A Single-center, Open-label, Randomized, Controlled, Crossover Study to Investigate the Nicotine Pharmacokinetic Profile and Safety of Tobacco Heating System 2.2 Menthol (THS 2.2 Menthol) Following Single Use in Smoking, Healthy Subjects Compared to Menthol Conventional Cigarettes and Nicotine Gum.
Phase: NA
Conditions: Smoking
Sponsor: Philip Morris Products S.A.

 
 
 
Clinical Study Protocol 
ZRHM-PK-05-JP 
 
Study title: 
A single-center, open-label, randomized, controlled, crossover 
study to investigate the nicotine pharmacokinetic profile and 
safety of Tobacco Heating System 2.2 Menthol (THS 2.2 
Menthol) following single use in smoking, healthy subjects 
compared to menthol conventional cigarettes and nicotine gum 
Product name: 
Tobacco Heating System 2.2 Menthol (THS 2.2 Menthol) 
Short name 
Nicotine pharmacokinetic profile and safety of the Tobacco 
Heating System 2.2 Menthol (THS 2.2 Menthol) 
Sponsor: 
Philip Morris Products S.A.  
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Version number: 
Final 1.0  
Date: 
21 June 2013 
Authors: 
, PhD, Manager Clinical Science 
, PhD, Biostatistician 
, MD, Medical Safety Officer 
 Medical Writer 
 
 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets 
and confidential commercial information, and the legal protections provided to such trade 
secrets and confidential information are hereby claimed under the provisions of applicable 
law. No part of this document may be publicly disclosed without the written consent of Philip 
Morris Products S.A. 

 
 
 
 
 
Philip Morris Products S.A.  
Clinical Study Protocol 
Confidential 
ZRHM-PK-05-JP 
Final 1.0  / 21 June 2013 
Page 2 of 124 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
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SYNOPSIS 
Sponsor: 
Philip Morris Products S.A.  
Study Title: 
A single-center, open-label, randomized, controlled, crossover study to investigate the 
nicotine pharmacokinetic profile and safety of Tobacco Heating System 2.2 Menthol (THS 
2.2 Menthol) following single use in smoking, healthy subjects compared to menthol 
conventional cigarettes and nicotine gum 
Name of Product: 
Tobacco Heating System 2.2 Menthol (THS 2.2 Menthol). 
Study Number and Acronym: 
ZRHM-PK-05-JP, no acronym 
Primary Objective: 
 To evaluate the rate and the 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 THS 2.2 
Menthol relative to menthol conventional cigarettes (mCC), following single use of THS 
2.2 Menthol and mCC. 
 
Secondary Objectives: 
 To determine if Cmax and AUC(0-last) of plasma nicotine of the THS 2.2 Menthol are 
higher relative to nicotine replacement therapy gum (NRT gum) following single use of 
the THS 2.2 Menthol and NRT gum. 
 To evaluate the difference on nicotine pharmacokinetic (PK) absorption parameters 
(AUC from start of product use extrapolated to time of last quantifiable concentration to 
infinity [AUC(0-∞)] and partial AUC, where t’ is the subject-specific time of maximum 
nicotine concentration following single use of the mCC or NRT gum [AUC(0-t’)]) between 
the THS 2.2 Menthol and mCC, as well as the THS 2.2 Menthol and NRT gum. 
 To evaluate the time to the maximum concentration (tmax) of plasma nicotine for the THS 
2.2 Menthol as compared to mCC and to determine if the tmax for THS 2.2 Menthol is 
shorter as compared to NRT gum. 
 To describe the terminal half-life (t1/2) of nicotine for the THS 2.2 Menthol, mCC, and 
NRT gum. 
 To describe the differences on urge-to-smoke over time between the THS 2.2 Menthol 

 
 
 
 
 
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Final 1.0  / 21 June 2013 
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and mCC, as well as between the THS 2.2 Menthol and NRT gum. 
 To describe product evaluation in the THS 2.2 Menthol and mCC users. 
 To describe the levels of carbon monoxide (CO) exposure for the THS 2.2 Menthol, as 
compared to mCC and NRT gum users. 
 To monitor the safety during the study. 
  
Primary Endpoints: 
 Primary nicotine PK parameters (THS 2.2 Menthol vs. mCC): 
o Cmax. 
o AUC(0-last). 
 
Evaluation criterion: The study will be considered successful if the 95% confidence intervals 
(CI) of the THS 2.2 Menthol:mCC ratio for the primary nicotine PK parameters are estimated 
with a precision of ±20%. 
 
Secondary Endpoints: 
• Primary nicotine PK parameters (THS 2.2 Menthol vs. NRT gum) 
• Secondary nicotine PK parameters: 
o AUC(0-∞). 
o Partial AUC(0-t’).  
o tmax. 
o t1/2. 
 Subjective smoking effects: 
o Urge-to-smoke questionnaire (Questionnaire of Smoking Urges brief [QSU-
brief]). 
o Product 
evaluation 
questionnaire 
(Modified 
Cigarette 
Evaluation 
Questionnaire [MCEQ]). 
 CO exposure biomarkers: levels of exhaled CO and carboxyhemoglobin (COHb) in 
blood. 
 Safety variables: 
o Incidence of adverse events (AEs)/serious adverse events (SAEs), and 
including THS 2.2 Menthol malfunction/misuse. 
o Respiratory symptoms: cough assessment by visual analogue and Likert scales 
and one open question. 
o Vital signs. 

 
 
 
 
 
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o Spirometry. 
o Electrocardiogram (ECG). 
o Clinical chemistry, hematology, and urine analysis safety panel. 
o Physical examination. 
o Concomitant medications. 
 
Additional Study Assessments: 
 Serology for human immunodeficiency virus 1/2 and Hepatitis B and C. 
 Urine pregnancy test (females 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 (nicotine metabolic molar ratio) in plasma. 
 
Study Design: 
This is a randomized, controlled, 2-period, 4-sequence, single-use crossover study. An 
incomplete block design is adopted, where each subject will receive only two of the three 
products (Figure S1): 
 THS 2.2 Menthol. 
 mCC. 
 NRT gum. 

 
 
 
 
 
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Final 1.0  / 21 June 2013 
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•
Cross over with incomplete block design, 4 sequences
•
62 smokers to be randomized
Day 4 Discharge
Day -1
Day 0
Day 1
Day 2
Day 3
THS 2.2 
Menthol
n=22
THS 2.2 
Menthol
n=9
NRT gum
n=9
mCC
n=22 
THS 2.2 
Menthol
n=9
THS 2.2 
Menthol
n=22
NRT gum
n=9
mCC
n=22 
Admission
Wash-out
Safety
follow-up
Day 4-11
6 days of confinement
mCC 
ad libitum
Single 
use
Single 
use
Screening
Screening 
within 1-4 weeks 
prior to admission
7 days of follow-up
Abbreviations: THS: Tobacco Heating System; mCC = menthol conventional cigarette; NRT = Nicotine Replacement Therapy
Figure S1: Study Design
  
A Screening Visit will be conducted within 4 weeks prior to Admission to the investigational 
site (Day -29 to Day -2) (Figure S1). A demonstration of the THS 2.2 Menthol product and 
the NRT gum will also be done by the site study collaborator during the Screening Visit. 
Subjects will be admitted to the clinic on Day -1. On Day -1, as the last procedure of the 
eligibility assessments on that day, all subjects will undergo a product test prior to enrolment, 
first THS 2.2 Menthol (using of up to 3 Menthol Tobacco Sticks) and subsequently NRT 
gum. In female subjects, the urine pregnancy test must be negative before any product test is 
performed with either the THS 2.2 Menthol or the NRT gum. After all inclusion and 
exclusion criteria have been satisfactorily met, only subjects willing and ready to use both the 
THS 2.2 Menthol and the NRT gum products can be enrolled. Screening procedures do not 
necessarily have to be conducted on the same day.  
The confinement period will then consist of 2 periods (Period 1, Period 2) with each period 
consisting of at least 24-hour nicotine wash-out (nicotine abstinence) and 1 day of single 
product use.  
Period 1: Day 0: Wash-out; Day 1: single product use (THS 2.2 Menthol/mCC/NRT gum). 
Period 2: Day 2: Wash-out; Day 3: single product use (THS 2.2 Menthol/mCC/NRT gum). 

 
 
 
 
 
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Clinical Study Protocol 
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Final 1.0  / 21 June 2013 
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In total, 62 eligible, healthy smoking subjects will be randomized into one of the 4 
sequences: 
Sequence 1: THS 2.2 Menthol  
→  
mCC (N=22) 
Sequence 2: mCC  
 
 
 
→  
THS 2.2 Menthol (N=22) 
Sequence 3: THS 2.2 Menthol 
→  
NRT gum (N=9) 
Sequence 4: NRT gum 
 
 
→  
THS 2.2 Menthol (N=9) 
Subjects will be discharged (time of discharge) from the investigational site in the morning of 
Day 4 after performance of the Day of Discharge assessments.  
From the time of discharge until Day 11: A 7-day safety follow-up will be done for the 
recording of spontaneously reported new AEs and SAEs, and the active follow-up of ongoing 
AEs/SAEs by the site.  
Study Population and Main Criteria for Inclusion:  
A total of 62 smoking, but healthy adult Japanese subjects, meeting the following main 
inclusion criteria: 
• Subject is aged from 23 to 65 years (inclusive). 
• Smoking, healthy subject as judged by the Investigator. 
• Subject is Japanese. 
• Subject smokes at least 10 commercially available mCC per day (no brand restrictions) 
for the last 4 weeks, based on self-reporting. 
• Subject does not plan to quit smoking in the next 3 months. 
• Subject is ready to accept interruptions of smoking for up to 4 days. 
• Subject is ready to accept using the THS 2.2 Menthol and the NRT gum product. 
 
Each sex and each of the smoking strata (International Organization for Standardization 
[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 population. This will be applied to subjects 
randomized to sequence 1 and 2 and independently to subjects randomized to sequence 3 and 
4. Subjects who do not complete the study after randomization will not be replaced. 
Investigational Products, Dose, and Mode of Use:  
• Test Product: THS 2.2 Menthol  
 
• Reference Product, Dose, and Mode of Use: 

 
 
 
 
 
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Clinical Study Protocol 
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Subject’s own supply of commercially available preferred single brand mCC. 
 
Reference Point Product (non-investigational): 
Nicotine replacement therapy gum 2 mg Nicorette® chewed for 35 ± 5 minutes. This will be 
supplied by the site and reimbursed by the Sponsor or designated Clinical Research 
Organization (CRO). 
Duration of Study: 
The entire study will last 14 to 41 days, including a Screening period of up to 4 weeks prior 
to Admission (Day -29 to Day -2), 6 days of confinement (Day -1 to time of discharge on 
Day 4), and 7 days of safety follow-up (from time of discharge until Day 11). 
 
Expected Duration of the Entire Study: 
From 1st of July 2013 to 30th November 2013. 
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: the analysis populations for the PK endpoints will be composed of 
two analysis sets to allow the comparison between THS 2.2 Menthol and NRT gum 
separately from the comparison between THS 2.2 Menthol and mCC. Only subjects without 
major protocol deviations will be included in the PK analysis sets. 
Nicotine PK parameters will be derived from plasma nicotine versus time data using a 
non-compartmental technique. 
An analysis of variance (ANOVA) will be conducted on logarithmically transformed 
AUC(0-last) and Cmax primary endpoints. The model will include terms for sequence, subjects 
within sequence, period, and exposure group as fixed effect factors. The results of this 
analysis for each of AUC(0-last) and Cmax will be presented in terms of adjusted geometric least 
square means and 95% CIs for the THS 2.2 Menthol:mCC and THS 2.2 Menthol:NRT gum 
ratios. The lower bound of the 95% CI of the THS 2.2 Menthol:NRT gum ratio for Cmax and 
AUC(0-last) will be compared with 1.00, to determine if the rate and the amount of nicotine 
absorbed of the THS 2.2 Menthol are higher relative to NRT gum. 
The AUC(0-∞), AUC(0-t’), and t1/2 will be analyzed using the same approach adopted for the 
primary endpoints. The one-sided Wilcoxon Signed-Rank Test (α=0.025) will be used to test 
if the tmax in THS 2.2 Menthol is shorter than in NRT gum. The median tmax differences 
between THS 2.2 Menthol and mCC, as well as between THS 2.2 Menthol and NRT gum 
will be presented together with Hodges-Lehmann estimates of the 95% CI. 
Subjective effects of smoking: mixed effects ANOVA using period, sequence, and product 
exposure as fixed effects and subjects within sequence as random effects will be adopted to 

 
 
 
 
 
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analyze the domain scores of the MCEQ questionnaire, for the comparison between THS 2.2 
Menthol and mCC. The same model will be evaluated for the analysis of 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 THS 2.2 Menthol-mCC and THS 2.2 
Menthol-NRT gum differences. 
Safety: The safety population will comprise all subjects who are exposed to THS 2.2 
Menthol during the study, including the THS 2.2 Menthol test at admission. Adverse event 
data will serve as the primary assessment of safety. All safety data will be listed and 
tabulated by sequence and by product use. 
Sample Size: 
A total of 62 subjects will be randomized. This sample size is the sum of the sample size 
requirements for the THS 2.2 Menthol:mCC comparison and the THS 2.2 Menthol:NRT gum 
comparison (as described in detail below). 
The anticipated within-subject coefficients of variation for nicotine Cmax and AUC(0-last) are 
36% and 21%, respectively. 
The sample sizes of this study assume a drop-out rate no larger than 10%.  
THS 2.2 Menthol:mCC comparison 
A total of 44 subjects are needed to estimate the mean Cmax parameter ratio between THS 2.2 
Menthol and mCC with a 90% probability of obtaining a margin of error (95% CI) of at most 
±20%, assuming that THS 2.2 Menthol have a nicotine Cmax similar to mCC (ratio equal 
to 1.00). This sample size is sufficient to provide 90% probability of obtaining a margin of 
error of at most ±20% for the AUC(0-last) ratio between THS 2.2 Menthol and mCC, assuming 
a similar extent of nicotine absorption for the 2 products (ratio equal to 1.00).  
THS 2.2 Menthol:NRT gum comparison 
A total of 18 subjects are needed to estimate the mean AUC(0-last) parameter ratio between 
THS 2.2 Menthol and NRT gum with a precision allowing for the lower bound of the 95% CI 
exceeding 1.00, with 90% power, assuming a geometrical ratio between THS 2.2 Menthol 
and NRT gum of 1.28. This sample size is sufficient to provide 90% power of obtaining a 
lower bound of the 95% CI of Cmax ratio between THS 2.2 Menthol and NRT gum, 
exceeding 1.00, assuming a geometrical mean ratio between THS 2.2 Menthol and NRT gum 
of 2.00. 

 
 
 
 
 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................13 
1 
ETHICS AND REGULATIONS .....................................................................................19 
1.1 
Institutional Review Board Approval ....................................................................19 
1.2 
Ethical Conduct of the Study .................................................................................20 
1.3 
Subject Information and Consent...........................................................................20 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................21 
2 
INTRODUCTION ...........................................................................................................22 
2.1 
Background ............................................................................................................22 
2.2 
Purpose of the Study ..............................................................................................24 
2.3 
Anticipated Benefits and Risks ..............................................................................24 
3 
STUDY OBJECTIVES ....................................................................................................26 
3.1 
Primary Objective ..................................................................................................26 
3.2 
Secondary Objectives.............................................................................................26 
3.3 
Primary Endpoints .................................................................................................27 
3.4 
Secondary Endpoints .............................................................................................27 
3.5 
Exploratory Endpoints ...........................................................................................28 
4 
INVESTIGATIONAL PLAN ..........................................................................................29 
4.1 
Overall Study Design and Plan ..............................................................................29 
4.2 
Rationale for Study Design and Control Group(s) ................................................31 
4.3 
Study Duration .......................................................................................................32 
4.4 
Appropriateness of Measurement ..........................................................................32 
5 
STUDY POPULATION ..................................................................................................33 
5.1 
Selection of Study Population ................................................................................33 
6 
INVESTIGATIONAL PRODUCTS AND REFERENCE POINT PRODUCT .............40 
6.1 
Description .............................................................................................................40 
6.2 
Use of Investigational and Reference Point Products ............................................42 
6.3 
Method for Assigning Subjects to Study Arms .....................................................44 
6.4 
Blinding..................................................................................................................44 
6.5 
Investigational Product Accountability and Compliance ......................................45 
6.6 
Restrictions ............................................................................................................46 
7 
STUDY PROCEDURES .................................................................................................50 

 
 
 
 
 
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7.1 
Informed Consent...................................................................................................50 
7.2 
Smoking Cessation Advice and Debriefing ...........................................................50 
7.3 
Support during Smoking Abstinence/Periods of Reduced Smoking .....................50 
7.4 
Clinical Assessments .............................................................................................51 
7.5 
Biomarker Assessment...........................................................................................54 
7.6 
Laboratory Assessments ........................................................................................56 
7.7 
Sample Handling, Storage, and Shipment .............................................................58 
7.8 
Questionnaires........................................................................................................59 
8 
ADVERSE EVENTS .......................................................................................................62 
8.1 
Definitions..............................................................................................................62 
8.2 
Assessment of Adverse Events ..............................................................................63 
8.3 
Reporting of Serious Adverse Events ....................................................................65 
8.4 
Reporting of Other Events Critical to Safety Evaluations .....................................66 
8.5 
Actions and Follow-up ...........................................................................................68 
9 
STUDY ACTIVITIES .....................................................................................................70 
9.1 
Screening Visit .......................................................................................................70 
9.2 
Admission ..............................................................................................................72 
9.3 
Investigational Period ............................................................................................75 
9.4 
Day of Discharge ...................................................................................................81 
9.5 
Safety Follow-up Period ........................................................................................83 
9.6 
Early Termination Procedures ...............................................................................83 
10 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................84 
10.1 
Monitoring .............................................................................................................84 
10.2 
Training of Study Collaborator ..............................................................................85 
10.3 
Audits and Inspections ...........................................................................................85 
11 DATA MANAGEMENT ACTIVITIES..........................................................................86 
11.1 
Data Capture ..........................................................................................................86 
11.2 
Data Handling ........................................................................................................87 
12 PLANNED STATISTICAL METHODS ........................................................................89 
12.1 
General Considerations ..........................................................................................89 
12.2 
Determination of Sample Size and Power Consideration ......................................90 
12.3 
Analysis Populations ..............................................................................................91 
12.4 
Demographics and Baseline Characteristics ..........................................................92 
12.5 
Primary Endpoints .................................................................................................92 
12.6 
Secondary Endpoints .............................................................................................93 

