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 Nasal Spray
Phase: NA
Conditions: Smoking
Sponsor: Philip Morris Products S.A.

 
Confidentiality Statement: Data and information contained in this document are considered to constitute trade secrets and 
confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
Clinical Study Protocol 
ZRHM-PK-06-US 
 
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 nasal spray 
Short name: 
Nicotine pharmacokinetic profile and safety of THS 2.2 Menthol 
Registration 
number: 
Not assigned 
Product name: 
Tobacco Heating System 2.2 Menthol 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
 
 
Version number: 
Final  
 
 
Date: 
22 May 2013 
Authors: 
, PhD, Manager Clinical Science 
 PhD, Biostatistician 
, MD, Medical Safety Officer 
 Medical Writer 
 
 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
ZRHM-PK-06-US 
Final /22 May 2013 
Page 2 of 119 
 
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confidential 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 International. 
 
 
SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Name of Product: 
Tobacco Heating System 2.2 Menthol 
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 nasal spray 
Short Study Title: 
Nicotine pharmacokinetic profile and safety of THS 2.2 Menthol 
Study Number and Acronym: 
ZRHM-PK-06-US, 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 the THS 2.2 Menthol are higher relative to 
nicotine nasal spray (NNS) following single use of the THS 2.2 Menthol and 
NNS. 
 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 NNS product [AUC(0-t’)]) between the THS 2.2 Menthol and mCC, as 
well as the THS 2.2 Menthol and NNS.  
 To evaluate the time to the maximum concentration (tmax) of 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 NNS. 
 To describe the terminal half-life (t1/2) of nicotine for the THS 2.2 Menthol, mCC, 
and NNS. 

 
 
 
 
 
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Clinical Study Protocol 
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 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 NNS. 
 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 NNS users. 
 To describe the plasma levels of cotinine in the THS 2.2 Menthol, mCC, and 
NNS. 
 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. NNS). 
 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. 
 Cotinine levels in plasma prior T0, T0 + 12 hours (T14), T0 + 24 hours (T15). 
 Safety variables: 
o Incidence of adverse events (AEs)/serious adverse events (SAEs) 
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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Clinical Study Protocol 
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without the written consent of Philip Morris International. 
 
 
o Spirometry. 
o Electrocardiogram (ECG). 
o Clinical chemistry, hematology, and urine analysis safety panel. 
o Physical examination. 
o Concomitant medication. 
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. 
 Socio-economic status questionnaire. 
 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. 
 NNS. 
 

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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without the written consent of Philip Morris International. 
 
 
•
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
NNS
n=9
mCC
n=22 
THS 2.2 
Menthol
n=9
THS 2.2 
Menthol
n=22
NNS
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
THS: Tobacco Heating System; mCC: menthol conventional cigarette(s); NNS: nicotine nasal spray
Figure S1: Study Flowchart
 
Subjects will be admitted to the clinic on Day -1. 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/NNS) 
Period 2: Day 2: Wash-out; Day 3: single product use (THS 2.2 Menthol/mCC/NNS). 
In total, 62 eligible, healthy smoking subjects will be randomized to one of 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 
 
NNS (N=9) 
Sequence 4:  
NNS 
 
THS 2.2 Menthol (N=9) 
Subjects will be discharged (time of discharge) from the investigational site in the morning of 

 
 
 
 
 
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Clinical Study Protocol 
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Final /22 May 2013 
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without the written consent of Philip Morris International. 
 
 
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, healthy adult subjects without any restriction to races and ethnicities, 
meeting the following main inclusion criteria:  
• Subject is aged from 22 to 65 years (inclusive). 
• Smoking, healthy subject as judged by the Investigator. 
• Subject smokes at least 10 commercially available mCCs per day of the 
following brands: Kool mild, Kool, Newport Menthol Short, Newport 
Menthol, Newport Menthol 100, Camel menthol silver, Camel menthol, 
Marlboro Menthol and sub-brands) for the last 4 weeks, based on self-
reporting. 
• Subject does not plan to quit smoking in the next 3 months. 
• The subject is ready to accept interruptions to smoking for up to 4 days. 
• The subject is ready to accept using the THS 2.2 Menthol and the NNS 
product. 
Subjects will be randomized to 1 of 4 sequences. Each sex and each of the smoking strata 
(International Organization for Standardization [ISO] nicotine levels ≤1 mg and >1 mg) will 
have a quota applied to ensure they represent at least 40% of the study population for each of 
the Group-1 and Group-2. 
Subjects who do not complete the study after randomization will not be replaced. 
Investigational Products 
• Test Product: Tobacco Heating System 2.2 Menthol 
• Reference Product: Subject’s own supply of commercially available 
preferred single brand mCC. 
Reference Point Product (non-investigational): Nicotine Nasal Spray (Nicotrol®NS 
10 mg/mL); 1 spray (resulting in the administration of 0.5 mg nicotine) per nostril/product 
use, as per label. This will be not supplied by the Sponsor. 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
ZRHM-PK-06-US 
Final /22 May 2013 
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confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
Duration of Study: 
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), 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). 
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 NNS 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% confidence intervals (CI) for the THS 2.2 Menthol:CC and THS 2.2 
Menthol:NNS ratios. The lower bound of the 95% CI of the THS 2.2 Menthol:NNS 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 NNS. 
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 NNS. The median tmax differences between 
THS 2.2 Menthol and mCC as well as between THS 2.2 Menthol and NNS, 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 
analyze the domain scores of the product evaluation (MCEQ) questionnaire, for the 
comparison between THS 2.2 Menthol and mCC. The same model will be evaluated for the 
analysis of cotinine and Urge-to-smoke (QSU-brief), including the assessment time points as 
repeated measurements. The results will be presented in terms of least square means and 95% 
CI for the THS 2.2 Menthol-mCC and THS 2.2 Menthol-NNS differences. 
Cotinine levels will be summarized by means of descriptive statistics reported by exposure. 

 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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Confidentiality Statement: Data and information contained in this document are considered to constitute trade secrets and 
confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
Safety: The safety population will comprise all subjects, who are exposed to THS 2.2 
Menthol during the study, including the product 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 is calculated by adding up sample sizes 
separately estimated for each analysis. 
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 PK profile similar to mCC (Cmax ratio 
equal to 1.00) and a 10% dropout rate. 
A total of 18 subjects are needed to estimate the mean Cmax parameter ratio between THS 2.2 
Menthol and NNS with a precision allowing for the lower bound of the 95% CI exceeding 
1.00, with 90% power and assuming a 10% dropout rate. The anticipated geometrical Cmax 
ratio between THS 2.2 Menthol and NNS is 1.55. 
The sample size of this study is based on our current understanding of THS 2.1 non-menthol, 
the previous prototype of THS 2.2 Menthol, where the within-subject coefficient of variation 
for nicotine Cmax and AUC(0-last) was found to be approximately equal to 36% and 21%, 
respectively. 
 
 
 
 
 

 
 
 
 
 
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Clinical Study Protocol 
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without the written consent of Philip Morris International. 
 
 
 
TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................13 
1. 
ETHICS AND REGULATIONS .....................................................................................18 
1.1 
Institutional Review Board Approval ....................................................................18 
1.2 
Ethical Conduct of the Study .................................................................................19 
1.3 
Subject Information and Consent...........................................................................19 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................20 
2 
INTRODUCTION ...........................................................................................................21 
2.1 
Background ............................................................................................................21 
2.2 
Purpose of the Study ..............................................................................................23 
2.3 
Anticipated Benefits and Risks ..............................................................................23 
3 
STUDY OBJECTIVES ....................................................................................................25 
3.1 
Primary Objective ..................................................................................................25 
3.2 
Secondary Objectives.............................................................................................25 
3.3 
Primary Endpoints .................................................................................................26 
3.4 
Secondary Endpoints .............................................................................................26 
3.5 
Exploratory Endpoints ...........................................................................................27 
4 
INVESTIGATIONAL PLAN ..........................................................................................28 
4.1 
Overall Study Design and Plan ..............................................................................28 
4.2 
Rationale for Study Design and Control Groups(s) ...............................................30 
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 ...............................................................................40 
6.1 
Description of Investigational Products .................................................................40 
6.3 
Use of Investigational and Reference Point Products ............................................42 
6.4 
Method for Assigning Subjects to Study Arms .....................................................43 
6.5 
Blinding..................................................................................................................44 
6.6 
Investigational Product Accountability and Compliance ......................................45 

 
 
 
 
 
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are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
6.7 
Restrictions ............................................................................................................46 
7 
STUDY PROCEDURES .................................................................................................50 
7.1 
Informed Consent Form/Subject Information Sheet ..............................................50 
7.2 
Smoking Cessation Advice and Debriefing ...........................................................50 
7.3 
Support during Smoking Abstinence/Periods of Reduced Smoking .....................51 
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 
9 
STUDY ACTIVITIES .....................................................................................................71 
9.1 
Screening Visit .......................................................................................................71 
9.2 
Admission ..............................................................................................................73 
9.3 
Investigational Period ............................................................................................74 
9.4 
Day of Discharge ...................................................................................................79 
9.5 
Safety Follow-up Period ........................................................................................79 
9.6 
Early Termination Procedures ...............................................................................80 
10 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................81 
10.1 
Monitoring .............................................................................................................81 
10.2 
Training of Staff .....................................................................................................82 
10.3 
Audits and Inspections ...........................................................................................82 
11 DATA MANAGEMENT ACTIVITIES..........................................................................83 
11.1 
Data Capture ..........................................................................................................83 
11.2 
Data Handling ........................................................................................................84 
12 PLANNED STATISTICAL METHODS ........................................................................86 
12.1 
General Considerations ..........................................................................................86 
12.2 
Determination of Sample Size and Power Consideration ......................................87 
12.3 
Analysis Populations ..............................................................................................88 
12.4 
Demographics and Baseline Characteristics ..........................................................88 
12.5 
Primary Endpoints .................................................................................................89 
12.6 
Secondary Endpoints .............................................................................................90 
12.7 
Exploratory Analyses .............................................................................................93 
12.8 
Interim Analysis .....................................................................................................93 
13 ADMINISTRATIVE CONSIDERATIONS ....................................................................94 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
13.1 
Investigators and Study Administrative Structure .................................................94 
13.2 
Subject Confidentiality ..........................................................................................95 
13.3 
Access to Source Documentation ..........................................................................96 
13.4 
Record Retention ...................................................................................................96 
13.5 
Clinical Study Report .............................................................................................98 
13.6 
Financial Disclosure...............................................................................................98 
13.7 
Publication and Disclosure Policy .........................................................................98 
14 REFERENCE LIST .......................................................................................................100 
 
 
 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
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 .......................................................................71 
Table 5. 
Time Schedule – Day -1 Admission ..........................................................73 
Table 6. 
Time Schedule – Day 0 Washout ...............................................................74 
Table 7. 
Time Schedule – Day 2 Washout ...............................................................76 
Table 8. 
Time Schedule – Day 1 and Day 3 Single Use ..........................................77 
Table 9. 
Time Schedule – Day 4 Discharge .............................................................79 
 
