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



 
 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
ZRHR-PK-01-EU 
Final  / 09 April 2013 
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without the written consent of Philip Morris Products SA. 
 
SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Name of Product: 
Tobacco Heating System 2.2 (THS 2.2)  
Study Title: 
A single-centre, open-label, randomized, controlled, crossover study to investigate the 
nicotine pharmacokinetic profile and safety of Tobacco Heating System 2.2 (THS 2.2) 
following single use in smoking, healthy subjects compared to conventional cigarettes and 
nicotine nasal spray. 
Short Study Title: 
Nicotine pharmacokinetic profile and safety of the Tobacco Heating System 2.2 (THS 2.2) 
Study Number and Acronym: 
ZRHR-PK-01-EU, 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 
relative to conventional cigarettes (CC), following single use of THS 2.2 and CC. 
Secondary Objectives: 
• To determine if Cmax and AUC(0-last) of the THS 2.2 are higher relative to nicotine 
nasal spray (NNS) following single use of the THS 2.2 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 CC or NNSproduct 
[AUC(0-t’)]) between the THS 2.2 and CC, as well as the THS 2.2 and NNS.  
• To evaluate the time to the maximum concentration (tmax) of nicotine for the THS 2.2 
as compared to CC and to determine if the tmax for THS 2.2 is shorter as compared to 
NNS. 
• To describe the terminal half-life (t1/2) of nicotine for the THS 2.2, CC, and NNS. 
• To describe the differences on urge-to-smoke over time between the THS 2.2 and CC, 
as well as between the THS 2.2 and NNS. 

 
 
 
 
 
 
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• To describe product evaluation in the THS 2.2 and CC users. 
• To describe the levels of carbon monoxide (CO) exposure for the THS 2.2, as 
compared to CC and NNS users. 
• To monitor the safety during the study. 
Primary Endpoints: 
• Primary nicotine PK parameters (THS 2.2 vs. CC): 
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:CC ratio for the primary nicotine PK parameters are estimated with a 
precision of ±20%. 
 
Secondary Endpoints: 
• Primary nicotine PK parameters (THS 2.2 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. 
• Safety variables: 
o Incidence of adverse events (AEs)/serious adverse events (SAEs) and 
device events, including THS 2.2 malfunction/misuse. 
o Respiratory symptoms: cough assessment by visual analogue and Likert 
scales and one open question. 
o Vital signs. 

 
 
 
 
 
 
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o Spirometry. 
o Electrocardiogram (ECG). 
o Clinical chemistry, haematology, 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.  
• 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. 
• CC. 
• NNS. 
 
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/CC/NNS). 
Period 2: Day 2: Wash-out; Day 3: single product use (THS 2.2/CC/NNS). 
 

 
 
 
 
 
 
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Final  / 09 April 2013 
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without the written consent of Philip Morris Products SA. 
 
Study Population and Main Criteria for Inclusion: 
A total of 62 smoking, healthy adult Caucasian subjects, meeting the following main 
inclusion criteria:  
 Subject is aged from 21 to 65 years (inclusive). 
 Smoking, healthy subject as judged by the Investigator. 
 Subject smokes at least 10 commercially available non-menthol CCs per 
day (no brand restrictions) for the last 4 weeks, based on self-reporting. 
 Subject does not plan to quit smoking in the next 3 months. 
 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 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 0.6 mg and >0.61 
mg) will have a quota applied to ensure they represent at least 40% of the study population. 
Subjects who do not complete the study after randomization will not be replaced. 
Investigational Products 
Test Product:  
 Tobacco Heating System 2.2 
Reference Product:  Subject’s own supply of commercially available preferred 
single brand CC. 
Reference Point Product (non-investigational):  
Nicotine Nasal Spray (Nicorette® 10 mg/mL); 1  spray 
(resulting in the administration of 0.5 mg nicotine) per 
nostril/product use, as per label. This will be supplied by the 
Investigator and reimbursed by the Sponsor. 
Duration of Study: 
The entire study will last 14 to 40 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). 
 

 
 
 
 
 
 
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Final  / 09 April 2013 
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without the written consent of Philip Morris Products SA. 
 
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 and NNS separately from the 
comparison between THS 2.2 and CC. 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:CC and THS 2.2:NNS ratios.The 
lower bound of the 95% CI of the THS 2.2:NNS ratio for Cmaxand 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 are higher relative to NNS. 
AUC(0-), AUC(0-t’), and t1/2 will be analysed using the same approach adopted for the 
primary endpoints. The one-sided Wilcoxon Signed-Rank Test (=0.025) will be used to test 
if the tmax in THS 2.2 is shorter than in NNS.The median tmax differences between THS 2.2 
and CC, as well as between THS 2.2 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 
analyse the domain scores of the product evaluation (MCEQ) questionnaire, for the 
comparison between THS 2.2 and CC. The same model will be evaluated for the analysis of 
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-CC 
and THS 2.2-NNS differences.  
Safety: The safety population will comprise all subjects, who are exposed to THS 2.2 during 
the study, including the THS 2.2 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. 

 
 
 
 
 
 
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Clinical Study Protocol 
Confidential 
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Final  / 09 April 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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products SA. 
 
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 
and CC with a 90% probability of obtaining a margin of error (95% CI) of at most ±20%, 
assuming that THS 2.2 have a nicotine PK profile similar to CC (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 
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 and NNS is 1.55. 
The sample size of this study is based on our current understanding of THS 2.1, the previous 
prototype of THS 2.2, 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 
Confidential 
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Final  / 09 April 2013 
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are hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products SA. 
 
 
TABLE OF CONTENTS 
SYNOPSIS ....................................................................................................................................... 2 
TABLE OF CONTENTS .................................................................................................................. 9 
LIST OF ABBREVIATIONS AND EXPLANATION OF TERMS ................................................. 13 
1 
ETHICS AND REGULATIONS ............................................................................................. 18 
1.1 
Independent Ethics Committee (IEC) 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 .................................................................................................................. 20 
2.1 
Background .................................................................................................................. 20 
2.2 
Purpose of the Study ..................................................................................................... 22 
2.3 
Anticipated Benefits and Risks ..................................................................................... 22 
3 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................... 24 
3.1 
Primary Objective ........................................................................................................ 24 
3.2 
Secondary Objectives ................................................................................................... 24 
3.3 
Primary Endpoints ........................................................................................................ 25 
3.4 
Secondary Endpoints .................................................................................................... 25 
3.5 
Exploratory Endpoints .................................................................................................. 26 
4 
INVESTIGATIONAL PLAN ................................................................................................. 27 
4.1 
Overall Study Design and Plan ..................................................................................... 27 
4.2 
Rationale for Study Design and Control Groups(s) ....................................................... 29 
4.3 
Study Duration ............................................................................................................. 30 
4.4 
Appropriateness of Measurements ................................................................................ 30 
5 
STUDY POPULATION ......................................................................................................... 32 
5.1 
Selection of Study Population ....................................................................................... 32 
6 
INVESTIGATIONAL AND REFERENCE POINT PRODUCTS ........................................... 39 
6.1 
Description ................................................................................................................... 39 
6.2 
Use of Investigational and Reference Point Products..................................................... 41 
6.3 
Method for Assigning Subjects to Study Arms .............................................................. 43 
6.4 
Blinding ....................................................................................................................... 43 
6.5 
Investigational and Reference Point Product Accountability and Compliance................ 44 
6.6 
Restrictions .................................................................................................................. 45 
6.7 
Concomitant Medication .............................................................................................. 46 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
7 
STUDY PROCEDURES ........................................................................................................ 49 
7.1 
Informed Consent ......................................................................................................... 49 
7.2 
Smoking Cessation Advice and Debriefing ................................................................... 49 
7.3 
Support during Smoking Abstinence/Periods of Reduced Smoking ............................... 50 
7.4 
Clinical Assessments .................................................................................................... 50 
7.5 
Biomarker Assessment ................................................................................................. 54 
7.6 
Laboratory Assessments ............................................................................................... 55 
7.7 
Sample Handling, Storage, and Shipment ..................................................................... 57 
7.8 
Questionnaires .............................................................................................................. 58 
8 
ADVERSE EVENTS .............................................................................................................. 62 
8.1 
Definitions ................................................................................................................... 62 
8.2 
Assessment of Adverse Events ..................................................................................... 63 
8.3 
Reporting and Follow-Up of Serious Adverse Events ................................................... 66 
8.4 
Reporting of Other Events Critical to Safety Evaluations .............................................. 67 
8.5 
Reporting and Follow-Up of Pregnancies...................................................................... 68 
8.6 
Adverse Events Leading to Withdrawal ........................................................................ 69 
8.7 
Investigational Device Misuse ...................................................................................... 69 
8.8 
Investigational Device Malfunction .............................................................................. 70 
9 
STUDY ACTIVITIES ............................................................................................................ 71 
9.1 
Screening Visit ............................................................................................................. 71 
9.2 
Admission .................................................................................................................... 72 
9.3 
Investigational Period ................................................................................................... 74 
9.4 
Day of Discharge .......................................................................................................... 79 
9.5 
Safety Follow-up Period ............................................................................................... 80 
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 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
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 
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 Products SA. 
 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1 
Measured Aerosol Fractions for THS Tobacco Sticks ......................................40 
Table 2. Examples of Drugs and Substances Considered Interacting with CYP2A6 .....47 
Table 3. Clinical Laboratory Parameters for Safety Panel ..............................................56 
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 ................................................................................................29 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events ...................................................................................107 
Appendix 2 
Participating Laboratories ........................................................................111 
Appendix 3 
Investigational Product and Instructions for Use .....................................112 
Appendix 4 
Product Label for the NNS product: Adverse Events ..............................113 
Appendix 5 
Abnormal Laboratory Values ..................................................................114 
Appendix 6 
Investigational Micro+TM Smokerlyzer® .................................................119 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
LIST OF ABBREVIATIONS AND EXPLANATION OF TERMS 
Abbreviations 
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 conventional 
cigarettes or nicotine nasal spray 
BMI 
Body mass index 
CC 
Conventional cigarette(s) 
CD 
Compact disc 
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 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
EOS 
End of Study Visit (referring to each subject’s individual last study 
visit) 
FDA 
US 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 
HPHC 
Harmful and Potentially Harmful Constituents in Tobacco Products 
and Tobacco Smoke 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
ISO 
International Organization for Standardization 
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 
SAP 
Statistical analysis plan 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
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 
z 
Terminal elimination rate constant 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
Explanation of Terms 
The following special terms are used in this protocol: 
Back-Up Subject 
Subject who is enrolled but not randomised  
CC 
The term ‘conventional cigarette’ refers to manufactured and 
commercially available cigarettes and excludes hand-rolled 
cigarettes, cigars, pipes, bidis, and other nicotine-containing 
products. 
Charger 
The function of the Charger (Model 4) is to recharge the Holder 
after use. It contains a battery with sufficient capacity to recharge 
the Holder approximately 20 times.  It is a convenient size to carry 
around, and can itself be recharged from a mains power source. 
 
Day of Discharge 
Day 4. 
End of Study 
End of Study is defined as the last day of the 7 day safety follow-
up subsequent to discharge from the unit. 
Enrolment 
On Day -1 for eligible subjects after all applicable inclusion and 
exclusion criteria have been satisfactorily met and the subjects is 
willing and ready to use both the THS 2.2 and NNS (the test of 
both THS 2.2 and NNS are the last assessments prior to enrolment) 
First product use time 
point 
Start of product use for THS 2.2 is defined as the time of the first 
puff. The start time for CC corresponds to the lighting of the CC, 
and the start time of the NNS product is the time of the spray in the 
first nostril. 
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 followed up until resolved, stabilized i.e. no worsening 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
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 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 Tobacco Sticks 
The Tobacco Stick (product code C3) contains tobacco which, 
when heated, generates an aerosol. It is custom-designed to be used 
with the Holder. 
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 except the Tobacco 
Stick. 
Tobacco Heating 
System 2.2 (THS 2.2) 
THS 2.2 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 Products SA. 
 
1 
ETHICS AND REGULATIONS 
1.1 
Independent Ethics Committee (IEC) Approval 
Prior to the start of the study, the clinical study protocol, together with its associated 
documents (informed consent form [ICF], subject information, 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 
Independent Ethics Committee [IEC]), will be submitted for review and approval to the 
relevant IEC. The IEC shall be appropriately constituted and perform its functions in 
accordance with the International Conference on Harmonization (ICH) Tripartite Guidance 
for Good Clinical Practice (ICH GCP E6 (R1), July 1996) and local requirements, as 
applicable. 
In accordance with GCP, a written confirmation of the IEC approval should be provided to 
the Sponsor. This should identify the study (Investigator’s name, study number and title) and 
the documents that have been approved by the IEC, with dates and version numbers, as well 
as the date of approval. The composition of the IEC, including the name and occupation of 
the chairperson, should be supplied to the Sponsor together with a GCP compliance 
statement. 
The written approval from the IEC will be filed in the Investigator file, and a copy will be 
filed in the Study Master File at the Sponsor or designated organization. The study must not 
start at a site before the Sponsor has obtained written confirmation of favourable 
opinion/approval from the concerned IEC. 
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the Principal Investigator. All amendments will be 
submitted to the IEC, and substantial amendments will only be implemented after approval 
by the IEC. 
These requirements for approval should in no way prevent any action from being taken by 
the Investigator or 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 IEC should be informed immediately. 
Relevant safety information will be submitted to the IEC during the course of the study in 
accordance with national regulations and requirements. 

 
 
 
 
 
 
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1.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki, 2008 and are consistent with ICH/GCP applicable regulatory 
principles. 
The Investigator agrees to conduct the clinical study in compliance with the protocol agreed 
with the Sponsor and approved by the IEC. 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, 2008should be located in the Investigator’s Study File. 
1.3 
Subject Information and Consent 
1.3.1 
Study Consent 
At the Screening Visit, the Investigator or person designated by the Investigator will ensure 
that  each subject is given full and adequate oral and written information about the nature, 
purpose, possible risks and benefits of the study, and the Investigator or the designee will 
answer all questions the subject might have to his/her full satisfaction. The subject will have 
sufficient time for consideration of his/her participation in the study and will be notified that 
he/she is free to discontinue his/her participation at any time. Once the subject has received 
all necessary information, and if he/she agrees to participate, this will be documented in the 
ICF by the date and signature of both the subject and the person who conducted the informed 
consent discussion. No study-specific procedures will be performed before the ICF has been 
signed. 
The original, dated and signed ICF(s) 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 and subject 
information may be required. If revision of the ICF and subject information is necessary, the 
Investigator will, with the support of the Sponsor, ensure that the documents have been 
reviewed and approved by a relevant IEC before subjects are required to re-sign the ICF. 
The subject will be informed that additional data analyses not mentioned in the protocol or 
the statistical analysis plan might be performed with the collected data at a later time. If any 
additional analyses will be performed, they will fully be covered by data confidentiality, as 
for the main analyses described in this protocol.  

 
 
 
 
 
 
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1.4 
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation 
and documentation of this study, are designed to ensure that the Sponsor, its authorized 
representative, and Investigator 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. 
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 a 
smoking 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/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 

 
 
 
 
 
 
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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, 
2009), and more than 100 of them have been categorized as harmful and potentially harmful 
constituents (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 (THS 2.2) (Tobacco Stick). With this product, the heating of the tobacco is 
maintained below 400°C, a temperature much lower than what is observed for CC, which can 
reach 900°C. The THS 2.2 is composed of the ‘THS Tobacco Stick Holder’ dedicated special 
Tobacco Sticks made of conventional tobacco, a charger, and different accessories. The 
energy of the THS Tobacco Stick Holder is sufficient to maintain approximately a 6 minute 
session. Unlike CC, the Tobacco Sticks do not burn down during their consumption and their 
lengths remain constant after use. 
The non-clinical assessment of THS 2.2 and its predecessors including THS 1.0 supports the 
initiation of the clinical studies described in this Investigator’s Brochure. 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 were increased compared to the CC. 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 are given in 
the Investigator’s’ Brochure (PMI, 2013a). 

 
 
 
 
 
 
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Several clinical studies have been conducted on THS 1.0, 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 the next 
development version of THS, namely THS 2.0.  
THS 2.1 was tested in two exploratory clinical studies to measure the nicotine plasma kinetic 
profile (PK) and to assess the reduction of exposure to HPHCs when switching from CC to 
THS 2.1. The observed nicotine plasma PK profile for THS 2.1 was similar to CC as well, 
there were significant reductions in the exposure to the majority of selected HPHCs. Clinical 
studies conducted so far revealed no safety concern for either of the previous version of THS 
2.2 tested. Further details on the clinical data are provided in the Investigators’ Brochure 
(PMI, 2013a). 
2.2 
Purpose of the Study 
The purpose of this clinical study is to compare the profile of nicotine uptake (rate and extent 
of nicotine absorbed) after single use of THS 2.2 and CC in smoking, healthy subjects. THS 
2.2 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 
Research conducted by the United Kingdom National Health Service has shown that up to 
75% of smokers want to quit. Despite associated health risks, however, only 2% of smokers 
make a cessation attempt each year. Advice on health risks associated with smoking and 
smoking cessation advice will be provided at Screening, at Admission, and at the Day of 
Discharge. The advice will follow the recommendations by the World Health Organization 
(Raw et al, 2002). 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 smoking cessation services for continuing support and counselling 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, haematoma, 
paresthesia, or infection. 

 
 
 
 
 
 
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• Risks related to chest X-rays, e.g., a small increase of risk to develop cancer later in life. 
• Risks related to drug application as part of testing procedures (i.e., spirometry with 
short-acting bronchodilator at Screening) per study protocol and scientifically accepted 
standards. 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product (THS 2.2 
and CC) or Reference Point Product (NNS) 
• 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,investigational product (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 support for 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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3 
STUDY OBJECTIVES AND ENDPOINTS 
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 relative to CC, following single use of THS 2.2 and 
CC. 
 
3.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To determine if Cmax and AUC(0-last) of the THS 2.2 are higher relative to NNS 
following single use of the THS 2.2 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 CC or NNS product [AUC(0-t’)]) between the THS 2.2 and CC, as well as the 
THS 2.2 and NNS.  
• To evaluate the  time to the maximum concentration (tmax) of nicotine for the THS 
2.2 as compared to CC and to determine if the tmax for THS 2.2 is shorter as 
compared to NNS. 
• To describe the terminal half-life (t1/2) of nicotine for the THS 2.2, CC, and NNS. 
• To describe the differences on urge-to-smoke over time between the THS 2.2 and 
CC, as well as between the THS 2.2 and NNS. 
• To describe product evaluation in the THS 2.2 and CC users. 
• To describe the levels of carbon monoxide (CO) exposure for the THS 2.2, as 
compared to CC and NNS users. 
• To monitor the safety during the study. 
 

 
 
 
 
 
 
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3.3 
Primary Endpoints 
• Primary nicotine PK parameters (THS 2.2 vs. CC): 
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:CC 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 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. 
• Safety variables: 
o Incidence of adverse events (AEs)/serious adverse events (SAEs) and 
device event including THS 2.2 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). 
o Clinical chemistry, haematology, and urine analysis safety panel. 

 
 
 
 
 
 
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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). 
 Cytochrome P450 2A6 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. 
• CC. 
• 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 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 (using up to three 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 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 
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/CC/NNS). 
Period 2: Day 2: Wash-out; Day 3: single product use (THS 2.2/CC/NNS). 
In total, 62 eligible, healthy smoking subjects will be randomized into one of the 4 
sequences: 
Sequence 1:  THS 2.2 
CC (N=22). 
Sequence 2:  CC 
THS 2.2 (N=22). 
Sequence 3:  THS 2.2 
NNS (N=9). 
Sequence 4:  NNS 
THS 2.2 (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 CC will not be considered:  
CC vs. THS 2.2  
(N=22 in both sequence 1 and 2). 
THS 2.2 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 0.6 mg and >0.61 mg) will have a quota applied to 
ensure they represent at least 40% of the total study population per group.  
Subjects will be dischargedat 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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The NNS has been selected as the reference point, 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).  
NNS will serve as a reference point for comparison with THS 2.2 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 (Benowitz et 
al, 2009).  
The use of oestrogen contraceptive is known to accelerate nicotine clearance by 20% to 30% 
in women as compared to women who do not take such contraceptives (Benowitz et 
al, 2006).  Therefore, for the purpose of this study, it is not allowed to use hormonal 
contraception containing oestrogens. This also applies to hormone replacement therapy. 
The activity of CYP2A6 will be measured at admission 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 40 days, including a Screening period of up to 4 
weeks prior to Admission (Day -29 to Day -2), and 6 days of confinement (Day -1 to 
morning of Day 4). In the morning of Day 4, the Day of Discharge examinations will be 
conducted. After the time of discharge, subjects will then enter a 7-day safety follow-up 
(until Day 11) for the recording of spontaneously reported new AEs/SAEs and the active 
follow-up of ongoing AEs/SAEs. 
4.4 
Appropriateness of Measurements 
The laboratory measures to be utilized in this study were selected based on the following 
criteria: 1) the availability of a validated analytical method, and 2)measure is known to be 
directly or indirectly affected by smoking; 3)measure is readily reversible after smoking 

 
 
 
 
 
 
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cessation, 4)timeframe of reversibility of measure in the perspective of the study duration, 
5)practicality/acceptability by subjects, and 6)robustness (rapid, simple, accurate). 
All questionnaires utilized for this study, except the cough and socio-economic status 
questionnaires,are available as validated questionnaires. 

 
 
 
 
 
 
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5 
STUDY POPULATION 
5.1 
Selection of Study Population 
Sixty-twoCaucasian female or male smoking healthy adult subjects, who smoke at least 10 
CC per day will be randomized into this study. The maximum number of CC is not limited. 
Subjects must have a smoking history of at least 3 years of consecutive smoking prior to 
Screening. The smoking status of the subjects will be verified based on a urine cotinine test 
(cotinine 200 ng/mL). 
5.1.1 
Inclusion Criteria 
Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -1) 
1. Subject has signed the ICF and is able 
to understand the information 
provided in the Subject Information 
Sheet and ICF. 
Administrative
X 
 
2. Caucasian subject is aged from 21 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 
post-bronchodilator FVC >0.8], vital 
signs, physical examination, ECG, 
chest X-ray, and medical history). 
Safety 
X 
X 
4. Subject smokes at least 10 
commercially available non-menthol 
CCs per day (no brand restrictions) 
Effect 
X 
X 

 
 
 
 
 
 
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Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -1) 
with a maximum yield of 1 mg 
nicotine ISO/CC, as labelled on the 
cigarette package, for the last 4 weeks, 
based on self-reporting. Furthermore, 
the subject has been smoking for at 
least the last three consecutive years. 
The smoking status will be verified 
based on a urinary cotinine test 
(cotinine 200 ng/mL). 
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 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 
study for any reason (e.g., medical, 
psychiatric and/or social reason).  
Safety  
X 
X 
2. A subject who is legally 
incompetent, physically or mentally 
incapable of giving consent (e.g., 
Administrative 
X 
 

 
 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
emergency situation, under 
guardianship, subject in a social or 
sanitary establishment, prisoners or 
subjects who are involuntarily 
incarcerated). 
3. The subject has medical condition 
requiring smoking cessation, or 
clinically relevant diseases 
(including but not limited to 
gastrointestinal, renal, hepatic, 
neurological, haematological, 
endocrine, oncological, urological, 
immunological, pulmonary and 
cardiovascular disease or any other 
medical condition [including but not 
limited to clinically relevant 
abnormal laboratory parameters]) in 
the judgment of the Investigator. 
Safety 
X 
X 
4. The subject has a body mass index 
(BMI) <18.5 or 32.0 kg/m2. 
Safety 
X 
 
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 
6. The subject has used 
nicotine-containing products other 
than commercially available CC 
(either tobacco-based products or 
nicotine-replacement therapy) as 
Effect 
X 
X 

 
 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
well as electronic cigarettes and 
similar devices, within 4 weeks prior 
to assessment. 
7. The subject has received medication 
(prescription or over-the-counter) 
within 14 days or within 5 half-lives 
of the drug prior to the Admission 
Day (Day -1; whichever is longer) 
that has an impact on Cytochrome 
P450 2A6 (CYP2A6) activity. 
Effect 
 
X 
8. In case the subject received any 
medication (prescribed or 
over-the-counter) within 14 days 
prior to Screening or prior to the 
Admission Day (Day -1) it will be 
decided at the discretion of the 
Investigator if these can potentially 
interfere with the study objectives 
and subject’s safety.  
Effect 
X 
X 
9. The subject has a positive alcohol 
test and/or the subject has a history 
of alcohol abuse that could interfere 
with subject’s participation in study. 
Administrative 
X 
X 
10. The subject has a positive urine drug 
test. 
Administrative 
X 
X 
11. Positive serology test for human 
immunodeficiency virus (HIV) 1/2, 
Hepatitis B or Hepatitis C.  
Safety 
X 
 
12. Donation or receipt of whole blood 
or blood products within 3 months 
prior to Admission. 
Safety 
X 
X 

 
 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
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 of childbearing 
potential* 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 of childbearing 
potential* only: 
Subject does not agree to use an 
acceptable method of effective 
contraception.** 
Safety 
X 
X 

 
 
 
 
 
 
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* Childbearing potential is defined as NOT premenarche, permanently sterilized or postmenopausal 
(i.e., 12 months with no menses without an alternative medical cause). 
** Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with 
spermicidal foam/gel/film/suppository, hormonal contraception containing progesterone only, vasectomized 
partner(s) or true abstinence (periodic abstinence and withdrawal are not effective methods) from Screening 
until the end of the safety follow-up period. Hormonal contraception with oestrogen 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) 
at the discretion of the Investigator. 
• Positive pregnancy testing (no invasive procedures including the drawing of blood 
must performed after detection of pregnancy, see Section 8.5). Female subjects 
starting contraception or hormone replacement therapy containing oestrogens 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 (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 were 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 AND REFERENCE POINT PRODUCTS 
6.1 
Description 
6.1.1 
Investigational Products 
THS 2.2 
The THS 2.2 will be provided by the Sponsor and its distribution will be limited to a 
qualified and appropriately trained staff personnel.  
THS 2.2 comprises the following components:  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) 
Tobacco Stick: 
The 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 CC. 
 
6.1.1.1 
Tar, Nicotine and Carbon Monoxide Yields 
Per cigarette/Tobacco Stick tar, nicotine, and carbon monoxide yields are normally 
determined by standardized test methods. The most widely used test method is ISO 4387. 
PMI has developed a modified version of this method, which improves the determination of 
tar in products with high water content, which is typical for heated tobacco products (PMI, 

 
 
 
 
 
 
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2012c, PMI, 2012b, 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). 
 
Table 1 
Measured Aerosol Fractions for THS Tobacco Sticks 
Constituent (mg/THS 
Tobacco Stick) 
Modified 
ISO 1 
Cigarette 
Pack 
Label 
Health Canada  Intense 
Regime 2 
Tar  
3.8 
4 
3.7 
Nicotine  
0.5 
0.5 
1.3 
Carbon monoxide 
0.3 
1 
0.5 
1 
Internally-modified ISO method, based on ISO 4387(PMI, 2012c, PMI, 2012b, PMI, 2013b) 
2 
Health Canada Intense machine-smoking regimen (55 mL puff volume, 2-second puff duration, 30-second 
inter-puff interval) (Health Canada, 1999)
 
CC 
In the study sequences 1 and 2, the comparator to THS 2.2 is commercially available single 
brand CC with a maximum yield of 1 mg nicotine ISO per cigarette. 
Conventional cigarettes will not be provided by the Sponsor. All eligible subjects will be 
asked to purchase their own preferred single-brand CC prior to Admission. As randomization 
takes place on Day 0, every study subject needs to buy his/her anticipated amount of 
single-brand CC for a total of 2 days plus 2 extra packs. 
6.1.2 
Reference Point Product 
The NNS Nicorette® (10 mg/mL) will be the reference point product to THS 2.2 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 
totaladministered dose of 1 mg nicotine/product use as per label.  
6.1.3 
Packaging and Labelling 
At Admission on Day -1, all study subjects will provide the anticipated amount of CC in 
sealed packs to the site staff. The cigarette packs provided by the subject should not be 
opened and the cellophane should be intact.  

 
 
 
 
 
 
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Each pack of cigarettes provided by the subject will be labelled to identify which subject the 
cigarettes belong to (labels should be affixed to the cellophane wrapper of the lower part of 
the pack).  
Packs of CC will be labelled to identify necessary information to match the subject with 
his/hers suppliers. 
For the Tobacco Sticks, the packs will be printed with the necessary information including 
but not limited to health warning, tar/nicotine/carbon monoxide ISO levels, product code. 
6.2 
Use of Investigational and Reference Point Products 
Subjects will never be requested or forced to smoke and will be free to stop smoking at any 
time during the study. Subjects caught using any nicotine/tobacco product which is different 
from the assigned product will be withdrawn from the study. During the screening period, 
subjects will be allowed to smoke according to their smoking habits except during the 
procedures of the screening visit 9.1 at the discretion of the site. 
6.2.1 
Admission (Day -1) 
Subject will be instructed not to smoke in the morning prior to Admission. Smoking ad 
libitum will be allowed throughout the day of admission except during the procedures until 
11:00 pm. All subjects will be allowed to continue smoking ad libitum their own preferred 
CC. All subjects (except women with a positive pregnancy test at Screening or Admission) 
will undergo a THS 2.2 test first and subsequently NNS test at Day -1 prior to enrolment. 
Following agreement that the THS2.2 and NNS is acceptable, subjects will be enrolled and 
further randomized to one of 4 treatment sequences using an Interactive Web/Voice 
Response System.  
6.2.2 
Investigational Period (Day 0 to Day 3) 
During the first washout, each subject will maintain nicotine abstinence from Day -1 at 11:00 
PM to the time of single use of his/her allocated product at Day 1. At Day 1, after the single 
use of the product, subjects will maintain nicotine abstinence for the rest of the day. During 
the second washout on Day 2, subjects will maintain nicotine abstinence until the time of 
single use of subject’s allocated product at Day 3. Subjects will not be allowed to smoke or 
use any other nicotine/tobacco-containing products other than the products they are allocated 
to. 

 
 
 
 
 
 
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Time point of first product use during study day (T0) will be defined as start of the single 
product use at the single use days. The start of product use for THS 2.2 is defined as the time 
of the first puff. The start time for CC corresponds to the lighting of the CC, 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 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.  
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 arm 
will use one Tobacco Stick, subjects in the CC arm will smoke one CC, and subjects in the 
NNS arm will administer one spray into each nostril (leading to an estimated total 
administered amount of 1 mg nicotine). 
 
Sequence 1 
Sequence 2 
Sequence 3 
Sequence 4 
Day 1 
THS 2.2 
CC 
THS 2.2 
NNS 
Day 3 
CC 
THS 2.2 
NNS 
THS 2.2 
 
6.2.3 
Day of Discharge/Time of Discharge 
On the Day of Discharge (Day 4), smoking will be only allowed after all laboratory 
procedures and the spirometry have been performed. All examinations of the Day of 
Discharge will be conducted on Day 4 prior to the time of Discharge.  
6.2.4 
Safety Period 
During the safety follow-up period, subjects are free to smoke according to their usual 
smoking habits. 
6.2.5 
Stopping Rules for Investigational Product 
For safety purposes, using the THS 2.2, smoking the CC, or use of the NNS should be 
temporarily stopped in the event of any signs suggesting nicotine overexposure, e.g., 
gastrointestinal disturbance (nausea, vomiting, diarrhoea, stomach or abdominal pain), cold 

 
 
 
 
 
 
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sweats, headache, dizziness and breathing problems or any reasons at the discretion of the 
Investigator. 
6.3 
Method for Assigning Subjects to Study Arms 
Randomization to product exposure sequence will be done through an Interactive Telephone 
and Web Response System. 
Each sex and each of the smoking level (ISO nicotine levels 0.6 mg and >0.6 to 1 mg) will 
have a quota applied to ensure they represent at least 40% of the total study population 
allocated within each of the following analysis groups: 
• 
Group-1: composed of sequences 1 and 2. 
• 
Group-2: composed of sequences 3 and 4. 
In particular, the maximum number of subjects having the same sex or nicotine level 
valuewill be limited to 26 in Group-1 and 10 in Group-2. 
The randomization of the planned sample size of 62 subjects will be ensured by applying 
quota to the number of subjects per each sequence (22 subjects for sequences in Group-1, and 
9 subjects for sequences in Group-2). 
Subjects will be randomly assigned to one of the four product exposure sequences by means 
of a permuted-block schema. Block size and other randomization details will be available in 
the randomization plan. 
The randomization plan will be generated by an independent statistician and none of the 
sponsor staff, investigators or study subjects will have access to the randomization schema 
prior to randomization. 
6.4 
Blinding 
This is an open-label study; therefore, the subjects and investigators will be unblinded to 
subject’s sequence. However, there will be a limited degree of blinding in the data review 
and data analysis process. In particular, PMI and CRO personnel will be blinded to the 
randomized sequence as summarized in the following table: 
 
 

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

 
 
 
 
 
 
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6.5.3 
Investigational and Reference Point Product Retention 
Unused Tobacco Sticks and NNS will be destroyed if possible, or returned to the Sponsor 
upon study completion. The Tobacco Heating Devices will be returned to the Sponsor. 
6.5.4 
Compliance to Investigational and Reference Point 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 (Benowitz et al, 2002). 
Furthermore, the CO breath test will be considered as one of the measures of compliance 
during the wash-out days in all subjects.  
6.6 
Restrictions 
6.6.1 
Smoking Restrictions 
On Day 1 and Day 3, to avoid nicotine cross contamination, smokers of THS 2.2 and CC will 
smoke in dedicated separate rooms: one room for THS 2.2 and one room for CC. 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, CC or Tobacco 
Sticks, which will be dispensed by the site staff individually as described in Section 6.5.1.  
Smoking is not allowed during study procedures except during blood sampling for nicotine 
PK on Day 1 and Day 3. Furthermore, smoking is not allowed on Day 4 until all laboratory 
tests and the spirometry have been conducted. 
During the days of wash-out or single product use (for 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. 