 
 
 
 
 
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12.7 
Exploratory Analyses .............................................................................................96 
12.8 
Interim Analysis .....................................................................................................96 
13 ADMINISTRATIVE CONSIDERATIONS ....................................................................97 
13.1 
Principal Investigators and Study Administrative Structure ..................................97 
13.2 
Subject Confidentiality ..........................................................................................99 
13.3 
Access to Source Documentation ........................................................................100 
13.4 
Record Retention .................................................................................................100 
13.5 
Clinical Study Report ...........................................................................................102 
13.6 
Financial Disclosure.............................................................................................102 
13.7 
Publication and Disclosure Policy .......................................................................102 
13.8 
Insurance ..............................................................................................................103 
14 REFERENCE LIST .......................................................................................................104 
 

 
 
 
 
 
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LIST OF IN-TEXT TABLES AND FIGURES 
Table 1 
Measured aerosol fractions for the THS Menthol Tobacco Sticks ............41 
Table 2 
Drugs and Substances Considered Interacting with CYP2A6 ...................47 
Table 3. 
Clinical Laboratory Parameters for Safety Panel.......................................57 
Table 4 
Time Schedule – Screening Visit ...............................................................70 
Table 5. 
Time Schedule – Day -1 Admission ..........................................................73 
Table 6. 
Time Schedule – Day 0 Washout ...............................................................75 
Table 7. 
Time Schedule – Day 2 Washout ...............................................................77 
Table 8. 
Time Schedule – Day 1 and Day 3 Single Use ..........................................79 
Table 9. 
Time Schedule – Day 4 Discharge .............................................................82 
 
Figure 1. 
Study Flow Chart .......................................................................................31 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events ...................................................................................111 
Appendix 2 
Participating Laboratories ........................................................................115 
Appendix 3 
Investigational Product and Instructions for Use .....................................116 
Appendix 4 
THS Package Label..................................................................................117 
Appendix 5 
Abnormal Laboratory Values ..................................................................120 

 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
ADL 
Activities of daily living 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC(0-∞) 
Area under the concentration-time curve from start of product use extrapolated 
to time of last quantifiable concentration to infinity 
AUC(0-last) 
Area under the concentration-time curve from start of product use to time of 
last quantifiable concentration 
AUC(0-t’) 
 
Partial AUC, where t’ is the subject-specific time of maximum nicotine 
concentration following single use of mentholated conventional cigarettes or 
NRT gum. 
BMI 
Body mass index 
CC 
Conventional cigarette(s) 
CD 
Compact disc 
CI 
Confidence Interval 
Clast 
Last quantifiable concentration 
Cmax 
Maximum plasma concentration 
CO 
Carbon monoxide 

 
 
 
 
 
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COHb 
Carboxyhemoglobin 
CRA 
Clinical Research Associate 
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 
Coefficient of variation 
CYP2A6 
Cytochrome P450 2A6 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End of Study Visit (referring to each subject’s individual last study visit) 
ePRO 
Electronic patient reported outcome 
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 

 
 
 
 
 
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are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
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 
LLN 
Lower limit of the normal range 
LLOQ 
Lower limit of quantification 
mCC 
Menthol conventional cigarette(s) 
MCEQ 
Modified Cigarette Evaluation Questionnaire  
MedDRA 
Medical Dictionary for Regulatory Activities 
MRTP 
Modified risk tobacco product 
n 
Number of subjects 
NRT gum 
Nicotine replacement therapy gum 
PK 
Pharmacokinetic(s) 
PMI 
Philip Morris International 
QC 
Quality control 
QSU-brief 
Questionnaire of Smoking Urges brief 
SA 
Smoking abstinence 

 
 
 
 
 
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SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SHM 
Sample handling manual 
SOP 
Standard Operating Procedure 
T0 
Time point of first product use during study day 
t1/2 
Terminal half-life 
THS 2.2 
Menthol 
Tobacco Heating System 2.2 Menthol 
tmax 
Time to the 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 
 

 
 
 
 
 
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Explanations of Terms 
The following special terms are used in this protocol: 
CC and mCC 
The term ‘conventional cigarette’ refers to manufactured and 
commercially available cigarettes and excludes hand-rolled 
cigarettes, cigars, pipes, bidis, and other nicotine-containing 
products. Menthol CC are designated “mCC”. 
Charger 
The function of the Charger (Model 4) is to recharge the Holder 
after use. It contains a battery with sufficient capacity to recharge 
the Holder approximately 20 times.  It is a convenient size to carry 
around, and can itself be recharged from a mains power source. 
Day of Discharge 
Day 4. 
End of Study 
End of Study is defined as the last day of the 7-day safety 
follow-up subsequent to discharge from the unit. 
Enrolment 
On Day -1 for eligible subjects after all applicable inclusion and 
exclusion criteria have been satisfactorily assessed and the subject 
is willing and ready to use both the Tobacco Heating System THS 
2.2 Menthol and nicotine replacement therapy gum (NRT gum). 
The test of both THS 2.2 Menthol and NRT gum are the last 
assessments prior to enrolment. 
Investigator 
Principal Investigator or sub-Investigator 
First product use time 
point 
Start of product use for THS 2.2 Menthol is defined as the time of 
the first puff. The start time for mCC corresponds to the lighting of 
the mCC, and the start time of the NRT gum product is the time of 
NRT gum intake. 
Randomization 
Assignment to product on Day 0 utilizing an Interactive Web and 
Voice Response System. 
Safety follow-up 
After the time of discharge, a 7-day safety follow-up will be done 
for the recording of spontaneously reported new AEs/SAEs and the 
active follow-up of ongoing adverse events (AEs)/serious adverse 
events (SAEs) by the site. In general any AE will be followed up 
until resolved, stabilized i.e., no worsening of the event or a 
plausible explanation for the event has been found.  

 
 
 
 
 
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Screening failure 
Subjects who do not meet the entry criteria from informed consent 
form (ICF) signature to the time of enrolment will be considered a 
screening failure and will be replaced by other subjects.  
THS Menthol Tobacco 
Stick (Menthol 
Tobacco Stick) 
The Menthol Tobacco Stick (product code C3 menthol) contains 
tobacco which, when heated, generates an aerosol. It is custom-
designed to be used with the Holder. 
Tobacco Stick  
Holder (Holder) 
The function of the Holder (Model 4.2) is to heat the Menthol 
Tobacco Stick, delivering an aerosol to the user. The electrical 
heating is powered from an internal battery which delivers power 
for about 6 minutes (allowing complete use of a single Menthol 
Tobacco Stick) 

 
 
 
 
 
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1 
ETHICS AND REGULATIONS 
1.1 
Institutional Review Board Approval 
Prior to the start of the study, the clinical study protocol, together with its associated 
documents (informed consent form [ICF] 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 
Principal Investigator’s curriculum vitae and/or other evidence of qualifications, the list of 
sub-Investigators and 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 Harmonisation (ICH) Tripartite Guidance for Good Clinical Practice (GCP), 
Ministerial Ordinance on GCP for Drugs, and local 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 (Principal 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 file, and another original 
copy will be filed in the Study Master File at the Sponsor or designated organization. The 
study must not start before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IRB. 
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the Principal Investigator. 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 Principal Investigator or sub-Investigator (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. 

 
 
 
 
 
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1.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (2008) and are consistent with ICH/GCP, Ethical Guidelines for 
Clinical Studies (Ministry of Health,  Labour and Welfare, 2003 (as last amended on July 31, 
2008)), Ministerial Ordinance on Good Clinical Practice for Drugs (Ministry of Health,  
Labour and Welfare, 1997 (as last amended by the Ordinance of Ministry of Health, Labour 
and Welfare No. 161 of December 28, 2012)), and applicable regulatory principles. 
The Principal Investigator agrees to conduct the clinical study in compliance with the 
protocol agreed upon with the Sponsor and approved by the IRB. The Principal Investigator 
and the Sponsor must sign the protocol (and protocol amendments, if applicable) to confirm 
this agreement. A copy of the Declaration of Helsinki (2008) should be located in the 
Investigator’s Study File. 
1.3 
Subject Information and Consent 
1.3.1 
Study Consent/Subject Information Sheet 
Before or 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 necessary information, and if 
he/she agrees to participate, this will be documented in the ICF by the date and signature of 
both the subject and the person who conducted the informed consent discussion. No 
study-specific procedures will be performed before the ICF sheet has been signed. 
The original, dated and signed ICF(s) must be kept in the Investigator file at the site, and a 
copy must be given to the subject. 
The subject will be informed that additional data analyses not mentioned in the protocol or 
the statistical analysis plan might be performed with the collected data at a later time. If any 
additional analyses will be performed, they will fully be covered by data confidentiality, as 
for the main analyses described in this protocol. 
1.3.2 
Amendment to the Informed Consent Form/Subject Information Sheet 
If a protocol amendment is required, or if new information regarding the risk profile of the 
Investigational Product (IP) becomes available, an amendment may be required to the ICF. If 
revision of the ICF is necessary, the Principal Investigator 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. 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A. 
1.4 
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation, 
and documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and the Principal Investigator abide by the principles of the ICH guidelines on 
GCP. These guidelines apply specifically to pharmaceutical development, but nevertheless 
provide a robust and ethical framework for conducting clinical studies of tobacco products. 
In addition, the Investigator will carry out the clinical study in accordance with GCP and 
Ethical Guidelines for Clinical Studies. 

 
 
 
 
 
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2 
INTRODUCTION 
2.1 
Background 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy 
Cigarette smoking causes pulmonary and cardiovascular diseases and other serious diseases 
in smokers (U.S. Department of Health and Human Services, 2010). The effects of smoking 
and smoking cessation on mortality from cardiovascular disease among the Japanese 
population were investigated in cohort studies in Japan. These studies confirmed the 
association between smoking and mortality from cardiovascular disease and highlighted the 
importance of smoking cessation at any age to prevent cardiovascular disease in the Japanese 
population (Honjo et al. 2010a, Iso et al. 2005). In 2000 in Japan, the proportion of adult 
deaths due to smoking ranges from 20.0% to 24.9% in males and from 10.0% to 14.6% in 
females. In 2007, Japan became part of the top 5 conventional cigarette (CC)-consuming 
countries with a consumption of 234 billion annually in 2009 (World Lung Foundation, 
2012). 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) (FDA, 2012c). 
The challenge in developing and commercializing MRTPs is two-fold, i.e. developing 
tobacco products that are shown to reduce risk and that are acceptable to smokers as 
substitutes for CCs. PMI is developing candidate MRTP that provide an inhalation 
experience without combustion. The novel approach to achieve this is by heating tobacco at 
significantly lower temperatures than required for CC. 
PMI’s approach to scientifically assessing the risk-reduction potential of its candidate 
MRTPs is described in the reference document (PMI White Paper Docket). Smoking 
cessation is the only intervention proven to reduce the risk of smoking-related diseases in 
smokers. Accordingly, PMI utilizes smoking cessation/smoking abstinence (SA) as the 
benchmark for assessing the risk reduction potential of its candidate MRTPs. The Institute of 
Medicine observed that cessation is the “gold standard” for assessing risk reduction, and that 
“the closer risks and exposures from the MRTP are to cessation products, the more confident 
a regulator can be of achieving a net public health benefit” (Institute of Medicine, 2012). 
PMI has already conducted studies and plans to conduct further clinical studies which 
observe measurable changes in blood chemistry, risk factors and health effects in smokers 
who switch to a candidate MRTP, comparing the changes with those observed in both 
smokers who continue smoking CC and smokers who stop using tobacco products. Longer-

 
 
 
 
 
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term data from adults who continue to use the candidate MRTP can further substantiate 
reductions in individual risk in smokers and population harm. 
2.1.2 
Description of the Product and Scientific Findings 
Thousands of chemicals - “smoke constituents” - are formed when tobacco is burned or 
combusted. More than 5,300 smoke constituents have been identified (Rodgman and Perfetti, 
2009), and more than 100 of them have been categorized as harmful and potentially harmful 
constituents (HPHC) (FDA, 2011). There is no convincing evidence that selective reduction 
of smoke constituents can reduce tobacco related diseases (Hatsukami et al., 2007). Philip 
Morris International’s focus has been the development of products that do not combust 
tobacco but which replicate the “smoking experience” traditionally obtained with CC, as 
much as possible. Our approach limits pyrolysis and combustion, by heating tobacco at 
significantly lower temperatures than CC. Philip Morris International believes that such 
products present the best opportunity for reducing harm because they produce vastly lower 
levels of harmful smoke constituents and are more likely to be accepted by smokers as 
substitutes for CCs. Important to this effort has been providing nicotine in a way that closely 
parallels CC. 
The product developed by PMI, and to be assessed in this study, is the Tobacco Heating 
System 2.2 Menthol (THS 2.2 Menthol). With this product, the heating of the tobacco is 
maintained below 400°C, a temperature much lower than what is observed for CC, which can 
reach 900°C. The THS 2.2 Menthol is composed of the ‘THS Tobacco Stick Holder’, 
dedicated special Menthol Tobacco Sticks made of conventional tobacco, a Charger, and 
different accessories. The energy of the THS Tobacco Stick Holder is sufficient to maintain 
approximately a 6 minute session. Unlike mCC, the Menthol Tobacco Sticks do not burn 
down during their consumption and their lengths remain constant after use. 
The non-clinical assessment of earlier development of THS 2.2 Menthol described in the 
Investigator’s Brochure (PMI, 2013a) supports the initiation of the clinical studies. No new 
or increased toxicological hazard in the product’s aerosol was detected compared with CC 
smoke. The aerosol was chemically analyzed confirming that none of the determined HPHCs 
in the THS 2.2 Menthol were increased compared to the conventional cigarettes. The 
biological activity was tested in a number of in vitro assays to assess the cytotoxicity and the 
genotoxicity of the aerosol fractions total particulate matter (TPM) and gas vapor phase 
(GVP). In vitro and in vivo results corroborated the concept that absence of combustion 
when consuming tobacco substantially lowers toxic effects seen in these biological models. 
Further details on the clinical data are provided in the Investigators’ Brochure (PMI, 2013a). 
Several clinical studies have been conducted on THS 1.0 and THS 1.0 Menthol, an earlier 
development version of THS 2.2 Menthol, in Europe, Asia, Africa and the United States. All 
studies showed reductions in exposure to the majority of measured HPHCs from both aerosol 
fractions, TPM and GVP, in subjects who used the THS 1.0 as compared to subjects 

 
 
 
 
 
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continuing smoking CC, both, in controlled and ambulatory conditions. No clinical studies 
were conducted with THS 2.2 Menthol. 
The previous version of THS 2.2 Menthol, namely THS 2.1 (non-menthol version) was tested 
in two exploratory clinical studies to measure the nicotine plasma kinetic profile (PK) 
(www.clinicaltrials.gov identifier: NCT01780688) and to assess the reduction of exposure to 
HPHCs (www.clinicaltrials.gov identifier: NCT01780714) when switching from CC to THS 
2.1. The observed nicotine plasma PK profile for THS 2.1 was similar to CC as well, there 
were significant reductions in the exposure to the majority of selected HPHCs. Clinical 
studies conducted so far revealed no safety concern for either of the previous version of THS 
2.2 Menthol tested. Further details on the clinical data are provided in the Investigators’ 
Brochures (PMI, 2013a). 
2.2 
Purpose of the Study 
The purpose of this clinical study is to compare the profile of nicotine uptake (rate and extent 
of nicotine absorbed) after single use of switching from menthol conventional cigarettes 
(mCC) to THS 2.2 Menthol and mCC in smoking Japanese healthy smokers. THS 2.2 
Menthol will also be compared with the nicotine replacement therapy gum (NRT gum), used 
as a reference point. 
2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
In Japan, research conducted by the Ministry of Health, Labour and Welfare has shown that 
35.9% of male and 43.6% of female respondents over 20 years of age expressed the wish to 
quit smoking (International Tobacco Online, 2012). In a large follow-up study of middle 
aged Japanese smokers, the predictors of smoking cessation were age, job, smoking habit, 
physical activity, health checkup participation, and health status (Honjo et al. 2010b). Advice 
on health risks associated with smoking and smoking cessation advice will be provided at 
Screening, at Admission, and at the Day of Discharge. The advice will follow the 
recommendations of the World Health Organization (WHO) (WHO, 2002) -“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 counseling at a higher level. Subjects who participate in this study will also 
benefit from repeated, detailed health check-ups, which may help to uncover undiagnosed 
medical conditions. 

 
 
 
 
 
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2.3.2 
Anticipated Foreseeable Risks due to Study Procedures 
• Risks related to blood sampling, e.g., excessive bleeding, fainting, hematoma, 
paresthesia, or infection. 
• Risks related to chest X-rays, e.g., a small increase of risk to develop cancer later in life. 
• Risks related to drug application 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 (THS 2.2 
Menthol/mCC) or Reference Point Product 
• Change in smoking habits due to study requirements and related concomitant symptoms, 
(e.g., craving, withdrawal symptoms). 
 