Figure 1 
Study Flowchart .........................................................................................30 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events ...................................................................................109 
Appendix 2 
Participating Laboratories ........................................................................113 
Appendix 3 
Investigational Product and Instructions for Use .....................................114 
Appendix 4 
Product Label for the NNS Product: Adverse Events ..............................115 
Appendix 5 
Abnormal Laboratory Values ..................................................................116 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
ADL 
Activities of daily living 
AE 
Adverse event 
ANOVA 
Analysis of variance 
AUC 
Area under the concentration-time curve 
AUC(0-∞) 
Area under the concentration-time curve from time 0 extrapolated to 
time of last quantifiable concentration to infinity 
AUC(0-last) 
Area under the concentration-time curve from T0 to time of last 
quantifiable concentration 
AUC(0-t’) 
Partial AUC, where t’ is the subject-specific time of maximum 
nicotine concentration following the single use of conventional 
cigarettes or nicotine nasal spray 
BMI 
Body mass index 
CC 
Conventional cigarette(s). The menthol CC are referred as mCC. 
CD 
Compact Disc 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Clast 
Last quantifiable concentration 
Cmax 
Maximum concentration 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events and Common 
Toxicity Criteria  
CTMS 
Clinical Trial Management System 
CV (documentation) 
Curriculum vitae 
CV (statistics) 
Coefficient of variation 
CYP2A6 
Cytochrome P450 2A6 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End-of-Study Visit  
FDA 
Food and Drug Administration  
FEV1  
Forced expiratory volume in 1 second 
FTND 
Fagerström Test for Nicotine Dependence (revised version) 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
HPHCs 
Harmful and potentially harmful constituents  
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IV 
Intravenous 
LLN 
Lower limit of the normal range 
LLOQ 
Lower limit of quantification 
MCEQ 
Modified Cigarette Evaluation Questionnaire  
MedDRA 
Medical Dictionary for Regulatory Activities 
MRTP 
Modified risk tobacco product 
NNS 
Nicotine nasal spray 
NRT 
Nicotine replacement therapy 
PK 
Pharmacokinetic(s) 
PMI 
Philip Morris International 
QC 
Quality control 
QSU-brief 
Questionnaire of Smoking Urges 
SAE 
Serious adverse event 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
SAP 
Statistical analysis plan 
SES 
Socio-economic status 
SHM 
Sample handling manual 
SOP 
Standard Operating Procedure 
T 
Time point  
T0 
Time point of first product use during study day 
t½ 
Half-life 
THS  
Tobacco Heating System  
tmax 
Time to maximum concentration 
 
 
ULN 
Upper limit of the normal range 
ULOQ 
Upper limit of quantification 
VAS 
Visual Analogue Scale 
WBC 
White blood cell (count) 
WHO 
World Health Organization 
λz 
Terminal elimination rate constant 
Explanation of Terms 
The following special terms are used in this protocol: 
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 main 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 met and the 
subjects is willing and ready to use both the THS 2.2 Menthol and 

 
 
 
 
 
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NNS (the test of both THS 2.2 Menthol and NNS are the last 
assessments prior to enrolment). 
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 NNS product is the time of the 
spray in the first nostril. 
mCC 
The term ‘menthol conventional cigarette’ refers to manufactured 
and commercially available menthol cigarettes and excludes hand-
rolled cigarettes, cigars, pipes, bidis, and other nicotine-containing 
products. 
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 AEs/SAEs by the site. In general any 
AE will be actively followed up until resolved, stabilized i.e. no 
worsening of the event or a plausible explanation for the event has 
been found.  
Screening failure 
Subjects who do not meet the entry criteria from ICF signature to 
the time of enrolment will be considered a screening failure and 
will be replaced by other subjects.  
THS Menthol Tobacco 
Sticks (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. 
THS Tobacco Stick 
Holder (Holder) 
The function of the Holder (Model 4.2) is to heat the 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 Tobacco Stick). 
Time of Discharge 
Time when the subject is released form the site after all the 
procedures of the day of discharge have been conducted. 
Tobacco Heating 
Device 
The Device comprises everything in THS 2.2 Menthol except the 
Menthol Tobacco Stick. 

 
 
 
 
 
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Tobacco Heating 
System 2.2 Menthol 
(THS 2.2 Menthol) 
THS 2.2 Menthol comprises the following components: Tobacco 
Stick, Holder, Charger, a Cleaning Tool, a mains power supply, 
and a USB cable. 
 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
1. ETHICS AND REGULATIONS 
1.1 
Institutional Review Board Approval 
Prior to the start of the study, the clinical study protocol, together with its associated 
documents (informed consent form [ICF], subject information sheet, subject recruitment 
procedures [e.g., advertisements], written information to be provided to the subjects, 
Investigator’s Brochure [IB], available safety information, the Investigator’s curriculum vitae 
[CV] and/or other evidence of qualifications, and any other documents requested by an 
Institutional Review Board [IRB]), will be submitted for review and approval to the relevant 
IRB according to the appropriate provisions found in 21 Code of Federal Regulations (CFR) 
part 50 (informed consent of human subjects) and 21 CFR 56. The IRB shall be appropriately 
constituted and perform its functions in accordance with the International Conference on 
Harmonization (ICH) Tripartite Guidance for Good Clinical Practice (GCP) and local 
requirements, as applicable. 
In accordance with GCP and 21 CFR part 56 (IRB review and approval of clinical 
investigation), a written confirmation of the IRB approval should be provided to the Sponsor. 
This should identify the study (Investigator’s name, study number, and title) and the 
documents that have been approved by the IRB, with dates and version numbers, as well as 
the date of approval. The composition of the IRB, including the name and occupation of the 
chairperson, should be supplied to the Sponsor together with a GCP compliance statement. 
The written approval from the IRB will be filed in the Investigator file, and a copy will be 
filed in the Study Master File at the Sponsor or designated organization. The study must not 
start at a site before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IRB.   
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the Principal Investigator. All amendments will be 
submitted to the IRB, and substantial amendments will only be implemented after approval 
by the IRB. 
These requirements for approval should in no way prevent any action from being taken by 
the Investigator or by the Sponsor in order to eliminate immediate hazards to the subjects. If 
such a change to the protocol is felt to be necessary by the Investigator, and is implemented 
for safety reasons, the Sponsor and the IRB should be informed immediately. 
Relevant safety information will be submitted to the IRB during the course of the study in 
accordance with national regulations and requirements. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
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 applicable regulatory 
principles. 
The Investigator agrees to conduct the clinical study in compliance with the protocol agreed 
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 
Informed Consent Form/Subject Information Sheet 
At the Screening Visit, the Investigator or person designated by 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 or the designee will 
answer all questions the subject might have to his/her full satisfaction. The subject will have 
sufficient time for consideration of his/her participation in the study and will be notified that 
he/she is free to discontinue his/her participation at any time. Once the subject has received 
all necessary information, and if he/she agrees to participate, this will be documented in the 
ICF/subject information sheet 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/subject information sheet has been signed. 
The original, dated, and signed ICF(s)/subject information sheets must be kept in the 
Investigator study file at the site, and a copy must be given to the subject. 
If a protocol amendment is required, or if new information regarding the risk profile of the 
Investigational Product (IP) becomes available, an amendment to the ICF/subject information 
sheet may be required. If revision of the ICF/subject information sheet is necessary, the 
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/subject information sheet. 
The subject will be informed that additional data analysis not mentioned in the protocol or 
the Statistical Analysis Plan (SAP) might be performed with the collected data at a later time. 
Any additional analysis performed will be covered by data confidentiality, as for the main 
analysis described in this protocol. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
1.4 
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation, 
and documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator 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 applicable 
national and local laws of the pertinent regulatory authorities. 
 
 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
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). 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 by the United States Food and Drug Administration (FDA) as 
modified risk tobacco products (MRTPs) (FDA, 2012a). 
The challenge in developing and commercializing MRTPs is two-fold, i.e., developing 
tobacco products that are shown to reduce risk and are acceptable to smokers as substitutes 
for conventional cigarette(s) (CC). PMI is developing candidate MRTPs that provide an 
inhalation experience without combustion. The novel approach to achieve this is by heating 
tobacco at significantly lower temperatures than 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 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-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, 

 
 
 
 
 
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2009), and more than 100 of them have been categorized as harmful and potentially harmful 
constituents (HPHCs) (FDA, 2011).  
PMI’s focus has been the development of products that do not combust tobacco but which 
replicate the “smoking experience” as much as possible. Our approach limits pyrolysis and 
combustion, by heating tobacco at significantly lower temperatures than CC. PMI believes 
that such products present the best opportunity for reducing harm because they produce 
vastly lower levels of harmful smoke constituents and are more likely to be accepted by 
smokers as substitutes for cigarettes. 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). This product will be assessed in current smokers of 
menthol CC. With this product, the heating of the tobacco is maintained below 400°C, a 
temperature much lower than what is observed for mCC, which can reach 900°C. The THS 
2.2 Menthol is composed of the tobacco heating device, referred to as the ‘THS Tobacco 
Stick Holder,’ dedicated special Menthol Tobacco Sticks made of conventional tobacco, 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 supports the 
initiation of the clinical studies described in this investigator’s brochure (PMI, 2013a). 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, 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 
continuing smoking CC, both, in controlled and ambulatory conditions. No clinical studies 
were conducted with THS 2.2 Menthol. 
THS 2.1 non-Menthol was tested in two exploratory clinical studies to measure the nicotine 
plasma kinetic profile (PK) (clinical trial.gov identifier: NCT 01780688) and to assess the 
reduction of exposure to HPHCs when switching from CC to THS 2.1 (clinical trial.gov 

 
 
 
 
 
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identifier: NCT 01780714). 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 (PMI, 2013a). 
Clinical studies conducted so far revealed no safety concern for either of the previous version 
of THS 2.2 Menthol tested. 
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 THS 2.2 Menthol and menthol conventional cigarette 
(mCC) in healthy smokers. THS 2.2 Menthol will also be compared with the nicotine nasal 
spray (NNS) product, used as a reference point. 
2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
According to a report from centers for disease control and prevention on quitting smoking 
among adults in US, 68.8% of current adult smokers report that they want to quit completely 
( 
CDC, 2011). Despite associated health risks, however, only 6.2% quit smoking successfully. 
Advice on health risks associated with smoking and smoking cessation advice will be 
provided on Screening, on Admission, on Day 4 (Day of Discharge). The advice will follow 
the recommendations of the U.S. Public Health Service (U.S. Public Health Service, 2008). 
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. 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures 
 Risks related to blood sampling, e.g., excessive bleeding, fainting, hematoma, 
paresthesia, or infection, and amount of blood taken over a period of time. 
 Risks related to chest X-rays, e.g., a small increase of risk to develop cancer later in life. 
 Risks related to drug application as part of testing procedures (i.e., spirometry with 
short-acting bronchodilator at Screening) per study protocol and scientifically accepted 
standards. 

 
 
 
 
 
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2.3.3 
Anticipated Foreseeable Risks due to Investigational Product (THS 2.2 
Menthol) or Reference Point Product 
 Change in smoking habits due to study requirements and related concomitant symptoms, 
e.g., craving.  
 Risks specific to the use of any NNS, as per the relevant summary of product 
characteristics. 
All risks related to study procedures, IP, reference product, or support for smoking 
abstinence 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 blood 
donation standards).Management and follow-up of adverse events (AEs)/serious adverse 
events (SAEs). 
2.3.4 
Unforeseeable Risks 
As with any IP, reference product or smoking abstinence, there may be unforeseeable risks 
and hazards that could occur. The possibility of such will be explained at Screening, 
Admission, and Day of Discharge. Mitigation will include close monitoring and medical 
supervision to detect any unforeseeable risk or safety signals at the earliest possibility. 
 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
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 the THS 2.2 Menthol are higher relative to 
NNS following single use of the THS 2.2 Menthol and NNS. 
 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 NNS product [AUC(0-t’)]) between the THS 2.2 Menthol and mCC, as 
well as the THS 2.2 Menthol and NNS.  
 To evaluate the  time to the maximum concentration (tmax) of 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 NNS. 
 To describe the terminal half-life (t1/2) of nicotine for the THS 2.2 Menthol, mCC, 
and NNS. 
 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 NNS. 
 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 NNS users. 
 To describe the plasma levels of cotinine in the THS 2.2 Menthol, mCC, and 
NNS. 
 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 NNS). 
 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]). 
 Carbon monoxide (CO) exposure biomarkers: levels of exhaled CO and 
carboxyhemoglobin (COHb) in blood. 
 Cotinine levels in plasma prior T0, T0 + 12 hours (T14), T0 + 24 hours (T15). 
 Safety variables: 
o Incidence of adverse events (AEs)/serious adverse events (SAEs) and 
device events 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. 
o Spirometry. 
o Electrocardiogram (ECG). 

