggered from his/her review of the subject questionnaires and the VAS. However, 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 
rather than individual signs and symptoms (e.g., record ‘pneumonia’ rather than ‘fever,’ 
‘cough,’ ‘pulmonary infiltrate,’ or ‘septicemia,’ rather than ‘fever’ and ‘hypotension’ 
following blood sample). 
Any AE that meets the serious criteria must be recorded both on the AE report form of the 
CRF and on a separate SAE report form (section 8.3). 
8.2.2 
Period of Collection 
From the signature of the ICF onwards until EOS, all AEs (includes SAEs) will be collected 
by the study site collaborators as described below.  
8.2.2.1 
Screening Period  
All existing health conditions identified during the Screening period starting at the time of ICF 
signature and judged by the Investigator as preexisting condition will be recorded as 
concomitant disease and the subject’s eligibility for admission to the study will be reviewed.  
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 
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 Study 
From Admission onwards until Discharge, all AEs will be actively collected by the study site 
collaborators.  
Any new, clinically significant, abnormal finding or worsening of a pre-existing 
condition/concomitant disease detected during the study will be documented as an AE and/or 
SAE.  
During the safety follow-up period AEs and/or SAEs will be recorded after spontaneous 
reporting by the subject. SAEs will be reported by the Investigator as described in this 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 56 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
document and the safety management plan (SMP). Any ongoing AEs/SAEs during the safety 
follow-up period will be actively followed up by the site until they have been resolved, 
stabilized (i.e., no worsening of condition), or an acceptable explanation has been found. 
At the end of the safety follow-up period, all ongoing AEs/SAEs 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 graded by the Investigator on a 3-point intensity scale (mild, 
moderate, severe) using the following definitions: 
Mild:   
 
The AE is easily tolerated and does not interfere with daily activity. 
Moderate: 
The AE interferes with daily activity, but the subject is still able to function. 
Severe:  
 
The AE is incapacitating and requires medical intervention. 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures 
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 
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 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. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 57 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
8.3 
Reporting and Follow-Up of Serious Adverse Events 
Any SAEs reported or observed during the study whether or not attributable to the IP, or to 
any study procedures, or any SAE related to the product and spontaneously reported after the 
safety follow-up must be reported by the Investigator within 24 hours after first awareness 
by any party involved in the study to 
 and to the Sponsor. 
An SAE report form must be faxed or e-mailed as an attachment to: 
: 
Fax number: 
 
E-mail: 
 
 
Address: 
 
 
 
 
 
 
1 May – 31 May 2015 Interim Period  
Sponsor: 
Contact: 
 
, MD, Medical 
Safety Officer 
Phone number: 
 
  
E-mail: 
 
 
 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube T3551 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
 
From 1st June 2015 onwards 
Sponsor: 
Contact: 
 
, MD, 
PhD, MFPM, Medical 
Safety Officer 
Phone number: 
 
 
   
 
E-mail: 
 
 
 
Address: 
 
 
 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 58 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
 
The Investigator/head of the investigational site is responsible for local reporting (i.e., to the 
IRB) of SAEs that occur during the study, according to local regulations. 
Any additional/follow-up information that becomes available after the initial SAE report form 
has been completed will be forwarded to 
 and the Sponsor 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 for form 
completion and only changed/new information needs to be specified. Information provided in 
the follow-up SAE report form supersedes any information that was initially reported. 
All SAEs will be followed up by the Investigator until their resolution or until the Investigator 
considers the event to be stabilized (i.e., no worsening of condition), or until an acceptable 
explanation has been found (e.g., a chronic condition). The details of the SAE management 
will be provided in a separate document which is included in the safety management plan 
(SMP). 
The SAE report form to be used in this study is provided as a separate document. All SAEs 
will be recorded on the relevant CRF page, in addition to the SAE report form. 
8.4 
Reporting of Other Events Critical to Safety Evaluations 
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator and assessed for clinical significance. If the Investigator considers 
the abnormal result to be clinically significant, then it must be recorded as a concomitant 
disease at Screening, or if not present at Screening, as an AE during the study. 
The grading scheme shown in section 15.4 will be used by the Investigator to assess abnormal 
laboratory AEs as follows: 
• All Grade 1 abnormal laboratory values will be evaluated by the Investigator with respect 
to Baseline value and clinical significance. If considered to be clinically significant, the 
Investigator 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 Screening it is at the 
discretion of the Investigator to enroll the subject or not. This decision must be documented 
in the source documentation and captured in the CRF. A grade 2 laboratory abnormal value 
at the Screening Visit must be recorded as concomitant disease. 
• If there is any worsening in grade from Grade 2 and above during the study, the Investigator 
must report this worsening as an AE. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 59 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
• Where there is no grading available, the abnormal laboratory value will be evaluated by 
the Investigator and assessed for clinical significance. If considered to be clinically 
significant, 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, be reviewed and assessed. 
Even if they do not meet the criteria of the CTCAE grading scheme (please see above), the 
Investigator may consider them to be of clinical significance and, if they are, must report 
them as AEs. 
• In general, laboratory values will be recorded as ‘increased <lab parameter>’ or ‘decreased 
<lab parameter>’ to ensure consistency of recording/coding. 
All other information (e.g., relationship to IP, intensity, seriousness, outcome) will be assessed 
as for other AEs. 
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. 
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 an 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 1.1 M 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. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 60 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
The Principal Investigator/head of the investigational site 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 EOS 
procedures, as described for Discharge, as soon as possible and will enter the period of safety 
follow-up. The Investigator will follow up these AEs until they have been resolved, stabilized 
(i.e., no worsening of condition), or an acceptable explanation has been found. 
8.7 
Investigational Product Malfunction and Misuse 
Any occurrences of the CHTP 1.1 M 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 quality complaint form.  
Investigational product misuse may result in use-related hazards. 
Furthermore, any misuse or malfunction of the CHTP 1.1 M that lead to an AE/SAE will follow 
the same processes as described above for the reporting of the AE/SAE. 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 61 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
9 
STUDY ACTIVITIES 
A detailed schedule of assessments can be found in Appendix A – Schedule of Events (section 
15.1). 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 is 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 (Day -31 to Day -4) 
The Screening Visit will be performed within 4 weeks (Day -31 to Day -4) prior to Admission 
on Day -3.  
The following assessments will be performed at the Screening Visit (the sequence of the 
assessment will be at the discretion of the site but all of them must be done after signature of 
the ICF): 
Table 6 
Time Schedule – Screening (Day -31 to Day -4) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of Procedure 
 
 
 
 
 
Informed consent  
 
 
 
Information on the risks of 
smoking, smoking cessation 
advice and debriefing 
 
 
 
Demographic data 
 
 
 
Smoking history 
Identification of current mCC 
brand 
 
 
 
Willingness to quit smoking in 
the next 3 months 
 
 
 
Readiness 
to 
accept 
interruptions of smoking for 
up to 6 days 
 
 
 
FTND questionnaire 
 
 
 
Prior medication (4 weeks 
prior 
to 
Screening 
Visit)/concomitant medication 
 
 
 
Medical history/concomitant 
diseases 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 62 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of Procedure 
 
 
 
 
 
Vital 
Signs 
(pulse 
rate, 
systolic and diastolic blood 
pressure, respiratory rate) 
At least 5 min in supine 
position 
prior 
to 
measurement. 
For 
every 
measurement, 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. 
 