All risks related to study procedures, IP, or support for SA will be explained in detail to the 
subjects. Mitigation will include, but will not be limited to: 
• Close monitoring and medical evaluation of potential safety signals throughout the study 
and follow-up. 
• Using accepted research and scientific standards, (e.g., blood samples not to exceed local 
blood donation standards). 
• Management and follow-up of adverse events (AEs)/serious adverse events (SAEs). 
• Risks specific to the use of any NRT gum, as per the relevant summary of product 
characteristics. 
2.3.4 
Unforeseeable Risks 
As with any new IP, and the reference point product, there may be unforeseeable risks and 
hazards that could occur. The possibility of such will be explained at Screening and at 
Admission. Mitigation will include close monitoring and medical supervision to detect any 
unforeseeable risk or safety signals at the earliest possibility. 

 
 
 
 
 
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3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is: 
• To evaluate the rate and the 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 THS 2.2 
Menthol relative to mCC, following single use of THS 2.2 Menthol and mCC. 
 
3.2 
Secondary Objectives 
The secondary objectives of this study are: 
 To determine if Cmax and AUC(0-last) of plasma nicotine of the THS 2.2 Menthol are 
higher relative to NRT gum following single use of the THS 2.2 Menthol and NRT gum. 
 To evaluate the difference on nicotine pharmacokinetic (PK) absorption parameters 
(AUC from start of product use extrapolated to time of last quantifiable concentration to 
infinity [AUC(0-∞)] and partial AUC, where t’ is the subject-specific time of maximum 
nicotine concentration following single use of mCC or NRT gum [AUC(0-t’)] between the 
THS 2.2 Menthol and mCC, as well as the THS 2.2 Menthol and NRT gum. 
 To evaluate the time to the maximum concentration (tmax) of plasma nicotine for the THS 
2.2 Menthol as compared to mCC and to determine if the tmax for THS 2.2 Menthol is 
shorter as compared to NRT gum. 
 To describe the terminal half-life (t1/2) of nicotine for the THS 2.2 Menthol, mCC, and 
NRT gum. 
 To describe the differences on urge-to-smoke over time between the THS 2.2 Menthol 
and mCC, as well as between the THS 2.2 Menthol and NRT gum. 
 To describe product evaluation in the THS 2.2 Menthol and mCC users. 
 To describe the levels of carbon monoxide (CO) exposure for the THS 2.2 Menthol, as 
compared to mCC and NRT gum users. 
 To monitor the safety during the study. 
 
 

 
 
 
 
 
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3.3 
Primary Endpoints 
 Primary nicotine PK parameters (THS 2.2 Menthol vs. mCC): 
o Cmax. 
o AUC(0-last). 
Evaluation criterion: 
The study will be considered successful if the 95% confidence intervals (CI) of the THS 2.2 
Menthol:mCC ratio for the primary nicotine PK parameters are estimated with a precision of 
±20%. 
3.4 
Secondary Endpoints 
 Primary nicotine PK parameters (THS 2.2 Menthol vs. NRT gum) 
 Secondary nicotine PK parameters 
o AUC(0-∞). 
o Partial AUC(0-t’).  
o tmax. 
o t1/2. 
 Subjective smoking effects: 
o Urge-to-smoke questionnaire (Questionnaire of Smoking Urges brief [QSU-brief]). 
o Product evaluation questionnaire (Modified Cigarette Evaluation Questionnaire 
[MCEQ]). 
 CO exposure biomarkers: levels of exhaled CO and carboxyhemoglobin (COHb) in 
blood. 
 Safety variables: 
o Incidence of AEs/SAEs and device events, including THS 2.2 Menthol 
malfunction/misuse. 
o Respiratory symptoms: cough assessment by Visual Analogue Scale (VAS) and 
Likert scales and one open question. 
o Vital signs. 
o Spirometry. 
o Electrocardiogram (ECG). 
o Clinical chemistry, hematology, and urine analysis safety panel. 
o Physical examination. 
o Concomitant medications. 

 
 
 
 
 
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Additional Study Assessments: 
• Serology for human immunodeficiency virus 1/2 and Hepatitis B and C. 
• Urine pregnancy test (females 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 
(FTND) revised version, FTND.  
• Cytochrome P450 2A6 (CYP2A6) activity (nicotine metabolic molar ratio) in plasma. 
 
3.5 
Exploratory Endpoints 
There are no exploratory analyses planned. 

 
 
 
 
 
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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a randomized, controlled, 2-period, 4-sequence, single use crossover study where 
each subject will receive two of the three products:  
 THS 2.2 Menthol. 
 mCC. 
 NRT gum. 
 
A Screening Visit will be conducted within 4 weeks prior to Admission to the investigational 
site (Day -29 to Day -2) (Figure 1). A demonstration of the THS 2.2 Menthol product and the 
NRT gum will also be done by the site staff during the Screening Visit. Subjects will be 
admitted to the clinic on Day -1. On Day -1, as the last procedure of the eligibility 
assessments on that day, all subjects will undergo a product test prior to enrolment: first THS 
2.2 Menthol and subsequently NRT gum (using up to 3 Menthol Tobacco Sticks). In female 
subjects, the urine pregnancy test must be negative before any product test is performed with 
either the THS 2.2 Menthol or the NRT gum. After all inclusion and exclusion criteria have 
been satisfactorily met, only subjects willing and ready to use both the THS 2.2 Menthol and 
the NRT gum products can be enrolled. Screening procedures do not necessarily have to be 
conducted on the same day.  
The confinement period will then consist of 2 periods (Period 1, Period 2) with each period 
consisting of at least 24-hour nicotine wash-out (nicotine abstinence) and 1 day of single 
product use.  
Period 1: Day 0: Wash-out; Day 1: single product use (THS 2.2 Menthol/mCC/NRT gum). 
Period 2: Day 2: Wash-out; Day 3: single product use (THS 2.2 Menthol/mCC/NRT gum). 
In total, 62 eligible, smoking subjects will be randomized into 1 of the 4 sequences: 
Sequence 1: THS 2.2 Menthol 
→ 
mCC (N=22). 
Sequence 2: mCC 
→ 
THS 2.2 Menthol (N=22). 
Sequence 3: THS 2.2 Menthol 
→ 
NRT gum (N=9). 
Sequence 4: NRT gum 
→ 
THS 2.2 Menthol (N=9). 
 

 
 
 
 
 
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This procedure will lead to an incomplete block design with every subject being exposed to 
2 of the 3 study products, as the comparison between NRT gum and mCC will not be 
considered.  
mCC vs. THS 2.2 Menthol 
→ 
(N=22 in both sequence 1 and 2) 
THS 2.2 Menthol vs. NRT gum → 
(N=9 in both sequence 3 and 4) 
 
Each sex and each of the smoking strata (International Organization for Standardization 
[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 population. This will be applied to subjects 
randomized to sequence 1 and 2 and independently to subjects randomized to sequence 3 and 
4.  
Subjects will be discharged (time of discharge) from the investigational site in the morning of 
Day 4 after all examinations of the Day of Discharge have been conducted. After the time of 
discharge, a 7-day safety follow-up will be started for the recording of spontaneously 
reported new AEs/SAEs and the active follow-up of ongoing AEs/SAEs by the site. 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. 

 
 
 
 
 
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Figure 1. 
Study Flow Chart 
•
Cross over with incomplete block design, 4 sequences
•
62 smokers to be randomized
Day 4 Discharge
Day -1
Day 0
Day 1
Day 2
Day 3
THS 2.2 
Menthol
n=22
THS 2.2 
Menthol
n=9
NRT gum
n=9
mCC
n=22 
THS 2.2 
Menthol
n=9
THS 2.2 
Menthol
n=22
NRT gum
n=9
mCC
n=22 
Admission
Wash-out
Safety
follow-up
Day 4-11
6 days of confinement
mCC 
ad libitum
Single 
use
Single 
use
Screening
Screening 
within 1-4 weeks 
prior to admission
7 days of follow-up
Abbreviations: THS: Tobacco Heating System; mCC = menthol conventional cigarette; NRT = Nicotine Replacement Therapy
 
4.2 
Rationale for Study Design and Control Group(s) 
The minimum age of 23 years age 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 and a market-approved pharmaceutical NRT gum 2 mg (Nicorette®) will be used as 
non-investigational reference point. The NRT gum has been selected as the reference point, 
because of its availability over the market. The NRT gum will serve as a reference point for 
comparison with THS 2.2 Menthol for the following endpoints:  
• Nicotine PK parameters. 
• Urge-to-smoke. 
• Safety profile. 

 
 
 
 
 
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The nicotine wash-out period was set to at least 24 hours (>5 x elimination t1/2) as the 
elimination t1/2 of nicotine in blood is around 2 hours in Caucasian smokers (Benowitz et 
al, 2009).  
The use of estrogen contraceptive is known to accelerate nicotine clearance by 20% to 30% 
in women as compared to women who do not take such contraceptives (Benowitz et 
al, 2006). Therefore, for the purpose of this study, it is not allowed to use hormonal 
contraception containing estrogens. This also applies to hormone replacement therapy. 
In this study, THS 2.2 Menthol will be tested against mCC and NRT gum will be used as a 
reference point product.  
In this study, smokers of mCC will be assessed because the menthol brands play a significant 
role within the Japanese market, with 20% of the overall market share in 2008 (Connolly et 
al., 2011). 
Furthermore, CYP2A6 activity will be assessed in this study. Asians on average metabolize 
nicotine more slowly than Caucasians do, at least in part due to a high prevalence of the 
CYP2A6 alleles associated with reduced or absent enzyme activity (Matta et al. 2006). 
4.3 
Study Duration  
The entire study per subject will last 14 to 41 days, including a Screening period of up to 4 
weeks prior to Admission (Day -29 to Day -2), and 6 days of confinement (Day -1 to 
morning of Day 4), and 7 days of safety follow-up (from time of discharge until Day 11).. In 
the morning of Day 4, the Day of Discharge examinations will be conducted. After the time 
of discharge, subjects will then enter a 7-day safety follow-up (until Day 11) for the 
recording of spontaneously reported new AEs/SAEs and the active follow-up of ongoing 
AEs/SAEs. 
4.4 
Appropriateness of Measurement 
All laboratory measures utilized for this study are validated and are appropriate for the study 
assessments.  
All used questionnaires, except the cough questionnaire, are either available as a validated 
questionnaire in the local language or will be forward-translated and back-translated with 
subsequent independent verification. 

 
 
 
 
 
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5 
STUDY POPULATION  
5.1 
Selection of Study Population 
Sixty-two Japanese female or male smoking healthy adult subjects, who smoke at least 10 
mCC per day will be randomized into this study. The maximum number of mCC 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). 
5.1.1 
Inclusion Criteria  
Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -1) 
1. Subject has signed the ICF and is able 
to understand the information 
provided in the Subject Information 
Sheet and ICF. 
Administrative 
X 
 
2. Subject is aged from 23 to 65 years 
(inclusive). 
Safety 
X 
 
3. Subject is Japanese. 
Effect 
X 
 
4. Smoking, healthy subject as judged by 
the Investigator based on all available 
assessments in the Screening 
period/day of Admission (e.g., safety 
laboratory, spirometry* [forced 
expiratory volume in 1 second 
{FEV1}/forced vital capacity {FVC} 
>0.7 at post-bronchodilator basal 
spirometry, post-bronchodilator FEV1 
>80% predicted value, and 
post-bronchodilator FVC >0.8], vital 
signs, physical examination, ECG, 
chest X-ray and medical history). 
Safety 
X 
X 

 
 
 
 
 
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Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -1) 
5. Subject smokes at least 10 
commercially available menthol CCs 
per day (no brand restrictions) 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 3consecutive 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 4 days.  
Safety 
X 
X 
8. The subject is ready to accept using 
both the THS 2.2 Menthol and NRT 
gum products.  
Effect 
 
X 
 
5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the 
study: 
Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
1. As per Investigator judgment, the 
subject cannot participate in the 
study for any reason (e.g., medical, 
psychiatric, and/or social reason).  
Safety  
X 
X 

 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
2. A subject who is legally 
incompetent, physically or mentally 
incapable of giving consent (e.g., 
emergency situation, under 
guardianship, , prisoners or subjects 
who are involuntarily incarcerated). 
Administrative 
X 
 
3. The subject has medical condition 
requiring smoking cessation, or 
clinically relevant diseases 
(including but not limited to 
gastrointestinal, renal, hepatic, 
neurological, hematological, 
endocrine, oncological, urological, 
immunological, pulmonary and 
cardiovascular disease or any other 
medical condition [including but not 
limited to clinically relevant 
abnormal laboratory parameters]) in 
the judgment of the Investigator. 
Safety 
X 
X 
4. The subject has a body mass index 
(BMI) <18.5 or ≥32.0 kg/m2. 
Safety 
X 
X 
5. As per Investigator 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 

 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
6. The subject has used 
nicotine-containing products other 
than commercially available mCC 
(either tobacco-based products or 
nicotine-replacement therapy) as 
well as electronic cigarettes and 
similar devices, within 4 weeks prior 
to assessment. 
Effect 
X 
X 
7. The subject has received medication 
(prescription or over-the-counter) 
within 14 days or within 5 half-lives 
of the drug prior to the Admission 
Day (Day -1; whichever is longer) 
that has an impact on CYP2A6 
activity. 
Effect 
 
X 
8. In case the subject received any 
medication (prescribed or 
over-the-counter) within 14 days 
prior to Screening or prior to the 
Admission Day (Day -1) it will be 
decided at the discretion of the 
Investigator if these can potentially 
interfere with the study objectives 
and subject’s safety.  
Effect 
X 
X 
9. The subject has a positive alcohol 
test and/or the subject has a history 
of alcohol abuse that could interfere 
with subject’s participation in study. 
Administrative 
X 
X 
10. The subject has a positive urine drug 
test. 
Administrative 
X 
X 
11. Positive serology test for human 
immunodeficiency virus (HIV) 1/2, 
Hepatitis B or Hepatitis C.  
Safety 
X 
 

 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
12. Donation or receipt of whole blood 
or blood products within 3 months 
prior to Admission. 
Safety 
X 
X 
13. The subject is a current or former 
employee of the tobacco industry or 
of their first-degree relatives (parent, 
sibling, child). 
Administrative 
X 
 
14. 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 
 
15. The subject has participated in a 
clinical study within 3 months prior 
to the Screening Visit. 
Safety 
X 
 
16. The subject has previously 
participated in the same study at a 
different time (i.e., each subject can 
be included in the study population 
only once). 
Administrative 
X 
 
17. For women only: 
Subject is pregnant (does not have 
negative pregnancy tests at 
Screening and at Admission) or is 
breast feeding. 
Safety 
X 
X 
18. For women only: 
Subject does not agree to use an 
acceptable method of effective 
contraception.* 
Safety 
X 
X 
 
* Intrauterine device, intrauterine system, barrier methods of contraception (condoms, 
occlusive caps) with spermicidal foam/gel/film/suppository, hormonal contraception 

 
 
 
 
 
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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. 
5.1.3 
Removal of Subjects from the Study  
Subjects will be informed that they are free to withdraw from the study at any time. Subjects 
should be questioned for the reason of premature withdrawal, although they are not obliged 
to disclose it. This needs to be fully documented in the Source Document and electronic Case 
Report Form (eCRF). 
When a subject withdraws or is removed from the study, the whole examination procedure 
planned on Day 4 must be performed as soon as possible after the time of withdrawal unless 
the subject has withdrawn their informed consent to do so. After the time of withdrawal, the 
subject will enter into the 7-day period of safety follow-up. Subjects withdrawn or removed 
from the study cannot re-enter the study. 
Subjects must be withdrawn from the study for any of the following reasons: 
 
Withdrawal of informed consent. 
 
Any AE or condition (including clinically relevant changes in a laboratory 
parameter), at the discretion of the Investigator. 
 
Positive pregnancy testing (any invasive procedures, including the drawing of blood 
MUST NOT be performed after diagnosis of pregnancy, see Section 8.5.1. 
 
The Sponsor or Principal Investigator terminates the study. If the Sponsor or the 
Principal Investigator decide to prematurely terminates the study, the head of the medical 
institution should be reported the fact and the reason in writing promptly. 
 
 Withdrawal is considered to be in the best interest of the subject or the other subjects. 
 
Subjects may be discontinued from the study for any of the following reasons: 
 
Lost to follow-up. 
 
Concomitant treatment with non-authorized medication as defined in the context of 
this study (in general, any concomitant medication should be discussed with the Contract 
Research Organization (CRO) Medical Monitor on an ongoing basis). 
 
If a subject uses any CC or nicotine/tobacco-containing product other than the 
product/regimen he/she is assigned to, it will be at the discretion of the Investigator to 
decide whether or not to withdraw the subject from the study. 

 
 
 
 
 
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 
Non-compliance to the study procedures. 
 
Subjects withdrawn prematurely after randomization will not be replaced and will not be 
allowed to re-enter the study. All subject withdrawals have to be documented properly in the 
source documentation and the eCRF. 
5.1.4 
Violation of Selection Criteria 
Subjects who are eligible at Screening, but who do not meet the entry criteria at Admission 
Day (Day -1) will be considered a screening failure and will be replaced by other subjects. 
Subjects who violate the entry criteria prior to enrolment, but who were considered eligible, 
will be immediately withdrawn from the study when the violation is detected. If subjects are 
not yet randomized, they can be replaced. 

 
 
 
 
 
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6 
INVESTIGATIONAL PRODUCTS AND REFERENCE POINT 
PRODUCT 
6.1 
Description  
6.1.1 
Investigational Products 
THS 2.2 Menthol 
THS 2.2 Menthol comprises the following components: Menthol Tobacco Stick, Holder, 
Charger, a Cleaning Tool, a mains power supply, and a USB cable: 
Charger:  
The function of the Charger (Model 4) is to recharge the Holder 
after use. It contains a battery with sufficient capacity to recharge 
the Holder approximately 20 times.  It is a convenient size to carry 
around, and can itself be recharged from a mains power source. 
 