 
 
 
 
 
 
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6.6.2 
Dietary Restrictions 
A standard diet will be designed by a dietician for the whole confinement period. For each 
meal, the caloric and fat content should be controlled in order to avoid a “high-fat” diet. The 
FDA guidance on food-effect studies for bioequivalency testing identifies a “high-fat” diet as 
a diet which 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 Sections 9.2, 9.3.1, 9.3.2 and9.4. 
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.  
6.7 
Concomitant Medication 
For the purpose of this study, no concomitant medication should be taken by the subjects. 
Any medication with an impact on the CYP2A6 metabolism (as prescription and 
over-the-counter products) as given below must be avoided as CYP2A6 is involved in the 
nicotine metabolism.  
In this study the use of hormonal contraception containing oestrogens is NOT allowed. This 
also applies to hormone replacement therapy. Only hormonal contraception with products 
containing progesterone is allowed during this study. Subjects using oestrogens during the 
study will be withdrawn.  
The following drugs and substances are considered as 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.  

 
 
 
 
 
 
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Table 2. 
Examples of 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, propranolol, lidocaine 
Antiarrhythmic  
Losartan, amlodipine, nifedipine, losartan 
Antihypertensive 
Drosperinone, oestrogens 
Hormonal contraceptives  
Agents for hormonal replacement 
therapy (oestrogens) 
Fluvastatin 
Cholesterol-lowering agent 
Theophylline 
Antispasmodic pulmonological 
agent/Bronchodilator agent 
Omeprazole, Lansoprazole 
Proton pump inhibitor 
Interferon 
Antiviral/Immunomodulating agent 
Methoxsalen   
Anti-psoriatic (substance class 
Furocoumarins) 
Modafinil, Diclofenac, Rofecoxib 
Analgesic 
Insulin 
Anti-diabetic 
Sildenafil 
Phosphodiesterase-Inhibitor (e.g., 

 
 
 
 
 
 
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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 7.4.6). Concomitant medications should be 
followed up with the CRO Medical Monitor on an ongoing basis.  
Concomitant medication will first be assessed at Screening Visit. To be eligible for the study 
any medication with impact on CYP2A6 metabolism must be discontinued at least 14 days 
prior to Admission to the clinic or for at least five half-lives (whichever is longer). They must 
not be used during the entire study until the time of discharge. It is at the discretion of the 
Investigator to assess if a termination of such medication at Screening is medically justified 
and safe for the subject. 

 
 
 
 
 
 
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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. Appropriate medical 
advice will be provided to the subject in case of any medical findings requiring health care. 
7.1 
Informed Consent 
Each subject must give his/her informed consent prior to participating in the study. During 
the consent process, the Investigator or designee 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 and must have sufficient time to 
read and understand and have adequate opportunity to ask questions. The ICF must be signed 
and dated prior to undertaking any study-specific procedures. A signed copy should be given 
to the subject.  
7.2 
Smoking Cessation Advice and Debriefing 
Each subject will be given advice on the risks of smoking 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 World Health Organization (WHO) 
recommendations (Raw et al, 2002). Details of the interview will be recorded in the Source 
Document File. Information on the risks 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 subjectswill be done at each 
smoking cessation advice sessionto address anyintended or unintended beliefs participants 
have about the candidate MRTP. The goal of thedebriefing would be to help ensure that 
subjects exit the study with anaccurate understanding of product risks, including an 
understanding that the candidate MRTP has notbeen demonstrated to be less harmful. 
 

 
 
 
 
 
 
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7.3 
Support during Smoking Abstinence/Periods of Reduced Smoking 
All subjects will be closely monitored by the site staff on D0, D1, D2, and D3. 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 behaviour, 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 e.g., laboratory 
values, vital signs and ECGs, detected during the Screening Visit. Any untoward medical 
occurrence in a subject detected during the study which was not present at the Screening 
Visit must be documented as an AE. Worsening of a pre-existing condition from the 
Screening Visit onwards will also be documented as an AE. If a clinically relevant finding is 
detected during the Screening period, the Investigator needs to check if inclusion criterion 
no. 3 is still fulfilled. 
7.4.1 
Demographic Data 
Demographic data (sex, date of birth/age, and race) will be recorded on the day of ICF 
signature.  
7.4.2 
Socio-Economic Status 
At Admission, subjects willbe asked questions, which will allow the Sponsor to infer their 
socio-economic status (see section 7.8.5).  
7.4.3 
Identification of the Current Cigarette Brand 
Identification of the current CC brand smoked by the subject will be done at the Screening 
Visit and at Day -1. For the Screening Visit, smokers will be asked to bring a packet of their 
current CC brand to the site. The site staff will document brand name and yields. At Day -1, 
subjects have to hand their CC 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 with information of ISO 
nicotine , CO and tar 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 Digital Versatile Disc (DVD) or Compact Disc (CD).  

 
 
 
 
 
 
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7.4.4 
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 CC smoked during the previous 4 weeks, 
and to evaluate if the CCs smoked during the previous 4 weeks were non-menthol. Yields 
will later be ascertained, from 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 CC (either tobacco-based products or NRT), electronic cigarettes or 
similar devices, within 4 weeks prior to assessment. 
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. 
7.4.5 
Demonstration and Product Tests of THS 2.2 and NNS 
All subjects will have a demonstrationof the THS 2.2and the NNS products by the site staff 
at the Screening Visit. On Day -1, as the last procedure of the eligibility assessments, 
subjects will have a product test for the THS 2.2 (using up to three Tobacco Sticks) first and 
subsequently a  product test of the NNS (spraying once in each nostril). In female subjects, 
the THS 2.2 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 and the 
NNS and be randomized to any of the study arms can be enrolled into the study. 
7.4.6 
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. 
Medication taken within 4 weeks prior to Screening Visit and any concomitant medication 
needs to be documented. Any medication which was started prior to the Screening Visit and 
is still being taken by the subject will be considered a concomitant medication. Medication 
initiated after Screening is also referred to as concomitant medication. This applies to both 
prescription and over-the-counter products. 

 
 
 
 
 
 
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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, for example, mg, 
mL, or IU), indication, 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. 
7.4.7 
Physical Examination 
A physical examination will be conducted at the Screening Visit, at Admission (Day -1) and 
at the Day of Discharge (Day 4).  
7.4.8 
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 one 
decimal place:  
 	
	

	

 
 
7.4.9 
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.  
7.4.10 
Other Clinical Assessments 
7.4.10.1 Spirometry 
Spirometry with and without a short-acting bronchodilator will be done at the Screening Visit 
to evaluate inclusion/exclusion criteria (the post-bronchodilator results). At screening, 
spirometry without bronchodilator will be done first, and then, spirometry with 
bronchodilator. Furthermore, spirometry without a bronchodilator will be performed on Day-
1 as well as on Day 4.  

 
 
 
 
 
 
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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 
the pulmonary function laboratory (including the records of the calibration, if applicable). 
The FEV1 and FVC will be recorded.  
The subject will be submitted to a spirometry with maximum voluntary ventilation 
measurement. 
For spirometry, assessed parameters will include: 
• FEV1. 
• FVC. 
• FEV1/FVC. 
 
7.4.10.2 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, initialled, dated, and 
stapled together for inclusion in the Source Data File. 
7.4.10.3 
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 

 
 
 
 
 
 
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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 
Report. A list of laboratories is provided in Appendix 2. 
The start time of the use of each product has to be documented on single use days (Day 1 and 
Day 3). 
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 Micro+™ Smokerlyzer® device (Bedfont 
Limited, Rochester, United Kingdom, see Appendix 6). The test will be performed for 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, 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 and then around 
12:00 PM, 4:00 PM, and 8:00 PM. On the wash-out days (Day 0 and Day 2) it will be 
conducted around 8:00 AM, 12:00 PM, 4:00 PM and 8:00 PM.  
Carboxyhemoglobin 
Tests for COHb measurement will be performed at a local laboratory.  

 
 
 
 
 
 
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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 T0are at 
15 minutes, 60 minutes, 4 hours and 12 hours post-T0. 
7.5.1.2 
Biomarkers of Exposure to Nicotine 
Blood samples to measure nicotine in plasma will be taken as follows: 
Single Use on Day 1 and Day 3: 
A total of 16 blood samples will be taken for a 24-hour profile (Day 1 and Day 3). The first 
blood sample will be taken within 15 minutes prior to the single use (T0). Times of sampling 
are thereafter in relation to T0: T1 after 2 minutes, T2 after 4 minutes, T3 after 6 minutes, T4 
after 8 minutes, T5 after 10 minutes, T6 after 15 minutes, T7 after 30 minutes, T8 after 45 
minutes, T9 after 60 minutes, T10 after 2 hours, T11 after 4 hours, T12 after 6 hours, T13 after 9 
hours, T14 after 12 hours and T15 after 24 hours (this sample will be drawn during the day 
following product use, i.e., wash-out).  
7.5.2 
CYP2A6 Activity 
CYP2A6 activity will be measured in plasma on Day -1 (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, Haematology, and Urine Analysis for Safety Panel  
Haematology, clinical chemistry and urine analysis for the safety panel will be measured at 
Screening, at day of Admission (Day -1) and at the Day of Discharge (Day 4). Tests will be 
conducted at a local laboratory or the site. Blood will be taken after no less than the 10 hours 
of fasting (see Section 6.6.2). The urine test will be performed semi-quantitatively as urine 
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 
Haematology 
Clinical chemistry 
Urine analysis 
- Haematocrit 
- Haemoglobin 
- Mean corpuscular 
haemoglobin  
- Mean corpuscular 
haemoglobin concentration  
- Mean corpuscular volume  
- Platelet count 
- Red blood cell count  
- White blood cell (count) 
(WBC) 
- Differential WBC count:  
• 
Neutrophils 
• 
Basophils  
• 
Eosinophils  
• 
Lymphocytes 
• 
Monocytes 
 
 
- Albumin 
- Total protein 
- Alkaline phosphatase 
- Alanine aminotransferase  
- Aspartate aminotransferase  
- Blood urea nitrogen 
- Creatinine 
- Gamma-glutamyl transferase  
- Fasting glucose 
- Lactate dehydrogenase  
- Potassium  
- Sodium 
- Total bilirubin 
- Direct bilirubin 
- Total cholesterol 
- Triglycerides 
 
- pH 
- Bilirubin 
- Glucose 
- Nitrite 
- Red blood cell traces 
- Protein 
- Specific gravity 
 
 
7.6.2 
Serology 
A test for Hepatitis B surface antigen, Hepatitis C virus and HIV (anti-HIV1/2 and p24 
antigen) will be done at Screening. In case of positive results, the subject will be referred to 
appropriate medical care. 
7.6.3 
Urine Drug Screen 
A urine drug screen will be performed at the site at the Screening Visit and at the day of 
Admission. The urine will be screened for amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, and opiates.  

 
 
 
 
 
 
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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 a newly calibrated alcometer device (e.g., Alcotest 7410 Plus, Dräger). 
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 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 
inSection 8.5. 
7.7 
Sample Handling, Storage, and Shipment 
Participating laboratories for blood samples testing will be decided prior to investigator 
meeting and site initiation. Safety laboratory samples will be tested at a local laboratory (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. 
Blood samples  

 
 
 
 
 
 
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Blood samples will be drawn by qualified and trained site personnel. Subjects should be in a 
seated position during blood collection.In total, around 260 mL will be drawn for this study 
including planned assessments, safety, and repeated analysis for safety. The required aliquots 
and volumes for assessments of blood/plasma parameters and tests are summarized in the 
SHM.  
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 
analysed 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 
Section 8).  
7.8.1 
Fagerström Test for Nicotine Dependence (revised version) 
Potential nicotine dependence will be assessed at Screening using the FTND in its revised 
version (Heatherton et al, 1991), as updated in 2012 (Fagerström et al, 2012).  
The questionnaire consists of 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 to 10 
points) (Fagerström et al, 2012). 
7.8.2 
Assessment of Cough 
Subjects will be asked if they have experienced a regular need to cough e.g. coughing several 
times in the last 24 hours prior to assessment. If the answer is ‘yes’, they will be asked to 
complete a VAS, three Likert scales and an open question also assessing the previous 
24 hours.  

 
 
 
 
 
 
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The VAS will assess how bothersome cough is to the subject ranging from ‘not bothering me 
at all’ to ‘extremely bothersome’.  
Furthermore, subjects will be asked to assess the intensity and frequency of cough and the 
amount of sputum production on Likert scales:  
 The intensity of cough will be assessed on a 5-point Likert scale ranging 
from 1 to 5: 1 = very mild; 2 = mild; 3 = moderate; 4 = severe; 5 = very 
severe.  
 The frequency of cough will be assessed on a 5-point Likert scale ranging 
from 1 to 5: 1 = rarely; 2 = sometimes; 3 = fairly often; 4 = often; 
5 = almost always. 
 The amount of sputum production will be assessed on a 4-point Likert scale 
ranging from 0 to 3: 0 = no sputum; 1 = a moderate amount of sputum; 2 = a 
larger amount of sputum; 3 = a very large amount of sputum.  
 
Finally, subjects will be asked with an open question if there are any other important 
observations that they would like to share with the staff about their coughing. 
Assessments will be done on a daily basis from Day 0 to Day 4. On Day 2 and Day 4, 
questionnaire must be asked 24 hours after T0of Day 1 and after 24 hours minus 5 minutes 
after T0of 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 or smoke CC 
during the study in sequence 1 and 2. The MCEQ will be completed by subjects on Day 1 
and Day 3.  
7.8.4 
Questionnaire of Smoking Urges (QSU-brief)  
To assess the urge-to-smoke, all subjects will be asked to complete a 10-item brief version of 
the QSU-brief (Cox et al, 2001). The QSU-brief is a self-reported questionnaire with 10 
items to be ratedon a 7-point scale, ranging from 1 (strongly disagree) to 7 (strongly agree). 
Higher scores in this questionnaire indicate a higher urge to smoke.  
The findings in this brief version were consistent with the expressions of craving found in the 
32-item version of the QSU-brief (Tiffany et al, 1991). The findings supported a 
multi-dimensional conceptualization of craving to smoke and demonstrated the utility of a 
brief multi-dimensional measure of craving (Cox et al, 2001).  
The QSU-brief will be completed by the subject himself/herself at single use study days (D1, 
D3). The first assessment will be done prior to T0. All other assessments will be done after 
T0, at 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours (with an allowed time window of 
+5 min each) and 4 hours, 6 hours, 9 hours, 12 hours (with an allowed time window of +10 
min each). 
7.8.5 
Socio-Economic Questionnaire 
At Screening, subjects will fill a questionnaire, which will allow the Sponsor to assign the 
subject household’s SES. Subjects will be asked a series of questions related to their 
education, occupation, and household. Then they will be asked a series of questions to assess 
the occupation, employment status and qualifications of the Chief Income Earner of their 
household that is the person with the largest income. The questionnaire will be administered 
by a trained interviewer. 
The social grading classification that will be used to determine the subject household’s SES 
is based upon the occupation and employment status of the Chief Income Earner (Meier & 
Moy, 2004). Based on the answers of the subjects, data will be recoded in order to assign the 
head of the household to one of the following socio-economic classes:  
Grade  
Social class 
A  
 
upper middle class 
B  
 
middle class 

 
 
 
 
 
 
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C1  
 
lower middle class 
C2  
 
skilled working class 
D  
 
working class 
E  
 
Those at the lowest levels of subsistence 

 
 
 
 
 
 
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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 unfavourable, whether or not it is considered related to the tobacco 
product, as defined by the MRTP guidelines. 
 
An AE is defined as any untoward medical occurrence in a subject, or clinical investigation 
subject administered an IP, which does not necessarily have a causal relationship with the IP 
or reference point product. An AE can therefore be any unfavourable and unintended sign 
(including a clinically relevant abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IP or reference point product, whether or not to the IP or 
reference point product 
 
 
8.1.2 
Serious Adverse Events 
An SAE is defined as, but not limited to, any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, 
they may jeopardize the subject or the subject may require medical or surgical intervention to 
prevent one of the outcomes listed in the above definitions. 

 
 
 
 
 
 
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Any pre-planned hospitalizations that are known at the time of signing the ICF will not be 
recorded as SAEs; however, they will be recorded as AEs only. Any AE that occurs during 
this pre-planned hospitalization will be considered according to the above definitions. 
8.2 
Assessment of Adverse Events 
The Investigator is responsible for obtaining, assessing and documenting all AEs during the 
study.  
8.2.1 
Collection of Information 
Adverse event information will be collected from the time of signature of the ICF onwards 
until 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 are you feeling since you were last asked?”). At 
the discretion of the Investigator, the collection of AE information may also be triggered 
from his/her review of the subject questionnaires and the VAS. However, the main source for 
AE collection will be 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 ‘septicaemia’ rather than ‘fever’ and ‘hypotension’ 
following blood sample). 
Any AE that meets the serious criteria must be recorded both on the AE report form of the 
eCRF and on a separate SAE report form (see Section 8.3). 
 
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.  

 
 
 
 
 
 
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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. 
 
8.2.2.2 
Admission Day until the End of Study 
From Admission onwards until Day of Discharge, all AEs will be actively collected by the 
study site 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.  
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. 

 
 
 
 
 
 
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8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures 
According to CIOMS VI Working Group, there are no definitive methods for distinguishing 
most adverse drug reactions (i.e., events that are causally attributed to the IP and reference 
point product) from clinical adverse events 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 as described below. In addition to the assessment of the relationship of the 
clinical event to the IP, the Investigator shall document a potential relationship of the clinical 
event to any particular study procedure. 
Not related: The temporal relationship of the clinical event to IP and reference point 
product administration or a study procedure makes a causal relationship 
unlikely, or, concomitant medication, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
 
Related: 
The temporal relationship of the clinical event to study IP and reference point 
product administration or a certain study procedure makes a causal 
relationship possible, and concomitant medication, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation for the observed 
event. 
8.2.5 
Expectedness 
An AE will be regarded as ‘unexpected’ if its nature or severity is not consistent with 
information already known about the IP, 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. 
 
 

 
 
 
 
 
 
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8.3 
Reporting and Follow-Up of Serious Adverse Events 
Any SAEs reported or observed during the study after signature of the ICF until the end of 
the safety follow-up period (i.e., up to 7 days after study Discharge) whether or not 
attributable to the IP, to any other medication or to any study procedures, or any SAE related 
to the product and spontaneously reported after the safety follow-up must be reported by the 
Investigator or other study site staff within 24 hours after first awareness by any party 
involved in the study to 
 (
 Safety 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: 
 
 
 
 
Sponsor: 
Contact: 
, 
MD, Medical Safety 
Officer 
Phone number:
+41 
 
E-mail: 
 
 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube 
5 Quai Jeanrenaud 
2000 Neuchâtel 
Switzerland 
The Investigator is responsible for local reporting (e.g., to the IEC) of SAEs that occur during 
the study, according to local regulations. 
Any additional/follow-up information that becomes available after the initial SAE report 
form has been completed will be forwarded to 
 and the Sponsor within 24 hours 

 
 
 
 
 
 
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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 investigator or designee and/or 
 
 until resolution 
or until the Investigator considers the event to be stabilized (i.e., no worsening of condition), 
or an acceptable explanation has been found (e.g., 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 eCRF, in addition to the SAE report form. 
8.4 
Reporting of Other Events Critical to Safety Evaluations 
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator and assessed for clinical relevance. If the Investigator considers 
the abnormal result to be of clinical relevance, then it must be recorded as a concomitant 
disease at Screening, or if not present at Screening, as an AE during the study. 
The grading scheme shown in (reference to the Common Terminology Criteria for Adverse 
Events and Common Toxicity Criteria [CTCAE] version 4.03) will be used by the 
Investigator to assess abnormal laboratory AEs as follows: 
• 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 enrol 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. 

 
 
 
 
 
 
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• 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 and reference point product, intensity, 
seriousness, outcome) will be assessed as for other AEs. 
8.5 
Reporting and Follow-Up of Pregnancies 
For pregnancies detected during the Screening Period and prior to first THS 2.2 use, the 
subject will be considered as a screening failure and removed from the study. No Pregnancy 
Form will be filled; however, the diagnosed pregnancy must be captured in the Screen 
Failure eCRF.  
All pregnancies occurring after signature of the ICF and diagnosed after first exposure to the 
IP and reference point product until completion of the study must be reported by the 
Investigator.  
Any pregnancy potentially associated to exposure to the IP and reference point product, 
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, and reference point product is defined as the conception date being calculated before the 
last exposure to the IP and reference point product.   
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.  

 
 
 
 
 
 
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 will follow up pregnancies only if they were detected after first product use (i.e., 
after THS 2.2 test on Admission Day). If pregnancies are to be followed up, they will be 
followed up until an outcome is reached (e.g., normal delivery, spontaneous abortion or 
voluntary termination). Any pregnancy complications, adverse pregnancy outcomes or 
maternal complications will be recorded. 
The Investigator is responsible for informing the IEC 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 on 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. 
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.  

 
 
 
 
 
 
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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 THS 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 THS Charger that lead 
to an AE/SAE will follow the same processes as described above. 
 
 

 
 
 
 
 
 
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9 STUDY ACTIVITIES 
A detailed schedule of assessments can be found in Appendix 1. The time points shown are 
to be considered the time of assessment for the first subject. As not all subjects can be treated 
at the same time, a short time window will be implemented for subsequent subjects. 
Measurements not conducted at the exact time point, but conducted within the given time 
window (if applicable) do not constitute a protocol deviation but an accepted variability for 
the given time point. 
In general, if no start time for the procedure is provided, then the procedure can be performed 
at any time during the day. 
9.1 
Screening Visit 
The Screening Visit will be performed within 4 weeks (Day -29 to Day -2) prior to 
Admission (Day -1). Subjects will attend the investigational site in at least a 10-hour fasting 
state for clinical laboratory to be assessed.  
The following assessments will be performed at the Screening Visit (Table 4) (the sequence 
of the assessment will be at the discretion of the site but all of them must be done after 
signature of the ICF. 
Table 4. 
Time Schedule – Screening 
Time 
Blood sample 
Procedures 
Additional information 
Start of 
procedure 
 
 
 
 
 
Informed consent 
 
 
 
Demographic data  
On the day of ICF signature 
 
 
Advice on the risks of smoking and 
debriefing 
 
 
 
Socio-economic status 
 
 
 
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/concomitant medication 
 

 
 
 
 
 
 
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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 
(haematology, urine analysis, clinical 
chemistry) 
 
 
 
Serology for HIV and Hepatitis B 
and C 
 
 
 
Identification of current CC brand 
 
 
 
Urine drug screen 
 
 
 
Alcohol breath test 
 
 
 
Urine pregnancy test for female 
subjects 
 
 
 
THS 2.2 and NNS product 
demonstration 
 
 
 
Spirometry without short-acting 
bronchodilator, and then with 
 
 
 
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; CC = 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 = Tobacco Heating System 
9.2 Admission 
The following assessments will be performed at Admission (Day -1) (Table 5): 

 
 
 
 
 
 
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Table 5. 
Time Schedule – Day -1 Admission 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
 
 
 
 
AE/SAE recording, concomitant 
medication 
All day 
 
 
Advice on the risks of smoking and 
debriefing 
 
 
 
Readiness to accept interruptions of 
smoking for up to 4 days 
 
 
 
trans-3’-hydroxycotinine and 
cotinine (CYP2A6 activity) in 
plasma 
The subject should not have 
smoked in the morning until this 
assessment 
Must be done prior smoking 
6:30 AM 
 
Beginning of smoking period 
 
 
 
Urine pregnancy test for female 
subjects 
 
 
 
Clinical laboratory parameters 
(haematology, urine analysis, 
clinical chemistry) 
 
 
 
Urine cotinine screening test 
 
 
 
Urine drug screen 
 
7:30 AM-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 
 
Physical examination, weight and 
calculated BMI 
 
10:00 AM-11:30 AM 
 
Spirometry 
 
10:00 AM-11:30 AM 
 
Identification of current CC brand 
 
10:00 AM-11:30 AM 
 
Smoking history 
 
10:00 AM-11:30 AM 
 
Alcohol breath test 
 
10:00 AM-11:30 AM 
 
CO breath test 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:30 PM-6:00 PM 
 
Snacks 
 

 
 
 
 
 
 
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4:30 PM-6:00 PM 
 
Product test for THS 2.2 and NNS 
The THS 2.2 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 
 
6:30 PM-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 
 
7:30 AM-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 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 

 
 
 
 
 
 
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4:30 PM-5:00 PM 
 
Snacks 
 
6:30 PM-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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Table 7. 
Time Schedule – Day 2 Washout 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
 
 
 
 
Nicotine abstinence 
All day 
 
 
Support during nicotine abstinence as 
required 
All day 
 
 
AE/SAE recording, concomitant 
medication 
All day 
 
 
Plasma nicotine PK sample 
24 hrs +5 min after T0 of Day 1  
 
 
Assessment of cough 
24 hrs minus 5 min after T0 of 
Day 1  
7:30 AM-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 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 
4:30 PM-5:00 PM 
 
Snacks 
 
6:30 PM-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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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 first 
blood draw of the day 
 
 
 
AE/SAE recording, concomitant 
medication 
All day 
 
 
Support as required 
All day 
 
 
Craving questionnaire 
(QSU-brief) 
First time prior to T0, then 15 min +5 
min, 30 min +5 min, 45 min +5 min, 
1 hr +5 min, 2 hrs +5 min, after T0, 
then and 4 hrs +10 min, 6 hrs +10 
min, 9 hrs +10 min, and 12 hrs +10 
min 
 
 
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) 
 
 
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 

 
 
 
 
 
 
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6:00 AM-9:00 AM 
 
Start of single product use 
 
7:30 AM-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 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 
5:00 PM-5:30 PM 
 
Snacks 
 
6:30 PM-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 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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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 
minus 5 min 
7:30 AM-9:00 AM 
 
Clinical laboratory parameters 
(haematology, urine analysis, clinical 
chemistry) 
 
7:30 AM-9:00 AM 
 
Urine pregnancy test 
 
9:00 AM-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 
 
CO breath test 
 
10:00 AM-11:30 AM 
 
Spirometry  
 
10:00 AM-11:30 AM 
 
Physical examination, weight and 
calculated BMI 
 
10:00 AM-11:30 AM 
 
Advice on risk of smoking and 
debriefing 
 
10:00 AM-11:30 AM 
 
Time of discharge 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; CO = Carbon monoxide; PK = Pharmacokinetic; SAE = 
Serious adverse event; T = Time point 
Smoking will be allowed after spirometry has been conducted. 

 
 
 
 
 
 
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9.5 
Safety Follow-up Period 
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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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 SOPsand 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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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, 
analysed, 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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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 paper copies. 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. 
11.1.1 
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 oestrogen 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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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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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(CC, THS 2.2, and NNS) to allow comparisons between 
THS 2.2 and CC in Group-1 (sequence 1 and 2), and between THS 2.2 and NNS in Group-2 
(sequence 3 and 4). 
Full details of the statistical analysis will be given in a SAP. Any changes to the planned 
statistical methods will be documented in the Clinical Study Report. The statistical 
evaluation will be performed using SAS®, version 9.2 or later. 
12.1.1 
Stratification Criteria 
For analysis, the following stratification criteria will be used:  
 Sex (male and female) 
 CC nicotine level at Admission (ISO nicotine levels 0.6 mg and >0.61 mg)  
 
In addition, for the safety data, the analysis will be stratified by sequence and by study 
periods (Screening, product test, product exposure, and safety follow-up period). 
12.1.2 
Definitions for Statistical Data Analysis 
Unless otherwise stated, for the purposes of statistical analyses, baseline is defined as the last 
available time point prior to T0 on Day 1, from 6:00 AM to 9:00 AM. 
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by sequence and subject, unless otherwise 
specified.  
Descriptive statistics for continuous variables (number of subjects [n], number and 
percentage of subjects with missing data, mean, standard deviation, median, first and third 
quartiles, minimum and maximum for continuous data, and the n and absolute and relative 
[%] frequency for categorical data) will presented by exposure and overall at each time point, 
where applicable.  
Descriptive statistics for PK parameters will also include the geometric mean and coefficient 
of variation.  

 
 
 
 
 
 
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Baseline, admission and screening data (i.e., anything prior to product exposure) will be 
summarized by sequence and overall where appropriate. 
12.1.4 
Handling of Missing Values and of Values outside the Detection Limits 
In general, missing data will not be imputed in this study, due to the nature of the 
measurements and the short periods of exposure and use. However, for questionnaire data 
total scores and domain or subscale scores may use a certain degree of imputation by 
averaging across individual item scores. Further details will be provided in the SAP. 
Values below the lower limit of quantification (LLOQ) will be imputed using 0.5 x 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 (CIs) will be two-sided 95% 
CIs. 
No formal adjustment of the test-wise alpha level for multiple testing is necessary, as no 
claim will be made based on the outcome of the individual tests. 
12.2 Determination of Sample Size and Power Consideration 
A total of 62smokers 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 
and CC with a 90% probability of obtaining a margin of error (95% CI) of at most ±20%, 
assuming that THS 2.2 have a nicotine PK profile similar to CC (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 
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 and NNS is 1.55, based on data reported by Gourlay and Benowitz, 1997, 
and Johansson et al, 1991. 

 
 
 
 
 
 
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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 (PMI, 2012a) comparing the 
nicotine PK profiles of THS 2.1, the predecessor of THS 2.2 and CC. In the absence of data 
comparing THS and NNS, the same CVs were assumed for the calculation of the sample size 
related to the THS 2.2:NNS comparison. 
Sample size calculationswere conducted using SAS version 9.2for 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, 1989was 
adopted to estimate the probability of obtaining at most the target confidence intervalof 
±20%. 
12.3 
Analysis Populations 
All analyses will be based on actual product exposure. All endpoints (other than safety) will 
be analysed using the PK Analysis sets. Safety will be analysed 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 and NNS separately from the comparison between THS 2.2 
and CC.  
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 (including the product test at Admission Day). 
12.4 Demographics and Baseline Characteristics 
Demographic and other baseline characteristics will be reportedfor the PK and safety 
populations. Appropriate summary statistics will be providedas described in Section 12.1.3. 
 

 
 
 
 
 
 
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12.5 Primary Endpoints 
12.5.1 
Primary Endpoint Analysis Variables 
Nicotine PK parameters will be derived from plasma nicotine versus time data using a 
non-compartmental technique. In particular: 
Cmax 
Maximum observed plasma concentration. Cmax will be reported as long 
as there is at least one quantifiable concentration post-exposure 
AUC(0-last) 
Area under the plasma concentration-time curve from start of product 
use to the time of the last quantifiable concentration (linear trapezoidal 
method).  
 
12.5.2 
Baseline Comparability 
Not applicable. 
12.5.3 
Descriptive Analysis 
Primary endpoints will be summarized as described in Section 12.1.3. 
An analysis of variance (ANOVA) will be conducted on AUC(0-last) and Cmax endpoints in the 
natural logarithmic scale. The model will include terms for sequence, subjects within 
sequence, period and product exposure as fixed effect factors. The results of this analysis for 
each of AUC(0-last) and Cmax are presented in terms of adjusted geometric least square means 
and 95% CIs for the THS 2.2:CC and THS 2.2: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, using 2000 bootstrap samples 
which preserve the number of subjects per sequence. 
12.5.4 
Confirmatory Analyses 
Given that the objective of this study is to determine the point estimate and precision of the 
ratio of THS 2.2:CC for Cmax and AUC(0-last), there is no statistical hypothesis to be tested. 
 
12.6 Secondary Endpoints 
12.6.1 
Secondary Endpoint Analysis Variables 
Nicotine PK parameters will be derived as follows: 
tmax 
Time of maximum observed plasma concentration. tmax will be reported 
as long as there is at least one quantifiable concentration post-exposure 
AUC(0-t’) 
Area under the plasma concentration-time curve from zero to the 
subject-specific time to maximum nicotine concentration following 
single use of CC or NNS(linear trapezoidal method) 
AUC(0-) Area under the plasma concentration-time curve from start of product 
use extrapolated to infinite time, according to: 
 
Where Clast is the last quantifiable concentration and z is the terminal 
elimination rate constant 
z 
Terminal elimination rate constant, estimated by linear regression 
analysis of the natural log-transformed concentration-time data 
t1/2 
Terminal elimination half-life, derived as ln(2)/z 
More details on PK parameter derivations will be provided in the SAP. 
Subjective effects of using THS 2.2 as compared to the CC and to the NNS will be evaluated 
by analysing 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
λ
0
-
0

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
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: 
 AUC(0-), AUC(0-t’), and t1/2 will be analysed using the same approach adopted for the 
primary endpoints. No statistical analysis will be performed on the elimination rate 
constant λz. Data will be summarized and presented together with 95% CI.  
 Hodges-Lehmann 95% CI estimates for the median tmax differences will be presented 
(Lingling, 2008). 
 The use of random effects model is suggested in the context of the analysis of 
subjective effects of smoking (Shiffman et al, 2004). Mixed effects ANOVA with the 
same model terms as planned for the sensitivity analysis of the primary endpoints will 
be adopted for the analysis of QSU-brief, including all of the different assessment 
time points as repeated measurements. The analysis will not be adjusted for the 
assessment prior to T0 (Fleiss et al, 1985). 
 Levels of exhaled CO and of blood COHb will be summarized by means of 
descriptive statistics reported by exposure. Analysis of COHb levels will be 
conducted using a mixed model for repeated measures, the same approach as for the 
QSU-brief. 
 