 
 
 
 
 
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o Clinical chemistry, hematology, and urine analysis safety panel. 
o Physical examination. 
o Concomitant medication. 
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.  
• Socio-economic questionnaire 
• 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. 
 NNS. 
A Screening Visit will be conducted within 4 weeks prior to Admission to the investigational 
site (Day -29 to Day -2). A demonstration of the THS 2.2 Menthol and NNS will also be 
done by the site staff during the Screening Visit. Screening procedures do not necessarily 
have to be conducted on the same day. Subjects will be admitted to the clinic on Day -1 
(Admission). On Day -1, as the last procedure of the eligibility assessments on that day, all 
subjects will undergo a product test: first for the THS 2.2 Menthol (using up to three Menthol 
Tobacco Sticks) and subsequently for NNS (1 spray of 0.5 mg per nostril as per label) prior 
to enrolment at Admission. In female subjects, the urine pregnancy test must be negative 
before any product test is performed (both the THS 2.2 Menthol and NNS). After all 
requested inclusion and exclusion criteria have been satisfactorily met, only subjects willing 
and ready to use both the THS 2.2 Menthol and NNS can be enrolled in order to minimize 
the drop-out rate during the course of the study.  
The confinement period will consist of 2 periods (Period 1, Period 2) with each period 
consisting of a nicotine wash-out period (24 hours nicotine abstinence minimum) and 1 day 
of single product use.  
Period 1: Day 0: Wash-out; Day 1: single product use (THS 2.2 Menthol/mCC/NNS). 
Period 2: Day 2: Wash-out; Day 3: single product use (THS 2.2 Menthol/mCC/NNS). 
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 
→ NNS (N=9). 
Sequence 4: NNS  
 
 
 
→ 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 NNS 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. NNS 
 
→ (N=9 in both sequence 3 and 4). 
 
Subjects will be randomized to sequence 1 and 2 (Group-1) and independently to sequence 3 
and 4 (Group-2). Each sex and each of the smoking strata (International Organization for 
Standardization [ISO] nicotine levels ≤1 mg and >1 mg) will have a quota applied to ensure 
they represent at least 40% of the total study population for each of the Group-1 and 
Group-2. 
Subjects will be discharged at 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 for active follow-up of ongoing AEs/SAEs. 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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confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
Figure 1 
Study Flowchart 
•
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
NNS
n=9
mCC
n=22 
THS 2.2 
Menthol
n=9
THS 2.2 
Menthol
n=22
NNS
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
THS: Tobacco Heating System; mCC: menthol conventional cigarette(s); NNS: nicotine nasal spray
 
 
The study will be conducted as a single-center study. For practical reasons, it will be 
conducted in several cohorts. 
4.2 
Rationale for Study Design and Control Groups(s) 
The minimum age of 22 years age in the inclusion criteria was selected based on: 
• The legal age of smoking in some US states is 19 years.  
• To account for the 3 years of smoking history. 
 
There are over 1,000 brands and sub-brands of CC that are sold in the United States. Most recent 
Federal Trade Commission (FTC) data show that menthol brands represented about 26% to 27% of 
market share of CC between 2003 and 2005. The leading mCC brands sold in the United States 
during that period were Newport, Marlboro Menthol, Kool, and Salem (FTC, 2009). Similar to 

 
 
 
 
 
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nonmenthol CC brands, the leading mCC brands have a variety of subbrands. Subbrands of the same 
brand vary in FTC-measured nicotine levels (Carabello et al, 2011). To reflect a representation of 
the market share of those brands in our study, a limited amount of sub-brands from each brand have 
been selected as reference products in our study, namely: Kool mild, Kool, Newport Menthol Short, 
Newport Menthol, Newport Menthol 100, Camel menthol silver, Camel menthol, Marlboro Menthol 
and sub-brands. 
In this study, the selected mCCs described above will be used as a reference product and a 
market-approved pharmaceutical NNS (Nicotrol®NS 10 mg/mL) will be used as non-
investigational reference point.  
In the US, the NNS has been selected as the reference because it is the only nicotine 
replacement therapy (NRT) product that provides a rapid absorption of nicotine and is most 
similar in nicotine absorption rate compared to smoking (Benowitz et al., 2009). Nicotine 
from other NRT products has a much slower rate of absorption and the level in the blood 
from these products increases at a slower rate compared to smoking (Henningfield, 1995).  
In the study, NNS will serve as a reference point in comparison with THS 2.2 Menthol for 
the following endpoints:  
• Nicotine PK parameters. 
• Urge-to-smoke. 
• Safety. 
 
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, the subjects who 
form the majority of the US population and therefore the majority of the expected study 
population (Benowitz et al., 2009, U.S. Census Bureau, 2010). There are no restrictions on 
race in the inclusion/exclusion criteria. 
Cotinine will be also measured in addition to nicotine in this study to get information on the 
levels of cotinine levels in the study popuplation as it is described in the literature that the 
levels of cotinine are higher in black smokers as compared to white smokers (Carabello et al, 
2011). 
 
The use of estrogen contraceptive is known to accelerate nicotine clearance by 20%-30% in 
women as compared to women who do not take such 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. 

 
 
 
 
 
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In this study, THS 2.2 Menthol will be tested against mCC. The effect of menthol on nicotine 
metabolism has been suggested but remains inconclusive to our knowledge (Hukkanen et al., 
2005). The activity of CYP2A6 will be measured at baseline as nicotine metabolism by 
CYP2A6 varies between individuals of the same ethnicity/race and across ethnicity/race due 
to genetic variations. These genetic differences could be associated with reduced/increased 
nicotine metabolism (Hukkanen et al., 2005). 
4.3 
Study Duration  
The entire study per subject will last 14 to 41 days, including a Screening period of up to 28 
days prior to Admission (Day -29 to Day -2), and 6 days of confinement (Day -1 to time of 
discharge on Day 4). 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 by the site. 
4.4 
Appropriateness of Measurement 
All laboratory measures utilized for this study are validated and are appropriate for the study 
assessments.  
All used questionnaires except cough and socio-economic status questionnaires are available 
as validated questionnaires.  

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
5 
STUDY POPULATION 
5.1 
Selection of Study Population 
Sixty-two 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. Subjects can smoke different brands until Admission to the clinic. From Admission to the 
clinic onwards, however, they must restrict themselves to one preferred mCC brand.There will be a 
brand restriction for menthol flavored cigarettes: Kool mild, Kool, Newport Menthol Short, 
Newport Menthol, Newport Menthol 100, Camel menthol silver, Camel menthol, Marlboro Menthol 
and sub-brands. 
 .  
The smoking status of the subjects will be verified based on a urine cotinine test (cotinine 
≥200 ng/mL). No restriction will be made with respect to races and ethnicities. 
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 22 to 65 years 
(inclusive). 
Safety 
X 
 
3. 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 
Safety 
X 
X 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -1) 
post-bronchodilator FVC >0.8], vital 
signs, physical examination, ECG, 
chest X-ray, and medical history). 
4. Subject smokes at least 10 
commercially available menthol CCs 
per day for the last 4 weeks, based on 
self-reporting (with brand restrictions). 
Furthermore, the subject has been 
smoking for at least the last 3 
consecutive years. The smoking status 
will be verified based on a urinary 
cotinine test (cotinine ≥200 ng/mL). 
Effect 
X 
X 
5. The subject does not plan to quit 
smoking in the next 3 months. 
Safety 
X 
 
6. The subject is ready to accept 
interruptions of smoking for up to 4 
days.  
Safety 
X 
X 
7. The subject is ready to accept using 
both the THS 2.2 Menthol and NNS 
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 
Safety  
X 
X 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
study for any reason (e.g., medical, 
psychiatric, and/or social reason).  
2. A subject who is legally 
incompetent, or physically or 
mentally incapable of giving consent 
(e.g., emergency situation, under 
guardianship, subject in a social or 
sanitary establishment, 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 ≥35.0 kg/m2. 
Safety 
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 
NRT), 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) 
which 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 HIV 1/2, 
Hepatitis B, or Hepatitis C.  
Safety 
X 
 
12. Donation or receipt of whole blood 
Safety 
X 
X 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
or blood products within 3 months 
prior to Admission. 
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 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
 
* Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with 
spermicidal foam/gel/film/suppository, hormonal contraception containing progesterone only, vasectomized 
partner(s), or true abstinence (periodic abstinence and withdrawal are not effective methods) from Screening 
until the end of the safety follow-up period. Hormonal contraception with estrogen containing products is 
NOT allowed in this study. 
5.1.3 
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 source documents and reported in the 
electronic Case Report Form (eCRF). 
When a subject withdraws or is removed from the study, the whole examination procedure 
planned at the Day of Discharge (Day 4) must be performed as soon as possible after the time 
of withdrawal unless subject withdrew the 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) 
which at the discretion of the Investigator. 
 Positive pregnancy testing (no invasive procedures including the drawing of blood 
must be performed after detection of pregnancy, see Section 8.5) 
 Female subjects starting estrogen containing contraception or hormone replacement 
therapy containing estrogens during the study. 
 The use of any nicotine/tobacco product which is different from the assigned product. 
 The Sponsor or Investigator terminates the study.  
 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. 

 
 
 
 
 
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 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). 
 Non-compliance to the study procedures. 
Subjects withdrawn prematurely after randomization will not be replaced and will not be 
allowed to re-enter. All withdrawals have to be documented properly in 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 -1) prior to enrolment will be considered a screening failure and will be replaced by 
other subjects.  
Subjects who violate the entry criteria after enrolment, but who are considered eligible, will 
be immediately withdrawn from the study when the violation is detected. Such subjects will 
not be replaced.  

 
 
 
 
 
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6 INVESTIGATIONAL PRODUCTS 
6.1 
Description of Investigational Products 
THS 2.2 Menthol  
The THS 2.2 Menthol will be provided by the Sponsor and its distribution will be limited to a 
qualified and appropriately trained investigator or designee.  
THS 2.2 Menthol comprises the following components: Menthol Tobacco Stick, Holder, 
Charger, a Cleaning Tool, a mains power supply, and a USB cable (see the user guide in 
Appendix 3): 
 
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. 
 
Tobacco Stick  
Holder (Holder): 
The function of the Holder (Model 4.2) is to heat the 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 Tobacco Stick) 
THS Menthol Tobacco 
Stick (Menthol 
Tobacco Sticks): 
The Menthol Tobacco Stick (product code C3) 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 
HPHC level in the aerosol is substantially reduced in comparison with CCs. 
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, 
2012b, PMI, 2012c, PMI, 2013b). Another method is the more intensive smoking method 
developed by Health Canada (Health Canada, 1999). 
Table 1 below lists the commonly reported measures (PMI, 2013a). 
 

 
 
 
 
 
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Table 1 
Measured Aerosol Fractions for the THS Menthol Tobacco Sticks 
Constituent (mg/THS 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) 
 
Menthol CC 
In the study sequences 1 and 2, the reference product to THS 2.2 Menthol is commercially 
available single brand mCC. 
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.  
6.2 
Reference Point Product 
The NNS Nicotrol®NS (10 mg/mL) will be the reference point product to THS 2.2 Menthol 
for sequences 3 and 4. The NNS will be supplied by the Investigator and reimbursed by the 
Sponsor. One spray will be administered into each nostril per product use, leading to a total 
administered dose of 1 mg nicotine/product use as per label.  
6.2.1 
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 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 to the cellophane of the lower part of the pack).  
Packs of mCC will be labeled to identify necessary information to match the subject with 
his/hers suppliers. 

 
 
 
 
 
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For the Menthol Tobacco Sticks, the packs will be printed with the necessary information 
including, but not limited to, health warning, tar, nicotine, and CO ISO levels, product code, 
and expiry date. 
6.3 
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 of 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 (see section 9.1). 
6.3.1 
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 own mCC. All 
subjects (except women with a positive pregnancy test at Screening or Admission) will 
undergo a THS 2.2 Menthol test first and subsequently a NNS test at Day -1 prior to 
enrolment. 
Following agreement that the THS 2.2 Menthol is acceptable, subjects will be randomized to 
one of 4 product exposure sequences using an Interactive Web Response System.  
6.3.2 
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 his allocated product at Day 3. Subjects will not be allowed to smoke or use any 
other nicotine/tobacco-containing products other than the products they are allocated to. 
Time point 0 will be defined as start of the single product use on the single use days or as 
start of the first product use on each study day. The start 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 product is the time of the spray in the first nostril. The 
30 seconds it takes to pre-heat the tobacco stick holder will not be taken into account. The 
subject must not take a puff of the tobacco stick during the pre-heating time. 
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. 