THS Tobacco Stick  
Holder (Holder): 
The function of the Holder (Model 4.2) is to heat the Menthol 
Tobacco Stick, delivering an aerosol to the user. The electrical 
heating is powered from an internal battery which delivers power 
for about 6 minutes (allowing complete use of a single Menthol 
Tobacco Stick) 
THS Menthol Tobacco 
Stick (Menthol 
Tobacco Sticks): 
The Menthol Tobacco Stick (product code C3 menthol) contains 
tobacco which, when heated, generates an aerosol. It is 
custom-designed to be used with the Holder. 
 
The overall objective of the design is to provide an acceptable experience in which the 
HPHCs level in the aerosol is substantially reduced in comparison with mCCs. 
The THS 2.2 Menthol will be provided by the Sponsor. 
Per cigarette/Tobacco Stick tar, nicotine, and carbon monoxide yields are normally 
determined by standardized test methods. The most widely used test method is ISO 4387. 
PMI has developed a modified version of this method, which improves the determination of 
tar in products with high water content, which is typical for heated tobacco products (PMI, 

 
 
 
 
 
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2012a; PMI, 2012b; PMI, 2013b). Another method is the more intensive smoking method 
developed by Health Canada (Health Canada, 1999). 
1 below lists the commonly reported measures (Table 1). 
Table 1 
Measured aerosol fractions for the THS Menthol Tobacco Sticks 
Constituent (mg/THS Menthol Tobacco 
Stick) 
ISO 1 
Health Canada  Intense 
regime 2 
Tar/NFDPM 
5 
12.6 
Nicotine  
0.5 
1.2 
Carbon monoxide 
1 
0.6 
1 
International Organization for Standardization ISO machine-smoking regimen. The analytical method has 
been modified to avoid inaccuracies as a result of condensation from high water-content aerosols. 
2 
Health Canada Intense machine-smoking regimen (55 mL puff volume, 2-second puff duration, 30-second 
inter-puff interval) (Health Canada, 1999) 
 
Reference Product: 
In the study sequences 1 and 2, the reference product to THS 2.2 Menthol is commercially 
available single brand mCC with a maximum yield of 1 mg nicotine ISO per cigarette. 
Menthol CC will not be provided by the Sponsor. All eligible subjects will be asked to 
purchase their own preferred single-brand mCC prior to Admission. As randomization takes 
place on Day 0, every study subject needs to buy his/her anticipated amount of single-brand 
mCC for a total of 2 days plus 2 extra packs. 
6.1.2 
Reference Point Product 
Nicotine replacement therapy gum (Nicorette® 2 mg gum) is the reference point product to 
THS 2.2 Menthol for sequences 3 and 4. The NRT gum will be supplied by the site and 
reimbursed by the Sponsor.  
6.1.3 
Packaging and Labeling 
At Admission on Day -1, all study subjects will provide the anticipated amount of mCC in 
sealed packs to the site staff. The cigarette packs provided by the subject should not be 
opened and the cellophane wrapper should be intact.  
Each pack of cigarettes provided by the subject will be labeled to identify which subject the 
cigarettes belong to (labels should be affixed by the study site trial collaborator to the 

 
 
 
 
 
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cellophane wrapper of the lower part of the pack). Packs of mCC will be labeled to identify 
necessary information to match the subject with his/hers suppliers. 
For the Menthol Tobacco Sticks, the packs and cartons will be pre-labeled with the necessary 
information including but not limited to product code. The labels will be written in Japanese 
(Appendix 4).  
6.2 
Use of Investigational and Reference Point Products 
Subjects will never be requested or forced to smoke and will be free to stop smoking at any 
time during the study. Subjects caught using any nicotine/tobacco product which is different 
from the assigned product will be withdrawn from 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 9.1 at the discretion of the site. 
6.2.1 
Admission (Day -1) 
Subject will be instructed not to smoke in the morning prior to Admission. Smoking ad 
libitum will be allowed throughout the day of admission except during the procedures until 
11:00 PM. All subjects will be allowed to continue smoking ad libitum their preferred mCC. 
All subjects (except women with a positive pregnancy test at Screening or Admission) will 
undergo a THS 2.2 Menthol test first (using up to 3 Menthol Tobacco Sticks) and 
subsequently NRT gum test at Day -1 prior to enrolment. Each subject will chew slowly the 
2 mg NRT gum for 35 ± 5 minutes while spacing each chew, leading to an administered dose 
of 1 mg nicotine/product use as per label similarly to the day of single use. 
Following agreement that the THS 2.2 Menthol and NRT gum is acceptable, subjects will be 
enrolled and further randomized to one of 4 treatment sequences using an Interactive Web/ 
Voice Response System. 
6.2.2 
Investigational Period (Day 0 to Day 3) 
During the first washout, each subject will maintain nicotine abstinence from Day -1 at 
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 nicotine abstinence for the rest of the day. 
During the second washout on Day 2, subjects will maintain nicotine abstinence until the 
time of single use of subject’s allocated product at Day 3. Subjects will not be allowed to 
smoke or use any other nicotine/tobacco-containing products other than the products/regimen 
they are allocated to. 
Time point of first product use during study day (T0) will be defined as start of the single 
product use at the single use days. The start time of the use of each product has to be 
documented on single use days (Day 1 and Day 3). The start of product use for THS 2.2 

 
 
 
 
 
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Menthol is defined as the time of the first puff. The start time for mCC corresponds to the 
lighting of the mCC, and the start time of the NRT is the time of the NRT gum intake. The 
30 seconds it takes to pre-heat the Holder will not be taken into account. The subject must 
not take a puff of the Menthol Tobacco Stick during the pre-heating time.  
For NRT gum, the start time and the stop time will be documented in appropriate log. 
The start of the first product use can be different for each subject both days of product use; 
however, it must be in the window of 6:00 AM to 9:00 AM.  
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 to 9:00 AM, and will abstain from the product or other 
nicotine/tobacco-containing items for the rest of the day, i.e., subjects in the THS 2.2 
Menthol arm will use one Menthol Tobacco Stick, subjects in the mCC arm will smoke one 
mCC, and subjects in the NRT gum arm will chew slowly the 2 mg NRT gum for 35 ± 5 
minutes while spacing each chew (leading to an administered dose of 1 mg nicotine/product 
use as per label 
 
Sequence 1 
Sequence 2 
Sequence 3 
Sequence 4 
Day 1 
THS 2.2 
Menthol 
mCC 
THS 2.2 
Menthol  
NRT gum 
Day 3 
mCC 
THS 2.2 
Menthol 
NRT gum 
THS 2.2 
Menthol 
 
 
6.2.3 
Day of Discharge/Time 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 of the Day of 
Discharge will be conducted on Day 4 prior to the time of Discharge. 
6.2.4 
Safety Period 
During the safety follow-up period, subjects are free to smoke according to their usual 
smoking habits. 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A. 
6.2.5 
Stopping Rules for Investigational Product 
For safety purposes, smoking the THS 2.2 Menthol or the mCC or the use of the NRT gum 
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. 
6.3 
Method for Assigning Subjects to Study Arms 
Randomization to produce exposure sequence will be done through an Interactive Telephone 
and Web Response System. 
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 population 
allocated within each of the following analysis groups: 
 Group 1: composed of sequences 1 and 2. 
 Group 2: composed of sequences 3 and 4. 
 
In particular, the maximum number of subjects having the same sex or nicotine level value 
will be limited to 26 in Group 1 and 10 in Group 2.The randomization of the planned sample 
size of 62 subjects will be ensured by applying quota to the number of subjects per each 
sequence (22 subjects for sequences in Group-1, and 9 subjects for sequences in Group-2). 
Subjects will be randomly assigned to one of the four 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 
sponsor staff, Investigators or study subjects will have access to the randomization schema 
prior to randomization. 
6.4 
Blinding 
This is an open-label study; therefore the subjects and investigators will be unblinded to 
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 the following table: 

 
 
 
 
 
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Blinded Study Personnel 
End of Blinding Period 
PMI and CRO study 
statisticians 
After the Statistical Analysis Plan (SAP) finalization or 
PMI blind database review(*), whichever comes last. 
PMI data manager 
After the finalization of PMI blind database review.(*) 
PMI safety and clinical 
scientist 
After the finalization of PMI blind database review(*). Can 
be actively un-blinded before that time point in case of the 
occurrence of any safety question, when appropriate. 
(*) As part of the PMI Quality Control (QC) activity, data listings will be reviewed by PMI 
before database lock, with no access to the randomization sequence information 
Any PMI and CRO personnel who are not listed in the above table will be unblinded by 
default.  
6.5 
Investigational Product Accountability and Compliance 
6.5.1 
Dispensing Investigational Product and Reference Point Products 
From Day -1 until Day 4, the THS 2.2 Menthol, NRT gum, and mCC will be dispensed by 
the Investigators or dedicated study collaborator, as per study design. Each dispense of the 
product will be recorded in a log. The log should include subject number, date and start time 
of product use. The product will not be promoted for commercial distribution or test market. 
6.5.2 
Storage and Accountability 
The THS 2.2 Menthol, NRT gum and mCC will be stored in a secured site storage place with 
access limited to the authorized personnel only. Full accountability of the distributed 
products will be ensured by designated collaborator. Subjects will return each butt of any 
used Menthol Tobacco Stick or mCC immediately after use to the site study collaborator for 
accountability. They will also return each used NRT gum after use to the site staff. This will 
be documented in appropriate log. On the time of discharge, unused mCCs given to the site 
study collaborator at Admission on Day -1 will be given back to the subjects. 

 
 
 
 
 
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6.5.3 
Investigational Product Retention 
Unused Menthol Tobacco Sticks and NRT gum will be destroyed if possible, or returned to 
the Sponsor upon study completion. The Tobacco Heating Devices will be returned to the 
Sponsor. 
6.5.4 
Compliance to Investigational Products 
Compliance for all arms will be ensured by strict distribution of the products (product by 
product) and collection of used Menthol Tobacco Sticks, the mCC butts and the NRT gum 
after use will be documented in appropriate logs.  
In addition, for subjects using NRT gum, the compliance will be chemically verified using 
exhaled CO breath. The cut-off point for the CO breath test value to distinguish tobacco use 
vs. no tobacco use will be 10 ppm (Benowitz et al. 2002). 
Furthermore, the CO breath test will be considered as one of the measures of compliance 
during the wash-out days in all subjects. 
6.6 
Restrictions 
6.6.1 
Smoking Restrictions 
On Day 1 and Day 3, to avoid nicotine cross contamination, users of THS 2.2 Menthol and 
smokers of mCC will use or smoke, as applicable, in dedicated separate rooms: one room for 
THS 2.2 Menthol and one room for mCC. Every subject must use or smoke, as applicable 
alone with an interval between subjects allowing ventilation of the room. Subjects receiving 
NRT gum must not have access to these rooms.  
In the morning prior admission, subjects will be instructed not to smoke. At admission, 
smoking is only allowed during the designated smoking times from 6:30 AM to 11:00 PM as 
detailed in the study design. Subjects will not have free access to their NRT gum, mCC or 
THS 2.2 Menthol, which will be dispensed by the site staff individually as described in 
Section 6.5.1.  
Smoking is not allowed during study procedures except during blood sampling for nicotine 
PK on Day 1 and Day 3. Furthermore, smoking is not allowed on Day 4 until all laboratory 
tests and the spirometry have been conducted. 
During the days of wash-out or single product use (for mCC and THS 2.2 Menthol arms), no 
NRT gum or other products supportive to SA must be used or will be provided to the 
subjects. 

 
 
 
 
 
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6.6.2 
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. The 
FDA guidance on food-effect studies for bioequivalency testing identifies a “high-fat” diet as 
a diet which maintains approximately 50 percent of total caloric content of the meal and is 
high in calories (approximately 800 to 1000 calories) (FDA, 2002).  
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 
snack, fruits, and raw vegetables can be distributed to the subjects without restrictions at any 
time during confinement as long as they fulfill the above requirements described in this 
section. Consumption of water is allowed as desired. The same menu and meal schedule will 
be administered uniformly for all subjects in all study arms.  
Fasting state has to be observed for at least 10 hours prior to blood draws for the safety 
laboratory at the Screening Visit, on Day -1, and Day 4. 
6.6.3 
Concomitant Medication 
For the purpose of this study, no concomitant medication should be taken by the subjects. 
Any medication with an impact on the CYP2A6 metabolism (as prescription and 
over-the-counter products) as given below must be avoided as CYP2A6 is involved in the 
nicotine metabolism (see Table 2).  
In this study the use of hormonal contraception containing estrogens is NOT allowed. This 
also applies to hormone replacement therapy. Only hormonal contraception with products 
containing progesterone is allowed during this study. Subjects using estrogens during the 
study will be withdrawn.  
The following drugs and substances are considered as having an impact on CYP2A6 activity 
(Lacy et al. 2007). Prior to database close, the concomitant medication will be assessed 
according to the potential impact on CYP2A6 activity and the potential impact on study 
results.  
Table 2 
Drugs and Substances Considered Interacting with CYP2A6 
Drug name 
Substance Class 
Fluoroquinolones, including ciprofloxacin and 
ofloxacin, nafcillin, rifampicin 
Antibiotic 
Fluvoxamine, fluoxetine, paroxetine, bupropion, 
Antidepressant 

 
 
 
 
 
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duloxetine, amitriptyline, imipramine, sertraline, 
mirtazapine, citalopram, thioridazine 
Haloperidol, perphenazine, chlorpromazine, 
propoxyphene fluphenazine, clozapine, olanzapine 
Neuroleptic 
Phenobarbital, primidone, carbamazepine 
Antiepileptic 
Cholorquine, quinidine 
Antirheumatic 
Clotrimazole, terbinafine, fluconazole, 
ketoconazole, miconazole 
Antimycotic 
Erythromycin, ciprofloxacin, clarithromycin, 
norfloxacin 
Antibiotic 
Cimetidine, chlorpheniramine, diphenhydramine, 
ranitidine 
H2-receptor antagonist 
Amiodarone, verapamil, mibefradil, mexiletin, 
propafenone, propranolol, lidocaine 
Antiarrhythmic   
Losartan, amlodipine, nifedipine  
Antihypertensive 
Drospirenone, oestrogens 
Hormonal contraceptives 
Agents for hormonal replacement 
therapy (oestrogens) 
Fluvastatin 
Cholesterol-lowering agent 
Theophylline 
Antispasmodic pulmonological 
agent/Bronchodilator agent 
Omeprazole, Lansoprazole 
Proton pump inhibitor 
Interferon 
Antiviral/Immunomodulating agent 
Methoxsalen 
Anti-psoriatic (substance class 
Furocoumarins) 
Modafinil, Diclofenac, Rofecoxib 
Analgesic 

 
 
 
 
 
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Insulin 
Anti-diabetic 
Sildenafil 
Phosphodiesterase-Inhibitor (e.g., 
used for treatment of Erectile 
dysfunction) 
Quinine 
Crystalline alkaloid 
St. John’s Wort 
Over-the-counter (herbal remedy) 
antidepressant 
Psoralen 
Anti-psoriatic (substance class 
Furocoumarins) 
Pilocapine 
Cholinergic agonists (e.g., used for 
Glaucoma Therapy) 
Data sources: Lacy et al. 2007. This list is not exhaustive. 
However, the Principal Investigator is responsible for the medical care of the subjects during 
their participation in this study. Any decisions regarding the prescription of 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 (for details, see Section 7.4.5) Concomitant medications should be 
followed up with the CRO Medical Monitor on an ongoing basis.  
Concomitant medication will first be assessed at 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 five half-lives (whichever is longer). They must 
not be used during the entire study until the time of 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. 
6.6.4 
Others 
From admission to discharge, practice of intensive exercise and physical work-out will be 
prohibited as it may impact nicotine absorption profile. 

 
 
 
 
 
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7 
STUDY PROCEDURES 
Personnel performing study measurements or recording must have the appropriate training 
fully documented. Quality control (QC) measures have to be in place. All study procedures 
are provided as an overview in the Schedule of Events (Appendix 1). 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 will be 
given for each study procedure and each time point in Section 9. Site study collaborator will 
adhere to the site’s Standard Operating Procedures (SOPs) for all activities. Appropriate 
medical advice will be provided to the subject in case of any medical findings requiring 
health care. 
7.1 
Informed Consent 
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, benefits of and alternatives to study participation. In addition, each subject must 
have sufficient time to review the ICF in order to understand it, and have adequate 
opportunity to ask questions. The ICF must be signed and dated by the subject prior to any 
study-specific procedures taking place. 
7.2 
Smoking Cessation Advice and Debriefing 
Each subject will be given advice on the risks of smoking 3 times during the study: at the 
Screening Visit, at Admission (Day -1), and at Day 4. This will take the form of a brief 
interview according to WHO recommendations (WHO, 2002). Details of the interview will 
be recorded in the Source Document File. Information on the risk of smoking 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 smoking cessation advice, a debriefing of subjects will be done at each 
smoking cessation advice session to address any intended or unintended beliefs participants 
have about the candidate MRTP. The goal of the debriefing would be to help ensure that 
subjects exit the study with an accurate understanding of product risks, including an 
understanding that the candidate MRTP has not been demonstrated to be less harmful. 
7.3 
Support during Smoking Abstinence/Periods of Reduced Smoking 
All subjects will be closely monitored by the site staff on Day 0, Day 1; Day 2, and Day 3. 
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. 