The following analyses will be conducted only in Group-1 PK analysis set: 
 Mixed effects ANOVA with the same model terms as planned for the sensitivity 
analysis of the primary endpoints will be adopted for the analysis of the MCEQ 
domain scores. 
 
The following analyses will be conducted in only Group-2 PK analysis set: 
 To test if the time to the maximum nicotine concentration in THS 2.2 is shorter than 
in NNS the following hypothesis will be evaluated: 
H0: XTHS - XNNS = 0 
HA: XTHS - XNNS < 0 

 
 
 
 
 
 
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whereXTHS and XNNS are the median values of the THS 2.2 and NNS, respectively. tmax 
will be analysed on the original scale using the Wilcoxon Signed-Rank Test with a 
type I error  = 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 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  
whereXTHS and XNNS are the adjusted geometrical means of THS 2.2 and NNS, 
respectively. H0 is rejected with a type I error  = 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. 
AEdata 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, haematology, and urine analysis safety panel; physical examination; 
and concomitant medication. 
The number and percentage of subjects with AEs andSAEs will be tabulated by system organ 
class and preferred term. Summaries will also be presented for AEs leading to withdrawal, 
AEs leading to Death, AEs by relatedness to product exposure, AEs by severity, and 
laboratory AEs. Tabulations will be performed for both the number of subjects experiencing 
an event and the number of events.The number and percentage of device events and of 
subjects with device events will be tabulated by sequence. 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
The number and percentage of subjects with clinical findings will be tabulated by sequence 
for laboratory parameters. Shift tables showing change from baseline of clinical findings will 
be provided for ECGs, physical examinations, and laboratory parameters (both shifts in 
normal ranges and toxicity grades). Descriptive statistics will be summarized by visit and 
change from baseline for laboratory parameters, ECG, respiratory symptoms, and vital signs. 
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 Products SA. 
 
13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Investigators and Study Administrative Structure 
13.1.1 
Investigator 
Principal Investigator: 
 
Johnston Stewart 
 
Celerion GB Ltd, 
 
 
 
 
 
 
 
 
 
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 
 
Fax: +41
 
Mobile: +41
 
E-mail:
 
, PhD 
Biostatistician 
Phone: +41 
 
Mobile: +41
 
E-mail: 
 
, MD 
Phone: +41 
 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
Medical Safety Officer 
Mobile: +41
 
E-mail: 
 
 
Medical Writer 
Phone: +41 
  
Mobile: +41 
 
E-mail: 
 
, PhD 
Clinical Study Manager 
Phone: +41 
 
Mobile: +41 
 
E-mail:
 
 
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 
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 confidentiality of data for subjects participating in this study will be maintained. 
Subjects will be identifiable by the Sponsor (or Sponsor’s authorized representative) on 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
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, IEC review, and regulatory 
inspection(s). 
13.4 
Record Retention 
All records of data, source data and source documents (original records or certified copies), 
in any form (including, but not limited to, written, electronic, 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 GCP 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 
• At least 2 years depending on, for example, the circumstances 
• After formal discontinuation of clinical development of the IP.  

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
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 IEC, composition of the 
IEC. 
• 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). 
• 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. 
• Information regarding subjects’ discontinuation and any follow-up. 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
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 IEC 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 
this document is allowed only to study personnel, IRB, or duly authorized representatives of 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
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 
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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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products SA. 
 
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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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products SA. 
 
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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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products SA. 
 
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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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products SA. 
 
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are hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products SA. 
 
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without the written consent of Philip Morris Products SA. 
 
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Withdrawal in Clinical Trials.Recommendation for the assessment of tobacco craving and 
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U.S. Department of Health and Human Services. How Tobacco Smoke Causes Disease: The 
Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon 
General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease 
Control and Prevention, National Center for Chronic Disease Prevention and Health 
Promotion, Office on Smoking and Health, 2010. Available on  
http://www.surgeongeneral.gov/library/tobaccosmoke/report/executivesummary.pdf. 
Raw et al, 2002 
Raw M, Anderson P, Batra A, Dubois G, Harrington P, Hirsch A et al. World Health 
Organization European Partnership Project to Reduce Tobacco Dependence. WHO Europe 
evidence based recommendations on the treatment of tobacco dependence. Tob Control. 
2002; 11 (1): 44-46.   
Ussher and West, 2009 
West R, Ussher M. Is the ten-item Questionnaire of Smoking Urges (QSU-brief) more 
sensitive to abstinence than shorter craving measures? Psychopharmacology, DOI 
10.1007/s00213-009-1742-x, available at 
http://www.ucl.ac.uk/hbrc/tobacco/pubs/ten_item_questionnaire_west_ussher.pdf (accessed 
on 05 Oct 2012). 

 
 
 
 
 
 
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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 and NNS 
 
 
 
 
 
 
 
 
Product test for THS 2.2 and 
NNS 
 
 
 
 
 
 
 
 
Identification of current CC 
brand 
 
 
 
 
 
 
 
 
Smoking history 
 
 
 
 
 
 
 
 
Readinessto accept interruption 
from smoking up to 4 days 
 
 
 
 
 
 
 
 
Willingness to quit smoking in 
the next 3 months 
 
 
 
 
 
 
 
 
Demographics a, socio-
economic status, medical 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
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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 
history, concomitant diseases 
Prior medication b / 
Concomitant medication 
 
 
 
 
 
 
 
 
Physical examination, body 
height, weight and related BMI c 
 
 
 
 
 
 
 
 
Vital signs d 
 
 
 
 
 
 
 
 
ECG 
 
 
 
 
 
 
 
 
Spirometry 
 
 
 
 
 
 
 
 
Chest X-ray e 
 
 
 
 
 
 
 
 
B/U:Haematology, clinical 
chemistry, urine analysis 
 
 
 
 
 
 
 
 
B: Serology  
 
 
 
 
 
 
 
 
U: Urine drug screen, urine 
cotinine screen 
 
 
 
 
 
 
 
 
Alcohol breath test  
 
 
 
 
 
 
 
 
U: Pregnancy test (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 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
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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 
cotinine (CYP2A6 activity) in 
plasma  
FTND questionnaire 
 
 
 
 
 
 
 
 
QSU–brief questionnaire i 
 
 
 
 
 
 
 
 
MCEQ (modified version, only 
after THS 2.2 and CC use  
 
 
 
 
 
 
 
 
Cough assessment j 
 
 
 
 
 
 
 
 
AE/SAE recording  
 
 
 
 
 
 
 
 
See also instructions and abbreviations on the following page. 
Abbreviations: AE = Adverse event; CC = 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; SAE = Serious adverse 
event; THS = Tobacco Heating System 
 
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 min +1 min, T2 after 4 min +1min, T3 after 6 min +1 min, 
T4 after 8 min +1 min, T5 after 10 min +1 min, T6 after 15 min +2 min, T7 after 30 min +2 min, T8 after 45 min +2 min, T9 after 60 

 
 
 
 
 
 
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min +3 min, T10 after 2 hours +5 min, T11 after 4 hours +5 min, T12 after 6 hours +5 min, T13 after 9 hours +5 min, T14 after 12 
hours +5 min, and T15 after 24 hours +5 min.  
g: COHb blood samples to be taken as follows: 
Single use: A total of 5 blood samples will be taken. The first sample within 15 minutes prior to T0 (start of single product use); thereafter in 
relation to T0 at 15 min +2 min, 60 min +3 min, 4 hours +5 min and 12 hours +5 min 
h: A CO breath test will be conducted once on Day -1 and Day 4. On Day 0, Day 1, Day 2, Day 3, four breath tests will be done per day. On Day 
1 and Day 3, the first test per day will be performed within 15 minutes prior to T0 (T0 = start of first product use) and then around 12:00 pm, 
4:00 pm and 8:00 pm. On the wash-out days (Day 0 and Day 2) it will be conducted around 8:00 am, 12:00 pm, 4:00pm, and 8:00 pm. 
i: QSU–brief will be assessed as follows:  
Single use: The QSU-brief will be completed by the subject himself/herself at single use study days. The first assessment will be done prior to 
T0. All other assessments will be done after T0, at 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours (with an allowed time window of +5 
min each) and 4 hours, 6 hours, 9 hours, 12 hours (with an allowed time window of +10 min each). 
j: Visual analogue scale, three Likert scales and one open question. Cough questionnaire should be asked on Day 0 between 06:30 and ’09:00, 
on Day 2 24 hours after T0 of Day 1, on Day 4, 24 hours after T0 of Day 3, and on Day 1 and Day 3, prior product use. 
k: All examinations listed at the Day of Discharge should also be conducted in subjects preliminarily terminating the study. 
l: Spontaneous reporting of new AEs/SAEs by the subject and active follow-up of ongoing AEs/SAEs by the site. 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
 
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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without the written consent of Philip Morris Products SA. 
 
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 NNSproduct label listing AEs relating to the product can be found at the internet 
link: http://www.medicines.org.uk/emc/medicine/20679  
Undesirable effects 
Some symptoms may be related to nicotine withdrawal associated with stopping smoking. These can include; 
irritability/aggression, dysphoria/depressed mood, anxiety, restlessness, poor concentration, increased 
appetite/weight gain, urges to smoke (cravings), night-time awakenings/sleep disturbance and decreased heart 
rate. Increased frequency of aphthous ulcer may occur after abstinence from smoking. The causality is unclear.  
Nicorette Nasal Spray may cause adverse reactions similar to those associated with nicotine given by other 
means, including smoking, and these are mainly dose-dependent. At recommended doses Nicorette Nasal Spray 
has not been found to cause any serious adverse effects. Excessive use of Nicorette Nasal Spray by those who 
have not been in the habit of inhaling tobacco smoke could possibly lead to nausea, faintness or headaches.  
During the first 2 days of treatment, nasal irritation as sneezing, running nose, watering eyes, cough was 
reported by nearly all (94%) of the patients. Both the frequency and severity declined with continued use. 
Reported adverse events associated with Nicorette Nasal Spray include: 
Body System 
Incidence* 
Reported adverse event 
Nervous system disorders:  
Common  
Dizziness, headache  
Cardiac disorders:  
Uncommon:  
Palpitations  
  
Very rare:  
Reversible atrial fibrillation  
Respiratory, thoracic and 
mediastinal disorders:  
Common:  
Coughing  
Gastrointestinal disorders:  
Common:  
Gastrointestinal discomfort, nausea, vomiting  
General disorders and 
administration site disorders:  
Very common:  
Epistaxis, running nose, sneezing, watering eyes.  
* Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1 000, < 1/100); rare (>1/10 000, <1/1 000); 
very rare (<1/10 000), including isolated reports.” 

 
 
 
 
 
 
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Appendix 5 
Abnormal Laboratory Values 
ABNORMAL LABORATORY VALUES RATING: SERUM CHEMISTRY PARAMETERS 
Serum Chemistry* 
Mild
(Grade 1) 
Moderate
(Grade 2) 
Severe
(Grade 3) 
Sodium – Hyponatremia (mmol/l) **
(1) 
<LLN - 130 
- 
<130 - 120 
Sodium – Hypernatremia (mmol/l) ** 
(1) 
>ULN - 150 
>150 - 155 
>155 - 160; 
hospitalization 
indicated 
Potassium – Hyperkalaemia 
(mmol/l)**(1) 
>ULN - 5.5 
>5.5 - 6.0 
>6.0 - 7.0; 
hospitalization 
indicated 
Potassium – Hypokalaemia (mmol/l) 
** (1) 
<LLN - 3.0 
<LLN - 3.0; 
symptomatic; 
intervention 
indicated 
<3.0 - 2.5; 
hospitalization 
indicated 
Glucose – Hypoglycaemia** (1)    
(mg/dL) 
                                                   
(mmol/l) 
<LLN – 55; 
<LLN – 3.0 
<55 – 40; 
<3.0 – 2.2 
<40 – 30; 
<2.2 – 1.7 
Blood Urea Nitrogen (BUN) (mg/dL) 
(2) 
23 – 26 
27 – 31 
>31 
Glucose – Hyperglycaemia: ** 
 
Fasting (1)( (mg/dL) 
                   (mmol/l) 
 
 
>ULN – 160; 
>ULN – 8.9 
 
>160 -250 
> 8.9-13.9 
 
 
>250 – 500; 
>13.9 – 27.8 
Hospitalization 
indicated 
Creatinine increased** (1) 
>1 – 1.5 x 
baseline; 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x 
baseline; 
>1.5 – 3.0 x ULN 
>3.0 x baseline;
>3.0 – 6.0 x ULN
Albumin – Hypoalbuminaemia** 
(1)(g/dL) 
                                                          
(g/l) 
<LLN – 3; 
<LLN - 30 
<3 – 2; 
<30 - 20 
<2; 
<20 
Total Protein – Hypoproteinaemia (2) 
(g/dL)
 
5.5 – 6.0 
 
5.0 – 5.4 
 
<5.0 

 
 
 
 
 
 
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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 ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 ULN 
Cholesterol high** (1)( 
 
 
 
 
 
 
 
 (mg/dL) 
(mmol/l)
 
>ULN – 300; 
>ULN – 7.75 
 
 
>300-400; 
>7.75-10.34 
 
 
>400-500; 
>10.34-12.92 
Triglycerides - Hypertriglyceridemia 
(1) 
(mg/dL)
(mmol/l)
 
150 – 300; 
1.71 – 3.42 
 
>300 – 500; 
>3.42 – 5.70 
 
>500 – 1000; 
>5.70 – 11.40 
Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; LLN = Lower 
limit of the normal range; ULN = Upper limit of the normal range. 
Data Sources: 
 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, U.S. Department of Health and Human Services, FDA, Center for 
Biologics 
Evaluation 
and 
Research 
- 
Guidance 
for 
Industry. 
 
       (2) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, 
FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
*  Those parameters that are not listed do not have grading categories in either the CTCAE or the 
FDA guidance documents and will therefore be reviewed by the Investigator and only reported as 
an AE if considered to be clinically relevant. 
** Where parameters in this table are listed in both the CTCAE and the FDA guidance documents, 
and each document has different values within each grading category, the grading in CTCAE 
guidance document predominates. 

 
 
 
 
 
 
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ABNORMAL LABORATORY VALUES RATING: HEMATOLOGY PARAMETERS 
Haematology* 
Mild
(Grade 1) 
Moderate
(Grade 2) 
Severe
(Grade 3) 
Haemoglobin (Female) – (g/dL) 
(1) 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
change from baseline value – 
(g/dL) (1)
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
Haemoglobin (Male) – (g/dL) (1) 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
change from baseline value – 
(g/dL) (1)
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
Haemoglobin increase – (g/dL) (2)
Increase in >0 – 2 
above ULN or 
above baseline if 
baseline is above 
ULN 
Increase in >2 – 4 
above ULN or above 
baseline if baseline 
is above ULN 
Increase in >4 
above ULN or 
above baseline if 
baseline is above 
ULN 
WBC Increase – (cell/mm3) (1) 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25,000 
WBC Decrease - (cell/mm3) (2)** 
<LLN – 3000; 
<LLN – 3.0 x 10-9/l 
<3000 - 2000; 
<3.0 – 2.0 x 10-9/l 
<2000 - 1000; 
<2.0 – 1.0 x 10-9/l 
Lymphocytes Increase - 
(cell/mm3) (2) 
- 
>4,000 – 20,000 
>20,000 
Lymphocytes Decrease - 
(cell/mm3) (2)** 
<LLN – 800; 
<LLN – 0.8 x 10-9/l 
<800 - 500; 
<0.8 – 0.5 x 10-9/l 
<500 - 200; 
<0.5 – 0.2 x 10-9/l 
Neutrophils Decrease - 
(cell/mm3) (2)** 
<LLN – 1500; 
<LLN – 1.5 x 10-9/l 
<1500 - 1000; 
<1.5 – 1.0 x 10-9/l 
<1000 - 500; 
<1.0 – 0.5 x 10-9/l 
Eosinophils - (cell/mm3) (1) 
650 – 1500 
1501 - 5000 
>5000 
Platelets Decrease - (cell/mm3) 
(2)** 
<LLN – 75,000; 
<LLN – 75.0 x 10-9/l
<75,000 – 50,000; 
<75.0 – 50.0 x 10-9/l 
<50,000 – 25,000; 
<50.0 – 25.0 x 10-9/l
Abbreviations: LLN = Lower limit of the normal range; ULN = Upper limit of the normal range; WBC = 
White blood cell. 
Data Sources: 
 
(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. 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
*  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. 

 
 
 
 
 
 
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without the written consent of Philip Morris Products SA. 
 
ABNORMAL LABORATORY VALUES RATING: URINALYSIS PARAMETERS 
Urine* 
Mild
(Grade 1) 
Moderate
(Grade 2) 
Severe
(Grade 3) 
Protein ** (1) 
1+ proteinuria; 
urinary protein <1.0 
g/24 hours 
2+ proteinuria; 
urinary protein 1.0-
3.4 g/24 hours 
Urinary protein 3.5 
g/24 hours 
Glucose (2) 
Trace 
1+ 
2+ 
Blood – Haematuria ** (1) 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; urinary 
catheter or bladder 
irrigation indicated; 
limiting instrumental 
ADL 
Gross haematuria; 
transfusion, IV 
medications or 
hospitalization 
indicated; elective 
endoscopic, radiologic 
or operative 
intervention indicated; 
limiting self-care ADL 
Abbreviations: ADL = Activities of daily living; IV = Intravenous. 
Data Sources: 
 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
 
(2) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, 
FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
*  Those parameters that are not listed do not have grading categories in either the CTCAE or the 
FDA guidance documents and will therefore be reviewed by the Investigator and only reported as 
an AE if considered to be clinically relevant. 
**  Where parameters in this table are listed in both the CTCAE and the FDA guidance documents, 
and each document has different values within each grading category, the grading in CTCAE 
guidance document predominates. 
 
 
 
 

 
 
 
 
 
 
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Appendix 6 
Investigational Micro+TM Smokerlyzer® 
The Micro+™ Smokerlyzer® carbon monoxide (CO) monitor is the new-and-improved 
version of the revolutionary Micro™ Smokerlyzer®. The Micro™ Smokerlyzer® is a 
longstanding benchmark device used in clinical studies and research. 
The Micro+™ is the most comprehensive CO monitor available. It analyses breath CO levels 
in adults and adolescents up to 250 ppm, and automatically converts CO readings of pregnant 
women to foetal %COHb. 
Micro+ Features 
• Analyses COHb and CO levels in a single breath. 
• Options for testing adults, adolescents and pregnant women. 
• Instant conversion to foetal %COHb at the touch of a button. 
• Clinically proven stop smoking help. 
• Easy-to-use colour touch screen instantly displays the exact result. 
• On-screen instructions with audio prompts. 
• Store up to 100 readings and view them as a table or a graph. 
• Improved electrochemical sensor and anti-humidity filter. 
• Antibacterial filter and one-way valve for optimal infection control. 
• Auto-zero and adjustable breath hold countdown. 
• Built-in maintenance reminders. 
• Minimal hydrogen cross-sensitivity. 
Operation 
The Micro+ analyses the amount of CO in a single exhaled breath. It uses this reading to 
automatically calculate the percentage of COHb in the blood. Carrying out a test: simply 
press the button to switch the monitor on, then follow the instructions on the touch screen 
display. Exhale into the monitor through the Flatpak™ mouthpiece and the result is displayed 
instantly in exact parts per million (ppm) for CO, and as a percentage for COHb (%COHb). 
The numbers are displayed either in green, amber or red (a familiar ‘traffic light’ system) to 
represent the level of CO. 

 
 
 
 
 
 
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Instrument cleansing wipes 
Instrument cleansing wipes specific to the instrument are provided. 
Calibration 
Calibration gas 
Calibration gas is supplied by Bedfont in lightweight disposable cylinders. Calibration of the 
Micro+™ should be carried out with Bedfont's 50 ppm CO in air calibration gas. No 
specialist technical knowledge or skills are required and Bedfont provides comprehensive 
calibration kits for ultimate ease of use. Calibration should be carried out at least every 
6 months. A calibration reminder will appear automatically when calibration is due. 
 
 
 

 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 

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Final 2.0, 14 May 2013 
Page 2 of 16 
 
consent of Philip Morris Products S.A. 
TABLE OF CONTENTS 
TABLE OF CONTENTS ...........................................................................................................2 
LIST OF APPENDICES ............................................................................................................2 
1 
INTRODUCTION .............................................................................................................3 
2 
MODIFICATIONS TO PROTOCOL................................................................................4 
2.1 
Modification 1 ..........................................................................................................4 
2.2 
Modification 2 ..........................................................................................................4 
2.3 
Modification 3 ..........................................................................................................5 
2.4 
Modification 4 ..........................................................................................................8 
2.5 
Modification 5 ........................................................................................................10 
 
LIST OF APPENDICES 
Appendix 1 
Sponsor Signatures.....................................................................................15 
Appendix 2 
Investigator’s Signature .............................................................................16 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol Amendment N°1 
Confidential 
ZRHR-PK-01-EU 
Final 2.0, 14 May 2013 
Page 3 of 16 
 
1 
INTRODUCTION 
The main purpose of this amendment is to: 
 
 Provide justification for the socio-economic questionnaire and to change the 
timepoint when this questionnaire will be asked to the subjects. 
 
 
More precise details on the protocol sections changed are provided in Section 2. For 
identification of the changes, the previous and the amended texts are provided. The new 
text has been highlighted in bold (e.g. new text) and deleted text has been crossed out 
(e.g. deleted text). 

Philip Morris Products S.A. 
Clinical Study Protocol Amendment N°1 
Confidential 
ZRHR-PK-01-EU 
Final 2.0, 14 May 2013 
Page 4 of 16 
 
2 
MODIFICATIONS TO PROTOCOL 
2.1 
Modification 1 
Section:  7.4.2 Socio-Economic Status 
Page:   
50 
 
Old Text 
At Screening, subjects will be asked questions, which will allow the Sponsor to infer their 
socio-economic status (see section 7.8.5).  
Amended Text 
At Screening, Day 2, subjects will be asked questions, which will allow the Sponsor to infer 
their socio-economic status (see section 7.8.5).  
Reason for Change 
The timepoint of the socio-economic status questionnaire was changed from Screening to 
Day 2 to avoid this questionnaire was asked to subjects who were screened failure. The 
socio-economic questionnaire will be asked only in subjects who are randomized in to the 
study 
2.2 
Modification 2 
Section:  7.8.5 Socio Economic Status Questionnaire 
Page:   
60 
 
Old Text 
At Screening, subjects will fill a questionnaire, which will allow the Sponsor to assign the 
subject household’s SES. Subjects will be asked a series of questions related to their 
education, occupation, and household. Then they will be asked a series of questions to assess 
the occupation, employment status and qualifications of the Chief Income Earner of their 
household that is the person with the largest income. The questionnaire will be administered 
by a trained interviewer. 
 
Amended Text 
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 

Philip Morris Products S.A. 
Clinical Study Protocol Amendment N°1 
Confidential 
ZRHR-PK-01-EU 
Final 2.0, 14 May 2013 
Page 5 of 16 
 
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. There will be a descriptive analysis of 
this data. 
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. 
At Screening, subjects will fill a questionnaire, which will allow the Sponsor to assign the 
subject household’s SES. On Day 2, subjects will be asked a series of questions related to 
their education, occupation, and household. Then they will be asked a series of questions to 
assess the occupation, employment status and qualifications of the Chief Income Earner of 
their household that is the person with the largest income. The questionnaire will be 
administered by a trained interviewer. 
 
Reason for Change 
The justification for collection of socio-economic data was not provided in the protocol and 
has been requested by the Ethic Committee. 
In addition, the timepoint of the socio-economic status questionnaire was changed from 
Screening to Day 2 to avoid this questionnaire was asked to subjects who were screened 
failure. The socio-economic questionnaire will be asked only in subjects who are randomized 
in to the study.  
 
2.3 
Modification 3 
Section:  9.1 Screening Visit 
Page:   
71 
Old Text 
Table 1. 
Time Schedule – Screening 
Time 
Blood sample 
Procedures 
Additional information 
Start of 
procedure 
 
 
 
 
 
Informed consent 
 
 
 
Demographic data  
On the day of ICF signature 
 
 
Advice on the risks of smoking and 
debriefing 
 
 
 
Socio-economic status 
 
 
 
Smoking history 
 
 
 
Willingness to quit smoking in the next 
3 months 
 

Philip Morris Products S.A. 
Clinical Study Protocol Amendment N°1 
Confidential 
ZRHR-PK-01-EU 
Final 2.0, 14 May 2013 
Page 6 of 16 
 
 
 
Readiness to accept interruptions of 
smoking for up to 4 days 
 
 
 
FTND questionnaire 
 
 
 
Prior/concomitant medication 
 
 
 
Medical history/concomitant diseases 
 
 
 
Vital signs (pulse rate, systolic and 
diastolic blood pressure, respiratory 
rate) 
At least 5 min in supine position 
prior to measurement 
 
 
Height, weight, including calculated 
BMI 
 
 
√ 
Clinical laboratory parameters 
(haematology, urine analysis, clinical 
chemistry) 
 
 
√ 
Serology for HIV and Hepatitis B 
and C 
 
 
 
Identification of current CC brand 
 
 
 
Urine drug screen 
 
 
 
Alcohol breath test 
 
 
 
Urine pregnancy test for female 
subjects 
 
 
 
THS 2.2 and NNS product 
demonstration 
 
 
 
Spirometry without short-acting 
bronchodilator, and then with 
 
 
 
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; CC = 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 = Tobacco Heating System 
 
Amended Text 
Table 2. 
Time Schedule – Screening 
Time 
Blood sample 
Procedures 
Additional information 
Start of 
procedure 
 
 
 
 
 
Informed consent 
 
 
 
Demographic data  
On the day of ICF signature 

Philip Morris Products S.A. 
Clinical Study Protocol Amendment N°1 
Confidential 
ZRHR-PK-01-EU 
Final 2.0, 14 May 2013 
Page 7 of 16 
 
 
 
Advice on the risks of smoking and 
debriefing 
 
 
 
Socio economic status 
 
 
 
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/concomitant medication 
 
 
 
Medical history/concomitant diseases 
 
 
 
Vital signs (pulse rate, systolic and 
diastolic blood pressure, respiratory 
rate) 
At least 5 min in supine position 
prior to measurement 
 
 
Height, weight, including calculated 
BMI 
 
 
√ 
Clinical laboratory parameters 
(haematology, urine analysis, clinical 
chemistry) 
 
 
√ 
Serology for HIV and Hepatitis B 
and C 
 
 
 
Identification of current CC brand 
 
 
 
Urine drug screen 
 
 
 
Alcohol breath test 
 
 
 
Urine pregnancy test for female 
subjects 
 
 
 
THS 2.2 and NNS product 
demonstration 
 
 
 
Spirometry without short-acting 
bronchodilator, and then with 
 
 
 
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; CC = 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 = Tobacco Heating System 
 
Reason for Change 

Philip Morris Products S.A. 
Clinical Study Protocol Amendment N°1 
Confidential 
ZRHR-PK-01-EU 
Final 2.0, 14 May 2013 
Page 8 of 16 
 
The timepoint of the socio-economic status questionnaire was changed from Screening to 
Day 2 to avoid this questionnaire was asked to subjects who were screened failure. The 
socio-economic questionnaire will be asked only in subjects who are randomized in to the 
study.  
 
2.4 
Modification 4 
Section:  9.3.2 Days of Smoking Abstinence 
Page:   
77 
Old Text 
 

Philip Morris Products S.A. 
Clinical Study Protocol Amendment N°1 
Confidential 
ZRHR-PK-01-EU 
Final 2.0, 14 May 2013 
Page 9 of 16 
 
Table 3. 
Time Schedule – Day 2 Washout 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
 
 
 
 
Nicotine abstinence 
All day 
 
 
Support during nicotine abstinence as 
required 
All day 
 
 
AE/SAE recording, concomitant 
medication 
All day 
 
√ 
Plasma nicotine PK sample 
24 hrs +5 min after T0 of Day 1  
 
 
Assessment of cough 
24 hrs minus 5 min after T0 of 
Day 1  
7:30 AM-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 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 
4:30 PM-5:00 PM 
 
Snacks 
 
6:30 PM-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. 
 
 
Amended Text 

Philip Morris Products S.A. 
Clinical Study Protocol Amendment N°1 
Confidential 
ZRHR-PK-01-EU 
Final 2.0, 14 May 2013 
Page 10 of 16 
 
Table 4. 
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 +5 min after T0 of Day 1  
 
 
Assessment of cough 
24 hrs minus 5 min after T0 of 
Day 1  
7:30 AM-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 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 
4:30 PM-5:00 PM 
 
Snacks 
 
6:30 PM-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. 
 
Reason for Change 
The timepoint of the socio-economic status questionnaire was changed from Screening to 
Day 2 to avoid this questionnaire was asked to subjects who were screened failure. The 
socio-economic questionnaire will be asked only in subjects who are randomized in to the 
study.  
 
2.5 
Modification 5 
Section:  9.3.2 Days of Smoking Abstinence 
Page:   
77 
Old Text 
 
 
Scree
ning 
Admis
sion 
Was
h-
out 
Singl
e use 
Wash
-out 
Singl
e use 
Day of 
Discharg
e k 
Safety 
follow-up l 

Philip Morris Products S.A. 
Clinical Study Protocol Amendment N°1 
Confidential 
ZRHR-PK-01-EU 
Final 2.0, 14 May 2013 
Page 11 of 16 
 
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 and NNS 
● 
 
 
 
 
 
 
 
Product test for THS 
2.2 and NNS 
 
● 
 
 
 
 
 
 
Identification of 
current CC brand 
● 
● 
 
 
 
 
 
 
Smoking history 
● 
● 
 
 
 
 
 
 
Readiness to accept 
interruption from 
smoking up to 4 days 
● 
● 
 
 
 
 
 
 
Willingness to quit 
smoking in the next 3 
months 
● 
 
 
 
 
 
 
 
Demographics a, 
socio-economic 
status, medical 
history, concomitant 
diseases  
● 
 
 
 
 
 
 
 
Prior medication b / 
Concomitant 
medication 
● 
● 
● 
● 
● 
● 
● 
● 
Physical examination, 
body height, weight 
and related BMI c 
● 
● 
 
 
 
 
● 
 
Vital signs d 
● 
● 
● 
● 
● 
● 
● 
 
ECG 
● 
 
 
● 
 
● 
 
 
Spirometry 
● 
● 
 
 
 
 
● 
 
Chest X-ray e 
● 
 
 
 
 
 
 
 
B/U: Haematology, 
clinical chemistry, 
urine analysis 
● 
● 
 
 
 
 
● 
 
B: Serology  
● 
 
 
 
 
 
 
 
U: Urine drug screen, 
urine cotinine screen 
● 
● 
 
 
 
 
 
 
Alcohol breath test  
● 
● 
 
 
 
 
 
 
U: Pregnancy test 
(females) 
● 
● 
 
 
 
 
● 
 

Philip Morris Products S.A. 
Clinical Study Protocol Amendment N°1 
Confidential 
ZRHR-PK-01-EU 
Final 2.0, 14 May 2013 
Page 12 of 16 
 
 
Scree
ning 
Admis
sion 
Was
h-
out 
Singl
e use 
Wash
-out 
Singl
e use 
Day of 
Discharg
e k 
Safety 
follow-up l 
Study Day 
-29 to 
-2  
-1 
0 
1 
2 
3 
4 
4 to 11 
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’-hydroxycotini
ne and cotinine 
(CYP2A6 activity) in 
plasma  
 
● 
 
 
 
 
 
 
FTND questionnaire 
● 
 
 
 
 
 
 
 
QSU–brief 
questionnaire i 
 
 
 
● 
 
● 
 
 
MCEQ (modified 
version, only after 
THS 2.2 and CC use  
 
 
 
● 
 
● 
 
 
Cough assessment j 
 
 
● 
● 
● 
● 
● 
 
AE/SAE recording  
● 
● 
● 
● 
● 
● 
● 
● 
 
 
Amended Text 
 
 
Scree
ning 
Admis
sion 
Was
h-
out 
Singl
e use 
Wash
-out 
Singl
e use 
Day of 
Discharg
e 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 and NNS 
● 
 
 
 
 
 
 
 
Product test for THS 
2.2 and NNS 
 
● 
 
 
 
 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol Amendment N°1 
Confidential 
ZRHR-PK-01-EU 
Final 2.0, 14 May 2013 
Page 13 of 16 
 
 
Scree
ning 
Admis
sion 
Was
h-
out 
Singl
e use 
Wash
-out 
Singl
e use 
Day of 
Discharg
e k 
Safety 
follow-up l 
Study Day 
-29 to 
-2  
-1 
0 
1 
2 
3 
4 
4 to 11 
Identification of 
current CC brand 
● 
● 
 
 
 
 
 
 
Smoking history 
● 
● 
 
 
 
 
 
 
Readiness to accept 
interruption from 
smoking up to 4 days 
● 
● 
 
 
 
 
 
 
Willingness to quit 
smoking in the next 3 
months 
● 
 
 
 
 
 
 
 
Demographics a, 
socio economic 
status, medical 
history, concomitant 
diseases  
● 
 
 
 
 
 
 
 
Socio-economic 
status 
questionnaire 
 
 
 
 
● 
 
 
 
Prior medication b / 
Concomitant 
medication 
● 
● 
● 
● 
● 
● 
● 
● 
Physical examination, 
body height, weight 
and related BMI c 
● 
● 
 
 
 
 
● 
 
Vital signs d 
● 
● 
● 
● 
● 
● 
● 
 
ECG 
● 
 
 
● 
 
● 
 
 
Spirometry 
● 
● 
 
 
 
 
● 
 
Chest X-ray e 
● 
 
 
 
 
 
 
 
B/U: Haematology, 
clinical chemistry, 
urine analysis 
● 
● 
 
 
 
 
● 
 
B: Serology  
● 
 
 
 
 
 
 
 
U: Urine drug screen, 
urine cotinine screen 
● 
● 
 
 
 
 
 
 
Alcohol breath test  
● 
● 
 
 
 
 
 
 
U: Pregnancy test 
(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’-hydroxycotini
ne and cotinine 
(CYP2A6 activity) in 
plasma  
 
● 
 
 
 
 
 
 
FTND questionnaire 
● 
 
 
 
 
 
 
 

Philip Morris Products S.A. 
Clinical Study Protocol Amendment N°1 
Confidential 
ZRHR-PK-01-EU 
Final 2.0, 14 May 2013 
Page 14 of 16 
 
 
Scree
ning 
Admis
sion 
Was
h-
out 
Singl
e use 
Wash
-out 
Singl
e use 
Day of 
Discharg
e k 
Safety 
follow-up l 
Study Day 
-29 to 
-2  
-1 
0 
1 
2 
3 
4 
4 to 11 
QSU–brief 
questionnaire i 
 
 
 
● 
 
● 
 
 
MCEQ (modified 
version, only after 
THS 2.2 and CC use  
 
 
 
● 
 
● 
 
 
Cough assessment j 
 
 
● 
● 
● 
● 
● 
 
AE/SAE recording  
● 
● 
● 
● 
● 
● 
● 
● 
 
Reason for Change 
The timepoint of the socio-economic status questionnaire was changed from Screening to 
Day 2 to avoid this questionnaire was asked to subjects who were screened failure. The 
socio-economic questionnaire will be asked only in subjects who are randomized in to the 
study.  
 