 
Height, 
weight, 
including 
calculated BMI 
 
 
√ 
Clinical 
laboratory 
parameters 
(hematology, 
clinical chemistry) 
  
 
√ 
Serology 
for 
HIV 
and 
Hepatitis B and C 
 
 
 
Safety urine analysis 
Urine drug screen 
 
 
 
Alcohol breath test 
 
 
 
Urine pregnancy test 
For all female subjects of 
childbearing potential 
 
 
CHTP 
1.1 
M 
product 
demonstration 
 
 
 
Spirometry pre- and post-
bronchodilatator 
Has to be done at least 1 hour 
of not smoking 
At rest for at least 15 minutes 
prior to pulmonary function 
testing. 
In sitting position. 
All 
post-bronchodilator 
spirometry testing will be 
performed 15-30 minutes post 
administration of salbutamol 
 
 
ECG 
At least 10 min in supine 
position prior to recording. 
 
 
Chest X-ray  
If not performed 6 months 
prior to Screening 
 
 
AE/SAE questioning 
If the Screening Visit is 
performed on two separate 
days the AE/SAE questions 
will be asked again. 
 
 
Physical examination 
 
 
 
Urine cotinine screen test 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 63 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of Procedure 
 
 
 
 
 
Inclusion/exclusion criteria 
 
Abbreviations: AE = adverse event; BMI = body mass index; mCC = menthol conventional cigarette(s); ECG = 
electrocardiogram; CHTP 1.1 M = Carbon Heated Tobacco Product 1.1 Menthol; FTND = Fagerström test for nicotine 
dependence (revised version); HIV = human immunodeficiency virus; SAE = serious adverse event. 
9.2 
Admission (Day -3)  
The following assessments will be performed at Admission (Day -3): 
Table 7 
Time Schedule – Admission (Day -3) 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of Procedure 
 
 
 
Start of the Day 
 
AE/SAE recording 
Concomitant medication 
All day 
All day 
 
 
Smoking abstinence 
In the morning until blood 
drawing 
for 
CYP2A6 
activity assessment and 
spirometry 
will 
be 
performed and after 11.00 
PM. 
 
 
 
 
 
 
Information 
on 
the 
risks 
of 
smoking/smoking cessation advice 
and debriefing 
 
 
 
Readiness to accept interruptions of 
smoking for up to 6 days 
Readiness to use the CHTP 1.1 M 
 
 
√ 
trans-3’-hydroxycotinine and cotinine 
(CYP2A6 activity) in plasma 
Must be done prior to 
smoking. 
 
 
Spirometry 
Has to be done prior 
smoking. At rest for at 
least 15 minutes prior to 
spirometry. 
In 
sitting 
position. 
 
 
Urine pregnancy test  
For all female subjects of 
childbearing potential 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 64 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Start of Procedure 
 
 
 
 
√ 
Clinical 
laboratory 
parameters 
(hematology, clinical chemistry) 
In at least 10 hours of 
fasting. 
 
 
Safety urine analysis 
Urine cotinine screen test 
 
 
 
Urine drug screen 
 
Prior to 10:00 AM 
 
Breakfast 
 
Prior to 11:30 AM 
 
Vital Signs 
At least 5 min in supine 
position 
prior 
to 
measurement. For every 
measurement, 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.  
Prior to 11:30 AM 
 
Physical examination, weight and 
calculated BMI 
 
Prior to 11:30 AM 
 
Identification of current mCC brand 
 
Prior to 11:30 AM 
 
Alcohol breath test 
 
Prior to 11:30 AM 
 
CO breath test 
 
Prior to 2:30 PM 
 
Lunch 
 
Afternoon 
 
Snacks 
Inclusion/exclusion criteria 
 
All eligibility criteria must 
be checked. 
 
 
Enrolment 
Product test for CHTP 1.1 M 
 
Use of 3 to 5 CHTPs 1.1 M  
 
 
Collection of used CHTP 1.1 M and 
mCC butts 
 
 
 
 
 
In the evening prior to 
9:00 PM 
 
Dinner 
 
Abbreviations: AE = adverse event; BMI = body mass index; mCC = menthol conventional cigarette(s); CHTP 1.1 M= Carbon 
Heated Tobacco Product 1.1 Menthol; CO = carbon monoxide; CYP2A6 = cytochrome P450 2A6; SAE = serious adverse 
event. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 65 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
9.3 
Investigational Period 
9.3.1 
Days of Smoking Abstinence (Day -2, Day -1 and Day 2) 
On the days of smoking abstinence (Day -2, Day -1 and Day 2) the following assessments will 
be performed: 
Table 8 
Time Schedule – Wash-out (Day -2, Day -1) 
Time 
Blood Sample 
Procedures 
Additional Information 
Start of Procedure 
 
 
 
 
 
Smoking abstinence 
All day 
 
 
Support during smoking 
abstinence as required 
All day 
 
 
AE/SAE recording 
Concomitant medication 
All day 
All day 
06:30AM-09:00 AM 
 
Assessment of cough 
Day -2 only 
Prior to 10:00 AM 
 
Breakfast 
 
8:00 AM-9:30 AM 
 
CO breath test 
 
10:00 AM-11:30 AM 
 
Vital Signs 
At least 5 minutes in supine 
position prior to measurement. 
12:00 PM-1:30 PM 
 
CO breath test 
 
Prior to 2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 
Afternoon  
 
Snacks 
 
In the evening prior to 
9:00 PM 
 
Dinner 
 
8:00 PM-9:30 PM 
 
CO breath test 
 
 
 
Randomization 
Day -1 
Abbreviations: AE = adverse event; CO = carbon monoxide; SAE = serious adverse event. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 66 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Table 9 
Time Schedule – Wash-out (Day 2) 
Time 
Blood Sample 
Procedures 
Additional Information 
Start of Procedure 
 
 
 
 
 
Smoking abstinence 
All day 
 
 
Support during smoking 
abstinence as required 
All day 
 
 
AE/SAE recording 
Concomitant medication 
All Day 
All day 
 
√ 
Plasma 
nicotine 
PK 
sample 
24 hours after T0 of Day 1  
(+ 5 minutes) 
 
 
 
Assessment of cough 
24 hours (- 30 minutes) after 
T0 of Day 1 
Prior to 10:00 AM 
 
Breakfast 
 
8:00 AM-9:30 AM 
 
CO breath test 
 
 
 
 
 
10:00 AM-11:30 AM 
 
Vital Signs 
At least 5 minutes in supine 
position 
prior 
to 
measurement.  
12:00 PM-1:30 PM 
 
CO breath test 
 
Prior to 2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 
Afternoon  
 
Snacks 
 
In the evening prior to 9:00 
PM 
 
Dinner 
 
8:00 PM-9:30 PM 
 
CO breath test 
 
Abbreviations: AE = adverse event; CO = carbon monoxide; PK = pharmacokinetic; SAE = serious adverse event; T = time 
point. 
9.3.2 
Days of Single Use (Day 1 and Day 3) 
On the days of single use (Day 1 and Day 3), the following assessments will be performed: 
Table 10 
Time Schedule – Single Use (Day 1 and Day 3) 
Time 
Blood Sample 
Procedures 
Additional Information 
Start of Procedure 
 
 
 
 
 
Optional: light snacks 
prior to first blood draw 
of the day 
 
 
 
AE/SAE recording 
All day 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 67 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Time 
Blood Sample 
Procedures 
Additional Information 
Start of Procedure 
 
 
 
Concomitant medication 
All day 
 
 
Support 
for 
smoking 
abstinence as required  
All day 
 
 
Craving 
questionnaire 
(QSU-brief) 
First assessment within 15 
minutes 
prior 
to 
T0, 
9 
assessments 
thereafter 
in 
relation to T0: 15 min, 30 min, 45 
min, 60 min, 2 hr, 4 hrs, 6 hrs, 9 
hrs, and 12 hrs after T0 with a 
time window of 10 minutes 
each. 
 