 
 
 
 
 
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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 NNS arm will spray once into each nostril (leading to an estimated 
total administered amount of 1 mg nicotine), as shown: 
 
Sequence 1 
Sequence 2 
Sequence 3 
Sequence 4 
Day 1 
THS 2.2 
Menthol 
mCC 
THS 2.2 
Menthol 
NNS 
Day 3 
mCC 
THS 2.2 
Menthol 
NNS 
THS 2.2 
Menthol 
 
6.3.3 
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.  
6.3.4 
Safety Period 
During the safety follow-up period, subjects are free to smoke according to their usual 
smoking habits. 
6.3.5 
Stopping Rules for Investigational Product 
For safety purposes, using the THS 2.2 Menthol or smoking the mCC or the use of the NNS 
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. 
6.4 
Method for Assigning Subjects to Study Arms 
Randomization to product exposure sequence will be done through an Interactive Telephone 
and Web Response System. 

 
 
 
 
 
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Each sex and each of the smoking level (ISO nicotine levels ≤1 mg and >1 mg) will have a 
quota applied to ensure they represent at least 40% of the total study population allocated 
within each of the two 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, and study subjects will have access to the randomization schema 
prior to randomization. 
6.5 
Blinding 
This is an open-label study; therefore the subjects and investigators or designee 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: 
Blinded Study Personnel 
End of Blinding Period 
PMI and CRO study 
statisticians 
After the 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. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
(*) As part of the PMI Quality Control 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. 
6.6 
Investigational Product Accountability and Compliance 
6.6.1 
Dispensing Investigational Product 
From Day -1 until Day 4, the THS 2.2 Menthol, NNS, and mCC will be dispensed by the 
Investigators or dedicated study staff, as per study design. Each dispense of the product will 
be recorded. In addition, the start times of using any product must be recorded for Day 1 and 
Day 3. The product will not be promoted for commercial distribution or test market. 
6.6.2 
Storage and Accountability 
The THS 2.2 Menthol, NNS, 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 staff. Subjects will return each butt of any used 
Menthol Tobacco Stick or mCC immediately after use to the site staff for accountability. 
They will also return the NNS after use to the site staff. The time of return of the products 
will be documented in appropriate log. At the end of the study, unused mCCs given to the 
site staff at Admission on Day -1 will be given back to the subjects. 
6.6.3 
Investigational Product Retention 
Unused Menthol Tobacco Sticks and NNS will be destroyed or returned to the Sponsor upon 
study completion. The Tobacco Heating Devices will be returned to the Sponsor as well. 
6.6.4 
Compliance to Investigational Products 
Compliance for all arms will be ensured by strict distribution of the products (product by 
product) and collection of used Tobacco Sticks, the CC butts and the NNS after use will be 
documented in appropriate logs.  
In addition, in subjects using NNS, 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 (Beal, 1989). 
Furthermore, the CO breath test will be considered as one of the measures of compliance 
during the wash-out days in all subjects.  

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
6.7 
Restrictions 
6.7.1 
Smoking Restrictions 
On Day 1 and Day 3, to avoid nicotine cross contamination, smokers of THS 2.2 Menthol 
and mCC will smoke in dedicated separate rooms: one room for THS 2.2 Menthol and one 
room for mCC. Every subject must smoke alone with an interval between subjects allowing 
ventilation of the room. Subjects receiving NNS 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 6:00 AM to 11:00 PM as 
detailed in the study design. Subjects will not have free access to their NNS, mCC or, 
Menthol Tobacco Sticks which will be dispensed by the site staff individually as described in 
Section 6.6.1.  
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 CC and THS 2.2 arms), no NNS or 
other products supportive to smoking abstinence must be used or will be provided to the 
subjects. 
6.7.2 
Dietary Restrictions 
A standard diet will be designed by a dietician for the whole confinement period. For each 
meal, the caloric and fat content should be controlled in order to avoid a “high-fat” diet. The 
FDA guidance on food-effect studies for bioequivalency testing identifies a “high-fat” diet as 
a diet which contains “approximately 50 percent of total caloric content of the meal [from 
fat] and is high in calories (approximately 800 to 1000 calories) (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 
snacks, fruits, and raw vegetables can be distributed to the subjects without restrictions at any 
time during confinement as long as they comply with the dietician’s standard diet. 
Consumption of water is allowed as desired. Consumption of quinine-containing drinks (e.g., 
tonic water) is not allowed. The same menu and meal schedule will be administered 
uniformly for all subjects in all study arms. Fasting state has to be observed for at least 10 
hours prior to blood drawings for the safety laboratory on the Screening Visit, on Day -1 and 
Day 4.  

 
 
 
 
 
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6.7.3 
Concomitant Medication 
For the purpose of this study, no concomitant medication should be taken from screening to 
the EOS (time of discharge plus 7 day safety period) by the subjects without prior informing 
the Investigator or designee. 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.  
In this study, it is NOT allowed to use hormonal contraception containing estrogens. This 
also applies to hormone replacement therapy. Hormonal contraception with products 
containing progesterone only is allowed during this study. Subjects using estrogens during 
the study will be withdrawn.  
The following drugs and substances are considered having an impact on CYP2A6 activity 
(Lacy et al., 2007: Table 2). 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, 
duloxetine, amitriptyline, imipramine, sertraline, 
mirtazapine, citalopram, thioridazine 
Antidepressant 
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, propanolol, lidocaine 
Antiarrhythmic   
Losartan, amlodipine, nifedipine, losartan 
Antihypertensive 

 
 
 
 
 
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Drug name 
Substance Class 
Drosperinone, estrogens 
Hormonal contraceptives,  
Agents for hormonal replacement 
therapy (estrogens) 
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 
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 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 

 
 
 
 
 
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Investigator to assess if a termination of such medication at Screening is medically justified 
and safe for the subject. 
6.7.4 
Other 
From admission to discharge, practice of intensive exercise and physical work-out will be 
prohibited as it may impact the nicotine absorption profile. 

 
 
 
 
 
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7 STUDY PROCEDURES 
Personnel performing study measurements or recording must have the appropriate training 
fully documented. Quality and control 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 personnel will adhere to 
the site’s Standard Operating Procedures (SOPs) for all activities relevant to the quality of 
the study. Appropriate medical advice will be provided to the subject in case of any medical 
findings requiring health care. 
7.1 
Informed Consent Form/Subject Information Sheet 
Each subject must give his/her informed consent prior to participating in the study. During 
the consent process, the Investigator obtaining consent must inform each subject of the 
nature, risks and benefits of, and alternatives to study participation. In addition, each subject 
must review the Subject Information Sheet and ICF/subject information sheet and must have 
sufficient time to understand and have adequate opportunity to ask questions. The 
ICF/subject information sheet must be signed and dated prior to undertaking any study-
specific procedures. A signed copy of the ICF/subject information sheet should be given to 
the subject. 
7.2 
Smoking Cessation Advice and Debriefing 
Each subject will be given advice on the risks of smoking, with smoking cessation advice, 
three times during the study: at the Screening Visit, at Admission (Day -1), and at Day of 
Discharge (Day 4). This will take the form of a brief interview according to current US 
recommendations (U.S. Public Health Service, 2008). 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 or designee 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 than 
CC. 
 

 
 
 
 
 
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7.3 
Support during Smoking Abstinence/Periods of Reduced Smoking 
All subjects will be closely monitored by the site staff. 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. 
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 in laboratory values, 
vital signs, and ECGs, detected during the Screening Visit. Any untoward medical 
occurrence in a subject detected during the study which was not present at the Screening 
Visit must be documented as an AE. Worsening of a pre-existing condition from the 
Screening Visit onwards will also be documented as an AE. If a clinically relevant finding is 
detected during the Screening period, the Investigator needs to check if inclusion criterion 
number 3 is still fulfilled.  
7.4.1 
Demographic Data 
Demographic data (sex, date of birth/age, and race) will be recorded at the Screening Visit. 
7.4.2 
Identification of the Current Cigarette Brand 
Identification of the current mCC brand smoked by the subject will be done at the Screening 
Visit and at Day -1. For the Screening Visit, subjects will be asked to bring a packet of their 
current mCC brand to the site. At Day -1, subjects have to hand their mCC supply for the 
confinement period to the site staff, who will take a photograph of the front and of the side of 
a cigarette pack supplied by the subject and will document brand name and yields. Photos 
will be considered as Source Documentation. A copy of the photos will be provided to the 
Sponsor electronically as DVD or CD.  
7.4.3 
Smoking History and Willingness to Quit Smoking 
Subjects will be questioned for their smoking history. At Screening and day of Admission, 
this will include questions to evaluate whether the subject was a smoker for at least the last 
three consecutive years, to determine the number of mCC smoked during the previous 4 
weeks, and to evaluate if the CCs smoked during the previous 4 weeks were menthol. Yields 
will later be ascertained, based on the cigarette brands. At the Screening Visit only, the 
subject will also be asked if he/she is planning to quit smoking during the next 3 months. In 
addition, the subject will be asked if he/she has used nicotine-containing products other than 
commercially available mCC (either tobacco-based products or NRT), electronic cigarettes, 
or similar devices, within 4 weeks prior to assessment. 

 
 
 
 
 
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Furthermore, subjects will be asked if they are ready to abstain from smoking/accept reduced 
smoking frequency for up to 4 days. Only subjects prepared and able to comply with this 
requirement will be considered for participation in the study. 
7.4.4 
Demonstration and Product Tests of THS 2.2 Menthol and NNS 
All subjects will have a demonstration of the THS 2.2 Menthol and the NNS products at the 
Screening Visit. On Day -1 as the last procedure of the eligibility assessments on that day, 
subjects will have a product test prior to enrolment, THS 2.2 Menthol (using up to three 
Menthol Tobacco Sticks) first and subsequently NNS (spraying once in each nostril). In 
female subjects, the THS 2.2 Menthol and NNS product tests must only be done after 
pregnancy is excluded by a negative urine pregnancy test. Only subjects willing and ready to 
use the THS 2.2 Menthol and the NNS and be randomized to any of the study arms 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. 
Priormedication taken within 4 weeks prior to Screening 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 should include the drug name (preferably both generic and trade name), route of 
administration (e.g., oral, intravenous), total daily dose/unit (expressed in metric units, for 
example, mg, mL, or IU), indication, and the start and, if applicable, the stop date (day, 
month, and year). Therapy changes (including changes of regimen) during the study are to be 
documented. If a concomitant medication is still being taken by the subject at the end of the 
study, this 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).  

 
 
 
 
 
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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 
be calculated from the body weight and height using the following formula, rounded to the 
first 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 has to 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. Spirometry with bronchodilator at screening  be used for eligibility 
Furthermore, spirometry without a bronchodilator will be performed on Day-1 as well as on 
Day 4.  
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 
(American Thoracic Society (ATS), 2005). Spirometry predicted values will be standardized 
to the National Health and Nutrition Examination Survey III predicted set (Hu and Cassano 
(NHANES III), 2000). 
All personnel performing lung function testing should have the appropriate training and 
quality control measures should be put into place and be properly documented and filed at 

 
 
 
 
 
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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 MVV 
measurement. 
For spirometry, assessed parameters will include: 
• FEV1. 
• FVC. 
• 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 eCRF for all ECGs assessed as 
abnormal – clinically relevant. ECG print-outs will be interpreted by a qualified physician. 
Any print-outs of ECGs on thermo-sensitive paper must be photocopied, initialed, dated, and 
stapled together for inclusion in the Source Data File. 
7.4.9.3 
Chest X-ray 
A chest X-ray (anterior-posterior and left lateral views) will be assessed during the Screening 
period to exclude subjects with relevant pulmonary diseases. Subjects will be referred to a 
radiology facility 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 
Reports. A list of laboratories is provided in Appendix 2. 