 

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Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
ZRHR-PK-01-EU 
Final 2.0   / 14 May 2013 
Page 2 of 113 
 
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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Name of Product: 
Tobacco Heating System 2.2 (THS 2.2)  
Study Title: 
A single-centre, open-label, randomized, controlled, crossover study to investigate the 
nicotine pharmacokinetic profile and safety of Tobacco Heating System 2.2 (THS 2.2) 
following single use in smoking, healthy subjects compared to conventional cigarettes and 
nicotine nasal spray. 
Short Study Title: 
Nicotine pharmacokinetic profile and safety of the Tobacco Heating System 2.2 (THS 2.2) 
Study Number and Acronym: 
ZRHR-PK-01-EU, 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 
relative to conventional cigarettes (CC), following single use of THS 2.2 and CC. 
Secondary Objectives: 
 To determine if Cmax and AUC(0-last) of the THS 2.2 are higher relative to nicotine 
nasal spray (NNS) following single use of the THS 2.2 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 CC or NNS product 
[AUC(0-t’)]) between the THS 2.2 and CC, as well as the THS 2.2 and NNS.  
 To evaluate the time to the maximum concentration (tmax) of nicotine for the THS 2.2 
as compared to CC and to determine if the tmax for THS 2.2 is shorter as compared to 
NNS. 
 To describe the terminal half-life (t1/2) of nicotine for the THS 2.2, CC, and NNS. 
 To describe the differences on urge-to-smoke over time between the THS 2.2 and CC, 
as well as between the THS 2.2 and NNS. 
 To describe product evaluation in the THS 2.2 and CC users. 
 To describe the levels of carbon monoxide (CO) exposure for the THS 2.2, as 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
ZRHR-PK-01-EU 
Final 2.0   / 14 May 2013 
Page 3 of 113 
 
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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
compared to CC and NNS users. 
 To monitor the safety during the study. 
Primary Endpoints: 
 Primary nicotine PK parameters (THS 2.2 vs. CC): 
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:CC ratio for the primary nicotine PK parameters are estimated with a 
precision of ±20%. 
 
Secondary Endpoints: 
 Primary nicotine PK parameters (THS 2.2 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. 
 Safety variables: 
o Incidence of adverse events (AEs)/serious adverse events (SAEs) and 
device events, including THS 2.2 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). 
o Clinical chemistry, haematology, and urine analysis safety panel. 
o Physical examination. 

 
 
 
 
 
Philip Morris Products S.A. 
Clinical Study Protocol 
Confidential 
ZRHR-PK-01-EU 
Final 2.0   / 14 May 2013 
Page 4 of 113 
 
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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
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.  
 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. 
 CC. 
 NNS. 
 
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/CC/NNS). 
Period 2: Day 2: Wash-out; Day 3: single product use (THS 2.2/CC/NNS). 
 

 
 
 
 
 
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inclusion criteria:  
□ Subject is aged from 21 to 65 years (inclusive). 
□ Smoking, healthy subject as judged by the Investigator. 
□ Subject smokes at least 10 commercially available non-menthol CCs per 
day (no brand restrictions) for the last 4 weeks, based on self-reporting. 
□ Subject does not plan to quit smoking in the next 3 months. 
□ 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 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 ≤0.6 mg and >0.6≤1 
mg) will have a quota applied to ensure they represent at least 40% of the study population. 
Subjects who do not complete the study after randomization will not be replaced. 
Investigational Products 
Test Product:  
 Tobacco Heating System 2.2 
Reference Product:  Subject’s own supply of commercially available preferred 
single brand CC. 
Reference Point Product (non-investigational):  
Nicotine Nasal Spray (Nicorette® 10 mg/mL); 1  spray 
(resulting in the administration of 0.5 mg nicotine) per 
nostril/product use, as per label. This will be supplied by the 
Investigator and reimbursed by the Sponsor. 
Duration of Study: 
The entire study will last 14 to 40 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 

 
 
 
 
 
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analysis sets to allow the comparison between THS 2.2 and NNS separately from the 
comparison between THS 2.2 and CC. 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:CC and THS 2.2:NNS ratios. The 
lower bound of the 95% CI of the THS 2.2: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 are higher relative to NNS. 
AUC(0-∞), AUC(0-t’), and t1/2 will be analysed 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 is shorter than in NNS. The median tmax differences between THS 2.2 
and CC, as well as between THS 2.2 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 
analyse the domain scores of the product evaluation (MCEQ) questionnaire, for the 
comparison between THS 2.2 and CC. The same model will be evaluated for the analysis of 
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-CC 
and THS 2.2-NNS differences.  
Safety: The safety population will comprise all subjects, who are exposed to THS 2.2 during 
the study, including the THS 2.2 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 
and CC with a 90% probability of obtaining a margin of error (95% CI) of at most ±20%, 
assuming that THS 2.2 have a nicotine PK profile similar to CC (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 

 
 
 
 
 
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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 and NNS is 1.55. 
The sample size of this study is based on our current understanding of THS 2.1, the previous 
prototype of THS 2.2, 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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TABLE OF CONTENTS 
SYNOPSIS ............................................................................................................................................. 2 
TABLE OF CONTENTS ....................................................................................................................... 9 
LIST OF ABBREVIATIONS AND EXPLANATION OF TERMS ................................................... 13 
1 
ETHICS AND REGULATIONS ................................................................................................. 17 
1.1 
Independent Ethics Committee (IEC) Approval ............................................................... 17 
1.2 
Ethical Conduct of the Study ............................................................................................ 18 
1.3 
Subject Information and Consent...................................................................................... 18 
1.4 
Good Clinical Practice and Regulatory Requirements ..................................................... 18 
2 
INTRODUCTION ....................................................................................................................... 19 
2.1 
Background ....................................................................................................................... 19 
2.2 
Purpose of the Study ......................................................................................................... 21 
2.3 
Anticipated Benefits and Risks ......................................................................................... 21 
3 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................... 23 
3.1 
Primary Objective ............................................................................................................. 23 
3.2 
Secondary Objectives ....................................................................................................... 23 
3.3 
Primary Endpoints ............................................................................................................ 23 
3.4 
Secondary Endpoints ........................................................................................................ 24 
3.5 
Exploratory Endpoints ...................................................................................................... 25 
4 
INVESTIGATIONAL PLAN ...................................................................................................... 26 
4.1 
Overall Study Design and Plan ......................................................................................... 26 
4.2 
Rationale for Study Design and Control Groups(s) .......................................................... 28 
4.3 
Study Duration .................................................................................................................. 29 
4.4 
Appropriateness of Measurements .................................................................................... 29 
5 
STUDY POPULATION .............................................................................................................. 30 
5.1 
Selection of Study Population ........................................................................................... 30 
6 
INVESTIGATIONAL AND REFERENCE POINT PRODUCTS ............................................. 36 
6.1 
Description ........................................................................................................................ 36 
6.2 
Use of Investigational and Reference Point Products ....................................................... 38 
6.3 
Method for Assigning Subjects to Study Arms ................................................................ 39 
6.4 
Blinding ............................................................................................................................ 40 
6.5 
Investigational and Reference Point Product Accountability and Compliance ................ 41 
6.6 
Restrictions ....................................................................................................................... 42 
6.7 
Concomitant Medication ................................................................................................... 43 
7 
STUDY PROCEDURES ............................................................................................................. 46 
7.1 
Informed Consent ............................................................................................................. 46 

 
 
 
 
 
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7.2 
Smoking Cessation Advice and Debriefing ...................................................................... 46 
7.3 
Support during Smoking Abstinence/Periods of Reduced Smoking ................................ 46 
7.4 
Clinical Assessments ........................................................................................................ 47 
7.5 
Biomarker Assessment ..................................................................................................... 50 
7.6 
Laboratory Assessments ................................................................................................... 51 
7.7 
Sample Handling, Storage, and Shipment ........................................................................ 53 
7.8 
Questionnaires .................................................................................................................. 54 
8 
ADVERSE EVENTS ................................................................................................................... 58 
8.1 
Definitions ........................................................................................................................ 58 
8.2 
Assessment of Adverse Events ......................................................................................... 59 
8.3 
Reporting and Follow-Up of Serious Adverse Events ...................................................... 62 
8.4 
Reporting of Other Events Critical to Safety Evaluations ................................................ 63 
8.5 
Reporting and Follow-Up of Pregnancies ......................................................................... 64 
8.6 
Adverse Events Leading to Withdrawal ........................................................................... 65 
8.7 
Investigational Device Misuse .......................................................................................... 65 
8.8 
Investigational Device Malfunction .................................................................................. 65 
9 
STUDY ACTIVITIES ................................................................................................................. 67 
9.1 
Screening Visit .................................................................................................................. 67 
9.2 
Admission ......................................................................................................................... 68 
9.3 
Investigational Period ....................................................................................................... 70 
9.4 
Day of Discharge .............................................................................................................. 74 
9.5 
Safety Follow-up Period ................................................................................................... 75 
9.6 
Early Termination Procedures .......................................................................................... 75 
10 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................... 76 
10.1 
Monitoring ........................................................................................................................ 76 
10.2 
Training of Staff ................................................................................................................ 76 
10.3 
Audits and Inspections ...................................................................................................... 77 
11 
DATA MANAGEMENT ACTIVITIES ..................................................................................... 78 
11.1 
Data Capture ..................................................................................................................... 78 
11.2 
Data Handling ................................................................................................................... 79 
12 
PLANNED STATISTICAL METHODS .................................................................................... 81 
12.1 
General Considerations ..................................................................................................... 81 
12.2 
Determination of Sample Size and Power Consideration ................................................. 82 
12.3 
Analysis Populations ......................................................................................................... 83 
12.4 
Demographics and Baseline Characteristics ..................................................................... 83 
12.5 
Primary Endpoints ............................................................................................................ 83 
12.6 
Secondary Endpoints ........................................................................................................ 85 
12.7 
Exploratory Analyses ........................................................................................................ 87 

 
 
 
 
 
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12.8 
Interim Analysis ................................................................................................................ 87 
13 
ADMINISTRATIVE CONSIDERATIONS ................................................................................ 88 
13.1 
Investigators and Study Administrative Structure ............................................................ 88 
13.2 
Subject Confidentiality ..................................................................................................... 89 
13.3 
Access to Source Documentation ..................................................................................... 90 
13.4 
Record Retention .............................................................................................................. 90 
13.5 
Clinical Study Report ........................................................................................................ 92 
13.6 
Financial Disclosure ......................................................................................................... 92 
13.7 
Publication and Disclosure Policy .................................................................................... 92 
14 
REFERENCE LIST ..................................................................................................................... 93 
 
 
 

 
 
 
 
 
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LIST OF IN-TEXT TABLES AND FIGURES 
Table 1 
Measured aerosol fractions for the THS Tobacco Sticks ..................................37 
Table 2. Examples of Drugs and Substances Considered Interacting with CYP2A6 .....44 
Table 3. Clinical Laboratory Parameters for Safety Panel ..............................................52 
Table 4. Time Schedule – Screening ...............................................................................67 
Table 5. Time Schedule – Day -1 Admission .................................................................69 
Table 6. Time Schedule – Day 0 Washout ......................................................................70 
Table 7. Time Schedule – Day 2 Washout ......................................................................71 
Table 8. Time Schedule – Day 1 and Day 3 Single Use .................................................72 
Table 9. Time Schedule – Day 4 Discharge ....................................................................74 
 
Figure 1. Study Flowchart ................................................................................................27 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events ...................................................................................100 
Appendix 2 
Participating Laboratories ........................................................................104 
Appendix 3 
Investigational Product and Instructions for Use .....................................105 
Appendix 4 
Product Label for the NNS product: Adverse Events ..............................106 
Appendix 5 
Abnormal Laboratory Values ..................................................................107 
Appendix 6 
Investigational Micro+TM Smokerlyzer® .................................................112 

 
 
 
 
 
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LIST OF ABBREVIATIONS AND EXPLANATION OF TERMS 
Abbreviations 
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 conventional 
cigarettes or nicotine nasal spray 
BMI 
Body mass index 
CC 
Conventional cigarette(s) 
CD 
Compact disc 
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 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End of Study Visit (referring to each subject’s individual last study 
visit) 

 
 
 
 
 
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FDA 
US 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 
HPHC 
Harmful and Potentially Harmful Constituents in Tobacco Products 
and Tobacco Smoke 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
ISO 
International Organization for Standardization 
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 
SAP 
Statistical analysis plan 
SES 
Socio-economic status 
SHM 
Sample handling manual 
SOP 
Standard Operating Procedure 
T 
Time point  

 
 
 
 
 
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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: 
Back-Up Subject 
Subject who is enrolled but not randomised  
CC 
The term ‘conventional cigarette’ refers to manufactured and 
commercially available cigarettes and excludes hand-rolled 
cigarettes, cigars, pipes, bidis, and other nicotine-containing 
products. 
Charger 
The function of the Charger (Model 4) is to recharge the Holder 
after use. It contains a battery with sufficient capacity to recharge 
the Holder approximately 20 times.  It is a convenient size to carry 
around, and can itself be recharged from a mains power source. 
 
Day of Discharge 
Day 4. 
End of Study 
End of Study is defined as the last day of the 7 day safety follow-
up subsequent to discharge from the unit. 
Enrolment 
On Day -1 for eligible subjects after all applicable inclusion and 
exclusion criteria have been satisfactorily met and the subjects is 
willing and ready to use both the THS 2.2 and NNS (the test of 

 
 
 
 
 
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both THS 2.2 and NNS are the last assessments prior to enrolment) 
First product use time 
point 
Start of product use for THS 2.2 is defined as the time of the first 
puff. The start time for CC corresponds to the lighting of the CC, 
and the start time of the NNS product is the time of the spray in the 
first nostril. 
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 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 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 Tobacco Sticks 
The Tobacco Stick (product code C3) contains tobacco which, 
when heated, generates an aerosol. It is custom-designed to be used 
with the Holder. 
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 except the Tobacco 
Stick. 
Tobacco Heating 
System 2.2 (THS 2.2) 
THS 2.2 comprises the following components: Tobacco Stick, 
Holder, Charger, a Cleaning Tool, a mains power supply, and a 
USB cable. 
 

 
 
 
 
 
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1 
ETHICS AND REGULATIONS 
1.1 
 Independent Ethics Committee (IEC) Approval 
Prior to the start of the study, the clinical study protocol, together with its associated 
documents (informed consent form [ICF], subject information, 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 
Independent Ethics Committee [IEC]), will be submitted for review and approval to the 
relevant IEC. The IEC shall be appropriately constituted and perform its functions in 
accordance with the International Conference on Harmonization (ICH) Tripartite Guidance 
for Good Clinical Practice (ICH GCP E6 (R1), July 1996) and local requirements, as 
applicable. 
In accordance with GCP, a written confirmation of the IEC approval should be provided to 
the Sponsor. This should identify the study (Investigator’s name, study number and title) and 
the documents that have been approved by the IEC, with dates and version numbers, as well 
as the date of approval. The composition of the IEC, including the name and occupation of 
the chairperson, should be supplied to the Sponsor together with a GCP compliance 
statement. 
The written approval from the IEC will be filed in the Investigator file, and a copy will be 
filed in the Study Master File at the Sponsor or designated organization. The study must not 
start at a site before the Sponsor has obtained written confirmation of favourable 
opinion/approval from the concerned IEC. 
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the Principal Investigator. All amendments will be 
submitted to the IEC, and substantial amendments will only be implemented after approval 
by the IEC. 
These requirements for approval should in no way prevent any action from being taken by 
the Investigator or 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 IEC should be informed immediately. 
Relevant safety information will be submitted to the IEC during the course of the study in 
accordance with national regulations and requirements. 

 
 
 
 
 
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1.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki, 2008 and are consistent with ICH/GCP applicable regulatory 
principles. 
The Investigator agrees to conduct the clinical study in compliance with the protocol agreed 
with the Sponsor and approved by the IEC. The Principal Investigator and the Sponsor must 
sign the protocol (and protocol amendments, if applicable) to confirm this agreement. A copy 
of the Declaration of Helsinki, 2008 should be located in the Investigator’s Study File. 
1.3 
Subject Information and Consent 
1.3.1 
Study Consent 
At the Screening Visit, the Investigator or person designated by the Investigator will ensure 
that  each subject is given full and adequate oral and written information about the nature, 
purpose, possible risks and benefits of the study, and the Investigator or the designee will 
answer all questions the subject might have to his/her full satisfaction. The subject will have 
sufficient time for consideration of his/her participation in the study and will be notified that 
he/she is free to discontinue his/her participation at any time. Once the subject has received 
all necessary information, and if he/she agrees to participate, this will be documented in the 
ICF by the date and signature of both the subject and the person who conducted the informed 
consent discussion. No study-specific procedures will be performed before the ICF has been 
signed. 
The original, dated and signed ICF(s) 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 and subject 
information may be required. If revision of the ICF and subject information is necessary, the 
Investigator will, with the support of the Sponsor, ensure that the documents have been 
reviewed and approved by a relevant IEC before subjects are required to re-sign the ICF. 
The subject will be informed that additional data analyses not mentioned in the protocol or 
the statistical analysis plan might be performed with the collected data at a later time. If any 
additional analyses will be performed, they will fully be covered by data confidentiality, as 
for the main analyses described in this protocol.  
1.4 
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 

 
 
 
 
 
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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. 
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 a 
smoking 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/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. 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A 
2.1.2 
Description of the Product and Scientific Findings 
Thousands of chemicals, “smoke constituents”, are formed when tobacco is burned or 
combusted. More than 5,300 smoke constituents have been identified (Rodgman and Perfetti, 
2009), and more than 100 of them have been categorized as harmful and potentially harmful 
constituents (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 (THS 2.2) (Tobacco Stick). With this product, the heating of the tobacco is 
maintained below 400°C, a temperature much lower than what is observed for CC, which can 
reach 900°C. The THS 2.2 is composed of the ‘THS Tobacco Stick Holder’ dedicated special 
Tobacco Sticks made of conventional tobacco, a charger, and different accessories. The 
energy of the THS Tobacco Stick Holder is sufficient to maintain approximately a 6 minute 
session. Unlike CC, the Tobacco Sticks do not burn down during their consumption and their 
lengths remain constant after use. 
The non-clinical assessment of THS 2.2 and its predecessors including THS 1.0 supports the 
initiation of the clinical studies described in this Investigator’s Brochure. 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 were increased compared to the CC. 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 are given in 
the Investigator’s’ Brochure (PMI, 2013a). 
Several clinical studies have been conducted on THS 1.0, 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 the next 
development version of THS, namely THS 2.0.  
THS 2.1 was tested in two exploratory clinical studies to measure the nicotine plasma kinetic 
profile (PK) and to assess the reduction of exposure to HPHCs when switching from CC to 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A 
THS 2.1. The observed nicotine plasma PK profile for THS 2.1 was similar to CC as well, 
there were significant reductions in the exposure to the majority of selected HPHCs. Clinical 
studies conducted so far revealed no safety concern for either of the previous version of THS 
2.2 tested. Further details on the clinical data are provided in the Investigators’ Brochure 
(PMI, 2013a). 
2.2 
Purpose of the Study 
The purpose of this clinical study is to compare the profile of nicotine uptake (rate and extent 
of nicotine absorbed) after single use of THS 2.2 and CC in smoking, healthy subjects. THS 
2.2 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 
Research conducted by the United Kingdom National Health Service has shown that up to 
75% of smokers want to quit. Despite associated health risks, however, only 2% of smokers 
make a cessation attempt each year. Advice on health risks associated with smoking and 
smoking cessation advice will be provided at Screening, at Admission, and at the Day of 
Discharge. The advice will follow the recommendations by the World Health Organization 
(Raw et al, 2002). 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 smoking cessation services for continuing support and counselling 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, haematoma, 
paresthesia, or infection. 
 Risks related to chest X-rays, e.g., a small increase of risk to develop cancer later in life. 
 Risks related to drug application as part of testing procedures (i.e., spirometry with 
short-acting bronchodilator at Screening) per study protocol and scientifically accepted 
standards. 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product (THS 2.2 
and CC) or Reference Point Product (NNS) 
 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, investigational product (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 support for 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 Products S.A 
3 
STUDY OBJECTIVES AND ENDPOINTS 
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 relative to CC, following single use of THS 2.2 and 
CC. 
 
3.2 
Secondary Objectives 
The secondary objectives of this study are: 
 To determine if Cmax and AUC(0-last) of the THS 2.2 are higher relative to NNS 
following single use of the THS 2.2 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 CC or NNS product [AUC(0-t’)]) between the THS 2.2 and CC, as well as the 
THS 2.2 and NNS.  
 To evaluate the  time to the maximum concentration (tmax) of nicotine for the THS 
2.2 as compared to CC and to determine if the tmax for THS 2.2 is shorter as 
compared to NNS. 
 To describe the terminal half-life (t1/2) of nicotine for the THS 2.2, CC, and NNS. 
 To describe the differences on urge-to-smoke over time between the THS 2.2 and 
CC, as well as between the THS 2.2 and NNS. 
 To describe product evaluation in the THS 2.2 and CC users. 
 To describe the levels of carbon monoxide (CO) exposure for the THS 2.2, as 
compared to CC and NNS users. 
 To monitor the safety during the study. 
 
3.3 
Primary Endpoints 
 Primary nicotine PK parameters (THS 2.2 vs. CC): 
o Cmax. 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A 
o AUC(0-last). 
 
Evaluation criterion: 
The study will be considered successful, if the 95% Confidence Intervals (CI) of the THS 
2.2:CC 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 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. 
 Safety variables: 
o Incidence of adverse events (AEs)/serious adverse events (SAEs) and 
device event including THS 2.2 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). 
o Clinical chemistry, haematology, 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. 

 
 
 
 
 
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□ Urine pregnancy test (females only), urine cotinine test, urine drug screen. 
□ Alcohol breath test. 
□ Chest X-ray. 
□ Nicotine dependence to be assessed with the Fagerström Test for Nicotine Dependence 
(revised version). 
□ Cytochrome P450 2A6 activity (nicotine metabolic molar ratio) in plasma. 
 
3.5 
Exploratory Endpoints 
There are no exploratory analyses planned. 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A 
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. 
 CC. 
 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 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 (using up to three 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 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 
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/CC/NNS). 
Period 2: Day 2: Wash-out; Day 3: single product use (THS 2.2/CC/NNS). 
In total, 62 eligible, healthy smoking subjects will be randomized into one of the 4 
sequences: 
Sequence 1:  THS 2.2 
CC (N=22). 
Sequence 2:  CC 
THS 2.2 (N=22). 
Sequence 3:  THS 2.2 
NNS (N=9). 
Sequence 4:  NNS 
THS 2.2 (N=9). 
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 CC will not be considered:  
CC vs. THS 2.2  
(N=22 in both sequence 1 and 2). 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A 
The study will be conducted as a single-centre 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 21 years in the inclusion criteria was selected based on: 
□ The legal age of smoking (purchasing) in the United Kingdom is 18 years.  
□ To account for the 3 years of smoking history. 
 
In this study, CC will be used a as the comparator to THS 2.2 and a market-approved 
pharmaceutical NNS Nicorette® (10 mg/mL) will be used as reference point product.  
The NNS has been selected as the reference point, 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).  
NNS will serve as a reference point for comparison with THS 2.2 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 (Benowitz et 
al, 2009).  
The use of oestrogen contraceptive is known to accelerate nicotine clearance by 20% to 30% 
in women as compared to women who do not take such contraceptives (Benowitz et 
al, 2006).  Therefore, for the purpose of this study, it is not allowed to use hormonal 
contraception containing oestrogens. This also applies to hormone replacement therapy. 
The activity of CYP2A6 will be measured at admission 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). 
 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A 
4.3 
Study Duration  
The entire study per subject will last 14 to 40 days, including a Screening period of up to 4 
weeks prior to Admission (Day -29 to Day -2), and 6 days of confinement (Day -1 to 
morning of Day 4). In the morning of Day 4, the Day of Discharge examinations will be 
conducted. After the time of discharge, subjects will then enter a 7-day safety follow-up 
(until Day 11) for the recording of spontaneously reported new AEs/SAEs and the active 
follow-up of ongoing AEs/SAEs. 
4.4 
Appropriateness of Measurements 
The laboratory measures to be utilized in this study were selected based on the following 
criteria: 1) the availability of a validated analytical method, and 2) measure is known to be 
directly or indirectly affected by smoking; 3) measure is readily reversible after smoking 
cessation, 4) timeframe of reversibility of measure in the perspective of the study duration, 5) 
practicality/acceptability by subjects, and 6) robustness (rapid, simple, accurate). 
All questionnaires utilized for this study, except the cough and socio-economic status 
questionnaires, are available as validated questionnaires. 

 
 
 
 
 
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5 
STUDY POPULATION 
5.1 
Selection of Study Population 
Sixty-two Caucasian female or male smoking healthy adult subjects, who smoke at least 10 
CC per day will be randomized into this study. The maximum number of CC is not limited. 
Subjects must have a smoking history of at least 3 years of consecutive smoking prior to 
Screening. The smoking status of the subjects will be verified based on a urine cotinine test 
(cotinine ≥200 ng/mL). 
5.1.1 
Inclusion Criteria 
Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -1) 
1. Subject has signed the ICF and is able 
to understand the information 
provided in the Subject Information 
Sheet and ICF. 
Administrative 
X 
 
2. Caucasian subject is aged from 21 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 
post-bronchodilator FVC >0.8], vital 
signs, physical examination, ECG, 
chest X-ray, and medical history). 
Safety 
X 
X 
4. Subject smokes at least 10 
commercially available non-menthol 
CCs per day (no brand restrictions) 
with a maximum yield of 1 mg 
nicotine ISO/CC, as labelled on the 
cigarette package, for the last 4 weeks, 
Effect 
X 
X 

 
 
 
 
 
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Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -1) 
based on self-reporting. Furthermore, 
the subject has been smoking for at 
least the last three consecutive years. 
The smoking status will be verified 
based on a urinary cotinine test 
(cotinine ≥200 ng/mL). 
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 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 
study for any reason (e.g., medical, 
psychiatric and/or social reason).  
Safety  
X 
X 
2. A subject who is legally 
incompetent, 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 
 

 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
3. The subject has medical condition 
requiring smoking cessation, or 
clinically relevant diseases 
(including but not limited to 
gastrointestinal, renal, hepatic, 
neurological, haematological, 
endocrine, oncological, urological, 
immunological, pulmonary and 
cardiovascular disease or any other 
medical condition [including but not 
limited to clinically relevant 
abnormal laboratory parameters]) in 
the judgment of the Investigator. 
Safety 
X 
X 
4. The subject has a body mass index 
(BMI) <18.5 or ≥32.0 kg/m2. 
Safety 
X 
 
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 
6. The subject has used 
nicotine-containing products other 
than commercially available CC 
(either tobacco-based products or 
nicotine-replacement therapy) as 
well as electronic cigarettes and 
similar devices, within 4 weeks prior 
to assessment. 
Effect 
X 
X 
7. The subject has received medication 
(prescription or over-the-counter) 
within 14 days or within 5 half-lives 
of the drug prior to the Admission 
Effect 
 
X 

 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
Day (Day -1; whichever is longer) 
that has an impact on Cytochrome 
P450 2A6 (CYP2A6) activity. 
8. In case the subject received any 
medication (prescribed or 
over-the-counter) within 14 days 
prior to Screening or prior to the 
Admission Day (Day -1) it will be 
decided at the discretion of the 
Investigator if these can potentially 
interfere with the study objectives 
and subject’s safety.  
Effect 
X 
X 
9. The subject has a positive alcohol 
test and/or the subject has a history 
of alcohol abuse that could interfere 
with subject’s participation in study. 
Administrative 
X 
X 
10. The subject has a positive urine drug 
test. 
Administrative 
X 
X 
11. Positive serology test for human 
immunodeficiency virus (HIV) 1/2, 
Hepatitis B or Hepatitis C.  
Safety 
X 
 
12. Donation or receipt of whole blood 
or blood products within 3 months 
prior to Admission. 
Safety 
X 
X 
13. The subject is a current or former 
employee of the tobacco industry or 
of their first-degree relatives (parent, 
sibling, child). 
Administrative 
X 
 
14. The subject is an employee of the 
investigational site or any other 
parties involved in the study or of 
their first-degree relatives (parent, 
sibling, child). 
Administrative 
X 
 

 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
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 of childbearing 
potential* 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 of childbearing 
potential* only: 
Subject does not agree to use an 
acceptable method of effective 
contraception.** 
Safety 
X 
X 
* Childbearing potential is defined as NOT premenarche, permanently sterilized or postmenopausal 
(i.e., 12 months with no menses without an alternative medical cause). 
** Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with 
spermicidal foam/gel/film/suppository, hormonal contraception containing progesterone only, vasectomized 
partner(s) or true abstinence (periodic abstinence and withdrawal are not effective methods) from Screening 
until the end of the safety follow-up period. Hormonal contraception with oestrogen 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 

 
 
 
 
 
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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) 
at the discretion of the Investigator. 
 Positive pregnancy testing (no invasive procedures including the drawing of blood 
must performed after detection of pregnancy, see Section 8.5). Female subjects 
starting contraception or hormone replacement therapy containing oestrogens 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. 
 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 (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 were 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 AND REFERENCE POINT PRODUCTS 
6.1 
Description  
6.1.1 
Investigational Products 
THS 2.2 
The THS 2.2 will be provided by the Sponsor and its distribution will be limited to a 
qualified and appropriately trained staff personnel.  
THS 2.2 comprises the following components:  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) 
Tobacco Stick: 
The 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 CC. 
 
6.1.1.1 
Tar, Nicotine and Carbon Monoxide Yields 
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, 
2012c, PMI, 2012b, 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 Tobacco Sticks 
Constituent (mg/THS Tobacco Stick) 
ISO 1 
Health Canada  Intense 
regime 2 
Tar/NFDPM 
4 
10.3 
Nicotine  
0.5 
1.32 
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) 
 
CC 
In the study sequences 1 and 2, the comparator to THS 2.2 is commercially available single 
brand CC with a maximum yield of 1 mg nicotine ISO per cigarette. 
Conventional cigarettes will not be provided by the Sponsor. All eligible subjects will be 
asked to purchase their own preferred single-brand CC prior to Admission. As randomization 
takes place on Day 0, every study subject needs to buy his/her anticipated amount of 
single-brand CC for a total of 2 days plus 2 extra packs. 
6.1.2 
Reference Point Product 
The NNS Nicorette® (10 mg/mL) will be the reference point product to THS 2.2 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.  
6.1.3 
Packaging and Labelling 
At Admission on Day -1, all study subjects will provide the anticipated amount of CC 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 labelled to identify which subject the 
cigarettes belong to (labels should be affixed to the cellophane wrapper of the lower part of 
the pack).  
Packs of CC will be labelled to identify necessary information to match the subject with 
his/hers suppliers. 