 
 
 
 
 
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7.4 
Clinical Assessments 
Any clinically relevant finding detected during the Screening Visit has to be documented as a 
concomitant disease. This also applies to clinically relevant findings (e.g., 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 relevant finding is detected during 
the Screening period, the Investigator needs to check if inclusion criterion no. 3 is still 
fulfilled. 
7.4.1 
Demographic Data 
Demographic data (sex, 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(s) smoked by the subject will be done at the 
Screening Visit and at Day -1. At the Screening Visit, smokers will be asked to bring a pack 
of their current mCC brand(s) to the site. On Day -1, subjects will hand their mCC supply for 
the entire confinement period to the site study collaborator. The site study collaborator will 
document the brand name and yields. A photograph of the front and the side of the cigarette 
pack supplied by the subject (bearing the tar, and nicotine yields) will be taken by the study 
site staff in addition to recording the brand name and yields. These photographs will be 
considered as Source Documentation. A copy of the photographs will be provided to the 
Sponsor electronically (as Digital Video Disk or Compact Disc [CD]). 
7.4.3 
Smoking History and Willingness to Quit Smoking 
Subjects will be questioned for their smoking history. At Screening and on the Day of 
Admission (Day -1) this will include questions to evaluate whether the subject has smoked 
for at least the last 3 consecutive years, to determine the number of CC smoked during the 
previous 4 weeks, and to evaluate if the CCs smoked during the previous 4 weeks were 
mCCs. At the Screening Visit only, the subject will also be asked if he/she plans to quit 
smoking within the next 3 months. In addition, the subject will be asked if he/she has used 
nicotine-containing products other than commercially available CC (either tobacco-based 
products or nicotine replacement therapy), electronic cigarettes or similar devices, within 
4 weeks prior to assessment. 
At Screening and on the Day of Admission (Day -1), subjects will also be asked if they are 
willing to abstain from smoking for at least 4 days (as required in the study protocol 
inclusion criteria). Only subjects who are prepared and able to comply with this requirement 
will be considered for participation in the study. 

 
 
 
 
 
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7.4.4 
Demonstration and Trial of the THS 2.2 Menthol and NRT Gum 
All subjects will have a demonstration of the THS 2.2 Menthol product and the NRT gum at 
the Screening Visit by the study site collaborator. On Day -1 as last procedure of the 
eligibility assessments on that day, subjects will have a product test prior to enrolment, first 
THS 2.2 Menthol (use of up to three Menthol Tobacco Sticks) and subsequently NRT gum. 
Each subject will chew slowly the 2 mg NRT gum for 35±5 minutes while spacing each 
chew, leading to an administered dose of 1 mg nicotine/product use as per label similarly to 
the day of single use. 
In female subjects, the THS 2.2 Menthol and NRT gum product tests must only be done after 
pregnancy is excluded by a urine pregnancy test. Only subjects willing and ready to use the 
THS 2.2 Menthol and NRT gum can be enrolled into the study. 
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 prior to and ended prior to 
Screening. A concomitant disease is defined as any condition that 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 a concomitant 
medication. Medication initiated after Screening is also referred to as concomitant 
medication. This applies to both prescription and over-the-counter products. 
Records of any medication taken must include the drug name (preferably both generic and 
trade name), route of administration (e.g., oral, intravenous), total daily dose/unit (e.g., 
expressed in mg, ml, or IU), indication, the start and (if applicable) the stop date (day, month, 
and year). Any therapy changes (including changes of regimen) during the study are to be 
documented. Any concomitant medication that is still being taken by the subject at EOS will 
be recorded on the eCRF. 
7.4.6 
Physical Examination 
A physical examination will be conducted at the Screening Visit, at Admission (Day -1), and 
at the Day of Discharge (Day 4).  
7.4.7 
Body Height and Weight 
Body weight will be recorded at the Screening Visit, at Admission (Day -1) and at the Day of 
Discharge (Day 4). Body height will be measured at the Screening Visit, only. The BMI will 

 
 
 
 
 
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be calculated from the body weight and height using the following formula, rounded to one 
decimal place:  
7.4.8 
Vital Signs 
Systolic and diastolic blood pressure, pulse rate, and respiratory rate will be measured at the 
Screening Visit, at Admission, and at every day in confinement. All parameters will be 
recorded in supine position after the subject has rested for at least 5 minutes.  
For every measurement, it will be documented if the subject has smoked within 15 minutes 
prior to the measurement.  
7.4.9 
Other Clinical Assessments 
7.4.9.1 
Spirometry 
Spirometry with and without a short-acting bronchodilator will be done at the Screening Visit 
to evaluate inclusion/exclusion criteria (the post-bronchodilator results). At screening, 
spirometry without bronchodilator will be done first, and then, spirometry with 
bronchodilator. Furthermore, spirometry without bronchodilator will be performed at Day -1 
(baseline values) and at Day 4 (for comparison with the baseline values). Spirometry has to 
be done prior to smoking the first cigarette of the day. 
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. 
Spirometry predicted values will be standardized to the NHANES III predicted set. 
All personnel performing lung function testing should have the appropriate training and 
quality control (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 and FVC will be recorded. 
The subject will be submitted to a spirometry with maximum voluntary ventilation 
measurement. 
For spirometry, assessed parameters will include: 
 FEV1. 
 FVC. 

 
 
 
 
 
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 FEV1/FVC. 
7.4.9.2 
Electrocardiogram 
An ECG will be recorded at Screening and on the following study days: Day 1 and Day 3. 
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 relevant, or abnormal – 
clinically relevant. A diagnosis has to be provided in the Case Report Form for all ECGs 
assessed as abnormal – clinically relevant. Electrocardiogram 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 for this procedure. No new examination is required if the subject can 
present a chest X-ray with anterior-posterior and left lateral views at the Screening Visit 
which is not older than 6 months.  
7.5 
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/Report. A list of laboratories is provided in Appendix 2. 
The start time of the use of each product has to be documented on single use days (Day 1 and 
Day 3). For NRT gum specifically, the time of NRT gum use (start time T0), and the stop 
time of NRT gum use needs to be recorded. 
Precautions should be taken during blood sampling and processing to prevent the 
contamination of samples with environmental nicotine or CO. 
 

 
 
 
 
 
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7.5.1 
Biomarker of Exposure  
7.5.1.1 
Biomarkers of Exposure to CO and COHb 
Carboxyhemoglobin measured in blood and exhaled CO will be investigated as a measure of 
exposure to CO. The CO breath test will also serve as a measure of compliance in subjects 
using NRT gum as well as on the wash-out days in all subjects.  
CO Breath Test 
CO in exhaled breath will be measured using the Smokerlyzer® device such as Micro+™ 
Smokerlyzer® device or similar. The test will be performed for all subjects including the 
subjects using the NRT gum.  
A CO breath test will be conducted once on Day -1 and Day 4:  
On Day 0, 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 
test will be conducted as described in section 9. On the wash-out days (Day 0 and Day 2), the 
first test  will be conducted between 8:00 AM-9:30 AM. The three other tests will be 
conducted as described in section 9.  
Carboxyhemoglobin 
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 5 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 on Day 1 and Day 3 for THS 2.2 Menthol and mCC only: 
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 minutes prior to the single use (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 

 
 
 
 
 
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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). 
Single Use on Day 1 and Day 3 for NRT gum only: 
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 minutes prior to the single use (T0’). Times of sampling 
are thereafter in relation to T0: T1’ after 10 minutes, T2’ after 20 minutes, T3’ after 25 minutes, 
T4’ after 30 minutes, T5’ after 35 minutes; T6’ after 40 minutes;  T7’ after 45 minutes, T8’ 
after 60 minutes, T9’ after 2 hours, T10’ after 3 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).  
7.5.2 
CYP2A6 Activity 
CYP2A6 activity will be measured in plasma on Day -1. 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 (Jacob et al. 2011). 
7.6 
Laboratory Assessments 
A list of laboratories is provided in Appendix 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 Day of Admission (Day -1), and at the Day of Discharge (Day 4). Tests will be 
conducted at a local laboratory or the site. Blood will be taken after no less than the 10 hours 
of fasting (see Section 6.6.2). The urine test will be performed semi-quantitatively as urine 
test at the site. Parameters to be measured are listed in Table 3.  

 
 
 
 
 
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Table 3. 
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 (count) 
(WBC) 
- Differential WBC count:  
 
Neutrophils 
 
Basophils  
 
Eosinophils  
 
Lymphocytes 
 
Monocytes 
 
 
- Albumin 
- Total protein 
- Alkaline phosphatase 
- Alanine aminotransferase  
- Aspartate aminotransferase  
- Blood urea nitrogen 
- Creatinine 
- Gamma-glutamyl transferase  
- Fasting glucose 
- Lactate dehydrogenase  
- Potassium  
- Sodium 
- Total bilirubin 
- Direct bilirubin 
- Total cholesterol 
- Triglycerides 
 
- pH 
- Bilirubin 
- Glucose 
- Nitrite 
- Red blood cell traces 
- Protein 
- Specific gravity 
 
 
7.6.2 
Serology 
A test for Hepatitis B surface antigen, Hepatitis C virus and HIV (anti-HIV1/2 and p24 
antigen) will be done at Screening. 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 at 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 cotinine test will be performed at Screening 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. 

 
 
 
 
 
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7.6.5 
Alcohol Breath Test 
Subjects will undertake a breath alcohol test at the Screening Visit and at Admission to the 
clinic using a newly calibrated alcometer device. 
7.6.6 
Urine Pregnancy Testing 
All female subjects will undergo pregnancy testing at the Screening Visit, at Admission to 
the clinic, and at the Day of Discharge (Day 4). Female subjects with a positive pregnancy 
test at the Screening Visit or on Day -1 cannot be enrolled and are considered a screening 
failure. Pregnancy in such subjects will not be followed up as no exposure to the THS 2.2 
Menthol will have occurred. Product test at Admission must be done only in female subjects 
with a negative pregnancy test. In any case of a positive pregnancy test, the Investigator will 
inform the subject about the risks associated with smoking during pregnancy. In the event of 
unclear urine pregnancy test in peri-menopausal women, absence of pregnancy should be 
confirmed by a serum follicle stimulating hormone level >20 IU/l.  
All pregnancies detected during the study must be reported and handled as described in 
Section 8.5.1. 
7.7 
Sample Handling, Storage, and Shipment 
All blood samples are to be tested at a central laboratory with the exception of COHb blood 
samples and the safety laboratory samples which will be tested at a local laboratory (see 
Appendix 2). The urine drug screen, urine pregnancy tests and urine cotinine tests will be 
done by the site study collaborator at the site. The tests will be provided by the sites.  
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 once the Clinical Study Report (CSR) has 
been finalized. 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. The maximal total volume of blood drawn for each 
subject will be around 190 mL. 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. 

 
 
 
 
 
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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 (ePRO) device. The 
questionnaires and the VAS will be reviewed for completeness by the study site collaborator 
and subjects will be requested to complete any missing information.  
Symptoms or worsening of symptoms as documented on any of the questionnaires or the 
VAS do not need to be documented as AEs because the questionnaire and the VAS will be 
analyzed as part of the report. However, it is at the discretion of the Investigator to document 
such symptoms also as AEs. The main source for AE collection will be the face-to-face 
interview between the subject and site study collaborator using, open, non-directive questions 
(see Section 8). 
7.8.1 
Fagerström Test for Nicotine Dependence (revised version) 
Potential nicotine dependence will be assessed at Screening using the FTND in its revised 
version (Heatherton et al, 1991), as updated in 2012 (Fagerström et al., 2012).  
The questionnaire consists of 6 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 to 10 
points) (Fagerström et al., 2012). 
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, 3 Likert scales and an open question also assessing the previous 
24 hours. The questionnaire will be asked prior to product use. 
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: 
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: 
1 = rarely; 2 = sometimes; 3 = fairly often; 4 = often; 5 = almost always. 

 
 
 
 
 
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• The amount of sputum production will be assessed on a 4-point Likert scale ranging from 
0 to 3: 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 staff about their coughing. 
Assessments will be done on a daily basis from Day 0 to Day 4. On Day 2 and Day 4, 
questionnaire must be asked 24 hours after T0 of Day 1 and after 24 hours after T0 of Day 3. 
7.8.3 
Modified Cigarette Evaluation Questionnaire (modified version)  
Product evaluation will be assessed using the MCEQ (Cappelleri et al., 2007). 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 THS 2.2 Menthol or 
smoke mCC during the study in sequence 1 and 2. The MCEQ will be completed by subjects 
on Day 1 and Day 3. 
7.8.4 
Questionnaire of Smoking Urges brief  
To assess the urge-to-smoke, all subjects will be asked to complete a 10-item brief version of 
the QSU-brief (Cox et al. 2001). 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-brief (Tiffany et al. 1991). The findings supported a 
multi-dimensional conceptualization of craving to smoke and demonstrated the utility of a 
brief multi-dimensional measure of craving (Cox et al. 2001).  
The QSU-brief will be completed by the subject himself/herself at single use study days. 

 
 
 
 
 
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7.8.4.1 
THS 2.2 Menthol and CC arms QSU-timing: 
For subject on THS 2.2 Menthol or on mCC: first sample within 15 min 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. 
7.8.4.2 
NRT gum arm QSU-timing: 
For subjects on NRT gum: first sample within 15 min prior to T0, 9 assessments thereafter in 
relation to T0: 20 min, 30 min, 45 min, 60 min, 2 hr, 4 hr, 6 hrs, 9 hrs, and 12 hrs after T0. 

 
 
 
 
 
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8 
ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
The FDA MRTP guidelines specify the following definition for AEs for tobacco products 
(FDA, 2012a): 
An AE is any health-related event associated with the use of a tobacco product in humans, 
which is adverse or unfavorable, whether or not it is considered related to the tobacco 
product, as defined by the MRTP guidelines. 
An AE is defined as any untoward medical occurrence in a subject, or clinical investigation 
subject administered an IP, which does not necessarily have a causal relationship with the IP 
or reference point product. An AE can therefore be any unfavorable and unintended sign 
(including a clinically relevant abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IP or reference point product, whether or not it is considered 
related to the IP or reference point 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, 
they may jeopardize the subject or the subject may require medical or surgical intervention to 
prevent one of the outcomes listed in the above definitions. 
Any pre-planned hospitalizations that are known at the time of signing the ICF will not be 
recorded as SAEs; however, they will be recorded as AEs only. Any AE that occurs during 
this pre-planned hospitalization will be considered according to the above definitions. 

 
 
 
 
 
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8.2 
Assessment of Adverse Events 
The Investigator is responsible for obtaining, assessing and documenting all AEs during the 
study. 
8.2.1 
Collection of Information 
Adverse event information will be collected from the time of signature of the ICF onwards 
until EOS either by the Investigator via spontaneous reporting or by the use of consistent, 
open, non-directive questions from study site collaborator (e.g., “Have you had any health 
problems since the previous visit/How are you feeling since you were last asked?”). At the 
discretion of the Investigator, 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 the face-to-face interview 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 
eCRF and on a separate SAE report form (see Section 8.2.3). 
8.2.2 
Period of Collection 
8.2.2.1 Screening Period  
All existing health conditions identified during the Screening period will be recorded as 
concomitant disease and the subject’s eligibility for admission to the study will be reviewed. 
Any AEs which occur during the screening period will be captured by the study site 
collaborator and assessed by the Investigator in order to establish relationship or relatedness 
in respect to study procedures. Only the study procedures-related AEs will be reported in the 
CSR and in accordance with respective regulatory guidelines.  

 
 
 
 
 
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8.2.2.2 Admission Day until the End of Study 
From Admission onwards until Day of Discharge, all AEs will be actively collected by the 
study site collaborator.  
Any new, clinically relevant, abnormal finding or worsening of a pre-existing 
condition/concomitant disease detected during the study will be documented as an AE and/or 
SAE as described in the safety management plan.  
During the safety follow-up period new AEs and/or SAEs will be recorded after spontaneous 
reporting by the subject. Serious AEs will be reported by the Investigator as described in this 
document and the Safety Management Plan. 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 followed up by the 
Investigator on behalf of the Sponsor (see Section 8.3) until they have resolved, stabilized 
(i.e., no worsening of condition), or an acceptable explanation has been found. 
 
 
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 activities of daily living  
 
 
 
(ADL). 
• Moderate: The AE interferes with ADL, 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 
According to the Council for International Organizations of Medical Sciences VI Working 
Group, there are no definitive methods for distinguishing most adverse drug reactions (i.e., 
events that are causally attributed to the IP or reference product) from clinical AEs that occur 
as background findings in the population and have only temporal association with the IP or 
reference product.  

 
 
 
 
 
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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 or reference product, 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 administration or a 
study procedure makes a causal relationship unlikely, or, concomitant medication, 
therapeutic interventions, or underlying conditions provide a sufficient explanation for 
the observed event. 
• Related: The temporal relationship of the clinical event to study IP administration or a 
certain study procedure makes a causal relationship possible, and concomitant 
medication, therapeutic interventions, or underlying conditions do not provide a sufficient 
explanation for the observed event. 
 