 
 
 
 
 
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The start time of the use of each product has to be documented on single use days (Day 1 and 
Day 3). 
Precautions should be taken during blood sampling and processing to prevent the 
contamination of samples with environmental nicotine or CO. 
7.5.1 
Biomarker of Exposure  
7.5.1.1 
Biomarkers of Exposure to CO and COHb 
COHb measured in blood and exhaled CO will be investigated as a measure of exposure to 
CO. The CO breath test will also serve as a measure of compliance in subjects using NNS 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 performed in all subjects including the subjects 
using the NNS.  
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 
tests will be conducted as described in section 9. On the wash-out days (Day 0 and Day 2), 
four 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 five blood samples will be taken. The first sample will be taken within 15 minutes 
prior to using the first product (T0). Thereafter the sampling times in relation to T0 are at 
15 minutes, 60 minutes, 4 hours, and 12 hours post-T0. 
7.5.1.2 
Biomarkers of Exposure to Nicotine 
Blood samples to measure nicotine in plasma will be taken as follows: 
Single Use Day 1 and Day 3: 
A total of 16 blood samples will be taken for a 24-hour profile. The first blood sample will be 
taken within 15 minutes prior to the single use (Day 1 and Day 3, T0). Times of sampling are 

 
 
 
 
 
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thereafter in relation to T0: T1 after 2 minutes, T2 after 4 minutes, T3 after 6 minutes, T4 after 
8 minutes, T5 after 10 minutes, T6 after 15 minutes, T7 after 30 minutes, T8 after 45 minutes, 
T9 after 60 minutes, T10 after 2 hours, T11 after 4 hours, T12 after 6 hours, T13 after 9 hours, 
T14 after 12 hours, and T15 after 24 hours (this sample will be drawn during the day following 
product use, i.e., wash-out). 
In these 16 blood samples, cotinine will be measured together with nicotine at all 
corresponding timepoints. However, only the data from the three following time points: prior 
T0, T0 + 12 hours (T14), T0 + 24 hours (T15) will be used for analysis.  This is to avoid additional 
blood sampling for the subject as nicotine and cotinine are measured in the same assay. 
7.5.2 
CYP2A6 Activity 
CYP2A6 activity will be measured in plasma on Day -1 (Jacob et al., 2011). CYP2A6 
activity drives the metabolism of nicotine to cotinine and subsequent metabolites. In this 
study the CYP2A6 activity will be measured using the metabolic molar ratio of 
trans-3’-hydroxycotinine/cotinine.  
7.6 
Laboratory Assessments 
A list of laboratories is provided in 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 6.7.2). The urine test will be performed semi-quantitatively as urine 
dip-stick 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 (WBC) 
count 
- Differential WBC count:  
 Neutrophils 
 Basophils  
 Eosinophils  
 Lymphocytes 
 Monocytes 
 
 
- Albumin 
- Total protein 
- Alkaline phosphatase 
- Alanine aminotransferase  
- Aspartate aminotransferase  
- Blood urea nitrogen 
- Creatinine 
- Gamma-glutamyl 
transferase  
- Fasting glucose 
- Lactate dehydrogenase  
- Potassium  
- Sodium 
- Total bilirubin 
- Direct bilirubin 
- Total cholesterol 
- Triglycerides 
 
- pH 
- Bilirubin 
- Glucose 
- Nitrite 
- Red blood cell traces 
- Protein 
- Specific gravity 
 
 
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.  

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
7.6.4 
Urine Cotinine Screening 
A urine dip-stick 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, (i.e., One-Step Cotinine Test 008A086, Ultimed, Belgium). 
7.6.5 
Alcohol Breath Test 
Subjects will undertake a breath alcohol test at the Screening Visit and at Admission to the 
clinic using an alcometer device. 
7.6.6 
Urine Pregnancy Testing 
All female subjects will have 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. 
7.7 
Sample Handling, Storage, and Shipment 
Participating laboratories for blood samples testing will be decided prior to the Investigator 
Meeting and site initiation. Safety laboratory samples will be tested at a local laboratory (see 
(see Appendix 2). The urine dipstick for the safety laboratory, urine drug screen, urine 
pregnancy tests, and urine cotinine tests will be done by the site personnel 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 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. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
7.7.1 
Blood samples  
Blood samples will be drawn by qualified and trained site personnel. Subjects should be in a 
seated position during blood collection. In total, around 190 mL will be drawn for this study 
including planned assessments, safety, and repeated analysis for safety. This is less than a 
standard blood draw. The required aliquots and volumes for assessments of blood/plasma 
parameters and tests are summarized in the SHM.  
7.7.2 
Urine samples 
Spot urine samples will be taken for urine drug screen, cotinine screen, pregnancy tests, and 
safety urinalysis. 
7.8 
Questionnaires 
The subject questionnaires and the VAS will be entered by the subject directly in the 
electronic patient reported outcomes device or in paper copy. The questionnaires and the 
VAS will be reviewed for completeness by the study site staff 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 staff using, open, non-directive questions (see Section 
8.2.1).  
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 six questions which have to be answered by the subject 
himself/herself. The scores obtained on the test permit the classification of nicotine 
dependence into three levels: Mild (0 to 3 points); Moderate (4 to 6 points); Severe (7-10 
points) (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 

 
 
 
 
 
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asked to complete a VAS, three Likert scales, and an open question also assessing the 
previous 24 hours.  
The VAS will assess how bothersome cough is to the subject ranging from ‘not bothering me 
at all’ to ‘extremely bothersome.’  
Furthermore, subjects will be asked to assess the intensity and frequency of cough and the 
amount of sputum production on Likert scales:  
• The intensity of cough will be assessed on a 5-point Likert scale ranging 
from 1 to 5, with 1 = very mild – 2 = mild – 3 = moderate – 4 = severe – 5 = 
very severe 
• The frequency of cough will be assessed on a 5-point Likert scale ranging 
from 1 to 5, with 1 = rarely – 2 = sometimes – 3 = fairly often – 4 = often – 
5 = almost always 
• The amount of sputum production will be assessed on a 4-point Likert scale 
ranging from 0 to 3, with 0 = no sputum – 1 = a moderate amount of sputum 
– 2 = a larger amount of sputum – 3 = a very large amount of sputum 
 
Finally, subjects will be asked with an open question if there are any other important 
observations that they would like to share with the 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). 

 
 
 
 
 
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This questionnaire will only be completed by the subjects, who use the THS 2.2 Menthol or 
smoke mCCs during the study. The MCEQ will be completed by subjects on Day 1 and 
Day 3.  
7.8.4 
Questionnaire of Smoking Urges  
To assess the urge-to-smoke, all subjects will be asked to complete a 10-item brief version of 
the QSU (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 (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 in all 
subjects. 
The first assessment will be done 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. 
 
7.8.5 
Socio-Economic Status Questionnaire 
As part of the characterization of the study population it is important to measure variables that have 
been shown to be related to nicotine dependence and product reinforcing value. Based on prior 
tobacco research these factors include age, gender, ethnicity, tobacco use history, educational as well 
as socio-economic status. 
Socio-economic status (SES) information is recorded in similar manner in the clinical program, in 
behavioral research and will be eventually assessed in postmarked studies once the product is 
commercialized. In order to predict and evaluate the effect of alternative, potentially less 
harmful  tobacco product use might have in adult smokers the socio-economic status constitutes an 
important demographic  characteristic. SES data will be reported cross the randomized clinical studies 
and will be collected in observational pre-market and post-market studies. This questionnaire will 
allow the Sponsor to assign the subject household’s SES 
At screening the subjects will be informed in detail about the exams and evaluations planned 
during the study, and similarly notified about the SES assessment which will be done on Day 
2 once they provided informed consent and were enrolled into the study. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
On Day 2, subjects will be asked a series of questions related to their education, occupational 
status, size and annual income of their household. These data will be used to create a measure 
for SES that categorizes subjects into low, moderate and high SES (King et al., 2011). The 
method used to create SES tertiles will be described in the SAP. 
 
 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
8 ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
The FDA MRTP guidelines specify the following definition for adverse events 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.  
 
 
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/subject 
information sheet will not be recorded as SAEs, however they will be recorded as AEs only. 
Any AE that occurs during this pre-planned hospitalization will be considered according to 
the above definitions. 
8.2 
Assessment of Adverse Events 
The Investigator is responsible for obtaining, assessing, and documenting all AEs during the 
study.  

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
8.2.1 
Collection of Information 
Adverse event information will be collected from the time of signature of the ICF onwards 
until the End-of-Study Visit (EOS) either by the Investigator via spontaneous reporting or by 
the use of consistent, open, non-directive questions from study site staff (e.g., “Have you had 
any health problems since the previous visit/How have you been 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 face-to-face interview(s) with the subject. 
Information recorded will include: verbatim description of the AE, start and stop dates and 
times, seriousness, severity (intensity), action taken (e.g., whether or not the AE led to the 
subject’s withdrawal from the study), and outcome (e.g., resolved, withdrawal due to AE). 
For each AE, the intensity will be graded on a 3-point intensity scale (mild, moderate, severe) 
using the definitions provided in Section 8.2.3. 
Any exacerbation/worsening or increased frequency of an AE or pre-existing condition shall 
be evaluated and recorded. 
Correct medical terminology/concepts are preferred when recording AE terms, and 
abbreviations must be avoided. Wherever possible, a diagnosis is to be used to describe an 
AE rather than individual signs and symptoms (e.g., record ‘pneumonia’ rather than ‘fever,’ 
‘cough,’ ‘pulmonary infiltrate,’ or ‘septicemia,’ 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 8.3). 
 
8.2.2 
Period of Collection 
From the signature of the ICF onwards until EOS, all AEs (includes SAEs) will be collected 
by the study site staff as described below.  
8.2.2.1 Screening Period  
All existing health conditions identified during the Screening period will be recorded as 
concomitant disease and the subject’s eligibility for admission to the study will be reviewed. 
Any AEs which occur during the screening period will be captured by the study site staff and 
assessed by the PI in order to establish relationship or relatedness in respect to study 
procedures. Only the study procedures-related AEs will be reported in the clinical study 
report and in accordance with respective regulatory guidelines. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
8.2.2.2 Admission Day until End of Study 
From Admission onwards until Day of Discharge, all AEs will be actively collected by the 
study site staff.  
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. SAEs 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 or its delegate 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 daily activity. 
Moderate: 
The AE interferes with daily activity, but the subject is still able to function. 
Severe:  
 
The AE is incapacitating and requires medical intervention. 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures 
According to the CIOMS VI Working Group, there are no definitive methods for 
distinguishing most adverse reactions (i.e., events that are causally attributed to the IP) from 
clinical AEs that occur as background findings in the population and have only temporal 
association with the IP and reference point product.  
In general, all AEs and/or SAEs will be assessed by the Investigator as either ‘related’ or ‘not 
related’ to IP or reference point product as described below. In addition to the assessment of 

 
 
 
 
 
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the relationship of the clinical event to the IP, the Investigator shall document a potential 
relationship of the clinical event to any particular study procedure. 
Not related: The temporal relationship of the clinical event to IP or reference point product 
administration makes a causal relationship unlikely, or concomitant 
medication, therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event. 
Related: 
The temporal relationship of the clinical event to study IP or reference point 
product  administration makes a causal relationship possible, and concomitant 
medication, therapeutic interventions, or underlying conditions do not provide 
a sufficient explanation for the observed event. 
8.2.5 
Expectedness 
An AE will be regarded as ‘unexpected’ if its nature or severity is not consistent with 
information already known about the IP or reference point 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. 
NNS-related AEs listed on the provided product label are included in Appendix 4.  
8.3 
Reporting and Follow-Up of Serious Adverse Events 
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 
Investigator or other study site staff within 24 hours after first awareness by any party 
involved in the study to 
 and to the Sponsor. 
An SAE report form must be faxed or e-mailed as an attachment to: 
 
Fax number: 
 
Phone number: 
 
E-mail: 
 
 
Address: 
 
 
 

 
 
 
 
 
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Switzerland 
Sponsor: 
Contact: 
, 
MD, Medical Safety 
Officer 
Phone number: 
Mobile: 
+41 
 
+41 
 
E-mail: 
@pmi.com 
 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube T3551 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
The Investigator is responsible for local reporting (e.g., to the IRB) of SAEs that occur 
during the study, according to local regulations. 
Any SAE will be reported to the CTP’s Office of Science within 15 business days after the 
report is received by the Sponsor. 
Any additional/follow-up information that becomes available after the initial SAE report 
form has been completed will be forwarded to 
 and the Sponsor within 24 hours 
after first awareness by any person at the site using a follow-up to the existing SAE report 
form. 
The follow-up SAE report form must include the minimum information required for form 
completion and only changed/new information needs to be specified. Information provided in 
the follow-up SAE report form supersedes any information that was initially reported. 
All SAEs will be followed up by the Investigator or designee and/or 
 until 
resolution or until the Investigator considers the event to be stabilized (i.e., no worsening of 
the condition), or an acceptable explanation has been found (e.g., a chronic condition). 
The SAE report form to be used in this study is provided as a separate document. 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 

 
 
 
 
 
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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: 
 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. 
8.5 
Reporting and Follow–Up of Pregnancies 
Pregnancies detected during the Screening Period and prior to first THS 2.2 Menthol  use, the 
subject will be considered as a screen failure and removed from the study. No Pregnancy 
Form will be filled, however the diagnosed pregnancy must be captured in the Screen Failure 
eCRF.  