 
 
 
 
 
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For the Tobacco Sticks, the packs will be printed with the necessary information including 
but not limited to health warning, tar/nicotine/carbon monoxide ISO levels, product code. 
6.2 
Use of Investigational and Reference Point Products 
Subjects will never be requested or forced to smoke and will be free to stop smoking at any 
time during the study. Subjects caught using any nicotine/tobacco product which is different 
from the assigned product will be withdrawn from the study. During the screening period, 
subjects will be allowed to smoke according to their smoking habits except during the 
procedures of the screening visit 9.1 at the discretion of the site. 
6.2.1 
Admission (Day -1) 
Subject will be instructed not to smoke in the morning prior to Admission. Smoking ad 
libitum will be allowed throughout the day of admission except during the procedures until 
11:00 pm. All subjects will be allowed to continue smoking ad libitum their own preferred 
CC. All subjects (except women with a positive pregnancy test at Screening or Admission) 
will undergo a THS 2.2 test first and subsequently NNS test at Day -1 prior to enrolment. 
Following agreement that the THS 2.2 and NNS is acceptable, subjects will be enrolled and 
further randomized to one of 4 treatment sequences using an Interactive Web/ Voice 
Response System.  
6.2.2 
Investigational Period (Day 0 to Day 3) 
During the first washout, each subject will maintain nicotine abstinence from Day -1 at 11:00 
PM to the time of single use of his/her allocated product at Day 1. At Day 1, after the single 
use of the product, subjects will maintain nicotine abstinence for the rest of the day. During 
the second washout on Day 2, subjects will maintain nicotine abstinence until the time of 
single use of subject’s allocated product at Day 3. Subjects will not be allowed to smoke or 
use any other nicotine/tobacco-containing products other than the products they are allocated 
to. 
Time point of first product use during study day (T0) will be defined as start of the single 
product use at the single use days. The start of product use for THS 2.2 is defined as the time 
of the first puff. The start time for CC corresponds to the lighting of the CC, 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 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 arm 
will use one Tobacco Stick, subjects in the CC arm will smoke one CC, and subjects in the 
NNS arm will administer one spray into each nostril (leading to an estimated total 
administered amount of 1 mg nicotine). 
 
Sequence 1 
Sequence 2 
Sequence 3 
Sequence 4 
Day 1 
THS 2.2 
CC 
THS 2.2 
NNS 
Day 3 
CC 
THS 2.2 
NNS 
THS 2.2 
 
6.2.3 
Day of Discharge/Time of Discharge 
On the Day of Discharge (Day 4), smoking will be only allowed after all laboratory 
procedures and the spirometry have been performed. All examinations of the Day of 
Discharge will be conducted on Day 4 prior to the time of Discharge.  
6.2.4 
Safety Period 
During the safety follow-up period, subjects are free to smoke according to their usual 
smoking habits. 
6.2.5 
Stopping Rules for Investigational Product 
For safety purposes, using the THS 2.2, smoking the CC, or use of the NNS should be 
temporarily stopped in the event of any signs suggesting nicotine overexposure, e.g., 
gastrointestinal disturbance (nausea, vomiting, diarrhoea, stomach or abdominal pain), cold 
sweats, headache, dizziness and breathing problems or any reasons at the discretion of the 
Investigator. 
6.3 
Method for Assigning Subjects to Study Arms 
Randomization to product exposure sequence will be done through an Interactive Telephone 
and Web Response System. 
Each sex and each of the smoking level (ISO nicotine levels ≤0.6 mg and >0.6 to ≤1 mg) will 
have a quota applied to ensure they represent at least 40% of the total study population 
allocated within each of the following analysis groups: 
• 
Group-1: composed of sequences 1 and 2. 

 
 
 
 
 
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• 
Group-2: composed of sequences 3 and 4. 
In particular, the maximum number of subjects having the same sex or nicotine level value 
will be limited to 26 in Group-1 and 10 in Group-2. 
The randomization of the planned sample size of 62 subjects will be ensured by applying 
quota to the number of subjects per each sequence (22 subjects for sequences in Group-1, and 
9 subjects for sequences in Group-2). 
Subjects will be randomly assigned to one of the four product exposure sequences by means 
of a permuted-block schema. Block size and other randomization details will be available in 
the randomization plan. 
The randomization plan will be generated by an independent statistician and none of the 
sponsor staff, investigators or study subjects will have access to the randomization schema 
prior to randomization. 
6.4 
Blinding 
This is an open-label study; therefore, the subjects and investigators will be unblinded to 
subject’s sequence. However, there will be a limited degree of blinding in the data review 
and data analysis process. In particular, PMI and CRO personnel will be blinded to the 
randomized sequence as summarized in the following table: 
 
 

 
 
 
 
 
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Blinded Study Personnel 
End of Blinding Period 
PMI and CRO study 
statisticians 
After the Statistical Analysis Plan (SAP) finalization or 
PMI blind database review(*), whichever comes last. 
PMI data manager 
After the finalization of PMI blind database review.(*) 
PMI safety and clinical 
scientist 
After the finalization of PMI blind database review(*). Can 
be actively un-blinded before that time point in case of the 
occurrence of any safety question, when appropriate. 
(*) As part of the PMI Quality Control (QC) activity, data listings will be reviewed by PMI before database 
lock, with no access to the randomization sequence information. 
Any PMI and CRO personnel who are not listed in the above table will be unblinded by 
default.  
6.5 
 Investigational and Reference Point Product Accountability and 
Compliance 
6.5.1 
Dispensing Investigational and Reference Point Products 
From Day -1 until Day 4, the THS 2.2, NNS, and CC will be dispensed by the Investigators 
or dedicated study staff, as per study design. Each dispense of the product will be recorded in 
a log. The log should include subject number, date and start time of product use. The product 
will not be promoted for commercial distribution or test market. 
6.5.2 
Storage and Accountability 
The THS 2.2, NNS, and CC 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 Tobacco Stick or CC 
immediately after use to the site staff for accountability. They will also return the NNS after 
use to the site staff. This will be documented in appropriate log. At the end of the study, 
unused CCs given to the site staff at Admission on Day -1 will be given back to the subjects.  
6.5.3 
Investigational and Reference Point Product Retention 
Unused Tobacco Sticks and NNS will be destroyed if possible, or returned to the Sponsor 
upon study completion. The Tobacco Heating Devices will be returned to the Sponsor. 

 
 
 
 
 
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6.5.4 
Compliance to Investigational and Reference Point 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 (Benowitz et al, 2002). 
Furthermore, the CO breath test will be considered as one of the measures of compliance 
during the wash-out days in all subjects.  
6.6 
Restrictions 
6.6.1 
Smoking Restrictions 
On Day 1 and Day 3, to avoid nicotine cross contamination, smokers of THS 2.2 and CC will 
smoke in dedicated separate rooms: one room for THS 2.2 and one room for CC. 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, CC or Tobacco 
Sticks, which will be dispensed by the site staff individually as described in Section 6.5.1.  
Smoking is not allowed during study procedures except during blood sampling for nicotine 
PK on Day 1 and Day 3. Furthermore, smoking is not allowed on Day 4 until all laboratory 
tests and the spirometry have been conducted. 
During the days of wash-out or single product use (for 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. 
6.6.2 
Dietary Restrictions 
A standard diet will be designed by a dietician for the whole confinement period. For each 
meal, the caloric and fat content should be controlled in order to avoid a “high-fat” diet. The 
FDA guidance on food-effect studies for bioequivalency testing identifies a “high-fat” diet as 
a diet which 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).  

 
 
 
 
 
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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 Sections 9.2, 9.3.1, 9.3.2 and 
9.4. 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.  
6.7 
Concomitant Medication 
For the purpose of this study, no concomitant medication should be taken by the subjects. 
Any medication with an impact on the CYP2A6 metabolism (as prescription and 
over-the-counter products) as given below must be avoided as CYP2A6 is involved in the 
nicotine metabolism.  
In this study the use of hormonal contraception containing oestrogens is NOT allowed. This 
also applies to hormone replacement therapy. Only hormonal contraception with products 
containing progesterone is allowed during this study. Subjects using oestrogens during the 
study will be withdrawn.  
The following drugs and substances are considered as 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.  

 
 
 
 
 
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Table 2. 
Examples of 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, propranolol, lidocaine 
Antiarrhythmic   
Losartan, amlodipine, nifedipine, losartan 
Antihypertensive 
Drosperinone, oestrogens 
Hormonal contraceptives  
Agents for hormonal replacement 
therapy (oestrogens) 
Fluvastatin 
Cholesterol-lowering agent 
Theophylline 
Antispasmodic pulmonological 
agent/Bronchodilator agent 
Omeprazole, Lansoprazole 
Proton pump inhibitor 
Interferon 
Antiviral/Immunomodulating agent 
Methoxsalen   
Anti-psoriatic (substance class 
Furocoumarins) 
Modafinil, Diclofenac, Rofecoxib 
Analgesic 
Insulin 
Anti-diabetic 
Sildenafil 
Phosphodiesterase-Inhibitor (e.g., 
used for treatment of Erectile 
dysfunction) 

 
 
 
 
 
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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 7.4.6). Concomitant medications should be 
followed up with the CRO Medical Monitor on an ongoing basis.  
Concomitant medication will first be assessed at Screening Visit. To be eligible for the study 
any medication with impact on CYP2A6 metabolism must be discontinued at least 14 days 
prior to Admission to the clinic or for at least five half-lives (whichever is longer). They must 
not be used during the entire study until the time of discharge. It is at the discretion of the 
Investigator to assess if a termination of such medication at Screening is medically justified 
and safe for the subject. 

 
 
 
 
 
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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. Appropriate medical 
advice will be provided to the subject in case of any medical findings requiring health care. 
7.1 
Informed Consent 
Each subject must give his/her informed consent prior to participating in the study. During 
the consent process, the Investigator or designee 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 and must have sufficient time to 
read and understand and have adequate opportunity to ask questions. The ICF must be signed 
and dated prior to undertaking any study-specific procedures. A signed copy should be given 
to the subject.  
7.2 
Smoking Cessation Advice and Debriefing 
Each subject will be given advice on the risks of smoking 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 World Health Organization (WHO) 
recommendations (Raw et al, 2002). Details of the interview will be recorded in the Source 
Document File. Information on the risks 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. 
 
7.3 
Support during Smoking Abstinence/Periods of Reduced Smoking 
All subjects will be closely monitored by the site staff on D0, D1, D2, and D3. 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 behaviour, AEs, and his/her mood.   

 
 
 
 
 
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7.4 
Clinical Assessments 
Any clinically relevant finding detected during the Screening Visit has to be documented as 
a concomitant disease. This also applies to clinically relevant findings in e.g., laboratory 
values, vital signs and ECGs, detected during the Screening Visit. Any untoward medical 
occurrence in a subject detected during the study which was not present at the Screening 
Visit must be documented as an AE. Worsening of a pre-existing condition from the 
Screening Visit onwards will also be documented as an AE. If a clinically relevant finding is 
detected during the Screening period, the Investigator needs to check if inclusion criterion 
no. 3 is still fulfilled. 
7.4.1 
Demographic Data 
Demographic data (sex, date of birth/age, and race) will be recorded on the day of ICF 
signature.  
7.4.2 
Socio-Economic Status 
At Day 2, subjects will be asked questions, which will allow the Sponsor to infer their socio-
economic status (see section 7.8.5).  
7.4.3 
Identification of the Current Cigarette Brand 
Identification of the current CC brand smoked by the subject will be done at the Screening 
Visit and at Day -1. For the Screening Visit, smokers will be asked to bring a packet of their 
current CC brand to the site. The site staff will document brand name and yields. At Day -1, 
subjects have to hand their CC 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 with information of ISO 
nicotine , CO and tar 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 Digital Versatile Disc (DVD) or Compact Disc (CD).  
7.4.4 
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 CC smoked during the previous 4 weeks, 
and to evaluate if the CCs smoked during the previous 4 weeks were non-menthol. Yields 
will later be ascertained, from 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 CC (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. 
7.4.5 
Demonstration and Product Tests of THS 2.2 and NNS 
All subjects will have a demonstration of the THS 2.2 and the NNS products by the site staff 
at the Screening Visit. On Day -1, as the last procedure of the eligibility assessments, 
subjects will have a product test for the THS 2.2 (using up to three Tobacco Sticks) first and 
subsequently a  product test of the NNS (spraying once in each nostril). In female subjects, 
the THS 2.2 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 and the 
NNS and be randomized to any of the study arms can be enrolled into the study. 
7.4.6 
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. 
Medication taken within 4 weeks prior to Screening Visit and any concomitant medication 
needs to be documented. Any medication which was started prior to the Screening Visit and 
is still being taken by the subject will be considered a concomitant medication. Medication 
initiated after Screening is also referred to as concomitant medication. This applies to both 
prescription and over-the-counter products. 
Records should include the drug name (preferably both generic and trade name), route of 
administration, (e.g., oral, intravenous), total daily dose/unit (expressed in, for example, mg, 
mL, or IU), indication, 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. 
7.4.7 
Physical Examination 
A physical examination will be conducted at the Screening Visit, at Admission (Day -1) and 
at the Day of Discharge (Day 4).  
7.4.8 
Body Height and Weight 
Body weight will be recorded at the Screening Visit, at Admission (Day -1) and at the Day of 
Discharge (Day 4). Body height will be measured at the Screening Visit, only. The BMI will 

 
 
 
 
 
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be calculated from the body weight and height using the following formula, rounded to one 
decimal place:  
 
7.4.9 
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.  
7.4.10 
Other Clinical Assessments 
7.4.10.1 Spirometry 
Spirometry with and without a short-acting bronchodilator will be done at the Screening Visit 
to evaluate inclusion/exclusion criteria (the post-bronchodilator results). At screening, 
spirometry without bronchodilator will be done first, and then, spirometry with 
bronchodilator. Furthermore, spirometry without 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 
the pulmonary function laboratory (including the records of the calibration, if applicable). 
The FEV1 and FVC will be recorded.  
The subject will be submitted to a spirometry with maximum voluntary ventilation 
measurement. 
For spirometry, assessed parameters will include: 
 FEV1. 
 FVC. 

 
 
 
 
 
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 FEV1/FVC. 
 
7.4.10.2 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, initialled, dated, and 
stapled together for inclusion in the Source Data File. 
7.4.10.3 
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 
Report. A list of laboratories is provided in Appendix 2. 
The start time of the use of each product has to be documented on single use days (Day 1 and 
Day 3). 
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.  

 
 
 
 
 
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CO Breath Test 
CO in exhaled breath will be measured using the Micro+™ Smokerlyzer® device (Bedfont 
Limited, Rochester, United Kingdom, see Appendix 6). The test will be performed for 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, 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 and then around 
12:00 PM, 4:00 PM, and 8:00 PM. On the wash-out days (Day 0 and Day 2) it will be 
conducted around 8:00 AM, 12:00 PM, 4:00 PM and 8:00 PM.  
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 on Day 1 and Day 3: 
A total of 16 blood samples will be taken for a 24-hour profile (Day 1 and Day 3). The first 
blood sample will be taken within 15 minutes prior to the single use (T0). Times of sampling 
are thereafter in relation to T0: T1 after 2 minutes, T2 after 4 minutes, T3 after 6 minutes, T4 
after 8 minutes, T5 after 10 minutes, T6 after 15 minutes, T7 after 30 minutes, T8 after 45 
minutes, T9 after 60 minutes, T10 after 2 hours, T11 after 4 hours, T12 after 6 hours, T13 after 9 
hours, T14 after 12 hours and T15 after 24 hours (this sample will be drawn during the day 
following product use, i.e., wash-out).  
7.5.2 
CYP2A6 Activity 
CYP2A6 activity will be measured in plasma on Day -1 (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. 

 
 
 
 
 
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7.6.1 
Clinical Chemistry, Haematology, and Urine Analysis for Safety Panel  
Haematology, clinical chemistry and urine analysis for the safety panel will be measured at 
Screening, at day of Admission (Day -1) and at the Day of Discharge (Day 4). Tests will be 
conducted at a local laboratory or the site. Blood will be taken after no less than the 10 hours 
of fasting (see Section 6.6.2). The urine test will be performed semi-quantitatively as urine 
dip-stick test at the site. Parameters to be measured are listed in Table 3.  
Table 3. 
Clinical Laboratory Parameters for Safety Panel 
Haematology 
Clinical chemistry 
Urine analysis 
- Haematocrit 
- Haemoglobin 
- Mean corpuscular 
haemoglobin  
- Mean corpuscular 
haemoglobin concentration  
- Mean corpuscular volume  
- Platelet count 
- Red blood cell count  
- White blood cell (count) 
(WBC) 
- Differential WBC count:  
 
Neutrophils 
 
Basophils  
 
Eosinophils  
 
Lymphocytes 
 
Monocytes 
 
 
- Albumin 
- Total protein 
- Alkaline phosphatase 
- Alanine aminotransferase  
- Aspartate aminotransferase  
- Blood urea nitrogen 
- Creatinine 
- Gamma-glutamyl transferase  
- Fasting glucose 
- Lactate dehydrogenase  
- Potassium  
- Sodium 
- Total bilirubin 
- Direct bilirubin 
- Total cholesterol 
- Triglycerides 
 
- pH 
- Bilirubin 
- Glucose 
- Nitrite 
- Red blood cell traces 
- Protein 
- Specific gravity 
 
 
7.6.2 
Serology 
A test for Hepatitis B surface antigen, Hepatitis C virus and HIV (anti-HIV1/2 and p24 
antigen) will be done at Screening. In case of positive results, the subject will be referred to 
appropriate medical care. 

 
 
 
 
 
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7.6.3 
Urine Drug Screen 
A urine drug screen will be performed at the site at the Screening Visit and at the day of 
Admission. The urine will be screened for amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, and opiates.  
7.6.4 
Urine Cotinine Screening 
A urine 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 a newly calibrated alcometer device (e.g., Alcotest 7410 Plus, Dräger). 
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 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 investigator 
meeting and site initiation. Safety laboratory samples will be tested at a local laboratory (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 

 
 
 
 
 
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facility/-ies at which the samples are stored will be informed in writing by the Sponsor when 
destruction of the samples shall be performed. 
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 260 mL will be drawn for this study 
including planned assessments, safety, and repeated analysis for safety. The required aliquots 
and volumes for assessments of blood/plasma parameters and tests are summarized in the 
SHM.  
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 
analysed 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 
Section 8).  
7.8.1 
Fagerström Test for Nicotine Dependence (revised version) 
Potential nicotine dependence will be assessed at Screening using the FTND in its revised 
version (Heatherton et al, 1991), as updated in 2012 (Fagerström et al, 2012).  
The questionnaire consists of 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 to 10 
points) (Fagerström et al, 2012). 
7.8.2 
Assessment of Cough  
Subjects will be asked if they have experienced a regular need to cough e.g. coughing several 
times in the last 24 hours prior to assessment. If the answer is ‘yes’, they will be asked to 

 
 
 
 
 
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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: 1 = very mild; 2 = mild; 3 = moderate; 4 = severe; 5 = very 
severe.  
□ The frequency of cough will be assessed on a 5-point Likert scale ranging 
from 1 to 5: 1 = rarely; 2 = sometimes; 3 = fairly often; 4 = often; 
5 = almost always. 
□ The amount of sputum production will be assessed on a 4-point Likert scale 
ranging from 0 to 3: 0 = no sputum; 1 = a moderate amount of sputum; 2 = a 
larger amount of sputum; 3 = a very large amount of sputum.  
 
Finally, subjects will be asked with an open question if there are any other important 
observations that they would like to share with the staff about their coughing. 
Assessments will be done on a daily basis from Day 0 to Day 4. On Day 2 and Day 4, 
questionnaire must be asked 24 hours after T0 of Day 1 and after 24 hours minus 5 minutes 
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 or smoke CC 
during the study in sequence 1 and 2. The MCEQ will be completed by subjects on Day 1 
and Day 3.  
7.8.4 
Questionnaire of Smoking Urges (QSU-brief)  
To assess the urge-to-smoke, all subjects will be asked to complete a 10-item brief version of 
the QSU-brief (Cox et al, 2001). The QSU-brief is a self-reported questionnaire with 10 
items to be rated on a 7-point scale, ranging from 1 (strongly disagree) to 7 (strongly agree). 
Higher scores in this questionnaire indicate a higher urge to smoke.  
The findings in this brief version were consistent with the expressions of craving found in the 
32-item version of the QSU-brief (Tiffany et al, 1991). The findings supported a 
multi-dimensional conceptualization of craving to smoke and demonstrated the utility of a 
brief multi-dimensional measure of craving (Cox et al, 2001).  
The QSU-brief will be completed by the subject himself/herself at single use study days (D1, 
D3). The first assessment will be done prior to T0. All other assessments will be done after 
T0, at 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours (with an allowed time window of 
+5 min each) and 4 hours, 6 hours, 9 hours, 12 hours (with an allowed time window of +10 
min 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. There will be a descriptive analysis of this 
data 
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. 
On Day 2, subjects will be asked a series of questions related to their education, occupation, 
and household. Then they will be asked a series of questions to assess the occupation, 
employment status and qualifications of the Chief Income Earner of their household that is 

 
 
 
 
 
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the person with the largest income. The questionnaire will be administered by a trained 
interviewer. 
The social grading classification that will be used to determine the subject household’s SES 
is based upon the occupation and employment status of the Chief Income Earner (Meier & 
Moy, 2004). Based on the answers of the subjects, data will be recoded in order to assign the 
head of the household to one of the following socio-economic classes:  
Grade  
Social class 
A  
 
upper middle class 
B  
 
middle class 
C1  
 
lower middle class 
C2  
 
skilled working class 
D  
 
working class 
E  
 
Those at the lowest levels of subsistence 

 
 
 
 
 
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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 unfavourable, whether or not it is considered related to the tobacco 
product, as defined by the MRTP guidelines. 
 
An AE is defined as any untoward medical occurrence in a subject, or clinical investigation 
subject administered an IP, which does not necessarily have a causal relationship with the IP 
or reference point product. An AE can therefore be any unfavourable and unintended sign 
(including a clinically relevant abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IP or reference point product, whether or not to the IP or 
reference point product 
 
 
8.1.2 
Serious Adverse Events 
An SAE is defined as, but not limited to, any untoward medical occurrence that: 
 Results in death. 
 Is life-threatening. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity, or 
 Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, 
they may jeopardize the subject or the subject may require medical or surgical intervention to 
prevent one of the outcomes listed in the above definitions. 
Any pre-planned hospitalizations that are known at the time of signing the ICF will not be 
recorded as SAEs; however, they will be recorded as AEs only. Any AE that occurs during 
this pre-planned hospitalization will be considered according to the above definitions. 

 
 
 
 
 
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8.2 
Assessment of Adverse Events 
The Investigator is responsible for obtaining, assessing and documenting all AEs during the 
study.  
8.2.1 
Collection of Information 
Adverse event information will be collected from the time of signature of the ICF onwards 
until 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 are you feeling since you were last asked?”). At 
the discretion of the Investigator, the collection of AE information may also be triggered 
from his/her review of the subject questionnaires and the VAS. However, the main source for 
AE collection will be 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 ‘septicaemia’ rather than ‘fever’ and ‘hypotension’ 
following blood sample). 
Any AE that meets the serious criteria must be recorded both on the AE report form of the 
eCRF and on a separate SAE report form (see Section 8.3). 
 
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 

 
 
 
 
 
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procedures. Only the study procedures-related AEs will be reported in the clinical study 
report and in accordance with respective regulatory guidelines. 
 
8.2.2.2 
Admission Day until the End of Study 
From Admission onwards until Day of Discharge, all AEs will be actively collected by the 
study site 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.  
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 CIOMS VI Working Group, there are no definitive methods for distinguishing 
most adverse drug reactions (i.e., events that are causally attributed to the IP and reference 
point product) from clinical adverse events that occur as background findings in the 
population and have only temporal association with the IP and reference point product.  

 
 
 
 
 
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In general all AEs and/or SAEs will be assessed by the Investigator as either ‘related’ or ‘not 
related’ to IP as described below. In addition to the assessment of the relationship of the 
clinical event to the IP, the Investigator shall document a potential relationship of the clinical 
event to any particular study procedure. 
Not related: The temporal relationship of the clinical event to IP and reference point 
product administration or a study procedure makes a causal relationship 
unlikely, or, concomitant medication, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
 
Related: 
The temporal relationship of the clinical event to study IP and reference point 
product administration or a certain study procedure makes a causal 
relationship possible, and concomitant medication, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation for the observed 
event. 
8.2.5 
Expectedness 
An AE will be regarded as ‘unexpected’ if its nature or severity is not consistent with 
information already known about the IP, 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. 
 
 

 
 
 
 
 
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8.3 
Reporting and Follow-Up of Serious Adverse Events 
Any SAEs reported or observed during the study after signature of the ICF until the end of 
the safety follow-up period (i.e., up to 7 days after study Discharge) whether or not 
attributable to the IP, to any other medication or to any study procedures, or any SAE related 
to the product and spontaneously reported after the safety follow-up must be reported by the 
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: 
 
 
 
 
Sponsor: 
Contact: 
, 
MD, Medical Safety 
Officer 
Phone number: 
 
E-mail: 
 
 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube 
5 Quai Jeanrenaud 
2000 Neuchâtel 
Switzerland 
The Investigator is responsible for local reporting (e.g., to the IEC) of SAEs that occur during 
the study, according to local regulations. 
Any additional/follow-up information that becomes available after the initial SAE report 
form has been completed will be forwarded to 
 
 and the Sponsor within 24 hours 
after first awareness by any person at the site using a follow-up to the existing SAE report 
form. 

 
 
 
 
 
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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 investigator or designee and/or 
 
 until resolution 
or until the Investigator considers the event to be stabilized (i.e., no worsening of condition), 
or an acceptable explanation has been found (e.g., 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 eCRF, in addition to the SAE report form. 
8.4 
Reporting of Other Events Critical to Safety Evaluations 
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator and assessed for clinical relevance. If the Investigator considers 
the abnormal result to be of clinical relevance, then it must be recorded as a concomitant 
disease at Screening, or if not present at Screening, as an AE during the study. 
The grading scheme shown in (reference to the Common Terminology Criteria for Adverse 
Events and Common Toxicity Criteria [CTCAE] version 4.03) will be used by the 
Investigator to assess abnormal laboratory AEs as follows: 
 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 enrol 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), 

 
 
 
 
 
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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 and reference point product, intensity, 
seriousness, outcome) will be assessed as for other AEs. 
8.5 
Reporting and Follow-Up of Pregnancies 
For pregnancies detected during the Screening Period and prior to first THS 2.2 use, the 
subject will be considered as a screening failure and removed from the study. No Pregnancy 
Form will be filled; however, the diagnosed pregnancy must be captured in the Screen 
Failure eCRF.  
All pregnancies occurring after signature of the ICF and diagnosed after first exposure to the 
IP and reference point product until completion of the study must be reported by the 
Investigator.  
Any pregnancy potentially associated to exposure to the IP and reference point product, 
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, and reference point product is defined as the conception date being calculated before the 
last exposure to the IP and reference point product.   
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 test on Admission Day). If pregnancies are to be followed up, they will be 
followed up until an outcome is reached (e.g., normal delivery, spontaneous abortion or 
voluntary termination). Any pregnancy complications, adverse pregnancy outcomes or 
maternal complications will be recorded. 
The Investigator is responsible for informing the IEC of any pregnancy that occurs during the 
study and its outcome, according to local regulations. 

 
 
 
 
 
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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 on 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. 
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 THS Charger will be 
documented by the Investigator or his/her designated staff using a Device Issue Log. 

 
 
 
 
 
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Furthermore, any malfunctions of the THS Tobacco Stick Holder or THS Charger that lead 
to an AE/SAE will follow the same processes as described above. 
 
 

 
 
 
 
 
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9 STUDY ACTIVITIES 
A detailed schedule of assessments can be found in Appendix 1. The time points shown are 
to be considered the time of assessment for the first subject. As not all subjects can be treated 
at the same time, a short time window will be implemented for subsequent subjects. 
Measurements not conducted at the exact time point, but conducted within the given time 
window (if applicable) do not constitute a protocol deviation but an accepted variability for 
the given time point. 
In general, if no start time for the procedure is provided, then the procedure can be performed 
at any time during the day. 
9.1 
Screening Visit 
The Screening Visit will be performed within 4 weeks (Day -29 to Day -2) prior to 
Admission (Day -1). Subjects will attend the investigational site in at least a 10-hour fasting 
state for clinical laboratory to be assessed.  
The following assessments will be performed at the Screening Visit (Table 4) (the sequence 
of the assessment will be at the discretion of the site but all of them must be done after 
signature of the ICF. 
Table 4. 
Time Schedule – Screening 
Time 
Blood sample 
Procedures 
Additional information 
Start of 
procedure 
 
 
 
 
 
Informed consent 
 
 
 
Demographic data  
On the day of ICF signature 
 
 
Advice on the risks of smoking and 
debriefing 
 
 
 
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/concomitant medication 
 
 
 
Medical history/concomitant diseases 
 

 
 
 
 
 
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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 
(haematology, urine analysis, clinical 
chemistry) 
 
 
√ 
Serology for HIV and Hepatitis B 
and C 
 
 
 
Identification of current CC brand 
 
 
 
Urine drug screen 
 
 
 
Alcohol breath test 
 
 
 
Urine pregnancy test for female 
subjects 
 
 
 
THS 2.2 and NNS product 
demonstration 
 
 
 
Spirometry without short-acting 
bronchodilator, and then with 
 
 
 
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; CC = 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 = Tobacco Heating System 
9.2 Admission 
The following assessments will be performed at Admission (Day -1) (Table 5): 

 
 
 
 
 
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Table 5. 
Time Schedule – Day -1 Admission 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
 
 
 
 
AE/SAE recording, concomitant 
medication 
All day 
 
 
Advice on the risks of smoking and 
debriefing 
 
 
 
Readiness to accept interruptions of 
smoking for up to 4 days 
 
 
√ 
trans-3’-hydroxycotinine and 
cotinine (CYP2A6 activity) in 
plasma 
The subject should not have 
smoked in the morning until this 
assessment 
Must be done prior smoking 
6:30 AM 
 
Beginning of smoking period 
 
 
 
Urine pregnancy test for female 
subjects 
 
 
√ 
Clinical laboratory parameters 
(haematology, urine analysis, 
clinical chemistry) 
 
 
 
Urine cotinine screening test 
 
 
 
Urine drug screen 
 
7:30 AM-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 
 
Physical examination, weight and 
calculated BMI 
 
10:00 AM-11:30 AM 
 
Spirometry 
 
10:00 AM-11:30 AM 
 
Identification of current CC brand 
 
10:00 AM-11:30 AM 
 
Smoking history 
 
10:00 AM-11:30 AM 
 
Alcohol breath test 
 
10:00 AM-11:30 AM 
 
CO breath test 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:30 PM-6:00 PM 
 
Snacks 
 
4:30 PM-6:00 PM 
 
Product test for THS 2.2 and NNS 
The THS 2.2 test should be done 
first and then the NNS test 
4:30 PM-6:00 PM 
 
Inclusion/exclusion criteria 
 

 
 
 
 
 
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4:30 PM-6:00 PM 
 
Enrolment 
 
6:30 PM-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 
 
7:30 AM-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 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 
4:30 PM-5:00 PM 
 
Snacks 
 
6:30 PM-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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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 +5 min after T0 of Day 1  
 
 
Assessment of cough 
24 hrs minus 5 min after T0 of 
Day 1  
7:30 AM-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 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 
4:30 PM-5:00 PM 
 
Snacks 
 
6:30 PM-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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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 first 
blood draw of the day 
 
 
 
AE/SAE recording, concomitant 
medication 
All day 
 
 
Support as required 
All day 
 
 
Craving questionnaire 
(QSU-brief) 
First time prior to T0, then 15 min +5 
min, 30 min +5 min, 45 min +5 min, 
1 hr +5 min, 2 hrs +5 min, after T0, 
then and 4 hrs +10 min, 6 hrs +10 
min, 9 hrs +10 min, and 12 hrs +10 
min 
 
√ 
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) 
 
√ 
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 
 
7:30 AM-10:00 AM 
 
Breakfast 
 

 
 
 
 
 
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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 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 
5:00 PM-5:30 PM 
 
Snacks 
 
6:30 PM-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 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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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 
minus 5 min 
7:30 AM-9:00 AM 
√ 
Clinical laboratory parameters 
(haematology, urine analysis, clinical 
chemistry) 
 
7:30 AM-9:00 AM 
 
Urine pregnancy test 
 
9:00 AM-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 
 
CO breath test 
 
10:00 AM-11:30 AM 
 
Spirometry  
 
10:00 AM-11:30 AM 
 
Physical examination, weight and 
calculated BMI 
 
10:00 AM-11:30 AM 
 
Advice on risk of smoking and 
debriefing 
 
10:00 AM-11:30 AM 
 
Time of discharge 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; CO = Carbon monoxide; PK = Pharmacokinetic; SAE = 
Serious adverse event; T = Time point 
Smoking will be allowed after spirometry has been conducted. 