8.2.5 
Expectedness 
An AE will be regarded as ‘unexpected’ if its nature or severity is not consistent with 
information already known about the IP or reference product, and/or has not been previously 
observed and is not listed in the current IB. The IB provides further detail on signs or 
symptoms that might be expected with the use of the IP, including information relating to 
device malfunction or misuse. 
NRT gum-related AEs are listed on the product label.  
8.3 
Reporting of Serious Adverse Events 
Any SAEs reported or observed during the study after signature of the ICF until the end of 
the safety follow-up period (i.e. up to 7 days after study Discharge), whether or not 
attributable to the IP, to any other medication or to any study procedures, or any SAE related 
to the product and spontaneously reported after the safety follow-up must be reported by the 
Principal Investigator within 24 hours after first awareness by any party to 
 
 and to the Sponsor, and the head of the Investigational 
site. 
An SAE report form must be faxed or e-mailed as attachment to: 
 
Phone number: 
 
E-mail: 
 
Address: 
 
 

 
 
 
 
 
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Sponsor Contact: 
 
Mobile: 
 
E-mail: 
@pmi.com  
 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube 
5 Quai Jeanrenaud 
2000 Neuchâtel 
Switzerland 
The Principal Investigator/the head of the investigational site is responsible for local 
reporting (e.g., to the IRB) of SAEs that occur during the study, according to local 
regulations. 
Any follow-up information will be detailed in a subsequent SAE report form and sent to 
 and the Sponsor 
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 is initially reported. 
All SAEs will be followed-up by the Investigator until resolution or until the Investigator 
considers the event to be stabilized (i.e., no worsening of condition), or an acceptable 
explanation has been found (e.g., chronic condition). 
The SAE report form to be used in this study is provided as a separate document. All SAEs 
will be recorded on the relevant eCRF 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 relevance. If the Investigator considers 
the abnormal result to be of clinical relevance, 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 (reference to the Common Terminology Criteria for Adverse 
Events and Common Toxicity Criteria [CTCAE] version 4.03) will be used by the 
Investigator to assess abnormal laboratory AEs as follows: 

 
 
 
 
 
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 All Grade 1 abnormal laboratory values will be evaluated by the Investigator with respect 
to baseline value and clinical relevance. If considered to be clinically relevant, 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 eCRF. 
 If there is any worsening in grade from Grade 2 and above during the study, the 
Investigator must report this worsening as an AE. 
 Where there is no grading available, the abnormal laboratory value will be evaluated by 
the Investigator, and assessed for clinical relevance. If considered to be clinically 
relevant, the Investigator will report it as an AE. 
 Any other abnormal clinical laboratory result (including those that are not part of the core 
safety assessments) can, at the discretion of the Investigator, 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 relevance and, if they are, must 
report them as AEs. 
 In general, laboratory values will be recorded as ‘increased <lab parameter>’ or 
‘decreased <lab parameter>’ to ensure consistency of recording/coding. 
All other information (e.g., relationship to IP, intensity, seriousness, outcome) will be 
assessed as for other AEs. 
8.4.2 
Abnormal Results of Others Tests or Investigations 
An ongoing medical condition or clinically relevant finding detected during the Screening 
Visit (including elevated laboratory parameters), will be considered a concomitant disease 
and the subject’s eligibility for admission to the study will be reviewed. 
Any new, clinically relevant, abnormal finding or worsening of a pre-existing condition 
detected during the study after Screening until the EOS will be documented as an AE. 
Any new onset of symptoms or worsening of pre-existing symptoms identified through the 
study questionnaires may be documented as AEs at the discretion of the Investigator. 

 
 
 
 
 
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8.5 
Actions and Follow-up 
8.5.1 
Reporting and Follow-up of Pregnancies 
For pregnancies detected during the Screening period and prior to first THS 2.2 Menthol use, 
the subject will be considered as a screening failure and removed from the study. No 
Pregnancy Form will be filled; however, the diagnosed pregnancy must be captured in the 
Screen Failure eCRF.  
All pregnancies occurring after signature of the ICF and diagnosed after first exposure to the 
IP until completion of the study must be reported by the Investigator.  
Any pregnancy potentially associated to exposure to the IP, including pregnancies 
spontaneously reported to the Investigator after the EOS must be reported by the Investigator 
and followed-up. Potential association with exposure to the IP is defined as the conception 
date being calculated before the last exposure to the IP.  
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 (see 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 THS 2.2 Menthol test on Admission Day). 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 complications, 
adverse pregnancy outcomes, or maternal complications will be recorded. 
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. 
8.5.2 
Adverse Events Leading to Withdrawal 
Subjects who are withdrawn from the study because of an AE will undergo the procedures, as 
described for the Day of Discharge, as soon as possible and will enter the period of safety 
follow-up. The Investigator will follow-up these AEs until they have resolved, stabilized 
(i.e., no worsening of condition), or an acceptable explanation has been found. 
 

 
 
 
 
 
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8.5.3 
Investigational Device Misuse  
Any occurrences of the THS Tobacco Stick Holder or THS Charger misuse (use not in 
accordance with its label and instruction) by a subject, will be documented by the 
Investigator or his/her designated study collaborator using a Device Issue Log.  
Investigational device misuse may result in use-related hazards. 
Use-related hazards are derived from the US Food and Drug Administration Medical Device 
Use-Safety Guidance (FDA, 2012b): 
 Hazards caused specifically by how a device is used 
 Unanticipated use scenarios (e.g., modification of Charger, applying any chemicals, 
using conventional cigarettes, mechanical damage of the device, etc.) that result in 
hazards must be documented and reported by the Investigator. 
According to FDA Device Regulation, data should be collected regarding the use-related 
hazards that have occurred with device and when information pertaining to device use safety 
is extensive, it is helpful to provide it in summary form that highlights the most important 
issues, considerations, resolutions, and conclusions. The level of detail of device use 
documentation submitted should be consistent with the level of concern of use-related 
hazards for the device.  
Furthermore, any misuse of the THS Tobacco Stick Holder or THS Charger, that lead to an 
AE/SAE will follow the same processes as described above.  
 
 
8.5.4 
Investigational Device Malfunction  
Any occurrences of malfunction of the Tobacco Stick Holder or Charger will be documented 
by the Investigator or his/her designated study collaborator using a Device Issue Log. 
Furthermore, any malfunctions of the Tobacco Stick Holder or Charger that lead to an 
AE/SAE will follow the same processes as described above. 

 
 
 
 
 
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9 
STUDY ACTIVITIES 
A detailed schedule of assessments can be found in Appendix 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 will be implemented for subsequent subjects. 
Measurements not conducted at the exact time point, but conducted within the given time 
window (if applicable) do not constitute a protocol deviation but an accepted variability for 
the given time point. 
In general, if no start time for the procedure is provided, then the procedure can be performed 
at any time during the day. 
9.1 
Screening Visit 
The Screening Visit will be performed within 4 weeks (Day -29 to Day -2) prior to 
Admission (Day -1). Subjects will attend the investigational site in at least a 10-hour fasting 
state for clinical laboratory to be assessed.  
The following assessments will be performed at the Screening Visit (Table 4) (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 4 
Time Schedule – Screening Visit 
Time 
Blood sample 
Procedures 
Additional information 
Start of 
procedure 
 
 
 
 
 
Informed consent/Subject Information 
Sheet 
 
 
 
Demographic data  
On the day of ICF signature 
 
 
Advice on the risks of smoking and 
debriefing 
 
 
 
Smoking history 
 
 
 
Willingness to abstain from smoking in 
the next 3 months 
 
 
 
Readiness to accept interruptions of 
smoking for up to 4 days 
 
 
 
FTND questionnaire 
 

 
 
 
 
 
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Prior medication ( 4 weeks prior to 
Screening visit)and concomitant 
medication 
 
 
 
Medical history/concomitant diseases 
 
 
 
Vital signs (pulse rate, systolic and 
diastolic blood pressure, respiratory 
rate) 
At least 5 min in supine position 
prior to measurement 
 
 
Height, weight, including calculated 
BMI 
 
 
√ 
Clinical laboratory parameters 
(hematology, urine analysis, clinical 
chemistry) 
At least in 10 hours fasting 
condition  
 
√ 
Serology for HIV and Hepatitis B 
and C 
 
 
 
Identification of current mCC brand 
 
 
 
Urine drug screen 
 
 
 
Alcohol breath test 
 
 
 
Urine pregnancy test for all female 
subjects 
 
 
 
THS 2.2 Menthol and NRT gum 
product demonstration 
 
 
 
Spirometry without short-acting 
bronchodilator first, and then with 
Has to be done at least 1 hour 
after smoking 
 
 
ECG 
At least 10 min in supine 
position prior to recording 
 
 
AE/SAE questioning 
If the Screening Visit is 
performed on two separate days 
the AE/SAE questions will be 
asked again 
 
 
Physical examination 
 
 
 
Chest X-ray (if not performed 6 
months prior to Screening) 
 
 
 
Urine cotinine screening test 
 
 
 
Inclusion/exclusion criteria 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; mCC = menthol conventional cigarette(s); ECG = 
Electrocardiogram; FTND = Fagerström Test for Nicotine Dependence (revised version); HIV = Human immunodeficiency 
virus; NRT gum = nicotine replacement therapy gum; SAE = Serious adverse event; THS = Tobacco Heating System 
 

 
 
 
 
 
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9.2 
Admission 
The following assessments will be performed at Admission (Day -1) (Table 5): 

 
 
 
 
 
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Table 5. 
Time Schedule – Day -1 Admission 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
 
 
 
 
AE/SAE recording, concomitant 
medication 
All day 
 
 
Advice on the risks of smoking and 
debriefing 
 
 
 
Readiness to accept interruptions of 
smoking for up to 4 days 
 
 
√ 
trans-3’-hydroxycotinine and cotinine 
(CYP2A6 activity) in plasma 
The subject should not have 
smoked in the morning until this 
assessment 
Must be done prior to smoking 
 
 
Spirometry 
Must be done prior smoking 
6:30 AM 
 
Beginning of smoking period 
 
 
√ 
Clinical laboratory parameters 
(hematology, urine analysis, clinical 
chemistry) 
To be done at least in 10-hour 
fasting condition 
Prior to 10:00 AM 
 
Breakfast 
 
 
 
Urine pregnancy test for all female 
subjects 
 
Prior to 11:30 AM 
 
Urine cotinine screening test 
 
Prior to 11:30 AM 
 
Urine drug screen 
 
Prior to 11:30 AM 
 
Vital signs 
At least 5 min in supine position 
prior to measurement 
Prior to 11:30 AM 
 
Physical examination, weight and 
calculated BMI 
 
Prior to 11:30 AM 
 
Identification of current mCC brand 
 

 
 
 
 
 
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Prior to 11:30 AM 
 
Smoking history 
 
Prior to 11:30 AM 
 
Alcohol breath test 
 
Prior to 11:30 AM 
 
CO breath test 
 
Prior to 2:30 PM 
 
Lunch 
 
Afternoon  
 
Snacks 
 
 
 
Product test for THS 2.2 Menthol and 
NRT 
The THS 2.2 Menthol test should 
be done first and then the NRT 
gum test.  
Subject on NRT gum should 
chew slowly for 35 ± 5 minutes, 
while spacing between each chew 
 
 
Inclusion/exclusion criteria 
 
 
 
Enrolment 
 
Prior to 9:00 PM 
 
Dinner 
 
11:00 PM 
 
End of smoking period 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; CO = Carbon monoxide; CYP2A6 = Cytochrome 
P450 2A6; mCC = menthol conventional cigarette(s); NRT gum = Nicotine replacement therapy gum; SAE = 
Serious adverse event; THS 2.2 Menthol= Tobacco Heating System 

 
 
 
 
 
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9.3 
Investigational Period 
9.3.1 
Days of Smoking Abstinence (Day 0 and Day 2) 
On the days of SA (Day 0 and Day 2) the following assessments will be performed (Table 6 
and Table 7): 
Table 6. 
Time Schedule – Day 0 Washout 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
 
 
 
 
Nicotine abstinence 
All day 
 
 
Support during nicotine abstinence as 
required 
All day 
 
 
AE/SAE recording, concomitant 
medication 
All day 
 
 
Randomization 
At any time of the day 
06:30AM-09:00 AM 
 
Assessment of cough 
 
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 min 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 
 
Prior to 9:00 PM 
 
Dinner 
 

 
 
 
 
 
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8:00 PM-9:30 PM 
 
CO breath test 
 
Abbreviations: AE = Adverse event; CO = Carbon monoxide; SAE = Serious adverse event. 
 

 
 
 
 
 
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Table 7. 
Time Schedule – Day 2 Washout 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
 
 
 
 
Nicotine abstinence 
All day 
 
 
Support during nicotine abstinence as 
required 
All day 
 
 
AE/SAE recording, concomitant 
medication 
All day 
 
√ 
Plasma nicotine PK sample 
24 hrs +5 min after T0 of Day 1 
(T15) 
 
 
Assessment of cough 
24 hrs minus 5 min 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 min 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 
 
Prior to 9:00 PM 
 
Dinner 
 
8:00 PM-9:30 PM 
 
CO breath test 
 
Abbreviations: CO = Carbon monoxide; PK = Pharmacokinetic; T = Time point. 

 
 
 
 
 
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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 8): 

 
 
 
 
 
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Table 8. 
Time Schedule – Day 1 and Day 3 Single Use 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
 
 
 
 
Optional: light snacks prior 
to first blood draw of the 
day 
 
 
 
AE/SAE recording, 
concomitant medication 
All day 
 
 
Craving questionnaire 
(QSU-brief) 
For subjects on THS 2.2 Menthol or on 
mCC: First sample within 15 min 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 
an allowed time window of +10 min each 
For subjects on NRT gum: First sample 
within 15 min prior to T0, 9 assessments 
thereafter in relation to T0: 20 min, 30 min, 
45 min, 60 min, 2 hr, 4 hr, 6 hrs, 9 hrs, and 
12 hrs after T0, with an allowed time 
window of +10 min each 

 
 
 
 
 
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√ 
Plasma nicotine sample 
For subjects on THS 2.2 Menthol or on 
mCC: 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).. 
For subjects on NRT gum: 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 10 
min + 1 min, T2
’ after 20 min + 1 min, 
T3
’ after 25 min + 1 min, T4
’ after 30 
min + 1 min, T5
’
 after 35 min + 1 min, 
T6
’
 after 40 min + 1 min, T7
’ after 45 min 
+ 1 min, T8
’ after 60 min + 3 min, T9
’ 
after 2 hrs + 5 min, T10
’ after 3 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 

 
 
 
 
 
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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 min in supine position prior to 
measurement 
10:00 AM-11:30 AM 
 
ECG 
At least 10 min 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; 
only in sequence 1 and 2) 
 
 
 
Collection of used Menthol 
Tobacco Sticks and mCC 
butts and NRT gum 
After the product use 
Abbreviations: AE = Adverse event; CO = Carbon monoxide; COHb = Carboxyhemoglobin; ECG = 
Electrocardiogram; mCC = menthol conventional cigarette(s); MCEQ = Modified Cigarette Evaluation 
Questionnaire; NRT gum = nicotine replacement therapy gum; QSU-brief = Questionnaire of Smoking Urges 
brief; SAE = Serious adverse event; T = Time point; THS 2.2 Menthol= Tobacco Heating System 2.2 Menthol  
 
 
9.4 
Day of Discharge 
The following assessments will be conducted prior to the time of Discharge on Day 4 (or 
after a subject is prematurely withdrawn from the study) (Table 9): 

 
 
 
 
 
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Table 9. 
Time Schedule – Day 4 Discharge 
Time 
Blood sample 
Procedures 
Additional information 
Start of procedure 
 
 
 
 
 
AE/SAE recording, concomitant 
medication 
All day 
 
√ 
Plasma nicotine: PK sample  
24 hrs +5 min since T0 of 
Day 3 (T15) 
 
 
Assessment of cough 
24 hrs minus 5 min since 
T0 of Day 3  
 
√ 
Clinical laboratory parameters 
(hematology, urine analysis, clinical 
chemistry) 
Has to be done in at least 
10 hour fasting condition 
 
 
Spirometry  
Has to be done prior to 
smoking 
prior to 10:00 AM 
 
Breakfast 
 
Prior to discharge  
 
CO breath test 
 
Prior to discharge 
 
Urine pregnancy test in all female 
 
Prior to discharge 
 
Vital signs 
At least 5 min in supine 
position prior to 
measurement 
Prior to discharge 
 
Physical examination, weight and 
calculated BMI 
 
Prior to discharge 
 
Advice on risk of smoking and 
debriefing 
 
 
 
Time of discharge 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; CO = Carbon monoxide; PK = Pharmacokinetic; 
SAE = Serious adverse event; T = Time point. 
Smoking will be allowed after spirometry has been conducted. 
 

 
 
 
 
 
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9.5 
Safety Follow-up Period 
All subjects participating in the product trial on Day -1 and are not enrolled into the study 
will enter a 7-day safety follow-up period.  
After the time of Discharge at Day 4 (or if prematurely withdrawn from the study), subjects 
will enter a 7-day safety follow-up period. 
During the 7-day safety follow-up period, there will be spontaneous reporting by the subject 
of new AEs and new SAEs. Any ongoing AEs/SAEs will be actively followed up by the site.  
Any AEs or SAEs that are ongoing at the end of the 7-day safety follow-up period will be 
handled as described in Section 8. 
9.6 
Early Termination Procedures 
The Day of Discharge assessments will be performed as early termination procedures (see 
Section 9.4). Early termination procedures will be the same as those described in the Day of 
Discharge. 

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

 
 
 
 
 
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10.2 Training of Study Collaborator 
A formal meeting (Investigator’s meeting) will be conducted prior to site initiation. During 
this meeting, the Sponsor or its authorized representative will discuss the requirements of the 
clinical study protocol and related documents and will also provide training in the relevant 
systems and other study-specific procedures. The activities of the Investigator’s meeting will 
be described in the monitoring plan.  
In addition to the Investigator meeting, the Investigator will ensure that appropriate training 
relevant to the study is provided to all study collaborator involved in the study, and that any 
new information relevant to the performance of this study is forwarded to the study 
collaborator involved in a timely manner. The record of all individuals involved in the study 
will be maintained in the Site Investigator File. 
10.3 Audits and Inspections 
Good Clinical Practice 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 Principal Investigator/head of investigational site 
will contact the Sponsor or the authorized representative immediately, if contacted by a 
regulatory agency about an inspection at their site. 
The Investigator and study collaborator are responsible for maintaining a comprehensive and 
accurate filing system of all study-related documentation that will be suitable for inspection 
at any time by the Sponsor, its authorized representative, and/or regulatory agencies. In 
signing this protocol, the Investigator understands and agrees to provide access to the 
necessary 
documentation 
and 
files.