 
 
 
 
 
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All pregnancies occurring after signature of the ICF/subject information sheet 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 end of study, must be reported by the 
Investigator and followed-up. Potential association with exposure to the IP is defined as the 
conception date being calculated to have been before the date of 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 complication, adverse pregnancy outcome, or 
maternal complications will be recorded. 
The Investigator is responsible for informing the IRB of any pregnancy that occurs during the 
study and its outcome, according to local regulations. 
8.6 
Adverse Events Leading to Withdrawal 
Subjects who are withdrawn from the study because of an AE will undergo the EOS 
procedures, as described for the day of Discharge, as soon as possible and will enter the 
period of safety follow-up. The Investigator and/or 
 will follow up these AEs until they 
have resolved, stabilized (i.e., no worsening of condition), or an acceptable explanation has 
been found. 
8.7 
Investigational Device Misuse 
Any occurrences of the THS Tobacco Stick Holder or Charger misuse (use not in accordance 
with its label and instruction) by a subject, will be documented by the Investigator or his/her 
designated staff using a Device Issue Log.  
Investigational device misuse may result in use-related hazards. 

 
 
 
 
 
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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 or designee. 
According to FDA Medical Device Regulation, data should be collected regarding the 
use-related hazards that have occurred with the 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 Charger that lead to an 
AE/SAE will follow the same processes as described above 
The process of capturing, assessing, and reporting is described in details in the Safety 
Management Plan. 
8.8 
Investigational Device Malfunction  
Any occurrences of malfunction of the THS Tobacco Stick Holder or Charger will be 
documented by the Investigator or his/her designated staff using a Device Issue Log. 
Furthermore, any malfunctions of the THS Tobacco Stick Holder or Charger unit that lead to 
an AE/SAE will follow the same processes as described above. 
 
 
 

 
 
 
 
 
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ZRHM-PK-06-US 
Final /22 May 2013 
Page 71 of 119 
 
Confidentiality Statement: Data and information contained in this document are considered to constitute trade secrets and 
confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
9 STUDY ACTIVITIES 
A detailed schedule of assessments can be found in Appendix 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 
Time 
Blood sample 
Procedures 
Additional information 
Start of 
procedure 
 
 
 
 
 
Informed consent  
 
 
 
Advice on the risks of smoking and 
debriefing 
 
 
 
Demographic data 
 
 
 
Smoking history 
 
 
 
Willingness to quit smoking in the next 
3 months 
 
 
 
Readiness to accept interruptions of 
smoking for up to 4 days 
 
 
 
FTND questionnaire 
 
 
 
Prior medication (4 weeks prior to 
screening visit)/concomitant 
medication 
 

 
 
 
 
 
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Clinical Study Protocol 
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Final /22 May 2013 
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confidential 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 International. 
 
 
 
 
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) 
In at least 10 hours of fasting 
 
√ 
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 NNS product 
demonstration 
 
 
 
Spirometry without short-acting 
bronchodilator first, and then with 
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; NNS = Nicotine nasal spray; SAE = Serious adverse event; THS 2.2 Menthol = Tobacco Heating System 2.2 
menthol 
 
 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
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Final /22 May 2013 
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confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
9.2 Admission 
The following assessments will be performed at Admission (Day -1) (Table 5): 
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 
Has to be done prior smoking 
6:30 AM 
 
Beginning of smoking period 
 
 
 
Urine pregnancy test for all female 
subjects 
 
 
√ 
Clinical laboratory parameters 
(hematology, urine analysis, clinical 
chemistry) 
In at least 10 hours of fasting 
 
 
Urine cotinine screening test 
 
 
 
Urine drug screen 
 
Prior to 10:00 AM 
 
Breakfast 
 
Prior to 11:30 AM 
 
Vital signs 
At least 5 min in supine position 
prior to measurement 
Prior to 11:30 AM 
 
Physical examination, weight and 
calculated BMI 
 
Prior to 11:30 AM 
 
Identification of current mCC brand 
 
Prior to 11:30 AM 
 
Smoking history 
 
Prior to 11:30 AM 
 
Alcohol breath test 
 
Prior to 11:30 AM 
 
CO breath test 
 
Prior to 2:30 PM 
 
Lunch 
 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
afternoon 
 
Snacks 
 
4:30 PM-6:00 PM 
 
Product test for THS 2.2 Menthol 
and NNS 
The THS 2.2 Menthol test should 
be done first and then the NNS 
test 
4:30 PM-6:00 PM 
 
Inclusion/exclusion criteria 
 
4:30 PM-6:00 PM 
 
Enrolment 
 
In the evening prior to 
9:00 PM 
 
Dinner 
 
11:00 PM 
 
End of smoking period 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; CC = conventional cigarette(s); CO = Carbon monoxide; 
CYP2A6 = Cytochrome P450 2A6; NNS = Nicotine nasal spray; SAE = Serious adverse event; THS = Tobacco Heating 
System 
9.3 Investigational Period 
9.3.1 
Days of Smoking Abstinence (Day 0 and Day 2) 
On the days of smoking abstinence (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 
 

 
 
 
 
 
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4:00 PM-5:30 PM 
 
CO breath test 
 
Afternoon  
 
Snacks 
 
In the evening prior to 
9:00 PM 
 
Dinner 
 
8:00 PM-9:30 PM 
 
CO breath test 
 
Abbreviations: AE = Adverse event; CO = Carbon monoxide; SAE = Serious adverse event. 

 
 
 
 
 
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Clinical Study Protocol 
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confidential 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 International. 
 
 
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 
 
 
Socio-economic status 
At any time of the day  
The questionnaire will be 
administered by a trained 
interviewer 
 
√ 
Plasma nicotine PK sample 
24 hrs after T0 of Day 1 +5 min 
 
 
Assessment of cough 
24 hrs after T0 of Day 1 minus 5 
min 
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 
 
In the evening prior to 
9:00 PM 
 
Dinner 
 
8:00 PM-9:30 PM 
 
CO breath test 
 
Abbreviations: AE = Adverse event; CO = Carbon monoxide; PK = Pharmacokinetic; SAE = Serious adverse event; T = 
Time point. 

 
 
 
 
 
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Clinical Study Protocol 
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without the written consent of Philip Morris International. 
 
 
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): 
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 
 
 
Support for smoking abstinence 
as required  
All day 
 
 
Craving questionnaire 
(QSU-brief) 
In all subjects: First assessment 
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. 
 
√ 
Plasma nicotine sample 
First sample within 15 min prior to 
T0, 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) 
Cotinine in addition to nicotine will 
be measured in plasma in all time 
points but only the data for the three 
following time points: prior T0, T0 + 12 
hours (T14), T0 + 24 hours (T15) will be used 
for analysis. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
 
√ 
COHb blood sampling 
Five blood samples to be taken, first 
sample within 15 min prior to T0, then 
after 15 min +2 min, 60 min +3 min, 
4 hrs +5 min, 12 hrs +5 min 
 
 
CO breath test 
First test to be done within 15 min 
prior to T0 
 
 
Assessment of cough 
Has to be done prior to product use 
6:00 AM-9:00 AM 
 
Start of single product use 
 
Prior to 10:00 AM 
 
Breakfast 
 
10:00 AM-11:30 AM 
 
Vital signs 
At least 5 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 CC butts 
and NNS 
After the product use 
Abbreviations: AE = Adverse event; CC = conventional cigarette(s); CO = Carbon monoxide; 
COHb = Carboxyhemoglobin; ECG = Electrocardiogram; MCEQ = Modified Cigarette Evaluation Questionnaire; NNS = 
nicotine nasal spray; QSU-brief = Questionnaire of Smoking Urges; SAE = Serious adverse event; T = Time point  
 
 
 

 
 
 
 
 
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Clinical Study Protocol 
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Confidentiality Statement: Data and information contained in this document are considered to constitute trade secrets and 
confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
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): 
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 since T0 of Day 3 
+5 min 
 
 
Assessment of cough 
24 hrs since T0 of Day 3 
+5 min 
 
√ 
Clinical laboratory parameters 
(hematology, urine analysis, clinical 
chemistry) 
At to be done in at least 10 
hours of fasting 
 
 
Spirometry  
Has to be done prior to 
smoking 
Prior to 10:00 AM 
 
Breakfast 
 
Prior to discharge 
 
Urine pregnancy test for all female 
subjects 
 
Prior to discharge 
 
Vital signs 
At least 5 min in supine 
position prior to 
measurement 
Prior to discharge 
 
CO breath test 
Irrespective of smoking 
Prior to discharge 
 
Physical examination, weight and 
calculated BMI 
 
Prior to discharge 
 
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 
 
9.5 
Safety Follow-up Period 
All subjects participating in the product trial on Day -2 and are not enrolled into the study will enter a 
28-day safety follow-up period.  

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
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 8.2.2. 
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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without the written consent of Philip Morris International. 
 
 
10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 
Monitoring 
A Clinical Research Associate (“Monitor”) from an independent CRO not involved with the 
study site will be responsible for the monitoring of the study. Monitoring will be performed 
according to the study CRO’s SOPs and as per the agreed monitoring plan with the Sponsor. 
The Investigator shall permit the Monitor to review study data as frequently as deemed 
necessary to ensure that data are being recorded in an adequate manner and that protocol 
adherence is satisfactory. 
The Investigator shall access medical records for the Monitor so that entries in the 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 performed and documented. 
Subsequent to the Investigator’s meeting, and before the first subject is screened, the site 
initiation visit will be conducted by the Monitor and, if necessary, with the Sponsor or its 
authorized representative. The purpose of the site initiation visit is detailed in the monitoring 
plan.   
Communication by telephone, mail, and e-mail may be used as needed to supplement site 
visits. The Investigator and study personnel will cooperate with the Monitor, provide all 
appropriate documentation, and will be available to discuss the study. 
The Monitor and the Sponsor’s personnel will be available between visits, should the 
Investigator or other staff at the sites need information and advice. 
Site visits will be made at regular intervals during the study. The frequency of the monitoring 
visits will be defined in the monitoring plan agreed with the Sponsor. 
The Investigator, or a designated member of the Investigator’s staff, must be available during 
the monitoring visit to review the data and resolve any queries, and to allow direct access to 
the subject’s records for source data verification. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
10.2 
Training of Staff 
A formal meeting (Investigator’s meeting) will be conducted prior to site initiation. During 
this meeting, the Sponsor or its authorized representative will discuss the requirements of the 
clinical study protocol and related documents and will also provide training in the relevant 
systems and other study-specific procedures. The activities of the Investigator’s meeting will 
be described in the monitoring plan. 
In addition to the Investigator’s meeting, the Principal Investigator will ensure that 
appropriate training relevant to the study is provided to all staff involved in the study, and 
that any new information relevant to the performance of this study is forwarded to the staff 
involved in a timely manner. The Principal Investigator will maintain a record of all 
individuals involved in the study. 
 