√ 
Plasma nicotine sample 
A total of 16 blood samples will 
be taken for a 24-hour profile 
(Day 1 and Day 3). The first 
blood sample will be taken 
within 15 min prior to T0 and 15 
samples thereafter in relation to 
T0: 
T1 after 2 min + 1 min, T2 after 4 
min + 1 min, T3 after 6 min + 1 
min, T4 after 8 min + 1 min, T5 
after 10 min + 1 min, T6 after 15 
min + 2 min, T7 after 30 min + 2 
min, T8 after 45 min + 2 min, T9 
after 60 min + 3 min, T10 after 2 
hrs + 5 min, T11 after 4 hrs + 5 
min, T12 after 6 hrs + 5 min, T13 
after 9 hrs + 5 min, T14 after 12 
hrs + 5 min, and T15 after 24 hrs 
+ 5 min (this sample will be 
drawn during the day following 
product use, i.e., wash-out). 
 
 
√ 
COHb blood sampling 
Five blood samples to be taken, 
first sample within 15 min prior 
to T0, then after 15 min + 2 min, 
60 min + 3 min, 4 hrs + 5 min, 
12 hrs + 5 min 
 
 
CO breath test 
First test to be done within 15 
min prior to T0. 
 
 
Assessment of cough 
Has to be done prior to product 
use. 
6:00 AM-9:00 AM 
 
Start of single product 
use 
 
Prior to 10:00 AM 
 
Breakfast 
 
10:00 AM-11:30 AM 
 
Vital Signs 
At least 5 minutes in supine 
position prior to measurement.  

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 68 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Time 
Blood Sample 
Procedures 
Additional Information 
Start of Procedure 
 
 
 
10:00 AM-11:30 AM 
 
ECG 
At least 10 minutes in supine 
position prior to recording. 
12:00 PM-1:30 PM 
 
CO breath test 
 
Prior to 2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 
Afternoon  
 
Snacks 
 
Prior to 9:00 PM 
 
Dinner 
 
8:00 PM-9:30 PM 
 
CO breath test 
 
8:00 PM-11:00 PM 
 
Product 
evaluation 
questionnaire (MCEQ) 
 
 
 
Collection of used CHTP 
1.1 M and mCC butts 
After the product use. 
Abbreviations: AE = adverse event; mCC = menthol conventional cigarette(s); CHTP 1.1 M= Carbon Heated Tobacco Product 
1.1 Menthol; CO = carbon monoxide; COHb = carboxyhemoglobin; ECG = electrocardiogram; MCEQ = modified cigarette 
evaluation questionnaire; QSU-brief = questionnaire of smoking urges; SAE = serious adverse event; Tx = time point x. 
9.4 
Discharge  
The following assessments will be conducted prior to time discharge on Day 4: 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 69 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Table 11 
Time Schedule – Day 4 Discharge 
Time 
Blood Sample 
Procedures 
Additional Information 
Start of Procedure 
 
 
 
 
 
Smoking abstinence 
Until all laboratory procedures 
and the spirometry have been 
performed. 
 
 
AE/SAE recording 
Concomitant medication 
All day 
All day 
 
√ 
Plasma 
nicotine 
PK 
sample  
24 hrs after T0 of Day 3  
(+ 5 minutes) 
 
 
 
Assessment of cough 
24 hours (- 30 minutes) after 
T0 of Day 3 
 
√ 
Clinical 
laboratory 
parameters (hematology, 
clinical chemistry) 
Safety urine analysis 
At to be done in at least 10 
hours of fasting 
 
 
Spirometry  
Has to be done prior to 
smoking. At rest for at least 15 
minutes prior to spirometry. In 
sitting position. 
Prior to 10:00 AM 
 
Breakfast 
 
Prior to discharge 
 
Urine pregnancy test  
For all female subjects of 
childbearing potential 
Prior to discharge 
 
Vital Signs 
At least 5 minutes in supine 
position prior to measurement.  
Prior to discharge 
 
CO breath test 
Irrespective of smoking. 
Prior to discharge 
 
Physical 
examination, 
weight and calculated 
BMI 
 
Prior to discharge 
 
Information on the risks 
of 
smoking/smoking 
cessation 
advice 
and 
debriefing  
 
 
 
Discharge 
 
Abbreviations: AE = adverse event; BMI = body mass index; CO = carbon monoxide; PK = pharmacokinetic; SAE = serious 
adverse event; T = time point. 
9.5 
Safety Follow-up Period 
All subjects participating in the product trial on Day -3 will enter a 7-day Safety Follow-up 
Period.  

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 70 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
After discharge at Day 4 (or if prematurely discontinued from the study), subjects will enter a 
7-day Safety Follow-up Period. 
During the 7-day Safety Follow-up Period, spontaneously reported AEs and SAEs by the 
subject will be recorded. Any ongoing AEs/SAEs will be actively followed up by the site.  
Any AEs or SAEs that are ongoing at the end of the 7-day Safety Follow-up Period will be 
managed as described in section 8.2.2. 
9.6 
Early Termination Procedures 
Early termination procedures will be as follows, if the subject agrees:  
Table 12 
Time Schedule – Early Termination Procedures 
Time 
Blood Sample 
Procedures 
Additional Information 
Start of Procedure 
 
 
 
 
 
AE/SAE 
recording, 
concomitant medication 
All day 
 
√ 
Clinical 
laboratory 
parameters 
(hematology, 
clinical 
chemistry) 
To be done in at least 10 hours 
of fasting if possible. 
 
 
Safety urine analysis 
Spirometry  
 
To be done 1 hour of not 
smoking. At rest for at least 15 
minutes prior to spirometry. In 
sitting position. 
 
 
Urine pregnancy test  
For all female subjects of 
childbearing potential 
 
 
Vital Signs 
At least 5 minutes in supine 
position prior to measurement. 
For every measurement, 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. 
 
 
Physical 
examination, 
weight and calculated 
BMI 
 
 
 
Information on the risks 
of 
smoking/smoking 
cessation advice and 
debriefing 
Discharge 
 