 
 
 
 
 
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11 DATA MANAGEMENT ACTIVITIES 
All Data Management Activities will be described in detail in the Data Management Plan 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 and then captured 
in the eCRFs at the study site. The subject questionnaires and the VAS will be entered by the 
subject directly in the ePRO device. 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 eCRF according to the eCRF 
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 eCRF must 
be signed by the Investigator to attest that the data contained in the eCRF 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 eCRF for each subject will be 
checked against the Source Documents at the study site by the CRA. Instances of missing or 
unclear data will be discussed with the Investigator for resolution. An eCRF will be 
generated for all subjects that sign the informed consent. 
11.1.2 
Protocol Deviations 
All protocol deviations will be entered into the Clinical Trial Management System (CTMS) 
or other approved format. 
Information from the Source Documents will represent the primary source of protocol 
deviations. Information following site monitoring and other manual reviews will be 
documented in the site visit reports, follow-up letters, audit documentation, or other manual 
review and will be recorded and tracked in the CTMS or other approved format. 
Telecommunications and other verbal communications regarding deviations will be 
considered and handled as important communication, documented and tracked as protocol 
deviations, as necessary. 

 
 
 
 
 
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Individual entries for protocol deviations that are recorded in the CTMS, or other approved 
format, following site monitoring and other manual reviews will be reviewed against the 
individual data points in the eCRF database but will not be formally reconciled with the 
eCRF database (e.g., their description or occurrence date). The overall procedure for 
managing protocol deviations are described in the SOPs of the CRO Data Management 
Team. All deviations will be reviewed periodically, as determined at study start, to identify 
trends to improve monitoring and/or potential impact on the statistical analysis. 
11.2 Data Handling 
All study data will be managed by the Data Management Team at the CRO. The overall 
procedures for quality assurance of clinical study data are described in the SOPs of the CRO 
Data Management Team. The Data Management Team at CRO will prepare a 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 Data Management related procedures 
and processes. 
All data of all subjects enrolled and screening failures who experience an AE during the 
study (from time of informed consent to 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 Validation 
The data will be validated as defined in the DMP and Data Validation Specifications. 
Discrepancies will be reported as defined in DMP and Data Validation Plan. 
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: 
Medical history: 
Medical Dictionary for Regulatory Activities (MedDRA®) 
Adverse events: 
MedDRA® 
Medications: 
WHO Drug Dictionary Enhanced and Anatomical Therapeutic 
and Chemical classification system 

 
 
 
 
 
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THS 2.2Menthol device  
issues and/or 
malfunctions: 
C54451/Medical_Device_Problem_Codes_FDA_CDRH 
 
11.2.3 
Database Lock 
When all outstanding Data Management issues have been resolved and all validation, quality 
review, and cleaning activities are complete, the database or selected data is/are declared soft 
locked. Access to change data in the soft-locked database or to change selected data at this 
time is limited. 
After the data is reviewed by the Sponsor, resolution of all raised queries and QC of the 
changed data, database, or selected data upon Sponsor approval as applicable, is declared 
locked. 
Any changes to the database after that time can only be made by written agreement between 
the Sponsor and the Data Management and Statistical 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 in Clinical Data Interchange Standards Consortium’s Study Data 
Tabulation Model Data Structure Specifications. 

 
 
 
 
 
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12 PLANNED STATISTICAL METHODS 
12.1 General Considerations 
An incomplete block design will be adopted in this study with every subject being exposed to 
2 out of the 3 study products (mCC, THS 2.2 Menthol, and NRT gum) to allow comparisons 
between THS 2.2 Menthol and mCC in Group-1 (sequence 1 and 2), and between THS 2.2 
Menthol and NRT gum in Group-2 (sequence 3 and 4). 
Full details of the statistical analysis will be given in a SAP. Any changes to the planned 
statistical methods will be documented in the Clinical Study Report. The statistical 
evaluation will be performed using SAS®, version 9.2 or later. 
12.1.1 
Stratification Criteria 
For analysis, the following stratification criteria will be used:  
• 
Sex (male and female) 
• 
mCC nicotine level at Admission (ISO nicotine levels ≤0.6 mg and 0.6 to 1 mg)  
In addition, for the safety data, the analysis will be stratified by sequence and by study 
periods (Screening, product test, product exposure, and safety follow-up period). 
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, from 6:00 AM to 9:00 AM. 
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 
percentage of subjects with missing data, mean, standard deviation, median, first and third 
quartiles, minimum and maximum for continuous data, and the n and absolute and relative 
[%] frequency for categorical data) will presented by exposure and overall at each time point, 
where applicable.  
Descriptive statistics for PK parameters will also include the geometric mean and coefficient 
of variation (CV).  

 
 
 
 
 
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Baseline, admission and screening data (i.e., anything prior to product exposure) will be 
summarized by sequence and overall where appropriate 
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. 
Values below the lower limit of quantification (LLOQ) will be imputed using 0.5 x LLOQ. 
For values above the upper limit of quantification (ULOQ), i.e., preceded by a “>”, for 
example “>xx”, the numerical xx will be used for calculation and reporting in summary 
tables. The number of values below LLOQ or above ULOQ will be presented in each 
summary table. 
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% CIs.  
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 tests. 
12.2 Determination of Sample Size and Power Consideration 
A total of 62 subjects will be randomized. This sample size is the sum of the sample size 
requirements for the THS 2.2 Menthol: mCC comparison and the THS 2.2 Menthol:NRT 
gum comparison (as described in detail below). 
The estimates for the within-subject CV for nicotine Cmax (36%) and AUC(0-last) (21%) are 
based on the data collected in the ZRHX-PK-02 clinical study (ZRHX-PK-02, 2012) 
comparing the nicotine PK profiles of  Tobacco Heating System 2.1, the predecessor of THS 
2.2 Menthol (regular tobacco stick) and CC. In the absence of data comparing THS and NRT 
gum, the same CVs were assumed for the calculation of the sample size related to the THS 
2.2 Menthol:NRT gum comparison. 
Anticipated mean Cmax and AUC(0-last) for THS 2.2 Menthol and mCC were based on data 
from the ZRHX-PK-02 study (ZRHX-PK-02, 2012). Anticipated mean Cmax and AUC(0-last) 
for NRT gum were based on data reported by Dautzenberg et al., 2007. 
The sample sizes of this study assume a drop-out rate no larger than 10%.  

 
 
 
 
 
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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 (Senn, 2002). The SAS® implementation of the method published by Beal, 1989 was 
adopted to estimate the probability of obtaining at most the target 95% CI of ±20%. 
THS 2.2 Menthol:mCC comparison 
A total of 44 subjects are needed to estimate the mean Cmax parameter ratio between THS 2.2 
Menthol and mCC with a 90% probability of obtaining a margin of error (95% CI) of at most 
±20%, assuming that THS 2.2 Menthol have a nicotine Cmax similar to mCC (ratio equal 
to 1.00). This sample size is sufficient to provide 90% probability of obtaining a margin of 
error of at most ±20% for the AUC(0-last) ratio between THS 2.2 Menthol and mCC, assuming 
a similar extent of nicotine absorption for the 2 products (ratio equal to 1.00).  
THS 2.2 Menthol:NRT gum comparison 
A total of 18 subjects are needed to estimate the mean AUC(0-last) parameter ratio between 
THS 2.2 Menthol and NRT gum with a precision allowing for the lower bound of the 95% CI 
exceeding 1.00, with 90% power, assuming a geometrical ratio between THS 2.2 Menthol 
and NRT gum of 1.28. This sample size is sufficient to provide 90% power of obtaining a 
lower bound of the 95% CI of Cmax ratio between THS 2.2 Menthol and NRT gum, 
exceeding 1.00, assuming a geometrical mean ratio between THS 2.2 Menthol and NRT gum 
of 2.00. 
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 analysis populations for the PK endpoints are composed of two analysis sets to allow the 
comparison between THS 2.2 Menthol and NRT gum separately from the comparison 
between THS 2.2 Menthol and mCC.  
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 (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 THS 2.2 Menthol (including the product test at Admission Day).  

 
 
 
 
 
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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 Endpoint Analysis Variables 
Nicotine PK parameters will be derived from plasma nicotine versus time data using a 
non-compartmental technique. 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, period and product exposure 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% CIs for the THS 2.2 Menthol:mCC and THS 2.2 Menthol:NRT gum ratios.  
This approach is consistent with the guidelines in the European Medicines Agency’s 
guidelines for bioequivalence investigations (EMA, 2008) and FDA’s Center for Drug 
Evaluation and Research (FDA, 2001). Carry-over effect will not be tested, as it cannot be 
statistically distinguished from the interaction between treatment and period in a 2x2 
crossover design (ICH E9, 1998). 
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 in the natural 
log scale, with a restricted maximum likelihood method to estimate mean differences and 
variances as suggested by FDA (FDA, 2001). Subjects within sequence will be used as 

 
 
 
 
 
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random effects and fixed effects are period, sequence, and product exposure. To evaluate the 
sensitivity to the distributional assumptions, point and interval estimates will also be 
estimated by means of the percentile bootstrap technique, using 2000 bootstrap samples 
which preserve the number of subjects per sequence. 
12.5.4 
Confirmatory Analyses 
Given that the objective of this study is to determine the point estimate and precision of the 
ratio of THS 2.2 Menthol: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 of maximum observed plasma 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 mCC or NRT gum (linear trapezoidal method) 
AUC(0-∞) Area under the plasma concentration-time curve from start of product 
use extrapolated to infinite time, according to: 










z
C
AUC
AUC
last
last

0
-
0
 
Where Clast is the last quantifiable concentration and λz is the terminal 
elimination rate constant 
λz 
Terminal elimination rate constant, estimated by linear regression 
analysis of the natural log-transformed concentration-time data 
t1/2 
Terminal elimination half-life, derived as ln(2)/λz 
 
More details on PK parameter derivations will be provided in the SAP. 
The subjective effects of using THS 2.2 Menthol as compared to mCC and NRT gum will be 
evaluated by analyzing domain scores of the QSU-brief and MCEQ. Full details of 
questionnaire domain scores derivation will be provided in the SAP. 

 
 
 
 
 
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12.6.2 
Baseline Comparability 
Not applicable. 
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 in both Group-1 and Group-2 PK analysis sets: 
• 
The AUC(0-∞), AUC(0-t’), and t1/2 will be analyzed using the same approach adopted for 
the primary endpoints. No statistical analysis will be performed on the elimination 
rate constant z. Data will be summarized and presented together with 95% CI. 
• The Hodges-Lehmann 95% CI estimates for the median tmax differences will be 
presented (Lingling, 2008). 
• 
The use of random effects model is suggested in the context of the analysis of 
subjective effects of smoking (Shiffman et al, 2004). 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 QSU-brief, including all of the different assessment 
time points as repeated measurements. The analysis will not be adjusted for the 
assessment prior to T0 (Fleiss et al, 1985). 
• Levels of exhaled CO and of blood COHb will be summarized by means of 
descriptive statistics reported by exposure. Analysis of COHb levels will be 
conducted using a mixed model for repeated measures, the same approach as for the 
QSU-brief. 
 
The following analyses will be conducted only in Group-1 PK analysis set: 
• 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. 
 
The following analyses will be conducted in only Group-2 PK analysis set: 
• 
To test if the time to the maximum nicotine concentration in THS 2.2 Menthol is 
shorter than in NRT gum the following hypothesis will be evaluated: 
H0: XTHS - XNRT= 0    HA: XTHS - XNRT < 0 
where XTHS and XNRT are the median values of the THS 2.2 Menthol and NRT gum, 
respectively. The tmax will be analyzed on the original scale using the Wilcoxon 

 
 
 
 
 
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Signed-Rank Test with a type I error α = 0.025 (one-sided test), as values are 
ordinal/discrete, and the assumption of normality may be questionable. 
• To determine if the rate and the amount of nicotine absorbed of the THS 2.2 Menthol 
is higher relative to NRT gum the following hypothesis will be tested for both Cmax 
and AUC(0-last) parameters: 
H0: XTHS / XNRT = 1.0     HA: XTHS / XNRT > 1.0  
where XTHS and XNRT are the adjusted geometrical means of THS 2.2 Menthol and 
NRT gum, respectively. H0 is rejected with a type I error α = 0.025 (one-sided test), if 
the lower bound of the 95% CI for the XTHS / XNRT ratio is higher than 1.0. 
 
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. Safety variables collected during exposure 
periods will also be reported by product exposure. 
AE 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; physical examination; 
and concomitant medications. 
The number and percentage of subjects with AEs and SAEs will be tabulated by system 
organ class and preferred term. Summaries will also be presented for AEs leading to 
withdrawal, AEs leading to Death, AEs by relatedness to product exposure, AEs by severity, 
and laboratory AEs. Tabulations will be performed for both the number of subjects 
experiencing an event and the number of events. The number and percentage of device 
events and of subjects with device events will be tabulated by sequence. 
The number and percentage of subjects with clinical findings will be tabulated by sequence 
for laboratory parameters. Shift tables showing change from baseline of clinical findings will 
be provided for: ECGs, physical examinations, and laboratory parameters (both shifts in 
normal ranges and toxicity grades). Descriptive statistics will be summarized by visit and 
change from baseline for laboratory parameters, ECG, respiratory symptoms, and vital signs. 

 
 
 
 
 
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12.7 Exploratory Analyses 
There are no planned exploratory analyses. 
12.8 Interim Analysis 
There are no planned interim analyses.

 
 
 
 
 
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13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Principal Investigators and Study Administrative Structure 
13.1.1 
Principal Investigator 
Principal Investigator:  
Fumimasa Nobuoka M.D. 
Ageo Medical Clinic 
 Japan         
Tel:+81
   
 
 
 

 
 
 
 
 
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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 
Manager Clinical Science 
Phone: +41
 
Mobile: +41
 
E-mail: 
@pmi.com 
, PhD 
Staff Scientist, Statistics 
Phone: +41 
 
Mobile: +41
 
Email:
@pmi.com 
 MD 
Medical Safety Officer 
Phone: +41 
 
Mobile: +41
 
E-mail:
@pmi.com 
 
Medical Writer 
Phone: +41 
  
Mobile: +41 
 
Email:
@pmi.com 
, MSc  
Clinical Study Manager 
Phone: +41 
 
Mobile: +41 
 
E-mail:
@pmi.com 

 
 
 
 
 
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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: 
 
 
 
 
 
 
  
 
 
Details of the laboratories conducting the clinical safety laboratory services, and 
biopharmaceutical analyses are shown in Appendix 2. 
13.2 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects' state of 
health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subject in writing and signed by the subject, in compliance with all local 
and national data protection and privacy legislation. 

 
 
 
 
 
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The anonymity of subjects participating in this study will be maintained. Subjects will be 
identifiable by the Sponsor (or Sponsor’s authorized representative) on eCRFs and other 
documents by their subject (or randomization) number/code, sex and date of birth, but not by 
name, initial, or any other details relating to identifiable person (e.g. address, health 
insurance ID 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 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 ID card, medical chart number, etc), the name or other identifiable details 
must be obscured before a copy of that document is supplied to the Sponsor or the Sponsor’s 
authorized representative. 
13.3 Access to Source Documentation 
Subjects will be informed that, during the course of the clinical study, the Sponsor, any 
authorized representatives of the Sponsor, IRB, or regulatory authorities may inspect their 
medical records to verify the information collected, and ensure that all personal information 
made available for inspection is handled in the strictest confidence and in accordance with 
national and local data protection and privacy legislation. 
The Investigator/head of the 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 
Principal Investigator/head of investigational site for the study, as required by ICH GCP and 
any other applicable local or national regulations. For X-rays at least the radiologist’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 (Ordinance of the Ministry of Health and Welfare No. 28 of 
March 27, 1997 (as last amended by the Ordinance of Ministry of Health, Labour and 
Welfare No. 161 of December 28, 2012). Essential documents must be retained by the 
Principal Investigator/head of investigational site for a minimum of: 

 
 
 
 
 
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 At least 15 years after completion or discontinuation of the study, or 
 At least 2 years depending on, for example, the circumstances, or 
 After formal discontinuation of clinical development of the IP. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. 
Examples of essential records/documents include, but are not limited to: 
 Signed informed consent documents for all subjects and Master ICF. 
 Subject identification code list, Screening Log and Enrolment Log (if applicable). 
 Record of all communications between the Principal Investigator and the IRB, 
composition of the IRB. 
 Record of all communications/contact between the Investigator, Sponsor, and its 
authorized representatives. 
 List of sub-Investigators and other appropriately qualified persons to whom the head of 
the investigational site has delegated significant study-related duties, together with their 
roles in the study. 
 Investigator Logs. 
 eCRFs, study specific questionnaires (and associated data/scoring), subject diaries. 
 Adverse event reports and details of follow-up investigations, details of concomitant 
medication. 
 All other Source Documents (e.g., chest X-rays, ECGs, consultation reports, physical 
examination, laboratory records) or any electronically captured study source data. 
 Clinical laboratory reports, laboratory normal ranges. 
 Original medical/hospital records, if applicable (the medical files of study subjects must 
be retained in accordance with local legislation and in accordance with the maximum 
period of time permitted by the hospital or study site). 
 Record of any body fluids or tissue samples collected and retained. 
 Device Issue Log, IP Accountability Logs, dispensing records. 
 Information regarding subjects’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the Principal Investigator/head of 
investigational site as to when these documents no longer need to be retained. 