 
 
 
 
 
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9.5 
Safety Follow-up Period 
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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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. 
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 

 
 
 
 
 
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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, 
analysed, 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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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 paper copies. 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. 
11.1.1 
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 oestrogen or other drugs that are known to affect 
CYP2A6 activity.  
All protocol deviations will be entered into the Clinical Trial Management System (CTMS) 
or other approved format. 
Information from the source documents will represent the primary source of protocol 
deviations. Information following site monitoring and other manual reviews will be 

 
 
 
 
 
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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. 
11.2.2 
Coding 
Adverse events, medical/surgical history, and prior/concomitant medication will be classified 
according to the terminology of the latest version of the following Dictionaries, at time of 
coding the first entry: 

 
 
 
 
 
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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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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 (CC, THS 2.2, and NNS) to allow comparisons between 
THS 2.2 and CC in Group-1 (sequence 1 and 2), and between THS 2.2 and NNS in Group-2 
(sequence 3 and 4). 
Full details of the statistical analysis will be given in a SAP. Any changes to the planned 
statistical methods will be documented in the Clinical Study Report. The statistical 
evaluation will be performed using SAS®, version 9.2 or later. 
12.1.1 
Stratification Criteria 
For analysis, the following stratification criteria will be used:  
□ Sex (male and female) 
□ CC nicotine level at Admission (ISO nicotine levels ≤0.6 mg and >0.6≤1 mg)  
 
In addition, for the safety data, the analysis will be stratified by sequence and by study 
periods (Screening, product test, product exposure, and safety follow-up period). 
12.1.2 
Definitions for Statistical Data Analysis 
Unless otherwise stated, for the purposes of statistical analyses, baseline is defined as the last 
available time point prior to T0 on Day 1, from 6:00 AM to 9:00 AM. 
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by sequence and subject, unless otherwise 
specified.  
Descriptive statistics for continuous variables (number of subjects [n], number and 
percentage of subjects with missing data, mean, standard deviation, median, first and third 
quartiles, minimum and maximum for continuous data, and the n and absolute and relative 
[%] frequency for categorical data) will presented by exposure and overall at each time point, 
where applicable.  
Descriptive statistics for PK parameters will also include the geometric mean and coefficient 
of variation.  
Baseline, admission and screening data (i.e., anything prior to product exposure) will be 
summarized by sequence and overall where appropriate. 

 
 
 
 
 
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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 (CIs) will be two-sided 95% 
CIs.  
No formal adjustment of the test-wise alpha level for multiple testing is necessary, as no 
claim will be made based on the outcome of the individual tests. 
12.2 Determination of Sample Size and Power Consideration 
A total of 62 smokers 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 
and CC with a 90% probability of obtaining a margin of error (95% CI) of at most ±20%, 
assuming that THS 2.2 have a nicotine PK profile similar to CC (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 
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 and NNS is 1.55, based on data reported by Gourlay and Benowitz, 1997, 
and Johansson et al, 1991.  
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 (PMI, 2012a) comparing the 
nicotine PK profiles of THS 2.1, the predecessor of THS 2.2 and CC. In the absence of data 
comparing THS and NNS, the same CVs were assumed for the calculation of the sample size 
related to the THS 2.2:NNS comparison.  

 
 
 
 
 
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Sample size calculations were conducted using SAS version 9.2 for the 95% CI of the mean 
differences between paired observations (proc power onesamplemeans) in the natural log 
scale (Senn, 2002). The SAS implementation of the method published by Beal, 1989 was 
adopted to estimate the probability of obtaining at most the target confidence interval of 
±20%. 
12.3 
Analysis Populations 
All analyses will be based on actual product exposure. All endpoints (other than safety) will 
be analysed using the PK Analysis sets. Safety will be analysed 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 and NNS separately from the comparison between THS 2.2 
and CC.  
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 (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.  
 
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: 

 
 
 
 
 
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Cmax 
Maximum observed plasma concentration. Cmax will be reported as long 
as there is at least one quantifiable concentration post-exposure 
AUC(0-last) 
Area under the plasma concentration-time curve from start of product 
use to the time of the last quantifiable concentration (linear trapezoidal 
method).  
 
12.5.2 
Baseline Comparability 
Not applicable. 
12.5.3 
Descriptive Analysis 
Primary endpoints will be summarized as described in Section 12.1.3. 
An analysis of variance (ANOVA) will be conducted on AUC(0-last) and Cmax endpoints in the 
natural logarithmic scale. The model will include terms for sequence, subjects within 
sequence, period and product exposure as fixed effect factors. The results of this analysis for 
each of AUC(0-last) and Cmax are presented in terms of adjusted geometric least square means 
and 95% CIs for the THS 2.2:CC and THS 2.2: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 
estimated by means of the percentile bootstrap technique, using 2000 bootstrap samples 
which preserve the number of subjects per sequence. 
12.5.4 
Confirmatory Analyses 
Given that the objective of this study is to determine the point estimate and precision of the 
ratio of THS 2.2:CC for Cmax and AUC(0-last), there is no statistical hypothesis to be tested. 
 

 
 
 
 
 
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12.6 Secondary Endpoints 
12.6.1 
Secondary Endpoint Analysis Variables 
Nicotine PK parameters will be derived as follows: 
tmax 
Time of maximum observed plasma concentration. tmax will be reported 
as long as there is at least one quantifiable concentration post-exposure 
AUC(0-t’) 
Area under the plasma concentration-time curve from zero to the 
subject-specific time to maximum nicotine concentration following 
single use of CC or NNS (linear trapezoidal method) 
AUC(0-∞) Area under the plasma concentration-time curve from start of product 
use extrapolated to infinite time, 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 
Terminal elimination half-life, derived as ln(2)/λz 
More details on PK parameter derivations will be provided in the SAP. 
Subjective effects of using THS 2.2 as compared to the CC and to the NNS will be evaluated 
by analysing domain scores of QSU-brief and MCEQ. Full details of questionnaire domain 
scores derivation will be provided in the SAP. 
 
12.6.2 
Baseline Comparability 
Not applicable. 
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: 
□ AUC(0-∞), AUC(0-t’), and t1/2 will be analysed 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.  

 
 
 
 
 
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□ Hodges-Lehmann 95% CI estimates for the median tmax differences will be presented 
(Lingling, 2008). 
□ The use of random effects model is suggested in the context of the analysis of 
subjective effects of smoking (Shiffman et al, 2004). Mixed effects ANOVA with the 
same model terms as planned for the sensitivity analysis of the primary endpoints will 
be adopted for the analysis of QSU-brief, including all of the different assessment 
time points as repeated measurements. The analysis will not be adjusted for the 
assessment prior to T0 (Fleiss et al, 1985). 
□ Levels of exhaled CO and of blood COHb will be summarized by means of 
descriptive statistics reported by exposure. Analysis of COHb levels will be 
conducted using a mixed model for repeated measures, the same approach as for the 
QSU-brief. 
 
The following analyses will be conducted only in Group-1 PK analysis set: 
□ Mixed effects ANOVA with the same model terms as planned for the sensitivity 
analysis of the primary endpoints will be adopted for the analysis of the MCEQ 
domain scores. 
 
The following analyses will be conducted in only Group-2 PK analysis set: 
□ To test if the time to the maximum nicotine concentration in THS 2.2 is shorter than 
in NNS the following hypothesis will be evaluated: 
H0: XTHS - XNNS = 0 
HA: XTHS - XNNS < 0 
where XTHS and XNNS are the median values of the THS 2.2 and NNS, respectively. 
tmax will be analysed 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 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 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. 
 
 

 
 
 
 
 
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12.6.4 
Confirmatory Analyses 
Not applicable. 
 
12.6.5 
Safety Endpoints  
In general, all safety data will be listed and tabulated on the safety population by sequence, 
using the approach described in Section 12.1.3. Safety variables collected during exposure 
periods will also be reported by product exposure. 
AE data will serve as the primary assessment of safety. Other safety variables monitored in 
this study include: respiratory symptoms (cough assessment VAS and Likert scales); vital 
signs (systolic and diastolic blood pressure, pulse rate, respiratory rate); spirometry; ECG 
data; clinical chemistry, haematology, and urine analysis safety panel; physical examination; 
and concomitant medication. 
The number and percentage of subjects with AEs and SAEs will be tabulated by system 
organ class and preferred term. Summaries will also be presented for AEs leading to 
withdrawal, AEs leading to Death, AEs by relatedness to product exposure, AEs by severity, 
and laboratory AEs. Tabulations will be performed for both the number of subjects 
experiencing an event and the number of events. The number and percentage of device 
events and of subjects with device events will be tabulated by sequence. 
The number and percentage of subjects with clinical findings will be tabulated by sequence 
for laboratory parameters. Shift tables showing change from baseline of clinical findings will 
be provided for ECGs, physical examinations, and laboratory parameters (both shifts in 
normal ranges and toxicity grades). Descriptive statistics will be summarized by visit and 
change from baseline for laboratory parameters, ECG, respiratory symptoms, and vital signs. 
12.7 Exploratory Analyses 
There are no planned exploratory analyses. 
12.8 
Interim Analysis 
There are no planned interim analyses. 

 
 
 
 
 
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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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Investigators and Study Administrative Structure 
13.1.1 
Investigator 
Principal Investigator: 
 
Johnston Stewart 
 
Celerion GB Ltd, 
 
 
 
 
 
 
 
 
 
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 
 
Fax: +41 
 
Mobile: +41 
 
E-mail: 
 
, PhD 
Biostatistician 
Phone: +41 
 
Mobile: +41
 
E-mail:
 
, MD 
Medical Safety Officer 
Phone: +41
 
Mobile: +41 
 
E-mail:
 

 
 
 
 
 
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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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
 
Medical Writer 
Phone: 
  
Mobile: 
 
E-mail:
 
, PhD 
Clinical Study Manager 
Phone: 
 
Mobile: 
 
E-mail:
 
 
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 
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 confidentiality of data for 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. 

 
 
 
 
 
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are hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
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, IEC review, and regulatory 
inspection(s). 
13.4 
Record Retention 
All records of data, source data and source documents (original records or certified copies), 
in any form (including, but not limited to, written, electronic, 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 GCP 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 
 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). 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A 
 Record of all communications between the Investigator and the IEC, composition of the 
IEC. 
 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). 
 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. 
 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. 

 
 
 
 
 
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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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
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 IEC 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 
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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are hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
14 REFERENCE LIST 
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Final 2.0   / 14 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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
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confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
FDA, 2011 
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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 applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
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confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
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confidential commercial information, and the legal protections provided to such trade secrets and  confidential information 
are hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
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without the written consent of Philip Morris Products S.A 
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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 and NNS 
● 
 
 
 
 
 
 
 
Product test for THS 2.2 and 
NNS 
 
● 
 
 
 
 
 
 
Identification of current CC 
brand 
● 
● 
 
 
 
 
 
 
Smoking history 
● 
● 
 
 
 
 
 
 
Readiness to accept 
interruption from smoking up to 
4 days 
● 
● 
 
 
 
 
 
 
Willingness to quit smoking in 
the next 3 months 
● 
 
 
 
 
 
 
 
Demographics a, medical 
history, concomitant diseases  
● 
 
 
 
 
 
 
 

 
 
 
 
 
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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 
Socio-economic status 
questionnaire 
 
 
 
 
● 
 
 
 
Prior medication b / 
Concomitant medication 
● 
● 
● 
● 
● 
● 
● 
● 
Physical examination, body 
height, weight and related BMI c 
● 
● 
 
 
 
 
● 
 
Vital signs d 
● 
● 
● 
● 
● 
● 
● 
 
ECG 
● 
 
 
● 
 
● 
 
 
Spirometry 
● 
● 
 
 
 
 
● 
 
Chest X-ray e 
● 
 
 
 
 
 
 
 
B/U: Haematology, clinical 
chemistry, urine analysis 
● 
● 
 
 
 
 
● 
 
B: Serology  
● 
 
 
 
 
 
 
 
U: Urine drug screen, urine 
cotinine screen 
● 
● 
 
 
 
 
 
 
Alcohol breath test  
● 
● 
 
 
 
 
 
 
U: Pregnancy test (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 
 
● 
 
 
 
 
 
 

 
 
 
 
 
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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 
plasma  
FTND questionnaire 
● 
 
 
 
 
 
 
 
QSU–brief questionnaire i 
 
 
 
● 
 
● 
 
 
MCEQ (modified version, only 
after THS 2.2 and CC use  
 
 
 
● 
 
● 
 
 
Cough assessment j 
 
 
● 
● 
● 
● 
● 
 
AE/SAE recording  
● 
● 
● 
● 
● 
● 
● 
● 
See also instructions and abbreviations on the following page. 
Abbreviations: AE = Adverse event; CC = 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; SAE = Serious adverse 
event; THS = Tobacco Heating System 
 
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 min +1 min, T2 after 4 min +1min, T3 after 6 min +1 min, 
T4 after 8 min +1 min, T5 after 10 min +1 min, T6 after 15 min +2 min, T7 after 30 min +2 min, T8 after 45 min +2 min, T9 after 60 
min +3 min, T10 after 2 hours +5 min, T11 after 4 hours +5 min, T12 after 6 hours +5 min, T13 after 9 hours +5 min, T14 after 12 
hours +5 min, and T15 after 24 hours +5 min.  

 
 
 
 
 
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protections provided to such trade secrets and  confidential information are hereby claimed under the applicable provisions of applicable law. No part of this document may be 
publicly disclosed without the written consent of Philip Morris Products S.A 
g: COHb blood samples to be taken as follows: 
Single use: A total of 5 blood samples will be taken. The first sample within 15 minutes prior to T0 (start of single product use); thereafter in 
relation to T0 at 15 min +2 min, 60 min +3 min, 4 hours +5 min and 12 hours +5 min 
h: A CO breath test will be conducted once on Day -1 and Day 4. On Day 0, Day 1, Day 2, Day 3, four breath tests will be done per day. On Day 
1 and Day 3, the first test per day will be performed within 15 minutes prior to T0 (T0 = start of first product use) and then around 12:00 pm, 
4:00 pm and 8:00 pm. On the wash-out days (Day 0 and Day 2) it will be conducted around 8:00 am, 12:00 pm, 4:00pm, and 8:00 pm. 
i: QSU–brief will be assessed as follows:  
Single use: The QSU-brief will be completed by the subject himself/herself at single use study days. The first assessment will be done prior to 
T0. All other assessments will be done after T0, at 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours (with an allowed time window of +5 
min each) and 4 hours, 6 hours, 9 hours, 12 hours (with an allowed time window of +10 min each).  
j: Visual analogue scale, three Likert scales and one open question. Cough questionnaire should be asked on Day 0 between 06:30 and ’09:00, 
on Day 2 24 hours after T0 of Day 1, on Day 4, 24 hours after T0 of Day 3, and on Day 1 and Day 3, prior product use. 
k: All examinations listed at the Day of Discharge should also be conducted in subjects preliminarily terminating the study. 
l: Spontaneous reporting of new AEs/SAEs by the subject and active follow-up of ongoing AEs/SAEs by the site.  

 
 
 
 
 
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without the written consent of Philip Morris Products S.A 
 
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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without the written consent of Philip Morris Products S.A 
Appendix 3 
Investigational Product and Instructions for Use 
The product user guide will be provided as a separate document. 
 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A 
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.medicines.org.uk/emc/medicine/20679:  
’Undesirable effects 
Some symptoms may be related to nicotine withdrawal associated with stopping smoking. These can include; 
irritability/aggression, dysphoria/depressed mood, anxiety, restlessness, poor concentration, increased 
appetite/weight gain, urges to smoke (cravings), night-time awakenings/sleep disturbance and decreased heart 
rate. Increased frequency of aphthous ulcer may occur after abstinence from smoking. The causality is unclear.  
Nicorette Nasal Spray may cause adverse reactions similar to those associated with nicotine given by other 
means, including smoking, and these are mainly dose-dependent. At recommended doses Nicorette Nasal Spray 
has not been found to cause any serious adverse effects. Excessive use of Nicorette Nasal Spray by those who 
have not been in the habit of inhaling tobacco smoke could possibly lead to nausea, faintness or headaches.  
During the first 2 days of treatment, nasal irritation as sneezing, running nose, watering eyes, cough was 
reported by nearly all (94%) of the patients. Both the frequency and severity declined with continued use. 
Reported adverse events associated with Nicorette Nasal Spray include: 
Body System 
Incidence* 
Reported adverse event 
Nervous system disorders:  
Common  
Dizziness, headache  
Cardiac disorders:  
Uncommon:  
Palpitations  
  
Very rare:  
Reversible atrial fibrillation  
Respiratory, thoracic and 
mediastinal disorders:  
Common:  
Coughing  
Gastrointestinal disorders:  
Common:  
Gastrointestinal discomfort, nausea, vomiting  
General disorders and 
administration site disorders:  
Very common:  
Epistaxis, running nose, sneezing, watering eyes.  
* Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1 000, < 1/100); rare (>1/10 000, <1/1 000); 
very rare (<1/10 000), including isolated reports.” 

 
 
 
 
 
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Final 2.0   / 14 May 2013 
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without the written consent of Philip Morris Products S.A 
Appendix 5 
Abnormal Laboratory Values 
ABNORMAL LABORATORY VALUES RATING: SERUM CHEMISTRY PARAMETERS 
Serum Chemistry* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Sodium – Hyponatremia (mmol/l) ** 
(1) 
<LLN - 130 
- 
<130 - 120 
Sodium – Hypernatremia (mmol/l) ** 
(1) 
>ULN - 150 
>150 - 155 
>155 - 160; 
hospitalization 
indicated 
Potassium – Hyperkalaemia 
(mmol/l)**(1) 
>ULN - 5.5 
>5.5 - 6.0 
>6.0 - 7.0; 
hospitalization 
indicated 
Potassium – Hypokalaemia (mmol/l) 
** (1) 
<LLN - 3.0 
<LLN - 3.0; 
symptomatic; 
intervention 
indicated 
<3.0 - 2.5; 
hospitalization 
indicated 
Glucose – Hypoglycaemia ** (1)    
(mg/dL) 
                                                   
(mmol/l)  
<LLN – 55; 
<LLN – 3.0 
<55 – 40; 
<3.0 – 2.2 
<40 – 30; 
<2.2 – 1.7 
Blood Urea Nitrogen (BUN) (mg/dL) 
(2) 
23 – 26 
27 – 31 
>31 
Glucose – Hyperglycaemia: ** 
  
Fasting (1)( (mg/dL) 
                   (mmol/l) 
 
 
>ULN – 160; 
>ULN – 8.9 
 
>160 -250 
> 8.9-13.9 
 
 
>250 – 500; 
>13.9 – 27.8 
Hospitalization 
indicated 
Creatinine increased** (1) 
>1 – 1.5 x 
baseline; 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x 
baseline; 
>1.5 – 3.0 x ULN 
>3.0 x baseline; 
>3.0 – 6.0 x ULN 
Albumin – Hypoalbuminaemia** 
(1)(g/dL) 
                                                          
(g/l) 
<LLN – 3; 
<LLN - 30 
<3 – 2; 
<30 - 20 
<2; 
<20 
Total Protein – Hypoproteinaemia (2) 
(g/dL) 
 
5.5 – 6.0 
 
5.0 – 5.4 
 
<5.0 
Alkaline phosphatase increased** (1) 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x 
ULN 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A 
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 ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 ULN 
Cholesterol high** (1)(                            
 
 
 
 
 
 
 
 
 
(mg/dL) 
(mmol/l) 
 
 
>ULN – 300; 
>ULN – 7.75 
 
 
>300-400; 
>7.75-10.34 
 
 
>400-500; 
>10.34-12.92 
Triglycerides - Hypertriglyceridemia 
(1) 
(mg/dL) 
(mmol/l) 
 
150 – 300; 
1.71 – 3.42 
 
>300 – 500; 
>3.42 – 5.70 
 
>500 – 1000; 
>5.70 – 11.40 
Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; LLN = Lower 
limit of the normal range; ULN = Upper limit of the normal range. 
Data Sources: 
 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, U.S. Department of Health and Human Services, FDA, Center for 
Biologics 
Evaluation 
and 
Research 
- 
Guidance 
for 
Industry. 
 
       (2) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, 
FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
*  Those parameters that are not listed do not have grading categories in either the CTCAE or the 
FDA guidance documents and will therefore be reviewed by the Investigator and only reported as 
an AE if considered to be clinically relevant. 
** Where parameters in this table are listed in both the CTCAE and the FDA guidance documents, 
and each document has different values within each grading category, the grading in CTCAE 
guidance document predominates. 

 
 
 
 
 
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are hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
ABNORMAL LABORATORY VALUES RATING: HEMATOLOGY PARAMETERS 
Haematology* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Haemoglobin (Female) – (g/dL) 
(1) 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
change from baseline value – 
(g/dL) (1) 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
Haemoglobin (Male) – (g/dL) (1) 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
change from baseline value – 
(g/dL) (1) 
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
Haemoglobin increase – (g/dL) (2) 
Increase in >0 – 2 
above ULN or 
above baseline if 
baseline is above 
ULN 
Increase in >2 – 4 
above ULN or above 
baseline if baseline 
is above ULN 
Increase in >4 
above ULN or 
above baseline if 
baseline is above 
ULN 
WBC Increase  – (cell/mm3) (1) 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25,000 
WBC Decrease - (cell/mm3) (2)** 
<LLN – 3000; 
<LLN – 3.0 x 10-9/l 
<3000 - 2000; 
<3.0 – 2.0 x 10-9/l 
<2000 - 1000; 
<2.0 – 1.0 x 10-9/l 
Lymphocytes Increase - 
(cell/mm3) (2) 
- 
>4,000 – 20,000 
>20,000 
Lymphocytes Decrease  - 
(cell/mm3) (2)** 
<LLN – 800; 
<LLN – 0.8 x 10-9/l 
<800 - 500; 
<0.8 – 0.5 x 10-9/l 
<500 - 200; 
<0.5 – 0.2 x 10-9/l 
Neutrophils Decrease  - 
(cell/mm3) (2)** 
<LLN – 1500; 
<LLN – 1.5 x 10-9/l 
<1500 - 1000; 
<1.5 – 1.0 x 10-9/l 
<1000 - 500; 
<1.0 – 0.5 x 10-9/l 
Eosinophils - (cell/mm3) (1) 
650 – 1500 
1501 - 5000 
>5000 
Platelets Decrease - (cell/mm3) 
(2)** 
<LLN – 75,000; 
<LLN – 75.0 x 10-9/l 
<75,000 – 50,000; 
<75.0 – 50.0 x 10-9/l 
<50,000 – 25,000; 
<50.0 – 25.0 x 10-9/l 
Abbreviations: LLN = Lower limit of the normal range; ULN = Upper limit of the normal range; WBC = 
White blood cell. 
Data Sources: 
 
(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. 

 
 
 
 
 
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are hereby claimed under the applicable provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
**  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. 

 
 
 
 
 
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without the written consent of Philip Morris Products S.A 
ABNORMAL LABORATORY VALUES RATING: URINALYSIS PARAMETERS 
Urine* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Protein ** (1) 
1+ proteinuria; 
urinary protein <1.0 
g/24 hours 
2+ proteinuria; 
urinary protein 1.0-
3.4 g/24 hours 
Urinary protein ≥3.5 
g/24 hours 
Glucose (2) 
Trace 
1+ 
2+ 
Blood – Haematuria ** (1) 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; urinary 
catheter or bladder 
irrigation indicated; 
limiting instrumental 
ADL 
Gross haematuria; 
transfusion, IV 
medications or 
hospitalization 
indicated; elective 
endoscopic, radiologic 
or operative 
intervention indicated; 
limiting self-care ADL 
Abbreviations: ADL = Activities of daily living; IV = Intravenous. 
Data Sources: 
 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
   (2) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, 
FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
*  Those parameters that are not listed do not have grading categories in either the CTCAE or the 
FDA guidance documents and will therefore be reviewed by the Investigator and only reported as 
an AE if considered to be clinically relevant. 
**  Where parameters in this table are listed in both the CTCAE and the FDA guidance documents, 
and each document has different values within each grading category, the grading in CTCAE 
guidance document predominates. 
 
 
 
 

 
 
 
 
 
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Appendix 6 
Investigational Micro+TM Smokerlyzer® 
The Micro+™ Smokerlyzer® carbon monoxide (CO) monitor is the new-and-improved 
version of the revolutionary Micro™ Smokerlyzer®. The Micro™ Smokerlyzer® is a 
longstanding benchmark device used in clinical studies and research. 
The Micro+™ is the most comprehensive CO monitor available. It analyses breath CO levels 
in adults and adolescents up to 250 ppm, and automatically converts CO readings of pregnant 
women to foetal %COHb. 
Micro+ Features 
 Analyses COHb and CO levels in a single breath. 
 Options for testing adults, adolescents and pregnant women. 
 Instant conversion to foetal %COHb at the touch of a button. 
 Clinically proven stop smoking help. 
 Easy-to-use colour touch screen instantly displays the exact result. 
 On-screen instructions with audio prompts. 
 Store up to 100 readings and view them as a table or a graph. 
 Improved electrochemical sensor and anti-humidity filter. 
 Antibacterial filter and one-way valve for optimal infection control. 
 Auto-zero and adjustable breath hold countdown. 
 Built-in maintenance reminders. 
 Minimal hydrogen cross-sensitivity. 
Operation 
The Micro+ analyses the amount of CO in a single exhaled breath. It uses this reading to 
automatically calculate the percentage of COHb in the blood. Carrying out a test: simply 
press the button to switch the monitor on, then follow the instructions on the touch screen 
display. Exhale into the monitor through the Flatpak™ mouthpiece and the result is displayed 
instantly in exact parts per million (ppm) for CO, and as a percentage for COHb (%COHb). 
The numbers are displayed either in green, amber or red (a familiar ‘traffic light’ system) to 
represent the level of CO. 
Instrument cleansing wipes 
Instrument cleansing wipes specific to the instrument are provided. 

 
 
 
 
 
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Calibration 
Calibration gas 
Calibration gas is supplied by Bedfont in lightweight disposable cylinders. Calibration of the 
Micro+™ should be carried out with Bedfont's 50 ppm CO in air calibration gas. No 
specialist technical knowledge or skills are required and Bedfont provides comprehensive 
calibration kits for ultimate ease of use. Calibration should be carried out at least every 
6 months. A calibration reminder will appear automatically when calibration is due. 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
  
 
  
  
 
  
  
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
  
  
 
 
   
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
  
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol 
ZRHR-PK-01-EU 
 
Study title: 
A single-centre, open-label, randomized, controlled, crossover study 
to investigate the nicotine pharmacokinetic profile and safety of 
Tobacco Heating System 2.2 (THS 2.2) following single use in 
smoking, healthy subjects compared to conventional cigarettes and 
nicotine nasal spray 
Short study title: 
Nicotine pharmacokinetic profile and safety of the Tobacco Heating 
System 2.2 (THS 2.2) 
EudraCT number: 
2013-003097-27  
Product name: 
Tobacco Heating System 2.2 (THS 2.2)  
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Version number: 
 Final 3.0  
Date: 
19 August 2013 
Authors: 
 
, PhD, Biostatistician 
, MD, Medical Safety Officer 
, Medical Writer 
 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 

 
 
 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
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without the written consent of Philip Morris Products S.A. 
 
 
SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Name of Product: 
Tobacco Heating System 2.2 (THS 2.2)  
Study Title: 
A single-centre, open-label, randomized, controlled, crossover study to investigate the 
nicotine pharmacokinetic profile and safety of Tobacco Heating System 2.2 (THS 2.2) 
following single use in smoking, healthy subjects compared to conventional cigarettes and 
nicotine nasal spray. 
Short Study Title: 
Nicotine pharmacokinetic profile and safety of the Tobacco Heating System 2.2 (THS 2.2) 
Study Number and Acronym: 
ZRHR-PK-01-EU, 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 
relative to conventional cigarettes (CC), following single use of THS 2.2 and CC. 
Secondary Objectives: 
• To determine if Cmax and AUC(0-last) of the THS 2.2 are higher relative to nicotine 
nasal spray (NNS) following single use of the THS 2.2 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 CC or NNS product 
[AUC(0-t’)]) between the THS 2.2 and CC, as well as the THS 2.2 and NNS.  
• To evaluate the time to the maximum concentration (tmax) of nicotine for the THS 2.2 
as compared to CC and to determine if the tmax for THS 2.2 is shorter as compared to 
NNS. 
• To describe the terminal half-life (t1/2) of nicotine for the THS 2.2, CC, and NNS. 
• To describe the differences on urge-to-smoke over time between the THS 2.2 and CC, 
as well as between the THS 2.2 and NNS. 

 
 
 
 
 
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• To describe product evaluation in the THS 2.2 and CC users. 
• To describe the levels of carbon monoxide (CO) exposure for the THS 2.2, as 
compared to CC and NNS users. 
• To monitor the safety during the study. 
Primary Endpoints: 
• Primary nicotine PK parameters (THS 2.2 vs. CC): 
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:CC ratio for the primary nicotine PK parameters are estimated with a 
precision of ±20%. 
 
Secondary Endpoints: 
• Primary nicotine PK parameters (THS 2.2 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. 
• Safety variables: 
o Incidence of adverse events (AEs)/serious adverse events (SAEs) and 
device events, including THS 2.2 malfunction/misuse. 
o Respiratory symptoms: cough assessment by visual analogue and Likert 
scales and one open question. 
o Vital signs. 

 
 
 
 
 
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o Spirometry. 
o Electrocardiogram (ECG). 
o Clinical chemistry, haematology, 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.  
• 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. 
• CC. 
• NNS. 
 
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/CC/NNS). 
Period 2: Day 2: Wash-out; Day 3: single product use (THS 2.2/CC/NNS). 
 

 
 
 
 
 
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Study Population and Main Criteria for Inclusion: 
A total of 62 smoking, healthy adult Caucasian subjects, meeting the following main 
inclusion criteria:  
□ Subject is aged from 21 to 65 years (inclusive). 
□ Smoking, healthy subject as judged by the Investigator. 
□ Subject smokes at least 10 commercially available non-menthol CCs per 
day (no brand restrictions) for the last 4 weeks, based on self-reporting. 
□ Subject does not plan to quit smoking in the next 3 months. 
□ 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 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 ≤0.6 mg and >0.6≤1 
mg) will have a quota applied to ensure they represent at least 40% of the study population. 
Subjects who do not complete the study after randomization will not be replaced. 
Investigational Products 
Test Product:  
 Tobacco Heating System 2.2 
Reference Product:  Subject’s own supply of commercially available preferred 
single brand CC. 
Reference Point Product (non-investigational):  
Nicotine Nasal Spray (Nicorette® 10 mg/mL); 1  spray 
(resulting in the administration of 0.5 mg nicotine) per 
nostril/product use, as per label. This will be supplied by the 
Investigator and reimbursed by the Sponsor. 
Duration of Study: 
The entire study will last 14 to 40 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). 
 

 
 
 
 
 
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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 and NNS separately from the 
comparison between THS 2.2 and CC. 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:CC and THS 2.2:NNS ratios. The 
lower bound of the 95% CI of the THS 2.2: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 are higher relative to NNS. 
AUC(0-∞), AUC(0-t’), and t1/2 will be analysed 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 is shorter than in NNS. The median tmax differences between THS 2.2 
and CC, as well as between THS 2.2 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 
analyse the domain scores of the product evaluation (MCEQ) questionnaire, for the 
comparison between THS 2.2 and CC. The same model will be evaluated for the analysis of 
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-CC 
and THS 2.2-NNS differences.  
Safety: The safety population will comprise all subjects, who are exposed to THS 2.2 during 
the study, including the THS 2.2 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. 