10.3 
Audits and Inspections 
GCP regulations require that there are independent inspections of clinical program activities. 
Such inspections may be performed at any time before, during, and/or after the study. 
Authorized representatives of the Sponsor, regulatory agencies and/or an IEC may perform 
audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, ICH/GCP guidelines, and any 
applicable regulatory requirements. The Investigator will contact the Sponsor or the 
authorized representative immediately, if contacted by a regulatory agency about an 
inspection at their site. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
accurate filing system of all study-related documentation that will be suitable for inspection 
at any time by the Sponsor, its authorized representative, and/or regulatory agencies. In 
signing this protocol, the Investigator understands and agrees to provide access to the 
necessary documentation and files. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
11 DATA MANAGEMENT ACTIVITIES 
All Data Management Activities will be described in detail in the Data Management Plan and 
documents specified therein. 
11.1 
Data Capture 
11.1.1 
Case Report Forms and Study Records 
With the exception of the subject-reported outcome data, all results from the clinical 
assessments will be recorded in the Source Documents by the Investigator or their authorized 
designee(s) and then captured in the eCRFs at the study site. The subject questionnaires and 
the VAS will be entered by the subject directly in the electronic patient-reported outcomes 
device or in a paper copy. Trained study personnel will be responsible for capturing the data 
from the observations, tests and assessments specified in the protocol in the source 
documents and then transferring the data into the eCRF, in accordance with the Case Report 
Form Completion Guidelines. 
The 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 Clinical Research Associate. 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 form. 
11.1.2 
Protocol Deviations 
Protocol deviations are defined as those deviations from any procedure as defined in this 
document, including but not limited to, as any violation of inclusion/exclusion criteria, 
mis-randomizations, use of any nicotine or tobacco-containing product other than the 
assigned product during each of the exposure period, use of any nicotine tobacco-containing 
product during wash-out days, assessments not performed or performed outside the 
scheduled time windows, or use of estrogen or other drugs that are known to affect CYP2A6 
activity.  
All protocol deviations will be entered into the Clinical Trial Management System (CTMS) 
or other approved format. 

 
 
 
 
 
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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. 
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 the CRO will prepare a Data 
Management Plan, to be reviewed and approved by the Sponsor, prior to the start of the 
study. This document will describe, in detail, the procedures and processes related to Data 
Management. 
All data of all subjects successfully enrolled, as well as subjects who failed screening, and/or 
experienced an AE during the study (from time of signing the informed consent form to the 
end of the safety follow-up period), will be captured and stored in the study database. 
All data collected during the study is property of the Sponsor, irrespective of the location of 
the database and the Data Management CRO. 
11.2.1 
Data Validation 
The data will be validated as defined in the Data Management Plan and Data Validation 
Specifications. Discrepancy lists will be generated electronically, as necessary. 
Data queries will be raised for discrepant or missing data. All changes to data will be 
captured in the database with a comprehensive audit trail. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
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 
THS 2.2 device 
issues and/or 
malfunctions: 
C54451/Medical_Device_Problem_Codes_FDA_CDRH (FDA, 2012b) 
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 data review by the Sponsor, resolution of all raised queries and QC of the changed data, 
the database or selected data thereof will be declared locked upon Sponsor approval, as 
applicable. 
Any changes to the database after that time can only be made by written agreement between 
the Sponsor and the Data Management and Statistical Team at the CRO. Any of those 
changes must be documented in the database log file. 
After study completion, the study database will be transferred to the Sponsor in the format 
specified in the Data Management Plan in the Clinical Data Interchange Standards 
Consortium Study Data Tabulation Model Data Structure Specifications. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
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 NNS) to allow comparisons 
between THS 2.2 Menthol and mCC in Group-1, and between THS 2.2 Menthol and NNS in 
Group-2. 
Full details of the statistical analysis will be given in a SAP. Any changes to the planned 
statistical methods will be documented in the CSR. The statistical evaluation will be 
performed using SAS®, version 9.2 or later. 
12.1.1 
Stratification Criteria 
For analysis, the following stratification criteria will be used:  
• 
Sex (male and female). 
• 
mCC nicotine level at Admission (ISO nicotine levels ≤ 1 mg or >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 percent 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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without the written consent of Philip Morris International. 
 
 
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 lower 
limit of quantification. For values above the upper limit of quantification (ULOQ), i.e., 
preceded by a “>”, for example “>xx,” the numerical xx will be used for calculation and 
reporting in summary tables. The number 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% 
confidence intervals.  
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 is calculated by adding up sample sizes 
separately estimated for each analysis. 
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% confidence 
interval) of at most ±20%, assuming that THS 2.2 Menthol have a nicotine PK profile similar 
to mCC (Cmax ratio equal to 1.00) and a 10% dropout rate. 
A total of 18 subjects are needed to estimate the mean Cmax parameter ratio between THS 2.2 
Menthol and NNS with a precision allowing for the lower bound of the 95% confidence 
interval exceeding 1.00, with 90% power and assuming a 10% dropout rate. The anticipated 
geometrical Cmax ratio between THS 2.2 Menthol and NNS is 1.55, based on data reported by 
Gourlay and Benowitz, 1997, and Johansson et al., 1991. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
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 (non-menthol) and CC. In the absence of data comparing THS Menthol and NNS, the 
same CVs were assumed for the calculation of the sample size related to the THS 2.2 
Menthol:NNS comparison. 
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 confidence interval of ± 
20%. 
 
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 NNS 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). 
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. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
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 exposure group as fixed effect factors. The results of this analysis for 
each of AUC(0-last) and Cmax are presented in terms of adjusted geometric least square means 
and 95% confidence intervals for the THS 2.2 Menthol:mCC and THS 2.2 Menthol:NNS 
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 
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 

 
 
 
 
 
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estimated by means of the percentile bootstrap technique, which uses 2000 bootstrap samples 
to 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 to maximum concentration. tmax will be reported as long as there 
is at least one quantifiable concentration post-exposure 
AUC(0-t’) 
Area under the plasma concentration-time curve from start of product 
use to the subject-specific time of maximum nicotine concentration 
following singe use of mCC or NNS (linear trapezoidal method) 
AUC(0-∞) Area under the concentration-time curve from start of product use 
extrapolated to time of last quantifiable concentration to infinity, 
according to: 
 
Where Clast is the last quantifiable concentration and λz is the terminal 
elimination rate constant 
λz 
Terminal elimination rate constant, estimated by linear regression 
analysis of the natural log-transformed concentration-time data 
t1/2 
Half-life (terminal elimination), derived as ln(2)/λz 
More details on PK parameter derivations will be provided in the SAP. 
Subjective effects of using THS 2.2 Menthol as compared to the mCC and to the NNS will be 
evaluated by analyzing domain scores of QSU-brief and MCEQ. Full details of questionnaire 
domain scores derivation will be provided in the SAP. 
 










z
C
AUC
AUC
last
last

0
-
0

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
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 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. 
• Cotinine levels will be summarized by means of descriptive statistics reported by 
exposure. 
 
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 NNS the following hypothesis will be evaluated: 

 
 
 
 
 
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H0: XTHS - XNNS = 0 
HA: XTHS - XNNS < 0 
where XTHS and XNNS are the median values of the THS 2.2 Menthol and NNS, 
respectively. tmax will be analyzed on the original scale using the Wilcoxon 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 NNS the following hypothesis will be tested for both Cmax and 
AUC(0-last) parameters: 
H0: XTHS / XNNS = 1.0   HA: XTHS / XNNS > 1.0  
where XTHS and XNNS are the adjusted geometrical means of THS 2.2 Menthol and 
NNS, 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 / XNNS 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. 
Adverse event data will serve as the primary assessment of safety. Other safety variables 
monitored in this study include: respiratory symptoms (cough assessment VAS and Likert 
scales); vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate); 
spirometry; ECG data; clinical chemistry, hematology, and urine analysis safety panel; 
concomitant medication and physical examination. 
The number and percentage subjects with AEs and SAEs will be tabulated by system organ 
class and preferred term. Summaries will also be presented for AEs leading to withdrawal, 
AEs leading to Death, AEs by relatedness to product exposure, AEs by severity, and 
laboratory AEs. Tabulations will be performed for both the number of subjects experiencing 
an event and the number of events. 
The number and percentage of subjects with clinical findings will be tabulated by sequence 
for laboratory parameters. Shift tables showing change from baseline of clinical findings will 
be provided for: ECGs, physical examinations, and laboratory parameters (both shifts in 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
normal ranges and toxicity grades). Descriptive statistics will be summarized by visit and 
change from baseline for laboratory parameters, ECG, respiratory symptoms, and vital signs. 
12.7 
Exploratory Analyses 
There are no planned exploratory analyses. 
12.8 
Interim Analysis 
There are no planned interim analyses. 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
13 ADMINISTRATIVE CONSIDERATIONS 
13.1 
Investigators and Study Administrative Structure 
13.1.1 
Investigator 
Principal Investigator: 
James L. Borders, MD 
 
Central Kentucky Research Associates 
3475 Richmond Road 
Third Floor 
Lexington, KY  40509 
USA 
 
Phone:  
 
 
Fax: 
 
 
E-mail: 
  
Site contacts: 
 
 
 
13.1.2 
Sponsor 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5, 
2000 Neuchâtel, 
Switzerland. 
Tel: +41 (58) 242 2111 
Fax: +41 (58) 242 2811 
, PhD 
Manager Clinical Science 
Phone: +41 
 
Mobile: +41 
 
E-mail: 
@pmi.com 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
, PhD 
Staff Scientist, Statistics 
Phone: +41 
 
Mobile: +41 
 
E-mail: 
@pmi.com 
, MD 
Medical Safety Officer 
Phone: +41 
 
Mobile: +41 
 
E-mail: 
@pmi.com 
 
Medical Writer 
Phone: +41 
  
Mobile: +41 
 
E-mail: 
@pmi.com 
, PhD 
Clinical Study Manager 
Phone: +41 
 
Mobile: +41 
  
E-mail: 
@pmi.com  
 
13.1.3 
Other Responsibilities 
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 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subject in writing and signed by the subject, in compliance with all local 
and national data protection and privacy legislation. 
The anonymity of subjects participating in this study will be maintained. Subjects will be 
identifiable by the Sponsor (or Sponsor’s authorized representative) on 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 an identifiable person (e.g., address, social 
security number, medical chart number, etc.) The assignment of a subject number/code for 
subject identification will be based on the appropriate data protection rules. 
Any documents that allow full identification of the subject (e.g., the subject’s signed study 
information sheet and ICF) must be maintained in confidence by the Investigator. If any 
document relating to this study shows a subject’s name or any other details relating to an 
identifiable person (e.g., address, social security number, medical chart number, etc.), the 
name or other identifiable details must be obscured before a copy of that document is 
supplied to the Sponsor or the Sponsor’s authorized representative. 
13.3 
Access to Source Documentation 
The Investigator and all study site staff involved with the study must permit direct access to 
source data/documents for study related monitoring, audits, IRB review, and regulatory 
inspection(s). 
13.4 
Record Retention 
All records of data, source data, and source documents (original records or certified copies), 
in any form (including, but not limited to, written, electronic, magnetic, optical records and 
scans, X-rays, and ECGs) that describe or record the methods, conduct, and/or results of the 
study, the factors affecting the study, and the actions taken will be maintained by the 
Investigator/study site for the study, as required by ICH GCP and any other applicable local 
or national regulations. 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 a 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 Section 8 of the 
ICH Tripartite Guideline for Good Clinical Practice (ICH Guideline for Good Clinical 
Practice E6 (R1), July 1996). 
Essential documents must be retained by the Investigator for a minimum of: 
 At least 15 years after completion or discontinuation of the study, or 

 
 
 
 
 
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 At least 2 years depending on, for example, the circumstances. 
 After formal discontinuation of clinical development of the IP. 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. 
Examples of essential records/documents include, but are not limited to: 
 Signed informed consent documents for all subjects and Master ICF 
 Subject identification code list, Screening Log (if applicable), and Enrolment Log (if 
applicable) 
 Record of all communications between the Investigator and the IRB, composition of the 
IRB 
 Record of all communications/contact between the Investigator, Sponsor, and its 
authorized representatives 
 List of sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in the 
study, CVs, and their signatures 
 Investigator Logs 
 eCRFs, study specific questionnaires (and associated data/scoring), subject diaries 
 AE reports and details of follow-up investigations, details of concomitant medication 
 All other source documents (e.g., chest X-rays, ECGs, consultation reports, physical 
examination, and laboratory records) or any electronically captured study source data 
 Clinical laboratory reports, laboratory normal ranges 
 Original medical/hospital records, if applicable (the medical files of study subjects must 
be retained in accordance with local legislation and in accordance with the maximum 
period of time permitted by the hospital or study site) 
 Record of any body fluids or tissue samples collected and retained 
 Device issue Log, IP Accountability Logs, dispensing records 

 
 
 
 
 
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 Information regarding subjects’ discontinuation and any follow-up 
It is the responsibility of the Sponsor to inform the Investigator/study site as to when these 
documents no longer need to be retained. 
The Investigator/study site must take measures to prevent accidental or premature destruction 
of these documents. 
If an Investigator wishes to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
The Investigator must obtain written approval from the Sponsor before destruction of any 
records. Normally, these records will be held in the Investigator’s archives. If an Investigator 
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. 
13.6 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor. In 
addition, the Investigators must agree with the Sponsor to commit to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
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 

 
 
 
 
 
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this document is allowed only to study personnel, IRB, or duly authorized representatives of 
regulatory agencies for this purpose under the condition that confidentiality is maintained. 
The contents of this document may not be used in any other clinical study, disclosed to any 
other person or entity without the prior written permission of the Sponsor. The foregoing 
shall not apply to disclosure required by any regulations. 
The Sponsor plans to disclose details of the study protocol on a web-based, publicly 
available, clinical trial register database (e.g., ClinicalTrials.gov). 