Abbreviations: AE = Adverse Event; BMI = Body Mass Index; SAE = Serious Adverse Event. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 71 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
10 
QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
A Clinical Research Associate (“Monitor”) from an independent CRO not involved with the 
study site will be responsible for the monitoring of the study. Monitoring will be performed 
according to the study CRO’s SOPs and as per the agreed monitoring plan with the Sponsor. 
The Investigator/head of the investigational site shall permit the Monitor to review study data 
as frequently as deemed necessary to ensure that data are being recorded in an adequate manner 
and that protocol adherence is satisfactory. 
The Investigator shall access medical records for the Monitor so that entries in the CRFs may 
be verified. The Investigator, as part of their 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 
performed and documented. 
Subsequent to the Investigator’s meeting, and before the first subject is screened, the 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 detailed in the monitoring 
plan. 
Communication by telephone, mail, and e-mail may be used as needed to supplement site 
visits. The Investigator and study personnel will cooperate with the Monitor, provide all 
appropriate documentation, and will be available to discuss the study. 
The Monitor and the Sponsor’s personnel will be available between visits, should the 
Investigator or other staff at the sites need information and advice. 
Site visits will be made at regular intervals during the study. The frequency of the monitoring 
visits will be defined in the monitoring plan agreed with the Sponsor. 
The Investigator 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 
An Investigator’s meeting will be conducted prior to site initiation. During this meeting, the 
Sponsor or its authorized representative will discuss the requirements of the clinical study 
protocol and related documents and will also provide training in the relevant systems and other 
study-specific procedures. The activities of the Investigator’s meeting will be described in the 
monitoring plan. 
In addition to the Investigator’s meeting, the Investigator will ensure that appropriate training 
relevant to the study is provided to all collaborators involved in the study, and that any new 
information relevant to the performance of this study is forwarded to the collaborators involved 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 72 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
in a timely manner. The Investigator will maintain a record of all individuals involved in the 
study. 
10.3 Audits and Inspections 
GCP regulations require that there are independent inspections of clinical program activities.  
Such inspections may be performed at any time before, during, and/or after the study. 
Authorized representatives of the Sponsor, regulatory agencies and/or an IRB may perform 
audits or inspections, including source data verification. The purpose of an audit or inspection 
is to systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, ICH/GCP guidelines,  and any applicable 
regulatory requirements. The Investigator/head of the investigational site will contact the 
Sponsor or the authorized representative immediately, if contacted by a regulatory agency 
about an inspection at their site. 
The Investigator and study collaborators are responsible for maintaining a comprehensive and 
accurate filing system of all study-related documentation that will be suitable for inspection at 
any time by the Sponsor, its authorized representative, and/or regulatory agencies. In signing 
this protocol, the Investigator understands and agrees to provide access to the necessary 
documentation and files. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 73 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
11 
DATA MANAGEMENT ACTIVITIES 
All data management activities will be described in detail in the data management plan and 
documents specified therein. 
11.1 Data Capture 
11.1.1 
Case Report Forms and Study Records 
With the exception of the subject-reported outcome data, all results from the clinical 
assessments will be recorded in the source documents by the Investigator or their authorized 
designee(s) and then captured in the CRFs at the study site. The subject questionnaires and the 
VAS will be entered by the subject directly in the electronic patient-reported outcomes device 
or in a paper copy. Trained study personnel will be responsible for capturing the data from the 
observations, tests and assessments specified in the protocol in the source documents and then 
transferring the data into the CRF, in accordance with the Case Report Form Completion 
Guidelines. 
The Principal Investigator has ultimate responsibility for the collection and reporting of all 
data related to the clinical study and ensuring that the data are accurate, authentic/original, 
legible, timely (contemporaneous), enduring and available when required. The CRF must be 
signed by the Investigator to attest that the data contained in the CRF are true and accurate. 
Any corrections made to source documents must be clearly recorded, without obscuring the 
original values and be accompanied by the date of change, reason for change and identification 
of the person making the change. The CRF for each subject will be checked against the source 
documents at the study site by the Clinical Research Associate. Instances of missing or unclear 
data will be discussed with the Investigator for resolution. A CRF will be generated for all 
subjects that sign the informed consent form. 
11.1.2 
Protocol Deviations 
Protocol deviations are defined as those deviations from any procedure as defined in this 
document, including but not limited to, any violation of inclusion/exclusion criteria, 
mis-randomizations, use of any nicotine or tobacco-containing product other than the assigned 
product during each of the exposure period, use of any nicotine tobacco-containing product 
during wash-out days, assessments not performed or performed outside the scheduled time 
windows, or use of estrogen or other drugs that are known to affect CYP2A6 activity.  
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 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 74 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
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 are defined in the SOPs and study specific procedures of the CRO data 
management team. All deviations will be reviewed, 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 data management 
plan (DMP) to be reviewed and approved by the Sponsor, prior to the start of the study. This 
document will describe, in detail, the procedures and processes related to data management. 
All data of all subjects successfully enrolled, as well as subjects who failed Screening, and/or 
experienced an AE during the study (from time of signing the informed consent form to the 
end of the safety follow-up period), will be captured and stored in the study database. 
All data collected during the study is property of the Sponsor, irrespective of the location of 
the database and the data management CRO. 
11.2.1 
Data 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: 
Adverse 
events, 
concomitant 
disease, 
medical history: 
Medical Dictionary for Regulatory Activities (MedDRA®) 
Medications: 
WHO Drug Dictionary Enhanced and Anatomical Therapeutic 
and Chemical classification system 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 75 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
CHTP 1.1 M issues 
and/or malfunction: 
C54451/Medical Device Problem Codes FDA CDRH [23] 
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”. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 76 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
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 CSR. The statistical evaluation will be performed 
using SAS®, version 9.2 or later. 
12.1.1 
Stratification Criteria 
For analysis, the following stratification criteria will be used:  
• Gender (male and female) 
• mCC nicotine level at Admission (ISO nicotine levels ≤ 0.6 mg and 0.6 to 1 mg) 
12.1.2 
Definitions for Statistical Data Analysis 
Unless otherwise stated, for the purposes of statistical analyses, Baseline is defined as the last 
available time point prior to T0 on Day 1. 
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by sequence and subject, unless otherwise 
specified.  
Descriptive statistics for continuous variables (number of subjects [n], number and percent of 
subjects with missing data, mean, standard deviation, median, first and third quartiles, 
minimum and maximum) and categorical data (n, number and percent of subjects with missing 
data, by category) will presented by product exposure and overall. Summaries will be presented 
at Baseline and at each subsequent time point, where applicable.   
Descriptive statistics for PK parameters will also include the geometric mean and coefficient 
of variation (CV).  
12.1.4 
Handling of Missing Values and of Values outside the Detection Limits 
In general, missing data will not be imputed in this study, due to the nature of the measurements 
and the short periods of exposure and use. However, 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. 
In general, values below the lower limit of quantification (LLOQ) will be imputed using 0.5 x 
lower limit of quantification. For values above the upper limit of quantification (ULOQ), i.e., 
preceded by a “>”, for example “>xx,” the numerical xx will be used for calculation and 
reporting in summary tables. The number and percent of values below LLOQ or above ULOQ 
will be presented in each summary table. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 77 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
12.1.5 
Significance Level for Inferential Analysis 
For all endpoints, unless otherwise stated, statistical tests will be two-sided and conducted at 
the 5% significance level and all quoted confidence intervals will be two-sided 95% confidence 
intervals (CI).  
No formal adjustment of the test-wise alpha level for multiple testing is necessary, as no claim 
will be made based on the outcome of the individual CI values. 
12.2 Determination of Sample Size and Power Consideration 
A total of 48 subjects will be randomized. 
The estimates for the within-subject CV for nicotine Cmax (60%) and AUC(0-last) (50%) are 
based on the data collected in the ZRHM-PK-05 clinical study [9] comparing the nicotine PK 
profiles of the Tobacco Heating System 2.2 Menthol, another MRTP candidate, and mCC in a 
Japanese population.  
The sample sizes of this study assume a 5% drop-out rate.  
Sample size calculations were conducted using SAS® version 9.2 for the 95% CI of the mean 
differences between paired observations (proc power onesamplemeans) in the natural log scale 
[24]. The SAS® implementation of the method published by [25] was adopted to estimate the 
probability of obtaining at most the target 95% CI of ±30%. 
A total of 48 subjects are needed to estimate the mean Cmax parameter ratio between CHTP 1.1 
M and mCC with a 80% probability of obtaining a margin of error (95% CI) of at most ±30%, 
assuming that CHTP 1.1 M has a nicotine Cmax similar to mCC (ratio equal to 1.00). This 
sample size is sufficient to provide 80% probability of obtaining a margin of error of at most 
±30% for the AUC(0-last) ratio between CHTP 1.1 M and mCC, assuming a similar extent of 
nicotine absorption for the 2 products (ratio equal to 1.00).  
12.3 Analysis Populations 
All analyses will be based on actual product exposure. All endpoints (other than safety) will 
be analyzed using the PK Analysis sets. Safety will be analyzed using the safety population. 
12.3.1 
PK Populations  
The PK populations consist of all the randomized subjects who give informed consent, 
completed at least one of the single use Day 1 or Day 3, and for whom at least one PK parameter 
can been derived. Only subjects without major protocol deviations that impact evaluability of 
the data (to be defined in the SAP) will be included in the PK analysis sets. 
12.3.2 
Safety Population 
The safety population consists of all the subjects who give informed consent and have at least 
one exposure to CHTP 1.1 M (including the product test at Admission). 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 78 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
12.4 Demographics and Baseline Characteristics 
Demographic and other Baseline characteristics will be reported for the PK and safety 
populations. Appropriate summary statistics will be provided as described in section 12.1.3. 
12.5 Primary Endpoints 
12.5.1 
Primary Endpoints Analysis Variables 
Nicotine PK parameters will be derived from plasma nicotine versus time data by 
non-compartmental analysis. In particular: 
Cmax 
Maximum observed plasma concentration. Cmax will be reported 
as long as there is at least one quantifiable concentration post-
exposure 
AUC(0-last) 
Area under the plasma concentration-time curve from start of 
product use to the time of the last quantifiable concentration 
(linear trapezoidal method) 
12.5.2 
Baseline Comparability 
Not applicable. 
12.5.3 
Descriptive Analysis 
Primary endpoints will be summarized as described in section 12.1.3. 
An analysis of variance (ANOVA) will be conducted on AUC(0-last) and Cmax endpoints in the 
natural logarithmic scale. The model will include terms for sequence, subjects within sequence, 
product exposure, and period as fixed effect factors. The results of this analysis for each of 
AUC(0-last) and Cmax are presented in terms of adjusted geometric least square means and 95% 
confidence intervals for the CHTP 1.1 M:mCC ratio.  
This approach is consistent with the guidelines in the European Medicines Agency’s guidelines 
for bioequivalence investigations [26] and FDA’s Center for Drug Evaluation and Research 
[27]. Carry-over effect will not be tested, as it cannot be statistically distinguished from the 
interaction between treatment and period in a 2x2 crossover [28].  
In case of any nicotine levels at T0 greater than 5% of their Cmax value being observed, a 
supportive analysis of the primary endpoints will be performed as described above, where the 
whereby data of these subjects with nicotine levels at T0 greater than 5% of their Cmax value 
will not be considered for this supportive excluded from the analysis. 
A sensitivity analysis will be conducted should there be 20% or more missing PK parameter 
values by repeating the above analyses using mixed effects ANOVA model including period, 
sequence, and product exposure as fixed effects and subjects within sequence as a random 
effect. Additional details will be provided in the SAP. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 79 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
12.5.4 
Confirmatory Analyses 
Given that the objective of this study is to evaluate the point estimate and precision of the ratio 
of CHTP 1.1 M:mCC for Cmax and AUC(0-last), there is no statistical hypothesis to be tested. 
12.6 Secondary Endpoints 
12.6.1 
Secondary Endpoint Analysis Variables 
Nicotine PK parameters will be derived as follows: 
tmax 
Time to maximum concentration. tmax will be reported as long as 
there is at least one quantifiable concentration post-exposure 
AUC(0-t’) 
Area under the plasma concentration-time curve from start of 
product use to the subject-specific time of maximum nicotine 
concentration following singe use of mCC or CHTP 1.1 M (linear 
trapezoidal method) 
AUC(0-12) 
Area under the plasma concentration-time curve from start of 
product use to the 12 hours time point 
AUC(0-∞) 
Area under the concentration-time curve from start of product use 
extrapolated to time of last quantifiable concentration to infinity, 
according to: 
 