 
 
 
 
 
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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 
and CC with a 90% probability of obtaining a margin of error (95% CI) of at most ±20%, 
assuming that THS 2.2 have a nicotine PK profile similar to CC (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 
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 and NNS is 1.55. 
The sample size of this study is based on our current understanding of THS 2.1, the previous 
prototype of THS 2.2, 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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TABLE OF CONTENTS 
SYNOPSIS ............................................................................................................................................. 2 
TABLE OF CONTENTS ....................................................................................................................... 9 
LIST OF ABBREVIATIONS AND EXPLANATION OF TERMS ................................................... 13 
LIST OF ABBREVIATIONS AND EXPLANATION OF TERMS ................................................... 13 
1 
ETHICS AND REGULATIONS................................................................................................. 18 
1.1 
Independent Ethics Committee (IEC) and Competent Regulatory Authorities 
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....................................................................................................................... 20 
2.1 
Background....................................................................................................................... 20 
2.2 
Purpose of the Study......................................................................................................... 22 
2.3 
Anticipated Benefits and Risks......................................................................................... 22 
3 
STUDY OBJECTIVES AND ENDPOINTS............................................................................... 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.................................................................................................................. 31 
4.4 
Appropriateness of Measurements.................................................................................... 32 
5 
STUDY POPULATION.............................................................................................................. 33 
5.1 
Selection of Study Population........................................................................................... 33 
6 
INVESTIGATIONAL AND REFERENCE POINT PRODUCTS ............................................. 40 
6.1 
Description........................................................................................................................ 40 
6.2 
Use of Investigational and Reference Point Products....................................................... 42 
6.3 
Method for Assigning Subjects to Study Arms ................................................................ 44 

 
 
 
 
 
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6.4 
Blinding ............................................................................................................................ 44 
6.5 
Investigational and Reference Point Product Accountability and Compliance ................ 45 
6.6 
Restrictions ....................................................................................................................... 46 
6.7 
Concomitant Medication................................................................................................... 47 
7 
STUDY PROCEDURES............................................................................................................. 50 
7.1 
Informed Consent ............................................................................................................. 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 ..................................................................................................... 55 
7.6 
Laboratory Assessments ................................................................................................... 56 
7.7 
Sample Handling, Storage, and Shipment ........................................................................ 58 
7.8 
Questionnaires .................................................................................................................. 59 
8 
ADVERSE EVENTS................................................................................................................... 63 
8.1 
Definitions ........................................................................................................................ 63 
8.2 
Assessment of Adverse Events......................................................................................... 64 
8.3 
Reporting and Follow-Up of Serious Adverse Events...................................................... 67 
8.4 
Reporting of Other Events Critical to Safety Evaluations ................................................ 68 
8.5 
Reporting and Follow-Up of Pregnancies......................................................................... 69 
8.6 
Adverse Events Leading to Withdrawal ........................................................................... 70 
8.7 
Investigational Device Misuse.......................................................................................... 70 
8.8 
Investigational Device Malfunction.................................................................................. 71 
9 
STUDY ACTIVITIES................................................................................................................. 72 
9.1 
Screening Visit.................................................................................................................. 72 
9.2 
Admission......................................................................................................................... 74 
9.3 
Investigational Period ....................................................................................................... 76 
9.4 
Day of Discharge .............................................................................................................. 81 
9.5 
Safety Follow-up Period ................................................................................................... 82 
9.6 
Early Termination Procedures .......................................................................................... 82 
10 
QUALITY CONTROL AND QUALITY ASSURANCE........................................................... 83 
10.1 
Monitoring ........................................................................................................................ 83 
10.2 
Training of Staff................................................................................................................ 84 
10.3 
Audits and Inspections...................................................................................................... 84 
11 
DATA MANAGEMENT ACTIVITIES ..................................................................................... 85 
11.1 
Data Capture ..................................................................................................................... 85 

 
 
 
 
 
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11.2 
Data Handling................................................................................................................... 86 
12 
PLANNED STATISTICAL METHODS .................................................................................... 88 
12.1 
General Considerations..................................................................................................... 88 
12.2 
Determination of Sample Size and Power Consideration................................................. 89 
12.3 
Analysis Populations......................................................................................................... 90 
12.4 
Demographics and Baseline Characteristics..................................................................... 90 
12.5 
Primary Endpoints ............................................................................................................ 91 
12.6 
Secondary Endpoints ........................................................................................................ 92 
12.7 
Exploratory Analyses........................................................................................................ 95 
12.8 
Interim Analysis................................................................................................................ 95 
13 
ADMINISTRATIVE CONSIDERATIONS................................................................................ 96 
13.1 
Investigators and Study Administrative Structure ............................................................ 96 
13.2 
Subject Confidentiality ..................................................................................................... 97 
13.3 
Access to Source Documentation ..................................................................................... 98 
13.4 
Record Retention .............................................................................................................. 98 
13.5 
Clinical Study Report...................................................................................................... 100 
13.6 
Financial Disclosure ....................................................................................................... 100 
13.7 
Publication and Disclosure Policy .................................................................................. 100 
14 
REFERENCE LIST................................................................................................................... 102 
 

 
 
 
 
 
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LIST OF IN-TEXT TABLES AND FIGURES 
Table 1 
Measured aerosol fractions for the THS Tobacco Sticks..................................41 
Table 2. Examples of Drugs and Substances Considered Interacting with CYP2A6.....48 
Table 3. Clinical Laboratory Parameters for Safety Panel..............................................57 
Table 4. Time Schedule – Screening...............................................................................72 
Table 5. Time Schedule – Day -1 Admission .................................................................75 
Table 6. Time Schedule – Day 0 Washout......................................................................76 
Table 7. Time Schedule – Day 2 Washout......................................................................78 
Table 8. Time Schedule – Day 1 and Day 3 Single Use.................................................79 
Table 9. Time Schedule – Day 4 Discharge....................................................................81 
 
Figure 1. Study Flowchart ................................................................................................30 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events...................................................................................109 
Appendix 2 
Participating Laboratories........................................................................114 
Appendix 3 
Investigational Product and Instructions for Use.....................................115 
Appendix 4 
Product Label for the NNS product: Adverse Events..............................116 
Appendix 5 
Abnormal Laboratory Values ..................................................................117 
Appendix 6 
Investigational Micro+TM Smokerlyzer® .................................................122 

 
 
 
 
 
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LIST OF ABBREVIATIONS AND EXPLANATION OF TERMS 
Abbreviations 
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 conventional 
cigarettes or nicotine nasal spray 
BMI 
Body mass index 
CC 
Conventional cigarette(s) 
CD 
Compact disc 
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 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 

 
 
 
 
 
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EOS 
End of Study Visit (referring to each subject’s individual last study 
visit) 
FDA 
US 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 
HPHC 
Harmful and Potentially Harmful Constituents in Tobacco Products 
and Tobacco Smoke 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IP 
Investigational Product 
ISO 
International Organization for Standardization 
LLN 
Lower limit of the normal range 
LLOQ 
Lower limit of quantification 
MCEQ 
Modified Cigarette Evaluation Questionnaire  
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Regulatory Agency 
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 

 
 
 
 
 
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SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SES 
Socio-economic status 
SHM 
Sample handling manual 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
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 

 
 
 
 
 
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Explanation of Terms 
The following special terms are used in this protocol: 
Back-Up Subject 
Subject who is enrolled but not randomised  
CC 
The term ‘conventional cigarette’ refers to manufactured and 
commercially available cigarettes and excludes hand-rolled 
cigarettes, cigars, pipes, bidis, and other nicotine-containing 
products. 
Charger 
The function of the Charger (Model 4) is to recharge the Holder 
after use. It contains a battery with sufficient capacity to recharge 
the Holder approximately 20 times.  It is a convenient size to carry 
around, and can itself be recharged from a mains power source. 
 
Day of Discharge 
Day 4. 
End of Study 
End of Study is defined as the last day of the 7 day safety follow-
up subsequent to discharge from the unit. 
Enrolment 
On Day -1 for eligible subjects after all applicable inclusion and 
exclusion criteria have been satisfactorily met and the subjects is 
willing and ready to use both the THS 2.2 and NNS (the test of 
both THS 2.2 and NNS are the last assessments prior to enrolment) 
First product use time 
point 
Start of product use for THS 2.2 is defined as the time of the first 
puff. The start time for CC corresponds to the lighting of the CC, 
and the start time of the NNS product is the time of the spray in the 
first nostril. 
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 followed up until resolved, stabilized i.e. no worsening 

 
 
 
 
 
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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 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 Tobacco Sticks 
The Tobacco Stick (product code C3) contains tobacco which, 
when heated, generates an aerosol. It is custom-designed to be used 
with the Holder. 
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 except the Tobacco 
Stick. 
Tobacco Heating 
System 2.2 (THS 2.2) 
THS 2.2 comprises the following components: Tobacco Stick, 
Holder, Charger, a Cleaning Tool, a mains power supply, and a 
USB cable. 
 

 
 
 
 
 
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1 ETHICS AND REGULATIONS 
1.1 
 Independent Ethics Committee (IEC) and Competent Regulatory 
Authorities Approval 
Prior to the start of the study, the clinical study protocol, together with its associated 
documents (informed consent form [ICF], subject information, 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 
Independent Ethics Committee [IEC] and the local Regulatory Authority (Medicines and 
Healthcare Regulatory Agency [MHRA]), will be submitted for review and approval to the 
relevant IEC and to the local Regulatory Authority. The IEC shall be appropriately 
constituted and perform its functions in accordance with the International Conference on 
Harmonization (ICH) Tripartite Guidance for Good Clinical Practice (ICH GCP E6 (R1), 
July 1996) and local requirements, as applicable. 
In accordance with GCP, a written confirmation of the IEC approval should be provided to 
the Sponsor. This should identify the study (Investigator’s name, study number and title) and 
the documents that have been approved by the IEC, with dates and version numbers, as well 
as the date of approval. The composition of the IEC, including the name and occupation of 
the chairperson, should be supplied to the Sponsor together with a GCP compliance 
statement. 
The written approval from the IEC and the local Regulatory Authority 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 favourable opinion/approval from the concerned IEC and the local 
Regulatory Authority. 
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 IEC and the local Regulatory Authority, and substantial amendments will 
only be implemented after approval by the IEC and the local Regulatory Authority. 
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 IEC and the local Regulatory Authority should be 
informed immediately. 

 
 
 
 
 
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Relevant safety information will be submitted to the IEC during the course of the study in 
accordance with national regulations and requirements. Under the Clinical Trial Directive 
2001/20/EC, the sponsor has a responsibility to report Suspected Unexpected Serious 
Adverse Reactions (SUSARs) in CIOMS format to IEC, as well as to the Regulatory 
Authorities.  Therefore, all SUSARs occurring in the study with the study medication in the 
reference point arm (nicotine nasal spray: NNS), the “Investigational medicinal product” 
(IMP) will be reported to IEC and Regulatory Authorities by 
 
.  The Summary of Product Characteristics for NNS (IMP) will serve as the safety 
reference document for assessing assessments whether an adverse reaction is a SUSAR. 
 
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 IEC and the local Regulatory Authority. The Principal 
Investigator and the Sponsor must sign the protocol (and protocol amendments, if applicable) 
to confirm this agreement. A copy of the Declaration of Helsinki, 2008 should be located in 
the Investigator’s Study File. 
1.3 
Subject Information and Consent 
1.3.1 
Study Consent 
At the Screening Visit, the Investigator or person designated by the Investigator will ensure 
that  each subject is given full and adequate oral and written information about the nature, 
purpose, possible risks and benefits of the study, and the Investigator or the designee will 
answer all questions the subject might have to his/her full satisfaction. The subject will have 
sufficient time for consideration of his/her participation in the study and will be notified that 
he/she is free to discontinue his/her participation at any time. Once the subject has received 
all necessary information, and if he/she agrees to participate, this will be documented in the 
ICF by the date and signature of both the subject and the person who conducted the informed 
consent discussion. No study-specific procedures will be performed before the ICF has been 
signed. 
The original, dated and signed ICF(s) must be kept in the Investigator study file at the site, 
and a copy must be given to the subject. 

 
 
 
 
 
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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 and subject 
information may be required. If revision of the ICF and subject information is necessary, the 
Investigator will, with the support of the Sponsor, ensure that the documents have been 
reviewed and approved by a relevant IEC before subjects are required to re-sign the ICF. 
The subject will be informed that additional data analyses not mentioned in the protocol or 
the statistical analysis plan might be performed with the collected data at a later time. If any 
additional analyses will be performed, they will fully be covered by data confidentiality, as 
for the main analyses described in this protocol.  
1.4 
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. 
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 a 

 
 
 
 
 
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smoking 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/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, 
2009), and more than 100 of them have been categorized as harmful and potentially harmful 
constituents (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 (THS 2.2) (Tobacco Stick). With this product, the heating of the tobacco is 
maintained below 400°C, a temperature much lower than what is observed for CC, which can 
reach 900°C. The THS 2.2 is composed of the ‘THS Tobacco Stick Holder’ dedicated special 
Tobacco Sticks made of conventional tobacco, a charger, and different accessories. The 
energy of the THS Tobacco Stick Holder is sufficient to maintain approximately a 6 minute 
session. Unlike CC, the Tobacco Sticks do not burn down during their consumption and their 
lengths remain constant after use. 

 
 
 
 
 
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The non-clinical assessment of THS 2.2 and its predecessors including THS 1.0 supports the 
initiation of the clinical studies described in this Investigator’s Brochure. 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 were increased compared to the CC. 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 are given in 
the Investigator’s’ Brochure (PMI, 2013a). 
Several clinical studies have been conducted on THS 1.0, 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 the next 
development version of THS, namely THS 2.0.  
THS 2.1 was tested in two exploratory clinical studies to measure the nicotine plasma kinetic 
profile (PK) and to assess the reduction of exposure to HPHCs when switching from CC to 
THS 2.1. The observed nicotine plasma PK profile for THS 2.1 was similar to CC as well, 
there were significant reductions in the exposure to the majority of selected HPHCs. Clinical 
studies conducted so far revealed no safety concern for either of the previous version of THS 
2.2 tested. Further details on the clinical data are provided in the Investigators’ Brochure 
(PMI, 2013a). 
2.2 
Purpose of the Study 
The purpose of this clinical study is to compare the profile of nicotine uptake (rate and extent 
of nicotine absorbed) after single use of THS 2.2 and CC in smoking, healthy subjects. THS 
2.2 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 
Research conducted by the United Kingdom National Health Service has shown that up to 
75% of smokers want to quit. Despite associated health risks, however, only 2% of smokers 
make a cessation attempt each year. Advice on health risks associated with smoking and 
smoking cessation advice will be provided at Screening, at Admission, and at the Day of 

 
 
 
 
 
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Discharge. The advice will follow the recommendations by the World Health Organization 
(Raw et al, 2002). 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 smoking cessation services for continuing support and counselling 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, haematoma, 
paresthesia, or infection. 
• Risks related to chest X-rays, e.g., a small increase of risk to develop cancer later in life. 
• Risks related to drug application as part of testing procedures (i.e., spirometry with 
short-acting bronchodilator at Screening) per study protocol and scientifically accepted 
standards. 
2.3.3 Anticipated Foreseeable Risks due to Investigational Product (THS 2.2 
and CC) or Reference Point Product (NNS) 
• 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, investigational product (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). 

 
 
 
 
 
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2.3.4 Unforeseeable Risks 
As with any IP, reference product or support for 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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3 STUDY OBJECTIVES AND ENDPOINTS 
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 relative to CC, following single use of THS 2.2 and 
CC. 
 
3.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To determine if Cmax and AUC(0-last) of the THS 2.2 are higher relative to NNS 
following single use of the THS 2.2 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 CC or NNS product [AUC(0-t’)]) between the THS 2.2 and CC, as well as the 
THS 2.2 and NNS.  
• To evaluate the  time to the maximum concentration (tmax) of nicotine for the THS 
2.2 as compared to CC and to determine if the tmax for THS 2.2 is shorter as 
compared to NNS. 
• To describe the terminal half-life (t1/2) of nicotine for the THS 2.2, CC, and NNS. 
• To describe the differences on urge-to-smoke over time between the THS 2.2 and 
CC, as well as between the THS 2.2 and NNS. 
• To describe product evaluation in the THS 2.2 and CC users. 
• To describe the levels of carbon monoxide (CO) exposure for the THS 2.2, as 
compared to CC and NNS users. 
• To monitor the safety during the study. 
 

 
 
 
 
 
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3.3 
Primary Endpoints 
• Primary nicotine PK parameters (THS 2.2 vs. CC): 
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:CC 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 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. 
• Safety variables: 
o Incidence of adverse events (AEs)/serious adverse events (SAEs) and 
device event including THS 2.2 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). 
o Clinical chemistry, haematology, and urine analysis safety panel. 

 
 
 
 
 
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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). 
□ Cytochrome P450 2A6 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. 
• CC. 
• 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 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 (using up to three 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 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 
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/CC/NNS). 
Period 2: Day 2: Wash-out; Day 3: single product use (THS 2.2/CC/NNS). 
In total, 62 eligible, healthy smoking subjects will be randomized into one of the 4 
sequences: 
Sequence 1:  THS 2.2    → CC (N=22). 
Sequence 2:  CC 
→ THS 2.2 (N=22). 
Sequence 3:  THS 2.2 
→ NNS (N=9). 
Sequence 4:  NNS 
→ THS 2.2 (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 CC will not be considered:  
CC vs. THS 2.2  
→  (N=22 in both sequence 1 and 2). 
THS 2.2 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 ≤0.6 mg and >0.6≤1 mg) will have a quota applied to 
ensure they represent at least 40% of the total study population per group.  
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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The NNS has been selected as the reference point, 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).  
NNS will serve as a reference point for comparison with THS 2.2 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 (Benowitz et 
al, 2009).  
The use of oestrogen contraceptive is known to accelerate nicotine clearance by 20% to 30% 
in women as compared to women who do not take such contraceptives (Benowitz et 
al, 2006).  Therefore, for the purpose of this study, it is not allowed to use hormonal 
contraception containing oestrogens. This also applies to hormone replacement therapy. 
The activity of CYP2A6 will be measured at admission 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 40 days, including a Screening period of up to 4 
weeks prior to Admission (Day -29 to Day -2), and 6 days of confinement (Day -1 to 
morning of Day 4). 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. 

 
 
 
 
 
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4.4 
Appropriateness of Measurements 
The laboratory measures to be utilized in this study were selected based on the following 
criteria: 1) the availability of a validated analytical method, and 2) measure is known to be 
directly or indirectly affected by smoking; 3) measure is readily reversible after smoking 
cessation, 4) timeframe of reversibility of measure in the perspective of the study duration, 5) 
practicality/acceptability by subjects, and 6) robustness (rapid, simple, accurate). 
All questionnaires utilized for this study, except the cough and socio-economic status 
questionnaires, are available as validated questionnaires. 

 
 
 
 
 
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5 STUDY POPULATION 
5.1 
Selection of Study Population 
Sixty-two Caucasian female or male smoking healthy adult subjects, who smoke at least 10 
CC per day will be randomized into this study. The maximum number of CC is not limited. 
Subjects must have a smoking history of at least 3 years of consecutive smoking prior to 
Screening. The smoking status of the subjects will be verified based on a urine cotinine test 
(cotinine ≥200 ng/mL). 
5.1.1 
Inclusion Criteria 
Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -1) 
1. Subject has signed the ICF and is able 
to understand the information 
provided in the Subject Information 
Sheet and ICF. 
Administrative
X 
 
2. Caucasian subject is aged from 21 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 
post-bronchodilator FVC >0.8], vital 
signs, physical examination, ECG, 
chest X-ray, and medical history). 
Safety 
X 
X 
4. Subject smokes at least 10 
commercially available non-menthol 
CCs per day (no brand restrictions) 
Effect 
X 
X 

 
 
 
 
 
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Inclusion Criteria 
Rationale 
Screening 
Day of 
Admission 
(Day -1) 
with a maximum yield of 1 mg 
nicotine ISO/CC, as labelled on the 
cigarette package, for the last 4 weeks, 
based on self-reporting. Furthermore, 
the subject has been smoking for at 
least the last three consecutive years. 
The smoking status will be verified 
based on a urinary cotinine test 
(cotinine ≥200 ng/mL). 
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 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 
study for any reason (e.g., medical, 
psychiatric and/or social reason).  
Safety  
X 
X 
2. A subject who is legally 
incompetent, physically or mentally 
incapable of giving consent (e.g., 
Administrative 
X 
 

 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
emergency situation, under 
guardianship, subject in a social or 
sanitary establishment, prisoners or 
subjects who are involuntarily 
incarcerated). 
3. The subject has medical condition 
requiring smoking cessation, or 
clinically relevant diseases 
(including but not limited to 
gastrointestinal, renal, hepatic, 
neurological, haematological, 
endocrine, oncological, urological, 
immunological, pulmonary and 
cardiovascular disease or any other 
medical condition [including but not 
limited to clinically relevant 
abnormal laboratory parameters]) in 
the judgment of the Investigator. 
Safety 
X 
X 
4. The subject has a body mass index 
(BMI) <18.5 or ≥32.0 kg/m2. 
Safety 
X 
 
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 
6. The subject has used 
nicotine-containing products other 
than commercially available CC 
(either tobacco-based products or 
nicotine-replacement therapy) as 
Effect 
X 
X 

 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
well as electronic cigarettes and 
similar devices, within 4 weeks prior 
to assessment. 
7. The subject has received medication 
(prescription or over-the-counter) 
within 14 days or within 5 half-lives 
of the drug prior to the Admission 
Day (Day -1; whichever is longer) 
that has an impact on Cytochrome 
P450 2A6 (CYP2A6) activity. 
Effect 
 
X 
8. In case the subject received any 
medication (prescribed or 
over-the-counter) within 14 days 
prior to Screening or prior to the 
Admission Day (Day -1) it will be 
decided at the discretion of the 
Investigator if these can potentially 
interfere with the study objectives 
and subject’s safety.  
Effect 
X 
X 
9. The subject has a positive alcohol 
test and/or the subject has a history 
of alcohol abuse that could interfere 
with subject’s participation in study. 
Administrative 
X 
X 
10. The subject has a positive urine drug 
test. 
Administrative 
X 
X 
11. Positive serology test for human 
immunodeficiency virus (HIV) 1/2, 
Hepatitis B or Hepatitis C.  
Safety 
X 
 
12. Donation or receipt of whole blood 
or blood products within 3 months 
prior to Admission. 
Safety 
X 
X 

 
 
 
 
 
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Exclusion Criteria 
Rationale 
Screening 
Day of 
Admission  
(Day -1) 
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 of childbearing 
potential* 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 of childbearing 
potential* only: 
Subject does not agree to use an 
acceptable method of effective 
contraception.** 
Safety 
X 
X 

 
 
 
 
 
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* Childbearing potential is defined as NOT premenarche, permanently sterilized or postmenopausal 
(i.e., 12 months with no menses without an alternative medical cause). 
** Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with 
spermicidal foam/gel/film/suppository, hormonal contraception containing progesterone only, vasectomized 
partner(s) or true abstinence (periodic abstinence and withdrawal are not effective methods) from Screening 
until the end of the safety follow-up period. Hormonal contraception with oestrogen 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) 
at the discretion of the Investigator. 
• Positive pregnancy testing (no invasive procedures including the drawing of blood 
must performed after detection of pregnancy, see Section 8.5). Female subjects 
starting contraception or hormone replacement therapy containing oestrogens 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 (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 were 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 AND REFERENCE POINT PRODUCTS 
6.1 
Description  
6.1.1 
Investigational Products 
THS 2.2 
The THS 2.2 will be provided by the Sponsor and its distribution will be limited to a 
qualified and appropriately trained staff personnel.  
THS 2.2 comprises the following components:  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) 
Tobacco Stick: 
The 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 CC. 
 
6.1.1.1 Tar, Nicotine and Carbon Monoxide Yields 
Per cigarette/Tobacco Stick tar, nicotine, and carbon monoxide yields are normally 
determined by standardized test methods. The most widely used test method is ISO 4387. 
PMI has developed a modified version of this method, which improves the determination of 
tar in products with high water content, which is typical for heated tobacco products (PMI, 

 
 
 
 
 
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2012c, PMI, 2012b, 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). 
 
Table 1 
Measured aerosol fractions for the THS Tobacco Sticks 
Constituent (mg/THS Tobacco Stick) 
ISO 1 
Health Canada  Intense 
regime 2 
Tar/NFDPM 
4 
10.3 
Nicotine  
0.5 
1.32 
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) 
 
CC 
In the study sequences 1 and 2, the comparator to THS 2.2 is commercially available single 
brand CC with a maximum yield of 1 mg nicotine ISO per cigarette. 
Conventional cigarettes will not be provided by the Sponsor. All eligible subjects will be 
asked to purchase their own preferred single-brand CC prior to Admission. As randomization 
takes place on Day 0, every study subject needs to buy his/her anticipated amount of 
single-brand CC for a total of 2 days plus 2 extra packs. 
6.1.2 
Reference Point Product 
The NNS Nicorette® (10 mg/mL) will be the reference point product to THS 2.2 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.  
6.1.3 
Packaging and Labelling 
At Admission on Day -1, all study subjects will provide the anticipated amount of CC in 
sealed packs to the site staff. The cigarette packs provided by the subject should not be 
opened and the cellophane should be intact.  

 
 
 
 
 
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Each pack of cigarettes provided by the subject will be labelled to identify which subject the 
cigarettes belong to (labels should be affixed to the cellophane wrapper of the lower part of 
the pack).  
Packs of CC will be labelled to identify necessary information to match the subject with 
his/hers suppliers. 
For the Tobacco Sticks, the packs will be printed with the necessary information including 
but not limited to health warning, tar/nicotine/carbon monoxide ISO levels, product code. 
6.2 
Use of Investigational and Reference Point Products 
Subjects will never be requested or forced to smoke and will be free to stop smoking at any 
time during the study. Subjects caught using any nicotine/tobacco product which is different 
from the assigned product will be withdrawn from the study. During the screening period, 
subjects will be allowed to smoke according to their smoking habits except during the 
procedures of the screening visit 9.1 at the discretion of the site. 
6.2.1 
Admission (Day -1) 
Subject will be instructed not to smoke in the morning prior to Admission. Smoking ad 
libitum will be allowed throughout the day of admission except during the procedures until 
11:00 pm. All subjects will be allowed to continue smoking ad libitum their own preferred 
CC. All subjects (except women with a positive pregnancy test at Screening or Admission) 
will undergo a THS 2.2 test first and subsequently NNS test at Day -1 prior to enrolment. 
Following agreement that the THS 2.2 and NNS is acceptable, subjects will be enrolled and 
further randomized to one of 4 treatment sequences using an Interactive Web/ Voice 
Response System.  
6.2.2 
Investigational Period (Day 0 to Day 3) 
During the first washout, each subject will maintain nicotine abstinence from Day -1 at 11:00 
PM to the time of single use of his/her allocated product at Day 1. At Day 1, after the single 
use of the product, subjects will maintain nicotine abstinence for the rest of the day. During 
the second washout on Day 2, subjects will maintain nicotine abstinence until the time of 
single use of subject’s allocated product at Day 3. Subjects will not be allowed to smoke or 
use any other nicotine/tobacco-containing products other than the products they are allocated 
to. 

 
 
 
 
 
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Time point of first product use during study day (T0) will be defined as start of the single 
product use at the single use days. The start of product use for THS 2.2 is defined as the time 
of the first puff. The start time for CC corresponds to the lighting of the CC, 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 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.  
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 arm 
will use one Tobacco Stick, subjects in the CC arm will smoke one CC, and subjects in the 
NNS arm will administer one spray into each nostril (leading to an estimated total 
administered amount of 1 mg nicotine). 
 
Sequence 1 
Sequence 2 
Sequence 3 
Sequence 4 
Day 1 
THS 2.2 
CC 
THS 2.2 
NNS 
Day 3 
CC 
THS 2.2 
NNS 
THS 2.2 
 
6.2.3 
Day of Discharge/Time of Discharge 
On the Day of Discharge (Day 4), smoking will be only allowed after all laboratory 
procedures and the spirometry have been performed. All examinations of the Day of 
Discharge will be conducted on Day 4 prior to the time of Discharge.  
6.2.4 
Safety Period 
During the safety follow-up period, subjects are free to smoke according to their usual 
smoking habits. 
6.2.5 
Stopping Rules for Investigational Product 
For safety purposes, using the THS 2.2, smoking the CC, or use of the NNS should be 
temporarily stopped in the event of any signs suggesting nicotine overexposure, e.g., 
gastrointestinal disturbance (nausea, vomiting, diarrhoea, stomach or abdominal pain), cold 

 
 
 
 
 
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sweats, headache, dizziness and breathing problems or any reasons at the discretion of the 
Investigator. 
6.3 
Method for Assigning Subjects to Study Arms 
Randomization to product exposure sequence will be done through an Interactive Telephone 
and Web Response System. 
Each sex and each of the smoking level (ISO nicotine levels ≤0.6 mg and >0.6 to ≤1 mg) will 
have a quota applied to ensure they represent at least 40% of the total study population 
allocated within each of the following analysis groups: 
• 
Group-1: composed of sequences 1 and 2. 
• 
Group-2: composed of sequences 3 and 4. 
In particular, the maximum number of subjects having the same sex or nicotine level value 
will be limited to 26 in Group-1 and 10 in Group-2. 
The randomization of the planned sample size of 62 subjects will be ensured by applying 
quota to the number of subjects per each sequence (22 subjects for sequences in Group-1, and 
9 subjects for sequences in Group-2). 
Subjects will be randomly assigned to one of the four product exposure sequences by means 
of a permuted-block schema. Block size and other randomization details will be available in 
the randomization plan. 
The randomization plan will be generated by an independent statistician and none of the 
sponsor staff, investigators or study subjects will have access to the randomization schema 
prior to randomization. 
6.4 
Blinding 
This is an open-label study; therefore, the subjects and investigators will be unblinded to 
subject’s sequence. However, there will be a limited degree of blinding in the data review 
and data analysis process. In particular, PMI and CRO personnel will be blinded to the 
randomized sequence as summarized in the following table: 

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

 
 
 
 
 
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6.5.3 
Investigational and Reference Point Product Retention 
Unused Tobacco Sticks and NNS will be destroyed if possible, or returned to the Sponsor 
upon study completion. The Tobacco Heating Devices will be returned to the Sponsor. 
6.5.4 
Compliance to Investigational and Reference Point 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 (Benowitz et al, 2002). 
Furthermore, the CO breath test will be considered as one of the measures of compliance 
during the wash-out days in all subjects.  
6.6 
Restrictions 
6.6.1 
Smoking Restrictions 
On Day 1 and Day 3, to avoid nicotine cross contamination, smokers of THS 2.2 and CC will 
smoke in dedicated separate rooms: one room for THS 2.2 and one room for CC. 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, CC or Tobacco 
Sticks, which will be dispensed by the site staff individually as described in Section 6.5.1.  
Smoking is not allowed during study procedures except during blood sampling for nicotine 
PK on Day 1 and Day 3. Furthermore, smoking is not allowed on Day 4 until all laboratory 
tests and the spirometry have been conducted. 
During the days of wash-out or single product use (for 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. 

 
 
 
 
 
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6.6.2 
Dietary Restrictions 
A standard diet will be designed by a dietician for the whole confinement period. For each 
meal, the caloric and fat content should be controlled in order to avoid a “high-fat” diet. The 
FDA guidance on food-effect studies for bioequivalency testing identifies a “high-fat” diet as 
a diet which 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 Sections 9.2, 9.3.1, 9.3.2 and 
9.4. 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.  
6.7 
Concomitant Medication 
For the purpose of this study, no concomitant medication should be taken by the subjects. 
Any medication with an impact on the CYP2A6 metabolism (as prescription and 
over-the-counter products) as given below must be avoided as CYP2A6 is involved in the 
nicotine metabolism.  
In this study the use of hormonal contraception containing oestrogens is NOT allowed. This 
also applies to hormone replacement therapy. Only hormonal contraception with products 
containing progesterone is allowed during this study. Subjects using oestrogens during the 
study will be withdrawn.  
The following drugs and substances are considered as 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.  

 
 
 
 
 
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Table 2. 
Examples of 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, propranolol, lidocaine 
Antiarrhythmic   
Losartan, amlodipine, nifedipine, losartan 
Antihypertensive 
Drosperinone, oestrogens 
Hormonal contraceptives  
Agents for hormonal replacement 
therapy (oestrogens) 
Fluvastatin 
Cholesterol-lowering agent 
Theophylline 
Antispasmodic pulmonological 
agent/Bronchodilator agent 
Omeprazole, Lansoprazole 
Proton pump inhibitor 
Interferon 
Antiviral/Immunomodulating agent 
Methoxsalen   
Anti-psoriatic (substance class 
Furocoumarins) 
Modafinil, Diclofenac, Rofecoxib 
Analgesic 
Insulin 
Anti-diabetic 

 
 
 
 
 
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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 7.4.6). Concomitant medications should be 
followed up with the CRO Medical Monitor on an ongoing basis.  
Concomitant medication will first be assessed at Screening Visit. To be eligible for the study 
any medication with impact on CYP2A6 metabolism must be discontinued at least 14 days 
prior to Admission to the clinic or for at least five half-lives (whichever is longer). They must 
not be used during the entire study until the time of discharge. It is at the discretion of the 
Investigator to assess if a termination of such medication at Screening is medically justified 
and safe for the subject. 

 
 
 
 
 
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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. Appropriate medical 
advice will be provided to the subject in case of any medical findings requiring health care. 
7.1 
Informed Consent 
Each subject must give his/her informed consent prior to participating in the study. During 
the consent process, the Investigator or designee 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 and must have sufficient time to 
read and understand and have adequate opportunity to ask questions. The ICF must be signed 
and dated prior to undertaking any study-specific procedures. A signed copy should be given 
to the subject.  
7.2 
Smoking Cessation Advice and Debriefing 
Each subject will be given advice on the risks of smoking 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 World Health Organization (WHO) 
recommendations (Raw et al, 2002). Details of the interview will be recorded in the Source 
Document File. Information on the risks 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. 
 

 
 
 
 
 
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7.3 
Support during Smoking Abstinence/Periods of Reduced Smoking 
All subjects will be closely monitored by the site staff on D0, D1, D2, and D3. 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 behaviour, 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 e.g., laboratory 
values, vital signs and ECGs, detected during the Screening Visit. Any untoward medical 
occurrence in a subject detected during the study which was not present at the Screening 
Visit must be documented as an AE. Worsening of a pre-existing condition from the 
Screening Visit onwards will also be documented as an AE. If a clinically relevant finding is 
detected during the Screening period, the Investigator needs to check if inclusion criterion 
no. 3 is still fulfilled. 
7.4.1 
Demographic Data 
Demographic data (sex, date of birth/age, and race) will be recorded on the day of ICF 
signature.  
7.4.2 
Socio-Economic Status 
At Day 2, subjects will be asked questions, which will allow the Sponsor to infer their socio-
economic status (see section 7.8.5).  
7.4.3 
Identification of the Current Cigarette Brand 
Identification of the current CC brand smoked by the subject will be done at the Screening 
Visit and at Day -1. For the Screening Visit, smokers will be asked to bring a packet of their 
current CC brand to the site. The site staff will document brand name and yields. At Day -1, 
subjects have to hand their CC 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 with information of ISO 
nicotine , CO and tar 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 Digital Versatile Disc (DVD) or Compact Disc (CD).  

 
 
 
 
 
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7.4.4 
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 CC smoked during the previous 4 weeks, 
and to evaluate if the CCs smoked during the previous 4 weeks were non-menthol. Yields 
will later be ascertained, from 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 CC (either tobacco-based products or NRT), electronic cigarettes or 
similar devices, within 4 weeks prior to assessment. 
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. 
7.4.5 
Demonstration and Product Tests of THS 2.2 and NNS 
All subjects will have a demonstration of the THS 2.2 and the NNS products by the site staff 
at the Screening Visit. On Day -1, as the last procedure of the eligibility assessments, 
subjects will have a product test for the THS 2.2 (using up to three Tobacco Sticks) first and 
subsequently a  product test of the NNS (spraying once in each nostril). In female subjects, 
the THS 2.2 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 and the 
NNS and be randomized to any of the study arms can be enrolled into the study. 
7.4.6 
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. 
Medication taken within 4 weeks prior to Screening Visit and any concomitant medication 
needs to be documented. Any medication which was started prior to the Screening Visit and 
is still being taken by the subject will be considered a concomitant medication. Medication 
initiated after Screening is also referred to as concomitant medication. This applies to both 
prescription and over-the-counter products. 