 
 
 
 
 
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14 REFERENCE LIST 
American Thoracic Society (ATS), 2005 
Standardization of spirometry. Available from 
http://www.thoracic.org/statements/resources/pfet/PFT2.pdf (accessed 04 Oct 2012). 
Beal, 1989 
Beal SL. Sample Size Determination for Confidence Intervals on the Population Means and 
on the Difference between Two Population Means. 1989; Biometrics, 45, 969–977. 
Benowitz et al., 2002 
SNRT subcommittee on biochemical verification. Biochemical verification of tobacco use 
and cessation. Nicotine Tob Res. 2002;4(2):149-159. 
Benowitz et al., 2006 
Benowitz NL, Lessov-Schlaggar CN, Swan GE, Jacob P 3rd. Female sex and oral 
contraceptive use accelerate nicotine metabolism. Clin Pharmacol Ther. 2006;79(5):480-488. 
Benowitz et al., 2009 
Benowitz NL, Hukkanen J, Jacob P. Nicotine chemistry, metabolism, kinetics and 
biomarkers. Handb Exp Pharmacol. 2009;192:29-60. 
Cappelleri et al., 2007 
Cappelleri JC, Bushmakin AG, Baker CL, Merikle E, Olufade AO, Gilbert DG. 
Confirmatory factor analyses and reliability of the modified cigarette evaluation 
questionnaire. Addict Behav. 2007;32(5):912-923. 

 
 
 
 
 
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confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
Carabello et al, 2011 
Ralph S. Caraballo, David B. Holiday, Steven D. Stellman, Paul D. Mowery, Gary A. Giovino, 
Joshua E. Muscat, Michael P. Eriksen, John T. Bernert, Patricia A. Richter, and Lynn T. Kozlowski 
Comparison of Serum Cotinine Concentration within and across Smokers of Menthol and No 
nmenthol Cigarette. Brands among Non-Hispanic Black and Non-Hispanic White U.S. Adult 
Smokers. Cancer Epidemiol Biomarkers . 201120(7); 1329–40. 
CDC, 2011 
Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report. 
November 
11, 
2011. 
Vol. 
60/No. 
44. 
Available 
at 
http://www.cdc.gov/mmwr/pdf/wk/mm6044.pdf. 
Cox et al., 2001 
Cox LS, Tiffany ST, Christen AG. Evaluation of the brief questionnaire of smoking urges 
(QSU-brief) in laboratory and clinical settings. Nicotine Tob Res. 2001;3(1):7-16. 
Declaration of Helsinki, 2008 
Declaration of Helsinki. World Medical Association. Available from: 
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Final /22 May 2013 
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confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
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confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
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Final /22 May 2013 
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Confidentiality Statement: Data and information contained in this document are considered to constitute trade secrets and 
confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
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confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
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without the written consent of Philip Morris International. 
 
 
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without the written consent of Philip Morris International. 
 
 
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without the written consent of Philip Morris International. 
 
 
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 
● 
 
 
 
 
 
 
 
Advice on the risks of smoking 
and debriefing 
● 
● 
 
 
 
 
● 
 
Inclusion/exclusion criteria 
● 
● 
 
 
 
 
 
 
Enrolment 
 
● 
 
 
 
 
 
 
Randomization 
 
 
● 
 
 
 
 
 
Product use  
 
 
 
● 
 
● 
 
 
Support during periods of 
reduced smoking/smoking 
abstinence (as required) 
 
 
● 
● 
● 
● 
 
 
Product demonstration of THS 
2.2 Menthol and NNS 
● 
 
 
 
 
 
 
 
Product test for THS 2.2 
Menthol and NNS 
 
● 
 
 
 
 
 
 
Identification of current CC 
brand 
● 
● 
 
 
 
 
 
 
Smoking history 
● 
● 
 
 
 
 
 
 
Willingness to quit smoking in 
the next 3 months 
 
 
 
 
 
 
 
 
Readiness to abstain from 
smoking for up to 4 days 
● 
● 
 
 
 
 
 
 
Demographics a, medical 
history, concomitant diseases  
● 
 
 
 
 
 
 
 
Socio-economic questionnaire 
 
 
 
 
● 
 
 
 
Prior medication b / 
Concomitant medication 
● 
● 
● 
● 
● 
● 
● 
● 

 
 
 
 
 
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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 
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 Tobacco 
Sticks and CC  butts 
 
 
 
● 
 
● 
 
 
B: Plasma nicotine f 
 
 
 
● 
● 
● 
● 
 
B: COHb g 
 
 
 
● 
(5x) 
 
● 
(5x) 
 
 
CO breath test h 
 
● 
(1x) 
● 
(4x) 
● 
(4x) 
● 
(4x) 
● 
(4x) 
● 
(1x) 
 
trans-3’-hydroxycotinine and 
cotinine (CYP2A6 activity) in 
plasma  
 
● 
 
 
 
 
 
 
FTND questionnaire 
● 
 
 
 
 
 
 
 
QSU–brief questionnaire i 
 
 
 
● 
 
● 
 
 
MCEQ (modified version, only 
after THS 2.2 and CC use  
 
 
 
● 
 
● 
 
 

 
 
 
 
 
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publicly disclosed without the written consent of Philip Morris International. 
 
 
 
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 
Cough assessment j 
 
 
● 
● 
● 
● 
● 
 
AE/SAE recording  
● 
● 
● 
● 
● 
● 
● 
● 
Abbreviations: AE = Adverse event; BMI = Body mass index; mCC = Menthol conventional cigarette(s); CO = Carbon monoxide; COHb = Carboxyhemoglobin; 
CYP2A6 = Cytochrome P450 2A6; ECG = Electrocardiogram; FTND = Fagerström Test for Nicotine Dependence (revised version); MCEQ = Modified Cigarette Evaluation 
Questionnaire; NNS = Nicotine nasal spray; QSU-brief = Questionnaire of Smoking Urges-brief; SAE = Serious adverse event; THS 2.2 = Tobacco Heating System 2.2. 
 
B : Blood sample required. 
U : Urine sample required.  
 
a: Sex, date of birth/age, race. 
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: 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 minutes, T2 after 4 minutes, T3 after 6 minutes, T4 after 8 minutes, T5 after 10 minutes, T6 after 15 minutes, T7 after 30 minutes, T8 
after 45 minutes, T9 after 60 minutes, T10 after 2 hours, T11 after 4 hours, T12 after 6 hours, T13 after 9 hours, T14 after 12 hours, and T15 after 24 hours.  
Cotinine in addition to nicotine will be measured in plasma in all time points but only the data for the three following time points: prior T0, T0 + 12 hours (T14), T0 
+ 24 hours (T15) will be used for analysis.. 
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 minutes, 60 minutes, 4 
hours, and 12 hours 
h: A CO breath test will be conducted once on Day -1 and Day 4. On Day 1, Day 2, Day 3, and Day 4, the first test per day will be performed within 15 minutes prior to T0 (T0 = start of 
first product use) and the three other test will be conducted as described in section 9. On the wash-out days (Day 0 and Day 2), it will be conducted 8:00 am-09:30 am. The three 
other test will be conducted as described in section 9. 
i: QSU–brief will be assessed as follows: 
Single use: The QSU-brief at single use study days in all subjects.  
The  first assessment  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. 

 
 
 
 
 
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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 terminating the study early and all subjects who have tried the product at admission but are 
not enrolled. 
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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without the written consent of Philip Morris International. 
 
 
 
Appendix 2 
Participating Laboratories 
Participating laboratories for blood samples testing will be decided prior to the Investigator 
Meeting and site initiation. Safety laboratory samples will be tested at a local laboratory. 
 
 

 
 
 
 
 
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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 
Product Label for the NNS Product: Adverse Events 
The NNS product label listing AEs relating to the product can be found at the internet link:    
 http://www.pfizer.com/products/#nicotrol.  
An excerpt of the AE section in the Nicotrol® NS package insert cited above is provided 
below. Full copies are available in each Nicotrol® NS package and upon request. 
 
“Effects of the Spray 
NICOTROL NS and the pepper-containing placebo were both associated with irritant side 
effects on the nasopharyngeal and ocular tissues. During the first 2 days of treatment, nasal 
irritation was reported by nearly all (94%) of the patients, the majority of whom rated it as 
either moderate or severe. Both the frequency and severity of nasal irritation declined with 
continued use of NICOTROL NS but was still experienced by most (81%) of the patients after 
3 weeks of treatment, with most patients rating it as moderate or mild. Other common side-
effects for both active and placebo groups were: runny nose, throat irritation, watering eyes, 
sneezing, and coughing. 
The following local events were reported somewhat more commonly for active than for 
placebo spray: nasal congestion, subjective comments related to the taste or use of the 
dosage form, sinus irritation, transient epistaxis, eye irritation, transient changes in sense of 
smell, pharyngitis, paraethesias of the nose, mouth or head, numbness of the nose, or mouth, 
burning of the nose or eyes, earache, facial flushing, transient changes in sense of taste, 
hoarseness, nasal ulcer or blister. 
Effects of Nicotine 
Feelings of dependence on the spray were reported by more patients on active spray than 
placebo. Drug-like effects such as calming were also more frequent on active spray.” 
 
 

 
 
 
 
 
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without the written consent of Philip Morris International. 
 
 
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 – Hyperkalemia (mmol/L)**(1) 
>ULN - 5.5 
>5.5 - 6.0 
>6.0 - 7.0; 
hospitalization 
indicated 
Potassium – Hypokalemia (mmol/L) ** (1) 
<LLN - 3.0 
<LLN - 3.0; symptomatic; 
intervention indicated 
<3.0 - 2.5; 
hospitalization 
indicated 
Glucose – Hypoglycemia ** (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 – Hyperglycemia: ** 
  
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 – Hypoalbuminemia** (1)(g/dL) 
                                                          (g/l) 
<LLN – 3; 
<LLN - 30 
<3 – 2; 
<30 - 20 
<2; 
<20 
Total Protein – Hypoproteinemia (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 (GGT) 
increased (1) 
>ULN – 2.5 x 
ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
Blood bilirubin increased ** (1) 
>ULN – 1.5 x 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 ULN 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
ZRHM-PK-06-US 
Final /22 May 2013 
Page 117 of 119 
 
Confidentiality Statement: Data and information contained in this document are considered to constitute trade secrets and 
confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
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; BUN = Blood urea nitrogen; GGT = 
Gamma-glutamyl transferase; LLN = Lower limit of the normal range; ULN = Upper limit of the normal range. 
Data Source: (1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.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-06-US 
Final /22 May 2013 
Page 118 of 119 
 
Confidentiality Statement: Data and information contained in this document are considered to constitute trade secrets and 
confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
ABNORMAL LABORATORY VALUES RATING: HEMATOLOGY PARAMETERS 
Hematology* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Hemoglobin (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 
Hemoglobin (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 
Hemoglobin 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. 
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. 
*  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-06-US 
Final /22 May 2013 
Page 119 of 119 
 
Confidentiality Statement: Data and information contained in this document are considered to constitute trade secrets and 
confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris International. 
 
 
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 – Hematuria ** (1) 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Symptomatic; 
urinary catheter or 
bladder irrigation 
indicated; limiting 
instrumental ADL 
Gross hematuria; 
transfusion, IV 
medications or 
hospitalization 
indicated; elective 
endoscopic, 
radiologic or 
operative 
intervention 
indicated; limiting 
self-care ADL 
Abbreviations: ADL = Activities of daily living; BUN = Blood urea nitrogen; IV = Intravenous. 
Data Source: (1) Common Terminology Criteria for Adverse Events and Common Toxicity Criteria (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.