Where Clast is the last quantifiable concentration and λz is the 
terminal elimination rate constant 
t1/2 
Half-life (terminal elimination), derived as ln(2)/λz, where λz is 
defined as  the terminal elimination rate constant, estimated by 
linear regression analysis of the natural log-transformed 
concentration-time data 
More details on PK parameter derivations will be provided in the SAP. 
Subjective effects of using CHTP 1.1 M as compared to the mCC will be evaluated by 
analyzing domain scores of QSU-brief and MCEQ. Full details of questionnaire domain scores 
derivation will be provided in the SAP. 
12.6.2 
Baseline Comparability 
Not applicable. 










z
C
AUC
AUC
last
last

0
-
0

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 80 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
12.6.3 
Descriptive Analysis 
In general, secondary endpoints will be summarized using the approach described in section 
12.1.3. 
The following analyses will be conducted: 
• The AUC(0-∞), AUC(0-12), AUC(0-t’), and t1/2 will be analyzed using the same approach 
adopted for the primary endpoints. Data will be summarized and presented together with 
95% CI.  
• The Hodges-Lehmann estimates for the median tmax differences and 95% CI will be 
presented [29]. 
• In case of any nicotine levels at T0 greater than 5% of their Cmax value being observed, a 
supportive analysis of the secondary PK parameters will be performed as described in 
section 12.5.3, where the data for subjects with nicotine levels at T0 greater than 5% of 
their Cmax value will not be considered for this supportive analysis. 
• A mixed effects ANOVA for repeated measurements will be used to analyze the QSU-brief 
scores over time. Additional details will be provided in the SAP. Summaries will be 
produced for the QSU-brief scores over time, including the percent change from the value 
assessed prior to T0. The maximum percent decrease over time and the time to maximum 
percent decrease over time will be summarized for the QSU-brief total score by product 
exposure and analyzed using the Hodges-Lehmann method.  
• Levels of exhaled CO and of blood COHb will be summarized over time by means of 
descriptive statistics reported by product exposure. Analysis of exhaled CO and COHb 
levels will be conducted using a mixed model for repeated measures, the same approach as 
for the QSU-brief. COHb levels will be analyzed in the logarithmic scale. 
• Mixed effects ANOVA with the same model terms as planned for the sensitivity analysis 
of the primary endpoints will be adopted for the analysis of the MCEQ domain scores. 
12.6.4 
Confirmatory Analyses 
Not applicable. 
12.6.5 
Safety Endpoints  
In general, all safety data will be listed and tabulated on the safety population by sequence, 
using the approach described in section 12.1.3. 
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, and urine analysis safety panel; 
concomitant medication and physical examination. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 81 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
The number and percentage 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 data showing change from Baseline of clinical findings will be 
provided in listings 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. 
12.7 Exploratory Analyses 
There are no exploratory analyses currently planned. However, after or during the execution 
of the planned statistical analyses it may become necessary, useful or of interest to conduct 
additional analyses in support or to aid the interpretation of the original results; these analyses 
will be documented and reported as post-hoc analyses.  
12.8 Interim Analysis 
There are no planned interim analyses. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 82 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
13 
ADMINISTRATIVE CONSIDERATIONS 
13.1 Investigator’s and Study Administrative Structure 
13.1.1 
Investigator  
Investigator : 
 
Fumimasa Nobuoka MD 
Ageo Medical Clinic 
             
   
 
 
13.1.2 
Sponsor 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Phone: +41 (58) 242 2111 
Fax: 
+41 (58) 242 2811 
, PhD 
Clinical Scientist 
Phone: +41 
 
Mobile: +41 
  
E-mail: 
 
 
, MEng MSc 
Biostatistician 
Phone: +41 
 
Mobile: +41 
 
E-mail:
 
, MSc 
Clinical Study Manager 
Phone: +41 
 
Mobile: +41 
 
E-mail: 
 
1 May – 31 May 2015 Interim Period 
, MD 
Medical Safety Officer 
Phone: +41 
 
E-mail 1: 
 
E-mail 2: 
  

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 83 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
13.1.3 
Other Responsibilities 
 
 is the local contract research organization designated by PMI to manage and monitor 
the study: all duties and responsibilities transferred to 
 by PMI will be defined in the 
agreement signed between the two parties.  
  