 
 
 
 
 
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The Principal Investigator/head of investigational site must take measures to prevent 
accidental or premature destruction of these documents. 
If the head of the investigational site wishes to assign the study records to another party or 
move them to another location, the Sponsor must be notified in advance. 
The head of the investigational site must obtain written approval from the Sponsor before 
destruction of any records. Normally, these records will be held in the Investigator’s 
archives. If the head of the investigational site is unable to meet this obligation, they must ask 
the Sponsor for permission to make alternative arrangements. Details of these arrangements 
must be documented. 
The Sponsor 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. 
The results of the additional variables for analysis will be presented in reports separate from 
the study CSR. 
13.6 Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor. In 
addition, the Investigators must provide to the Sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year following the completion of the study. 
13.7 Publication and Disclosure Policy 
This document contains data, information, and 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 

 
 
 
 
 
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Confidential 
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Final 1.0  / 21 June 2013 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
other person or entity without the prior written permission of the Sponsor. The foregoing 
shall not apply to disclosure required by any regulations; however, prompt notice will be 
given to the Sponsor prior to any such disclosure. 
The Sponsor plans to disclose details of the study protocol on a web-based, publicly 
available, clinical trial register database (e.g., ClinicalTrials.gov). 
13.8 Insurance 
The Sponsor is responsible for AEs and health damage of the subjects that are associated 
with the THS 2.2 Menthol 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 
cried 
out 
by 
the 
insured.

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
14 REFERENCE LIST 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
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E. Borgida, C. Le, and S.S. Hecht, Developing the science base for reducing tobacco harm, 
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Health Canada, 1999 
Health Canada. Determination of “Tar”, Nicotine and Carbon, Monoxide in Mainstream 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Heatherton et al, 1991 
Heatherton TF, Kozlowski LT, Frecker RC, Fagerström KO. The Fagerström test for nicotine 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
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Jacob P 3rd, Yu L, Duan M, Ramos L, Yturralde O, Benowitz NL. Determination of the 
Nicotine Metabolites Cotinine and Trans-3'-Hydroxycotinine in Biologic fluids of Smokers 
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for Tobacco Smoke Exposure and for Phenotyping Cytochrome P450 2A6 Activity. J 
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PMI, 2012a 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
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without the written consent of Philip Morris Products S.A. 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Zeller and Hatsukami, 2009 
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Strategic Dialogue on Tobacco Harm Reduction: a vision and blueprint for action in the US. 
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ZRHX-PK-02, 2012 
Philip Morris International, Switzerland. 2012. Clinical study. A Single-center, Open-label, 
Randomized, Controlled, Crossover Study to Explore the Nicotine Pharmacokinetic Profile 
and Safety of Tobacco Heating System (THS) 2.1 Compared to Conventional Cigarettes 
Following Single and ad Libitum Use in Smoking, But Otherwise Healthy Subjects. 
Available at http://clinicaltrials.gov/ct2/show/NCT01780688?term=NCT01780688&rank=1  
 

 
 
 
 
 
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Appendix 1 
Schedule of Events 
 
Screening 
Admission 
Wash-
out 
Single 
use 
Wash-out 
Single 
use 
Day of 
Discharge k 
Safety follow-up l 
Study Day 
-29 to -2  
-1 
0 
1 
2 
3 
4 
4 to 11 
Informed consent/subject 
information sheet 
● 
 
 
 
 
 
 
 
Advice on the risks of smoking 
and debriefing 
● 
● 
 
 
 
 
● 
 
Inclusion/exclusion criteria 
● 
● 
 
 
 
 
 
 
Enrolment 
 
● 
 
 
 
 
 
 
Randomization 
 
 
● 
 
 
 
 
 
Product test for THS 2.2 
Menthol and NRT gum 
 
● 
 
 
 
 
 
 
Product demonstration of THS 
2.2 Menthol and NRT gum 
● 
 
 
 
 
 
 
 
Product use  
 
 
 
● 
 
● 
 
 
Support during periods of 
reduced smoking/smoking 
abstinence (as required) 
 
 
● 
● 
● 
● 
 
 
Identification of current mCC 
brand 
● 
● 
 
 
 
 
 
 
Smoking history 
● 
● 
 
 
 
 
 
 
Readiness to abstain from 
smoking for up to 4 days 
● 
● 
 
 
 
 
 
 
Willingness to quit smoking in 
the next 3 months 
● 
 
 
 
 
 
 
 
Demographics a, medical 
history, concomitant diseases  
● 
 
 
 
 
 
 
 
Prior medication b / 
● 
● 
● 
● 
● 
● 
● 
● 

 
 
 
 
 
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Screening 
Admission 
Wash-
out 
Single 
use 
Wash-out 
Single 
use 
Day of 
Discharge k 
Safety follow-up l 
Study Day 
-29 to -2  
-1 
0 
1 
2 
3 
4 
4 to 11 
Concomitant medication 
Physical examination, body 
height, weight and related BMI c 
● 
● 
 
 
 
 
● 
 
Vital signs d 
● 
● 
● 
● 
● 
● 
● 
 
ECG 
● 
 
 
● 
 
● 
 
 
Spirometry 
● 
● 
 
 
 
 
● 
 
Chest X-ray e 
● 
 
 
 
 
 
 
 
B/U: Hematology, clinical 
chemistry, urine analysis 
● 
● 
 
 
 
 
● 
 
B: Serology  
● 
 
 
 
 
 
 
 
U: Urine drug screen, urine 
cotinine screen 
● 
● 
 
 
 
 
 
 
Alcohol test  
● 
● 
 
 
 
 
 
 
U: Pregnancy test (all females) 
● 
● 
 
 
 
 
● 
 
Collection of used Menthol 
Tobacco Sticks and mCC  butts 
and NRT gum 
 
 
 
● 
 
● 
 
 
B: Plasma nicotine f 
 
 
 
● 
● 
● 
● 
 
B: COHb g 
 
 
 
● 
(5x) 
 
● 
(5x) 
 
 
CO breath test h 
 
● 
(1x) 
● 
(4x) 
● 
(4x) 
● 
(4x) 
● 
(4x) 
● 
(1x) 
 
B:trans-3’-hydroxycotinine and 
cotinine (CYP2A6 activity) in 
plasma  
 
● 
 
 
 
 
 
 
FTND questionnaire 
● 
 
 
 
 
 
 
 
QSU-brief questionnaire i 
 
 
 
● 
 
● 
 
 
MCEQ (modified version, only 
after THS 2.2 Menthol and 
 
 
 
● 
 
● 
 
 

 
 
 
 
 
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Screening 
Admission 
Wash-
out 
Single 
use 
Wash-out 
Single 
use 
Day of 
Discharge k 
Safety follow-up l 
Study Day 
-29 to -2  
-1 
0 
1 
2 
3 
4 
4 to 11 
mCC use  
Cough assessment j 
 
 
● 
● 
● 
● 
● 
 
AE/SAE recording  
● 
● 
● 
● 
● 
● 
● 
● 
Abbreviations: AE = Adverse event; BMI = Body mass index; CO = Carbon monoxide; COHb = Carboxyhemoglobin; CYP2A6 = Cytochrome P450 2A6; ECG = Electrocardiogram; 
FTND = Fagerström Test for Nicotine Dependence (revised version); mCC = menthol conventional cigarette(s); MCEQ = Modified Cigarette Evaluation Questionnaire; NRT gum = 
Nicotine replacement therapy gum; QSU-brief = Questionnaire of Smoking Urges brief; SAE = Serious adverse event; THS 2.2 Menthol= Tobacco Heating System 2.2 Menthol 
 
B : Blood sample required. 
U : Urine sample required.  
 
a: Sex, date of birth/age 
b: Prior medication at Screening and the 4 weeks prior to Screening. 
c: Including height (only at Screening), body weight and calculated BMI. 
d: Systolic and diastolic blood pressure, pulse rate, respiratory rate. 
e: Pre-study chest X-ray (anterior-posterior and left lateral views) to be used, if performed within 6 months prior to Screening. 
f: Nicotine blood samples to be taken as follows: 
Single use THS 2.2 Menthol and mCC only: 
For subjects on THS 2.2 Menthol or on mCC, a total of 16 blood samples will be taken. The first blood sample will be taken within 15 minutes prior to the product use. 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.  
Single Use on Day 1 and Day 3 for NRT gum only:  
For subjects on NRT gum: 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 T0, 15 samples 
thereafter in relation to T0: T1’ after 10 min + 1 min, T2’ after 20 minutes + 1 min, T3’ after 25 minutes + 1 min, T4’ after 30 minutes + 1 min, T5’ after 35 minutes + 1 min; T6’ after 
40 minutes + 1 min; T7’ after 45 minutes + 1 min, T8’ after 60 minutes + 3 min, T9’ after 2 hours + 5 min, T10’ after 3 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 (this sample will be drawn during the day following product use, i.e., wash-out).  
g: COHb blood samples to be taken as follows: 
Single use: A total of 5 blood samples will be taken. The first sample within 15 minutes prior to T0 (start of single product use); 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 -1 and Day 4. On Day 0, Day 1, Day 2, Day 3, four 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 (T0 = start of first product use). The three other tests will be conducted as described in section 9. On the wash-out days (Day 0 and 
Day 2) the first test  will be conducted between 8:00 am-09:30 am.  The three other tests will be conducted as described in section 9. 

 
 
 
 
 
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i: QSU–brief will be assessed as follows:  
Single use: The QSU-brief will be completed by the subject himself/herself at single use study days.  
THS 2.2 Menthol and mCC arms: First sample within 15 min 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. 
NRT arm: First sample within 15 min prior to T0, 9 assessments thereafter in relation to T0: 20 min, 30 min, 45 min, 60 min, 2 hr, 4 hr, 6 hrs, 9 hrs, and 12 hrs after T0 with a time 
window of 10 min each. 
j: Visual analogue scale, three Likert scales and one open question. 
k: All examinations listed at the Day of Discharge should also be conducted in subjects preliminarily terminating the study. 
l: Spontaneous reporting of new AEs/SAEs by the subject and active follow-up of ongoing AEs/SAEs by the site.  

 
 
 
 
 
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Appendix 2 
Participating Laboratories 
The following Laboratories will be used in the study: 
 
 
 
 
 
 
 
  
  
 
 
 
 
More details will be found in the study laboratory manuals.  
 
 

 
 
 
 
 
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Appendix 3 
Investigational Product and Instructions for Use 
The product user guide will be provided as a separate document. 

 
 
 
 
 
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Appendix 4 
THS Package Label 
The package label for the THS Menthol Tobacco Sticks (example): 

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
ZRHM-PK-05-JP 
Final 1.0  / 21 June 2013 
Page 119 of 124 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
The package label for the THS Menthol Tobacco Sticks carton (example): 
 

 
 
 
 
 
Philip Morris Products S.A.  
Clinical Study Protocol 
Confidential 
ZRHM-PK-05-JP 
Final 1.0  / 21 June 2013 
Page 120 of 124 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
Appendix 5 
Abnormal Laboratory Values 
ABNORMAL LABORATORY VALUES RATING: SERUM CHEMISTRY 
PARAMETERS 
Serum Chemistry* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Sodium – Hyponatremia (mmol/l) ** (1) 
<LLN - 130 
- 
<130 - 120 
Sodium – Hypernatremia (mmol/l) ** (1) 
>ULN - 150 
>150 - 155 
>155 - 160; 
hospitalization 
indicated 
Potassium – Hyperkalaemia (mmol/l)**(1) 
>ULN - 5.5 
>5.5 - 6.0 
>6.0 - 7.0; 
hospitalization 
indicated 
Potassium – Hypokalaemia (mmol/l) ** (1) 
<LLN - 3.0 
<LLN - 3.0; 
symptomatic; 
intervention indicated 
<3.0 - 2.5; 
hospitalization 
indicated 
Glucose – Hypoglycaemia ** (1)    (mg/dL) 
                                                   (mmol/l)  
<LLN – 55; 
<LLN – 3.0 
<55 – 40; 
<3.0 – 2.2 
<40 – 30; 
<2.2 – 1.7 
Blood Urea Nitrogen (BUN) (mg/dL) (2) 
23 – 26 
27 – 31 
>31 
Glucose – Hyperglycaemia: ** 
  
Fasting (1)( (mg/dL) 
                   (mmol/l) 
 
 
>ULN – 160; 
>ULN – 8.9 
 
>160 -250 
> 8.9-13.9 
 
 
>250 – 500; 
>13.9 – 27.8 
Hospitalization 
indicated 
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 
Albumin – Hypoalbuminaemia** (1)(g/dL) 
                                                          (g/l) 
<LLN – 3; 
<LLN - 30 
<3 – 2; 
<30 - 20 
<2; 
<20 
Total Protein – Hypoproteinaemia (2) 
(g/dL) 
 
5.5 – 6.0 
 
5.0 – 5.4 
 
<5.0 
Alkaline phosphatase increased** (1) 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 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 
Gamma-glutamyl transferase  
increased (1) 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 

 
 
 
 
 
Philip Morris Products S.A.  
Clinical Study Protocol 
Confidential 
ZRHM-PK-05-JP 
Final 1.0  / 21 June 2013 
Page 121 of 124 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Blood bilirubin increased ** (1) 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 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 
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 
 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
LLN = lower limit of the normal range; ULN = upper limit of the normal range. 
Data Sources: 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials, U.S. Department of Health and Human Services, FDA, Center for Biologics 
Evaluation and Research - Guidance for Industry. 
(2) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, FDA, 
Center for Biologics Evaluation and Research - Guidance for Industry. 
 
*  Those parameters that are not listed do not have grading categories in either the CTCAE or 
the FDA guidance documents and will therefore be reviewed by the Investigator and only 
reported as an AE if considered to be clinically relevant. 
** Where parameters in this table are listed in both the CTCAE and the FDA guidance 
documents, and each document has different values within each grading category, the 
grading in CTCAE guidance document predominates. 

 
 
 
 
 
Philip Morris Products S.A.  
Clinical Study Protocol 
Confidential 
ZRHM-PK-05-JP 
Final 1.0  / 21 June 2013 
Page 122 of 124 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
ABNORMAL LABORATORY VALUES RATING: HEMATOLOGY PARAMETERS 
Haematology* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Haemoglobin (Female) – (g/dL) (1) 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
change from baseline value – (g/dL) (1) 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
Haemoglobin (Male) – (g/dL) (1) 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
change from baseline value – (g/dL) (1) 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
Haemoglobin increase – (g/dL) (2) 
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 Increase  – (cell/mm3) (1) 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25,000 
WBC Decrease - (cell/mm3) (2)** 
<LLN – 3000; 
<LLN – 3.0 x 10-9/l 
<3000 - 2000; 
<3.0 – 2.0 x 10-9/l 
<2000 - 1000; 
<2.0 – 1.0 x 10-9/l 
Lymphocytes Increase - (cell/mm3) (2) 
- 
>4,000 – 20,000 
>20,000 
Lymphocytes Decrease  - (cell/mm3) (2)** 
<LLN – 800; 
<LLN – 0.8 x 10-9/l 
<800 - 500; 
<0.8 – 0.5 x 10-9/l 
<500 - 200; 
<0.5 – 0.2 x 10-9/l 
Neutrophils Decrease  - (cell/mm3) (2)** 
<LLN – 1500; 
<LLN – 1.5 x 10-9/l 
<1500 - 1000; 
<1.5 – 1.0 x 10-9/l 
<1000 - 500; 
<1.0 – 0.5 x 10-9/l 
Eosinophils - (cell/mm3) (1) 
650 – 1500 
1501 - 5000 
>5000 
Platelets Decrease - (cell/mm3) (2)** 
<LLN – 75,000; 
<LLN – 75.0 x 10-9/l 
<75,000 – 50,000; 
<75.0 – 50.0 x 10-9/l 
<50,000 – 25,000; 
<50.0 – 25.0 x 10-9/l 
Abbreviations: LLN = Lower limit of the normal range; ULN = Upper limit of the normal 
range; WBC = White blood cell (count). 
Data Source: (1) 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. 
       (2) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 

 
 
 
 
 
Philip Morris Products S.A.  
Clinical Study Protocol 
Confidential 
ZRHM-PK-05-JP 
Final 1.0  / 21 June 2013 
Page 123 of 124 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
*  Those parameters that are not listed do not have grading categories in either the CTCAE or 
the FDA guidance documents and will therefore be reviewed by the Investigator and only 
reported as an AE if considered to be clinically relevant. 
**  Where parameters in this table are listed in both the CTCAE and the FDA guidance 
documents, and each document has different values within each grading category, the 
grading in CTCAE guidance document predominates. 

 
 
 
 
 
Philip Morris Products S.A.  
Clinical Study Protocol 
Confidential 
ZRHM-PK-05-JP 
Final 1.0  / 21 June 2013 
Page 124 of 124 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
ABNORMAL LABORATORY VALUES RATING: URINALYSIS PARAMETERS 
Urine* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
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 
Glucose (2) 
Trace 
1+ 
2+ 
Blood – Haematuria ** (1) 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Symptomatic; 
urinary catheter or 
bladder irrigation 
indicated; limiting 
instrumental ADL 
Gross haematuria; 
transfusion, IV 
medications or 
hospitalization 
indicated; elective 
endoscopic, 
radiologic or 
operative 
intervention 
indicated; limiting 
self-care ADL 
Abbreviations: ADL = Activities of daily living; IV = Intravenous. 
Data Source: (1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
   (2) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, FDA, 
Center for Biologics Evaluation and Research - Guidance for Industry. 
*  Those parameters that are not listed do not have grading categories in either the CTCAE or 
the FDA guidance documents and will therefore be reviewed by the Investigator and only 
reported as an AE if considered to be clinically relevant. 
**  Where parameters in this table are listed in both the CTCAE and the FDA guidance 
documents, and each document has different values within each grading category, the 
grading in CTCAE guidance document predominates.