  
 
  
 
Responsible person (Clinical Pharmacology): 
  
  
 
 
Any SAEs or pregnancies will be handled by: 
 
  
E-mail: 
 
Responsible Medical Safety Officer : 
From 1 June 2015 onwards 
, 
MD, PhD, MFPM 
Medical Safety Officer 
 
Phone: +41
 
E-mail: 
 
 
Details of the laboratories conducting the clinical safety laboratory services and 
biopharmaceutical analyses are shown in section 15.2. 
13.2 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects’ state of 
health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subject in writing and signed by the subject, in compliance with all local and 
national data protection and privacy legislation. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 84 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
The anonymity of subjects participating in this study will be maintained. Subjects will be 
identifiable by the Sponsor (or Sponsor’s authorized representative) on CRFs and other 
documents by their subject (or randomization) number/code, sex and date of birth, but not by 
name, initial, or any other details relating to an identifiable person (e.g., address, health 
insurance identification card, medical chart number, etc.) The assignment of a subject 
number/code for subject identification will be based on the appropriate data protection rules. 
Any documents that allow full identification of the subject (e.g., the subject’s signed study 
information sheet and 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, health insurance identification card,, medical chart number, 
etc.), the name or other identifiable details must be obscured before a copy of that document 
is supplied to the Sponsor or the Sponsor’s authorized representative. 
13.3 Access to Source Documentation 
The Investigator, head of investigational site and all study site staff involved with the study 
must permit direct access to source data/documents for study related monitoring, audits, IRB 
review, and regulatory inspection(s). 
13.4 Record Retention 
All records of data, source data, and source documents (original records or certified copies), in 
any form (including, but not limited to, written, electronic, magnetic, optical records and scans, 
x-rays 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. 
X-rays will be evaluated by the investigator who can perform x-ray evaluation. At least the 
investigator’s assessment is required as source documentation. If the actual image is available 
it can be stored on CD as well. 
Essential study documents/records, which individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced, are described in Article 41 of 
Ministerial Ordinance on GCP [4]. 
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 E6.  
Essential documents must be retained by the Investigator and the study site for a minimum of: 
• At least 15 years after completion or discontinuation of the study, or 
• At least 2 years depending on, for example, the circumstances. 
• After formal discontinuation of clinical development of the IP. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 85 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
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 (if applicable), and enrolment log (if 
applicable). 
• Record of all communications between the Investigator and the IRB, composition of the 
IRB. 
• Record of all communications/contact between the Investigator, Sponsor, and its 
authorized representatives. 
• List of other appropriately qualified persons to whom the Investigator has delegated 
significant study-related duties, together with their roles in the study, CVs, and their 
signatures. 
• Investigator logs. 
• CRFs, study specific questionnaires (and associated data/scoring), subject diaries. 
• AE reports and details of follow-up investigations, details of concomitant medication. 
• All other source documents (e.g., ECGs, x-rays, consultation reports, physical 
examination, and 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. 
• Product issue log, IP accountability logs, dispensing records. 
• Information regarding subjects’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the Investigator/head of investigational site as 
to when these documents no longer need to be retained. 
The Investigator/ head of investigational site must take measures to prevent accidental or 
premature destruction of these documents. 
If the head of investigational site wishes to assign the study records to another party or move 
them to another location, the Sponsor must be notified in advance. 
The head of investigational site must obtain written approval from the Sponsor before 
destruction of any records. Normally, these records will be held in the Investigator’s archives. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 86 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
If the head of investigational site is unable to meet this obligation, he/she must ask the Sponsor 
for permission to make alternative arrangements. Details of these arrangements must be 
documented. 
The Sponsor or Sponsor’s authorized representative will maintain documentation relating to 
the study as long as the IP is on the market, and/or for 15 years after the CSR has been finalized. 
13.5 Clinical Study Report 
The Sponsor must ensure that a CSR for this study is prepared, regardless of whether the study 
is completed or prematurely terminated. 
The CSR will be written based on standards of the ICH Guideline for the Structure and Content 
of Clinical Study Reports. In certain circumstances, an abbreviated CSR may be acceptable. 
Submission of the CSR to the IRB will be complied with as requested by local requirements. 
13.6 Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor. In 
addition, the Investigators must agree with the Sponsor to commit 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 data, information and trades secretes that are confidential and 
proprietary to the Sponsor. This document is being provided solely for the purpose of 
evaluation and/or conducting this clinical study for the Sponsor. Disclosure of the content of 
this document is allowed only to study personnel, IRB, or duly authorized representatives of 
regulatory agencies for this purpose under the condition that confidentiality is maintained. The 
contents of this document may not be used in any other clinical study, disclosed to any other 
person or entity without the prior written permission of the Sponsor. The foregoing shall not 
apply to disclosure required by any regulations. 
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 1.1 M 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 trial 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. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 87 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
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/E6_R
1_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. 
Ministry of Health Labour and Welfare. Ethical guidelines for clinical studies (as 
amended in 2008 from 2003). 2008. 
4. 
Ministry of Health and Welfare. Ministerial ordinance on good clinical practice for 
drugs. Ordinance of the Ministry of Health and Welfare No. 28 of March 27, 1997, as last 
amended No. 161 of December 28, 2012. Provisional Translation (as of March 2013). 2013; 
Available from: http://www.pmda.go.jp/english/service/pdf/ministerial/20130329No_28.pdf 
(Accessed on 22 April 2014). 
5. 
FDA (Food and Drug Administration). Guidance for industry - Modified risk tobacco 
product applications - Draft Guidance. 2012. 
6. 
Rodgman A, Perfetti TA. The chemical components of tobacco and tobacco smoke. 2nd 
ed. Taylor & Francis Inc (United States), editor: CRC Press; 2013  
7. 
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. 
8. 
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. 
9. 
Philip Morris Products S.A. A single-center, randomized, controlled, crossover study to 
investigate the nicotine pharmacokinetic profile and safety of THS 2.2 Menthol following 
single use in smokers compared to menthol conventional cigarettes and nicotine gum [ZRHM-
PK-05-JP]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine 
(US). 2013- [cited 2013 Dec 02]. Available from: http://clinicaltrials.gov/show/NCT01967706 
NLM Identifier: NCT01967706. 
10. 
Benowitz NL, Hukkanen J, Jacob P, 3rd. Nicotine chemistry, metabolism, kinetics and 
biomarkers. Handb Exp Pharmacol. 2009(192):29-60. 
11. 
Hukkanen J, Jacob P, 3rd, Benowitz NL. Metabolism and disposition kinetics of nicotine. 
Pharmacol Rev. 2005;57(1):79-115. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 88 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
12. 
Global initiative for Chronic Obstructive Lung Disease: GOLD. Pocket guide to COPD 
diagnosis, management, and prevention. 2013. 
13. 
FDA (Food and Drug Administration). Food-effect bioavailability and fed 
bioequivalence studies. 2002. 
14. 
American Pharmacists Association. Cytochrome P450 enzymes: substrates, inhibitors, 
and inducers.  Drug information handbook. 23rd ed2014. p. 2316-24. 
15. 
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. 
16. 
Kubota M, Kobayashi H, Quanjer PH, Omori H, Tatsumi K, Kanazawa M. Reference 
values for spirometry, including vital capacity, in Japanese adults calculated with the LMS 
method and compared with previous values. Respir Investig. 2014;52(4):242-50. 
17. 
Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström test for 
Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict. 
1991;86(9):1119-27. 
18. 
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. 
19. 
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. 
20. 
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. 
21. 
Tiffany ST, Drobes DJ. The development and initial validation of a questionnaire on 
smoking urges. Br J Addict. 1991;86:1467-76. 
22. 
ICH E2A. Clinical safety data management: definitions and standards for expedited 
reporting. 
Available 
from: 
http://wwwichorg/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4
/E2A_Guidelinepdf (Accessed on 17 July 2014). 1994. 
23. 
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/PostmarketRequirement
s/ReportingAdverseEvents/EventProblemCodes/ucm135741.htm (Accessed on 3 April 2014). 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015 
Page 89 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
24. 
Senn S. Cross-over trials in clinical research: John Wiley & Sons; 2002. 
25. 
Beal SL. Sample size determination for confidence intervals on the population mean and 
on the difference between two population means. Biometrics. 1989;45:969-77. 
26. 
European Medicines Agency (EMA). Guideline on the investigation of bioequivalence 
(CPMP/EWP/QWP/1401/98 Rev.1/Corr). 2010. 
27. 
FDA (Food and Drug Administration). Guidance for industry - Statistical approaches to 
establishing bioequivalence. 2001. 
28. 
FDA (Food and Drug Administration). Guidance for industry - E9 Statistical Principles 
for Clinical Trials. 1998. 
29. 
Lingling H. Calculating the point estimate and confidence interval of Hodges-Lehmann's 
median using SAS® software. Paper (ST-154) presented at SESUG Proceedings in 
Birmingham, AL (USA). 2008; Available from: http://analytics.ncsu.edu/sesug/2008/ST-
154.pdf (Accessed on 10 July 2014). 
30. 
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). 
31. 
Food and Drug Administration (FDA). Guidance for industry - Toxicity grading scale 
for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. 2007; 
Available 
from: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInf
ormation/Guidances/Vaccines/ucm091977.pdf (Accessed on 18 September 2014). 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015  
Page 90 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris International. 
15 
APPENDICES 
15.1 Appendix A – Schedule of Events 
Table A1 
Schedule of Events 
 
Screening 
Admission 
Wash-out 
Single Use 
Wash-out 
Single Use 
Discharge k 
Safety 
Follow-up l 
Study Day 
-31 to -4  
-3 
-2/-1 
1 
2 
3 
4 
4 to 11 
Informed consent 
● 
 
 
 
 
 
 
 
Information on the risks of 
smoking/smoking cessation 
advice, and debriefing 
● 
● 
 
 
 
 
● 
 
Inclusion/exclusion criteria 
● 
● 
 
 
 
 
 
 
Enrolment 
 
● 
 
 
 
 
 
 
Randomization 
 
 
● m 
 
 
 
 
 
Single product use  
 
 
 
● 
 
● 
 
 
Support during periods of 
reduced smoking/smoking 
abstinence (as required) 
 
 
●  
● 
● 
● 
 
 
Product demonstration of 
CHTP 1.1 M  
● 
 
 
 
 
 
 
 
Product test for CHTP 1.1 M  
 
● 
 
 
 
 
 
 
Identification of current mCC 
brand 
● 
● 
 
 
 
 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015  
Page 91 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris International. 
 
Screening 
Admission 
Wash-out 
Single Use 
Wash-out 
Single Use 
Discharge k 
Safety 
Follow-up l 
Study Day 
-31 to -4  
-3 
-2/-1 
1 
2 
3 
4 
4 to 11 
Smoking history 
● 
 
 
 
 
 
 
 
Readiness to accept 
interruption from smoking up 
to 6 days 
● 
● 
 
 
 
 
 
 
Willingness to quit smoking in 
the next 3 months 
● 
 
 
 
 
 
 
 
X-ray a 
● 
 
 
 
 
 
 
 
Demographics b, medical 
history, concomitant diseases  
● 
 
 
 
 
 
 
 
Prior medicationc/Concomitant 
medication 
● 
● 
● 
● 
● 
● 
● 
● 
Physical examination, body 
height, weight and BMI d 
● 
● 
 
 
 
 
● 
 
Vital signs e 
● 
● 
● 
● 
● 
● 
● 
 
ECG 
● 
 
 
● 
 
● 
 
 
Spirometry 
● 
● 
 
 
 
 
● 
 
B/U: Hematology, clinical 
chemistry, urine analysis 
● 
● 
 
 
 
 
● 
 
B: Serology  
● 
 
 
 
 
 
 
 
U: Urine drug screen, urine 
cotinine screen 
● 
● 
 
 
 
 
 
 
Alcohol breath test  
● 
● 
 
 
 
 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015  
Page 92 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris International. 
 
Screening 
Admission 
Wash-out 
Single Use 
Wash-out 
Single Use 
Discharge k 
Safety 
Follow-up l 
Study Day 
-31 to -4  
-3 
-2/-1 
1 
2 
3 
4 
4 to 11 
U: Pregnancy test (female 
subjects of childbearing 
potential) 
● 
● 
 
 
 
 
● 
 
Collection of used CHTP 1.1 
M and mCC butts 
 
● 
 
● 
 
● 
 
 
B: Plasma nicotine f 
 
 
 
● 
● 
● 
● 
 
B: COHb g 
 
 
 
● 
 
● 
 
 
CO breath test h 
 
● 
● 
● 
● 
● 
● 
 
trans-3’-hydroxycotinine and 
cotinine (CYP2A6 activity) in 
plasma  
 
● 
 
 
 
 
 
 
FTND questionnaire 
● 
 
 
 
 
 
 
 
QSU–brief questionnaire i 
 
 
 
● 
 
● 
 
 
MCEQ (modified version) 
 
 
 
● 
 
● 
 
 
Cough assessment j 
 
 
● 
● 
● 
● 
● 
 
AE/SAE recording  
● 
● 
● 
● 
● 
● 
● 
● 
Abbreviations:  
AE = adverse event; BMI= body mass index; mCC = menthol conventional cigarette(s); CHTP 1.1 M = Carbon Heated Tobacco Product 1.1 Menthol; CO = carbon monoxide; 
COHb = carboxyhemoglobin; CYP2A6 = Cytochrome P450 2A6; ECG = electrocardiogram; FTND = Fagerström test for nicotine dependence (revised version); MCEQ = modified 
cigarette evaluation questionnaire; QSU-brief = questionnaire of smoking urges; SAE =   serious adverse event. 
B: blood sample required.  U: urine sample required.  
a: Pre-study chest X-ray (anterior-posterior and left lateral views) to be used, if performed within 6 months prior to Screening. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015  
Page 93 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris International. 
b: Sex, date of birth/age. 
c: Prior medication at Screening and the 4 weeks prior to Screening. 
d: Including height (only at Screening), body weight and calculated BMI. 
e: Systolic and diastolic blood pressure, pulse rate, respiratory rate. 
f: Nicotine blood samples (n=16) to be taken as follows: 
The first blood sample will be taken within 15 minutes prior to the product use (T0). Thereafter in relation to T0, blood will be drawn at the following time points: T1 after 2 min 
+ 1 min, T2 after 4 min + 1min, T3 after 6 min + 1 min, T4 after 8 min + 1 min, T5 after 10 min + 1 min, T6 after 15 min + 2 min, T7 after 30 min + 2 min, T8 after 45 min + 2 
min, T9 after 60 min + 3 min, T10 after 2 hours + 5 min, T11 after 4 hours + 5 min, T12 after 6 hours + 5 min, T13 after 9 hours + 5 min, T14 after 12 hours + 5 min, and T15 after 
24 hours + 5 min.. 
g: COHb blood samples (n=5) to be taken as follows: 
The first sample within 15 minutes prior to T0; thereafter in relation to T0 at 15 min + 2 min, 60 min + 3 min, 4 hours + 5 min and 12 hours + 5 min 
h: A CO breath test will be conducted once on Day -3 and Day 4. On Day -2, Day -1, Day 1, Day 2, Day 3, four breath tests will be done per day. See section 9 for the timing. 
i: QSU–brief will be assessed as follows:  
The QSU-brief will be completed by the subject himself/herself at single use study days. The first assessment will be done within 15 min prior to T0. All other assessments will 
be done after T0, at 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 9 hours, and 12 hours (with an allowed time window of 10 min each). 
j: Visual analogue scale, three Likert scales and one open question. Cough questionnaire should be asked on Day -2 between 06:30 and 09:00; on Day 2: 24 hours after T0 of Day 
1; on Day 4: 24 hours after T0 of Day 3; and on Day 1 and Day 3: prior to product use. 
k: All examinations listed in early termination procedures (section 9.6) should also be conducted in subjects prematurely terminating the study. 
l: Spontaneous reporting of AEs/SAEs by the subject and active follow-up of ongoing AEs/SAEs by the site.  
m: Randomization will take place on Day -1. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015  
Page 94 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
15.2 Appendix B - Participating Laboratories 
Participating laboratories for blood samples testing will be decided prior to the Investigator 
meeting and site initiation. Safety laboratory samples will be tested at a local laboratory or site. 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015  
Page 95 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
15.3 Appendix C - Investigational Product and Instructions for Use 
The product user guide will be provided as a separate document.

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015  
Page 96 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
15.4 Appendix D - Abnormal Laboratory Values 
Table D1 
Abnormal Laboratory Values Rating: Serum Chemistry Parameters 
Serum Chemistry 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
threatening 
 (Grade 4) 
Sodium – Hyponatremia (mmol/L)  (1) 
<LLN - 130 
- 
<130 - 120 
<120 
Sodium – Hypernatremia (mmol/L) (1) 
>ULN - 150 
>150 - 155 
>155 - 160; 
hospitalization 
indicated 
>160 
Potassium – Hyperkalemia (mmol/L)(1) 
>ULN - 5.5 
>5.5 - 6.0 
>6.0 -7.0; 
hospitalization 
indicated 
>7.0 
Potassium – Hypokalemia (mmol/L) (1) 
<LLN - 3.0 
<LLN - 3.0; 
symptomatic; 
intervention 
indicated 
<3.0 - 2.5; 
hospitalization 
indicated 
<2.5 
Glucose – Hypoglycemia  (1)    
 (mg/dL)                                                 
(mmol/L)  
<LLN – 55; 
<LLN – 3.0 
<55 – 40; 
<3.0 – 2.2 
<40 – 30; 
<2.2 – 1.7 
<30; 
<1.7 
Glucose – Hyperglycemia:  (1) 
 
 
 
 
 
  Fasting (mg/dL) 
(mmol/L) 
 
 
 
 
  
 
>ULN-160; 
>ULN-8.9 
 
 
>160-250; 
>8.9-13.9 
 
 
 
>250-500; 
>13.9-27.8; 
hospitalization 
indicated 
 
>500; 
>27.8 
Creatinine increased (1) 
>1 – 1.5 x 
Baseline; 
>ULN – 1.5 
x ULN 
>1.5 – 3.0 x 
Baseline; 
>1.5 – 3.0 x 
ULN 
>3.0 x Baseline; 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Albumin - Hypoalbuminemia (1) (g/dL) 
 (g/L) 
<LLN – 3; 
<LLN - 30 
<3 – 2; 
<30 - 20 
<2; 
<20 
- 
Alkaline phosphatase increased (1) 
>ULN – 2.5 
x ULN 
>2.5 – 5.0 x 
ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
ALT / AST increased (1) 
>ULN – 3.0 
x ULN 
>3.0 – 5.0 x 
ULN 
>5.0 – 20.0 x 
ULN 
>20.0 x ULN 
Gamma-glutamyl transferase (GGT) 
increased (1) 
>ULN – 2.5 x 
ULN 
>2.5 – 5.0 x 
ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Blood bilirubin increased  
(total and direct)  (1) 
>ULN – 1.5 
x ULN 
>1.5 – 3.0 x 
ULN 
>3.0 – 10.0 x 
ULN 
>10.0 x ULN 
Cholesterol high (1)                    
 
(mg/dL) 
(mmol/L) 
 
>ULN - 300; 
>ULN - 7.75 
 
>300-400; 
>7.75-10.34 
 
>400-500; 
>10.34-12.92 
 
>500; 
>12.92 
Triglycerides - Hypertriglyceridemia (1) 
(mg/dL) 
(mmol/L) 
150 – 300; 
1.71 – 3.42 
>300 – 500; 
>3.42 – 5.70 
>500 – 1000; 
>5.70 – 11.40 
 
>1000; 
>11.4  
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; GGT = 
gamma-glutamyl transferase; LLN = lower limit of the normal range; ULN = upper limit of the normal range. 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015  
Page 97 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Data Sources: 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, FDA, 
Center for Biologics Evaluation and Research - Guidance for Industry. 
 
Table D2 
Abnormal Laboratory Values Rating: Hematology Parameters 
Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
threatening 
 (Grade 4) 
Anemia 
(Hemoglobin) (1) 
(g/dL) 
(mmol) 
(g/L) 
 
<LLN-10.0 
<LLN-6.2 
< 100 
 
<10-8.0 
<6.2-4.9 
< 100-80 
 
<8.0 
<4.9 
<80 
Transfusion 
indicated 
 
Life 
threateming 
conseuqences; 
urgent 
intervention 
indicated 
Hemoglobin increase 
(1) – (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 (1) - 
(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 (1) - 
(cell/mm3)  
- 
>4,000 – 20,000 
>20,000 
- 
Lymphocytes 
Decrease (1) –  
(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 
(1) - (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 (1) - 
(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. 
Data Source: 
 (1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, FDA, 
Center for Biologics Evaluation and Research - Guidance for Industry. 
 

Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
P2M-PK-04-JP 
Version 2.0 / 18 May 2015  
Page 98 of 98 
 
 
 
 
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 applicable provisions of law. No part of this document may be publicly disclosed without the 
written consent of Philip Morris International. 
Table D3 Abnormal Laboratory Values Rating: Urinalysis Parameters 
Urine 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-threatening 
(Grade 4) 
Protein (1) 
1+ proteinuria; 
urinary protein 
<1.0 g/24 hours 
2+ proteinuria; 
urinary protein 
1.0-3.4 g/24 hours 
Urinary protein 
≥3.5 g/24 hours 
- 
Data Source: 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, FDA, 
Center for Biologics Evaluation and Research - Guidance for Industry.