 
 
 
 
 
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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, for example, mg, 
mL, or IU), indication, 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. 
7.4.7 
Physical Examination 
A physical examination will be conducted at the Screening Visit, at Admission (Day -1) and 
at the Day of Discharge (Day 4).  
7.4.8 
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 one 
decimal place:  
 
7.4.9 
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.  
7.4.10 
Other Clinical Assessments 
7.4.10.1 Spirometry 
Spirometry with and without a short-acting bronchodilator will be done at the Screening Visit 
to evaluate inclusion/exclusion criteria (the post-bronchodilator results). At screening, 
spirometry without bronchodilator will be done first, and then, spirometry with 
bronchodilator. Furthermore, spirometry without a bronchodilator will be performed on Day-
1 as well as on Day 4.  

 
 
 
 
 
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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 
the pulmonary function laboratory (including the records of the calibration, if applicable). 
The FEV1 and FVC will be recorded.  
The subject will be submitted to a spirometry with maximum voluntary ventilation 
measurement. 
For spirometry, assessed parameters will include: 
• FEV1. 
• FVC. 
• FEV1/FVC. 
 
7.4.10.2 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, initialled, dated, and 
stapled together for inclusion in the Source Data File. 
7.4.10.3 
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 

 
 
 
 
 
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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 
Report. A list of laboratories is provided in Appendix 2. 
The start time of the use of each product has to be documented on single use days (Day 1 and 
Day 3). 
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 Micro+™ Smokerlyzer® device (Bedfont 
Limited, Rochester, United Kingdom, see Appendix 6). The test will be performed for 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, 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 and then around 
12:00 PM, 4:00 PM, and 8:00 PM. On the wash-out days (Day 0 and Day 2) it will be 
conducted around 8:00 AM, 12:00 PM, 4:00 PM and 8:00 PM.  
Carboxyhemoglobin 
Tests for COHb measurement will be performed at a local laboratory.  

 
 
 
 
 
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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 on Day 1 and Day 3: 
A total of 16 blood samples will be taken for a 24-hour profile (Day 1 and Day 3). The first 
blood sample will be taken within 15 minutes prior to the single use (T0). Times of sampling 
are thereafter in relation to T0: T1 after 2 minutes, T2 after 4 minutes, T3 after 6 minutes, T4 
after 8 minutes, T5 after 10 minutes, T6 after 15 minutes, T7 after 30 minutes, T8 after 45 
minutes, T9 after 60 minutes, T10 after 2 hours, T11 after 4 hours, T12 after 6 hours, T13 after 9 
hours, T14 after 12 hours and T15 after 24 hours (this sample will be drawn during the day 
following product use, i.e., wash-out).  
7.5.2 
CYP2A6 Activity 
CYP2A6 activity will be measured in plasma on Day -1 (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, Haematology, and Urine Analysis for Safety Panel  
Haematology, clinical chemistry and urine analysis for the safety panel will be measured at 
Screening, at day of Admission (Day -1) and at the Day of Discharge (Day 4). Tests will be 
conducted at a local laboratory or the site. Blood will be taken after no less than the 10 hours 
of fasting (see Section 6.6.2). The urine test will be performed semi-quantitatively as urine 
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 
Haematology 
Clinical chemistry 
Urine analysis 
- Haematocrit 
- Haemoglobin 
- Mean corpuscular 
haemoglobin  
- Mean corpuscular 
haemoglobin concentration  
- Mean corpuscular volume  
- Platelet count 
- Red blood cell count  
- White blood cell (count) 
(WBC) 
- Differential WBC count:  
• 
Neutrophils 
• 
Basophils  
• 
Eosinophils  
• 
Lymphocytes 
• 
Monocytes 
 
 
- Albumin 
- Total protein 
- Alkaline phosphatase 
- Alanine aminotransferase  
- Aspartate aminotransferase  
- Blood urea nitrogen 
- Creatinine 
- Gamma-glutamyl transferase  
- Fasting glucose 
- Lactate dehydrogenase  
- Potassium  
- Sodium 
- Total bilirubin 
- Direct bilirubin 
- Total cholesterol 
- Triglycerides 
 
- pH 
- Bilirubin 
- Glucose 
- Nitrite 
- Red blood cell traces 
- Protein 
- Specific gravity 
 
 
7.6.2 
Serology 
A test for Hepatitis B surface antigen, Hepatitis C virus and HIV (anti-HIV1/2 and p24 
antigen) will be done at Screening. In case of positive results, the subject will be referred to 
appropriate medical care. 
7.6.3 
Urine Drug Screen 
A urine drug screen will be performed at the site at the Screening Visit and at the day of 
Admission. The urine will be screened for amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, and opiates.  

 
 
 
 
 
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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 a newly calibrated alcometer device (e.g., Alcotest 7410 Plus, Dräger). 
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 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 investigator 
meeting and site initiation. Safety laboratory samples will be tested at a local laboratory (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. 
Blood samples  

 
 
 
 
 
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Blood samples will be drawn by qualified and trained site personnel. Subjects should be in a 
seated position during blood collection. In total, around 260 mL will be drawn for this study 
including planned assessments, safety, and repeated analysis for safety. The required aliquots 
and volumes for assessments of blood/plasma parameters and tests are summarized in the 
SHM.  
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 
analysed 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 
Section 8).  
7.8.1 
Fagerström Test for Nicotine Dependence (revised version) 
Potential nicotine dependence will be assessed at Screening using the FTND in its revised 
version (Heatherton et al, 1991), as updated in 2012 (Fagerström et al, 2012).  
The questionnaire consists of 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 to 10 
points) (Fagerström et al, 2012). 
7.8.2 
Assessment of Cough  
Subjects will be asked if they have experienced a regular need to cough e.g. coughing several 
times in the last 24 hours prior to assessment. If the answer is ‘yes’, they will be asked to 
complete a VAS, three Likert scales and an open question also assessing the previous 
24 hours.  

 
 
 
 
 
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The VAS will assess how bothersome cough is to the subject ranging from ‘not bothering me 
at all’ to ‘extremely bothersome’.  
Furthermore, subjects will be asked to assess the intensity and frequency of cough and the 
amount of sputum production on Likert scales:  
□ The intensity of cough will be assessed on a 5-point Likert scale ranging 
from 1 to 5: 1 = very mild; 2 = mild; 3 = moderate; 4 = severe; 5 = very 
severe.  
□ The frequency of cough will be assessed on a 5-point Likert scale ranging 
from 1 to 5: 1 = rarely; 2 = sometimes; 3 = fairly often; 4 = often; 
5 = almost always. 
□ The amount of sputum production will be assessed on a 4-point Likert scale 
ranging from 0 to 3: 0 = no sputum; 1 = a moderate amount of sputum; 2 = a 
larger amount of sputum; 3 = a very large amount of sputum.  
 
Finally, subjects will be asked with an open question if there are any other important 
observations that they would like to share with the staff about their coughing. 
Assessments will be done on a daily basis from Day 0 to Day 4. On Day 2 and Day 4, 
questionnaire must be asked 24 hours after T0 of Day 1 and after 24 hours minus 5 minutes 
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 or smoke CC 
during the study in sequence 1 and 2. The MCEQ will be completed by subjects on Day 1 
and Day 3.  
7.8.4 
Questionnaire of Smoking Urges (QSU-brief)  
To assess the urge-to-smoke, all subjects will be asked to complete a 10-item brief version of 
the QSU-brief (Cox et al, 2001). The QSU-brief is a self-reported questionnaire with 10 
items to be rated on a 7-point scale, ranging from 1 (strongly disagree) to 7 (strongly agree). 
Higher scores in this questionnaire indicate a higher urge to smoke.  
The findings in this brief version were consistent with the expressions of craving found in the 
32-item version of the QSU-brief (Tiffany et al, 1991). The findings supported a 
multi-dimensional conceptualization of craving to smoke and demonstrated the utility of a 
brief multi-dimensional measure of craving (Cox et al, 2001).  
The QSU-brief will be completed by the subject himself/herself at single use study days (D1, 
D3). The first assessment will be done prior to T0. All other assessments will be done after 
T0, at 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours (with an allowed time window of 
+5 min each) and 4 hours, 6 hours, 9 hours, 12 hours (with an allowed time window of +10 
min 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. There will be a descriptive analysis of this data 
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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On Day 2, subjects will be asked a series of questions related to their education, occupation, 
and household. Then they will be asked a series of questions to assess the occupation, 
employment status and qualifications of the Chief Income Earner of their household that is 
the person with the largest income. The questionnaire will be administered by a trained 
interviewer. 
The social grading classification that will be used to determine the subject household’s SES 
is based upon the occupation and employment status of the Chief Income Earner (Meier & 
Moy, 2004). Based on the answers of the subjects, data will be recoded in order to assign the 
head of the household to one of the following socio-economic classes:  
Grade  
Social class 
A  
 
upper middle class 
B  
 
middle class 
C1  
 
lower middle class 
C2  
 
skilled working class 
D  
 
working class 
E  
 
Those at the lowest levels of subsistence 

 
 
 
 
 
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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 unfavourable, whether or not it is considered related to the tobacco 
product, as defined by the MRTP guidelines. 
 
An AE is defined as any untoward medical occurrence in a subject, or clinical investigation 
subject administered an IP, which does not necessarily have a causal relationship with the IP 
or reference point product. An AE can therefore be any unfavourable and unintended sign 
(including a clinically relevant abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IP or reference point product, whether or not to the IP or 
reference point product 
 
 
8.1.2 Serious Adverse Events 
An SAE is defined as, but not limited to, any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, 
they may jeopardize the subject or the subject may require medical or surgical intervention to 
prevent one of the outcomes listed in the above definitions. 

 
 
 
 
 
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Any pre-planned hospitalizations that are known at the time of signing the ICF will not be 
recorded as SAEs; however, they will be recorded as AEs only. Any AE that occurs during 
this pre-planned hospitalization will be considered according to the above definitions. 
8.2 
Assessment of Adverse Events 
The Investigator is responsible for obtaining, assessing and documenting all AEs during the 
study.  
8.2.1 
Collection of Information 
Adverse event information will be collected from the time of signature of the ICF onwards 
until 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 are you feeling since you were last asked?”). At 
the discretion of the Investigator, the collection of AE information may also be triggered 
from his/her review of the subject questionnaires and the VAS. However, the main source for 
AE collection will be 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 ‘septicaemia’ rather than ‘fever’ and ‘hypotension’ 
following blood sample). 
Any AE that meets the serious criteria must be recorded both on the AE report form of the 
eCRF and on a separate SAE report form (see Section 8.3). 
 
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.  

 
 
 
 
 
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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. 
 
8.2.2.2 Admission Day until the End of Study 
From Admission onwards until Day of Discharge, all AEs will be actively collected by the 
study site 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.  
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. 

 
 
 
 
 
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8.2.4 Relationship to Investigational Product and Relationship to Study Procedures 
According to CIOMS VI Working Group, there are no definitive methods for distinguishing 
most adverse drug reactions (i.e., events that are causally attributed to the IP and reference 
point product) from clinical adverse events 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 as described below. In addition to the assessment of the relationship of the 
clinical event to the IP, the Investigator shall document a potential relationship of the clinical 
event to any particular study procedure. 
Not related: The temporal relationship of the clinical event to IP and reference point 
product administration or a study procedure makes a causal relationship 
unlikely, or, concomitant medication, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
 
Related: 
The temporal relationship of the clinical event to study IP and reference point 
product administration or a certain study procedure makes a causal 
relationship possible, and concomitant medication, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation for the observed 
event. 
8.2.5 Expectedness 
An AE will be regarded as ‘unexpected’ if its nature or severity is not consistent with 
information already known about the IP, 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. 

 
 
 
 
 
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8.3 
Reporting and Follow-Up of Serious Adverse Events 
Any SAEs reported or observed during the study after signature of the ICF until the end of 
the safety follow-up period (i.e., up to 7 days after study Discharge) whether or not 
attributable to the IP, to any other medication or to any study procedures, or any SAE related 
to the product and spontaneously reported after the safety follow-up must be reported by the 
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: 
 
 
 
 
Phone number:
 
Sponsor: 
Contact: 
, 
MD, Medical Safety 
Officer 
E-mail: 
 
 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube 
5 Quai Jeanrenaud 
2000 Neuchâtel 
Switzerland 
The Investigator is responsible for local reporting (e.g., to the IEC) of SAEs that occur during 
the study, according to local regulations. 
Any additional/follow-up information that becomes available after the initial SAE report 
form has been completed will be forwarded to 
 
 and the Sponsor within 24 hours 

 
 
 
 
 
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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 investigator or designee and/or 
 
 until resolution 
or until the Investigator considers the event to be stabilized (i.e., no worsening of condition), 
or an acceptable explanation has been found (e.g., a chronic condition).  
Under the Clinical Trial Directive 2001/20/EC, the sponsor has a responsibility to report 
Suspected Unexpected Serious Adverse Reactions (SUSARs) in CIOMS format to IEC, as 
well as to the Regulatory Authorities.  Therefore, all SUSARs occurring in the study with the 
study medication in the reference point arm (nicotine nasal spray: NNS), the “Investigational 
medicinal product” (IMP) will be reported to IEC and Regulatory Authorities by 
 
.  The Summary of Product Characteristics for NNS (IMP) 
will serve as the safety reference document for assessing assessments whether an adverse 
reaction is a SUSAR. 
The SAE report form to be used in this study is provided as a separate document. All SAEs 
will be recorded on the eCRF, in addition to the SAE report form. 
8.4 
Reporting of Other Events Critical to Safety Evaluations 
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator and assessed for clinical relevance. If the Investigator considers 
the abnormal result to be of clinical relevance, then it must be recorded as a concomitant 
disease at Screening, or if not present at Screening, as an AE during the study. 
The grading scheme shown in (reference to the Common Terminology Criteria for Adverse 
Events and Common Toxicity Criteria [CTCAE] version 4.03) will be used by the 
Investigator to assess abnormal laboratory AEs as follows: 
• 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. 

 
 
 
 
 
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• If a subject has Grade 2 and higher abnormal laboratory values at Screening it is at the 
discretion of the Investigator to enrol 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 and reference point product, intensity, 
seriousness, outcome) will be assessed as for other AEs. 
8.5 
Reporting and Follow-Up of Pregnancies 
For pregnancies detected during the Screening Period and prior to first THS 2.2 use, the 
subject will be considered as a screening failure and removed from the study. No Pregnancy 
Form will be filled; however, the diagnosed pregnancy must be captured in the Screen 
Failure eCRF.  
All pregnancies occurring after signature of the ICF and diagnosed after first exposure to the 
IP and reference point product until completion of the study must be reported by the 
Investigator.  
Any pregnancy potentially associated to exposure to the IP and reference point product, 
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, and reference point product is defined as the conception date being calculated before the 
last exposure to the IP and reference point product.   

 
 
 
 
 
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The Investigator will complete a Pregnancy Form (provided as a separate document) for all 
pregnancies diagnosed (including positive urine pregnancy tests). 
The procedure to report a pregnancy and provide any additional/follow-up information to 
 
 and the Sponsor must be followed in the same manner and within the same 
timelines as described for 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 test on Admission Day). If pregnancies are to be followed up, they will be 
followed up until an outcome is reached (e.g., normal delivery, spontaneous abortion or 
voluntary termination). Any pregnancy complications, adverse pregnancy outcomes or 
maternal complications will be recorded. 
The Investigator is responsible for informing the IEC 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 on 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. 
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 

 
 
 
 
 
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• 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 THS 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 THS Charger that lead 
to an AE/SAE will follow the same processes as described above. 

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

 
 
 
 
 
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Prior/concomitant medication 
 
 
 
Medical history/concomitant diseases 
 
 
 
Vital signs (pulse rate, systolic and 
diastolic blood pressure, respiratory 
rate) 
At least 5 min in supine position 
prior to measurement 
 
 
Height, weight, including calculated 
BMI 
 
 
√ 
Clinical laboratory parameters 
(haematology, urine analysis, clinical 
chemistry) 
 
 
√ 
Serology for HIV and Hepatitis B 
and C 
 
 
 
Identification of current CC brand 
 
 
 
Urine drug screen 
 
 
 
Alcohol breath test 
 
 
 
Urine pregnancy test for female 
subjects 
 
 
 
THS 2.2 and NNS product 
demonstration 
 
 
 
Spirometry without short-acting 
bronchodilator, and then with 
 
 
 
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; CC = 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 = Tobacco Heating System 

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

 
 
 
 
 
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Table 5. 
Time Schedule – Day -1 Admission 
Time 
Blood 
sample 
Procedures 
Additional information 
Start of procedure 
 
 
 
 
 
AE/SAE recording, concomitant 
medication 
All day 
 
 
Advice on the risks of smoking and 
debriefing 
 
 
 
Readiness to accept interruptions of 
smoking for up to 4 days 
 
 
√ 
trans-3’-hydroxycotinine and 
cotinine (CYP2A6 activity) in 
plasma 
The subject should not have 
smoked in the morning until this 
assessment 
Must be done prior smoking 
6:30 AM 
 
Beginning of smoking period 
 
 
 
Urine pregnancy test for female 
subjects 
 
 
√ 
Clinical laboratory parameters 
(haematology, urine analysis, 
clinical chemistry) 
 
 
 
Urine cotinine screening test 
 
 
 
Urine drug screen 
 
7:30 AM-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 
 
Physical examination, weight and 
calculated BMI 
 
10:00 AM-11:30 AM 
 
Spirometry 
 
10:00 AM-11:30 AM 
 
Identification of current CC brand 
 
10:00 AM-11:30 AM 
 
Smoking history 
 
10:00 AM-11:30 AM 
 
Alcohol breath test 
 
10:00 AM-11:30 AM 
 
CO breath test 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:30 PM-6:00 PM 
 
Snacks 
 

 
 
 
 
 
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4:30 PM-6:00 PM 
 
Product test for THS 2.2 and NNS 
The THS 2.2 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 
 
6:30 PM-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 
 
7:30 AM-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 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 

 
 
 
 
 
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4:30 PM-5:00 PM 
 
Snacks 
 
6:30 PM-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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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 +5 min after T0 of Day 1  
 
 
Assessment of cough 
24 hrs minus 5 min after T0 of 
Day 1  
7:30 AM-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 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 
4:30 PM-5:00 PM 
 
Snacks 
 
6:30 PM-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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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 first 
blood draw of the day 
 
 
 
AE/SAE recording, concomitant 
medication 
All day 
 
 
Support as required 
All day 
 
 
Craving questionnaire 
(QSU-brief) 
First time prior to T0, then 15 min +5 
min, 30 min +5 min, 45 min +5 min, 
1 hr +5 min, 2 hrs +5 min, after T0, 
then and 4 hrs +10 min, 6 hrs +10 
min, 9 hrs +10 min, and 12 hrs +10 
min 
 
√ 
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) 
 
√ 
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 

 
 
 
 
 
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6:00 AM-9:00 AM 
 
Start of single product use 
 
7:30 AM-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 
 
1:00 PM-2:30 PM 
 
Lunch 
 
4:00 PM-5:30 PM 
 
CO breath test 
 
5:00 PM-5:30 PM 
 
Snacks 
 
6:30 PM-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 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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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 
minus 5 min 
7:30 AM-9:00 AM 
√ 
Clinical laboratory parameters 
(haematology, urine analysis, clinical 
chemistry) 
 
7:30 AM-9:00 AM 
 
Urine pregnancy test 
 
9:00 AM-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 
 
CO breath test 
 
10:00 AM-11:30 AM 
 
Spirometry  
 
10:00 AM-11:30 AM 
 
Physical examination, weight and 
calculated BMI 
 
10:00 AM-11:30 AM 
 
Advice on risk of smoking and 
debriefing 
 
10:00 AM-11:30 AM 
 
Time of discharge 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; CO = Carbon monoxide; PK = Pharmacokinetic; SAE = 
Serious adverse event; T = Time point 
Smoking will be allowed after spirometry has been conducted. 

 
 
 
 
 
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9.5 
Safety Follow-up Period 
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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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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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, 
analysed, 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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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 paper copies. 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. 
11.1.1 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 oestrogen 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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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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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 (CC, THS 2.2, and NNS) to allow comparisons between 
THS 2.2 and CC in Group-1 (sequence 1 and 2), and between THS 2.2 and NNS in Group-2 
(sequence 3 and 4). 
Full details of the statistical analysis will be given in a SAP. Any changes to the planned 
statistical methods will be documented in the Clinical Study Report. The statistical 
evaluation will be performed using SAS®, version 9.2 or later. 
12.1.1 
Stratification Criteria 
For analysis, the following stratification criteria will be used:  
□ Sex (male and female) 
□ CC nicotine level at Admission (ISO nicotine levels ≤0.6 mg and >0.6≤1 mg)  
 
In addition, for the safety data, the analysis will be stratified by sequence and by study 
periods (Screening, product test, product exposure, and safety follow-up period). 
12.1.2 
Definitions for Statistical Data Analysis 
Unless otherwise stated, for the purposes of statistical analyses, baseline is defined as the last 
available time point prior to T0 on Day 1, from 6:00 AM to 9:00 AM. 
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by sequence and subject, unless otherwise 
specified.  
Descriptive statistics for continuous variables (number of subjects [n], number and 
percentage of subjects with missing data, mean, standard deviation, median, first and third 
quartiles, minimum and maximum for continuous data, and the n and absolute and relative 
[%] frequency for categorical data) will presented by exposure and overall at each time point, 
where applicable.  
Descriptive statistics for PK parameters will also include the geometric mean and coefficient 
of variation.  

 
 
 
 
 
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Baseline, admission and screening data (i.e., anything prior to product exposure) will be 
summarized by sequence and overall where appropriate. 
12.1.4 
Handling of Missing Values and of Values outside the Detection 
Limits 
In general, missing data will not be imputed in this study, due to the nature of the 
measurements and the short periods of exposure and use. However, for questionnaire data 
total scores and domain or subscale scores may use a certain degree of imputation by 
averaging across individual item scores. Further details will be provided in the SAP. 
Values below the lower limit of quantification (LLOQ) will be imputed using 0.5 x 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 (CIs) will be two-sided 95% 
CIs.  
No formal adjustment of the test-wise alpha level for multiple testing is necessary, as no 
claim will be made based on the outcome of the individual tests. 
12.2 Determination of Sample Size and Power Consideration 
A total of 62 smokers 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 
and CC with a 90% probability of obtaining a margin of error (95% CI) of at most ±20%, 
assuming that THS 2.2 have a nicotine PK profile similar to CC (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 
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 and NNS is 1.55, based on data reported by Gourlay and Benowitz, 1997, 
and Johansson et al, 1991.  

 
 
 
 
 
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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 (PMI, 2012a) comparing the 
nicotine PK profiles of THS 2.1, the predecessor of THS 2.2 and CC. In the absence of data 
comparing THS and NNS, the same CVs were assumed for the calculation of the sample size 
related to the THS 2.2: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 analysed using the PK Analysis sets. Safety will be analysed 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 and NNS separately from the comparison between THS 2.2 
and CC.  
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 (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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12.5  Primary Endpoints 
12.5.1 
Primary Endpoint Analysis Variables 
Nicotine PK parameters will be derived from plasma nicotine versus time data using a 
non-compartmental technique. In particular: 
Cmax 
Maximum observed plasma concentration. Cmax will be reported as long 
as there is at least one quantifiable concentration post-exposure 
AUC(0-last) 
Area under the plasma concentration-time curve from start of product 
use to the time of the last quantifiable concentration (linear trapezoidal 
method).  
 
12.5.2 
Baseline Comparability 
Not applicable. 
12.5.3 
Descriptive Analysis 
Primary endpoints will be summarized as described in Section 12.1.3. 
An analysis of variance (ANOVA) will be conducted on AUC(0-last) and Cmax endpoints in the 
natural logarithmic scale. The model will include terms for sequence, subjects within 
sequence, period and product exposure as fixed effect factors. The results of this analysis for 
each of AUC(0-last) and Cmax are presented in terms of adjusted geometric least square means 
and 95% CIs for the THS 2.2:CC and THS 2.2: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 

 
 
 
 
 
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sensitivity to the distributional assumptions, point and interval estimates will also be 
estimated by means of the percentile bootstrap technique, using 2000 bootstrap samples 
which preserve the number of subjects per sequence. 
12.5.4 
Confirmatory Analyses 
Given that the objective of this study is to determine the point estimate and precision of the 
ratio of THS 2.2:CC for Cmax and AUC(0-last), there is no statistical hypothesis to be tested. 
 
12.6 Secondary Endpoints 
12.6.1 
Secondary Endpoint Analysis Variables 
Nicotine PK parameters will be derived as follows: 
tmax 
Time of maximum observed plasma concentration. tmax will be reported 
as long as there is at least one quantifiable concentration post-exposure 
AUC(0-t’) 
Area under the plasma concentration-time curve from zero to the 
subject-specific time to maximum nicotine concentration following 
single use of CC or NNS (linear trapezoidal method) 
AUC(0-∞) Area under the plasma concentration-time curve from start of product 
use extrapolated to infinite time, according to:  






+
=
−
∞
z
C
AUC
AUC
last
last
λ
0
-
0
 
Where Clast is the last quantifiable concentration and λz is the terminal 
elimination rate constant 
λz 
Terminal elimination rate constant, estimated by linear regression 
analysis of the natural log-transformed concentration-time data 
t1/2 
Terminal elimination half-life, derived as ln(2)/λz 
More details on PK parameter derivations will be provided in the SAP. 
Subjective effects of using THS 2.2 as compared to the CC and to the NNS will be evaluated 
by analysing domain scores of QSU-brief and MCEQ. Full details of questionnaire domain 
scores derivation will be provided in the SAP. 

 
 
 
 
 
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12.6.2 
Baseline Comparability 
Not applicable. 
12.6.3 
Descriptive Analysis 
In general, secondary endpoints will be summarized using the approach described in 
Section 12.1.3. 
The following analyses will be conducted in both Group-1 and Group-2 PK analysis sets: 
□ AUC(0-∞), AUC(0-t’), and t1/2 will be analysed using the same approach adopted for the 
primary endpoints. No statistical analysis will be performed on the elimination rate 
constant λz. Data will be summarized and presented together with 95% CI.  
□ Hodges-Lehmann 95% CI estimates for the median tmax differences will be presented 
(Lingling, 2008). 
□ The use of random effects model is suggested in the context of the analysis of 
subjective effects of smoking (Shiffman et al, 2004). Mixed effects ANOVA with the 
same model terms as planned for the sensitivity analysis of the primary endpoints will 
be adopted for the analysis of QSU-brief, including all of the different assessment 
time points as repeated measurements. The analysis will not be adjusted for the 
assessment prior to T0 (Fleiss et al, 1985). 
□ Levels of exhaled CO and of blood COHb will be summarized by means of 
descriptive statistics reported by exposure. Analysis of COHb levels will be 
conducted using a mixed model for repeated measures, the same approach as for the 
QSU-brief. 
 
The following analyses will be conducted only in Group-1 PK analysis set: 
□ Mixed effects ANOVA with the same model terms as planned for the sensitivity 
analysis of the primary endpoints will be adopted for the analysis of the MCEQ 
domain scores. 
 
The following analyses will be conducted in only Group-2 PK analysis set: 
□ To test if the time to the maximum nicotine concentration in THS 2.2 is shorter than 
in NNS the following hypothesis will be evaluated: 
H0: XTHS - XNNS = 0 
HA: XTHS - XNNS < 0 

 
 
 
 
 
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where XTHS and XNNS are the median values of the THS 2.2 and NNS, respectively. 
tmax will be analysed 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 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 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. 
AE data will serve as the primary assessment of safety. Other safety variables monitored in 
this study include: respiratory symptoms (cough assessment VAS and Likert scales); vital 
signs (systolic and diastolic blood pressure, pulse rate, respiratory rate); spirometry; ECG 
data; clinical chemistry, haematology, and urine analysis safety panel; physical examination; 
and concomitant medication. 
The number and percentage of subjects with AEs and SAEs will be tabulated by system 
organ class and preferred term. Summaries will also be presented for AEs leading to 
withdrawal, AEs leading to Death, AEs by relatedness to product exposure, AEs by severity, 
and laboratory AEs. Tabulations will be performed for both the number of subjects 
experiencing an event and the number of events. The number and percentage of device 
events and of subjects with device events will be tabulated by sequence. 

 
 
 
 
 
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The number and percentage of subjects with clinical findings will be tabulated by sequence 
for laboratory parameters. Shift tables showing change from baseline of clinical findings will 
be provided for ECGs, physical examinations, and laboratory parameters (both shifts in 
normal ranges and toxicity grades). Descriptive statistics will be summarized by visit and 
change from baseline for laboratory parameters, ECG, respiratory symptoms, and vital signs. 
12.7 Exploratory Analyses 
There are no planned exploratory analyses. 
12.8 Interim Analysis 
There are no planned interim analyses. 

 
 
 
 
 
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13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Investigators and Study Administrative Structure 
13.1.1 
Investigator 
Principal Investigator: 
 
Johnston Stewart 
 
Celerion GB Ltd, 
 
 
 
 
 
 
 
 
 
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
 
Fax: +41 
 
Mobile: +41 
 
E-mail: 
 
, PhD 
Biostatistician 
Phone: +41
 
Mobile: +41 
 
E-mail:
 
, MD 
Phone: +41 
 

 
 
 
 
 
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Medical Safety Officer 
Mobile: +41 
 
E-mail: 
 
 
Medical Writer 
Phone: +41 
  
Mobile: +41
 
E-mail: 
 
, PhD 
Clinical Study Manager 
Phone: +41 
 
Mobile: +41 
 
E-mail: 
 
 
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 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subject in writing and signed by the subject, in compliance with all local 
and national data protection and privacy legislation. 

 
 
 
 
 
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The confidentiality of data for 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, IEC review, and regulatory 
inspection(s). 
13.4 Record Retention 
All records of data, source data and source documents (original records or certified copies), 
in any form (including, but not limited to, written, electronic, 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 GCP 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 
• At least 2 years depending on, for example, the circumstances 
• After formal discontinuation of clinical development of the IP.  

 
 
 
 
 
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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 IEC, composition of the 
IEC. 
• 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). 
• 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. 
• Information regarding subjects’ discontinuation and any follow-up. 

 
 
 
 
 
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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 IEC 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 
this document is allowed only to study personnel, IRB, or duly authorized representatives of 

 
 
 
 
 
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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 
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without the written consent of Philip Morris Products S.A. 
 
 
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commercial information, and the legal protections provided to such trade secrets and confidential information 
are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
 
 
FDA, 2002 
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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 and NNS 
● 
 
 
 
 
 
 
 
Product test for THS 2.2 and 
NNS 
 
● 
 
 
 
 
 
 
Identification of current CC 
brand 
● 
● 
 
 
 
 
 
 
Smoking history 
● 
● 
 
 
 
 
 
 
Readiness to accept 
interruption from smoking up to 
● 
● 
 
 
 
 
 
 

 
 
 
 
 
 
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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 
4 days 
Willingness to quit smoking in 
the next 3 months 
● 
 
 
 
 
 
 
 
Demographics a, medical 
history, concomitant diseases  
● 
 
 
 
 
 
 
 
Socio-economic status 
questionnaire 
 
 
 
 
● 
 
 
 
Prior medication b / 
Concomitant medication 
● 
● 
● 
● 
● 
● 
● 
● 
Physical examination, body 
height, weight and related BMI c 
● 
● 
 
 
 
 
● 
 
Vital signs d 
● 
● 
● 
● 
● 
● 
● 
 
ECG 
● 
 
 
● 
 
● 
 
 
Spirometry 
● 
● 
 
 
 
 
● 
 
Chest X-ray e 
● 
 
 
 
 
 
 
 
B/U: Haematology, clinical 
chemistry, urine analysis 
● 
● 
 
 
 
 
● 
 
B: Serology  
● 
 
 
 
 
 
 
 
U: Urine drug screen, urine 
cotinine screen 
● 
● 
 
 
 
 
 
 
Alcohol breath test  
● 
● 
 
 
 
 
 
 

 
 
 
 
 
 
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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 
U: Pregnancy test (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  
 
 
 
● 
 
● 
 
 
Cough assessment j 
 
 
● 
● 
● 
● 
● 
 
AE/SAE recording  
● 
● 
● 
● 
● 
● 
● 
● 
See also instructions and abbreviations on the following page. 
Abbreviations: AE = Adverse event; CC = conventional cigarette(s); CO = Carbon monoxide; COHb = Carboxyhemoglobin; 
CYP2A6 = Cytochrome P450 2A6; ECG = Electrocardiogram; FTND = Fagerström Test for Nicotine Dependence (revised version); MCEQ = 

 
 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
 
 
 
Modified Cigarette Evaluation Questionnaire; NNS = Nicotine nasal spray; QSU-brief = Questionnaire of Smoking Urges; SAE = Serious adverse 
event; THS = Tobacco Heating System 
 
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 min +1 min, T2 after 4 min +1min, T3 after 6 min +1 min, 
T4 after 8 min +1 min, T5 after 10 min +1 min, T6 after 15 min +2 min, T7 after 30 min +2 min, T8 after 45 min +2 min, T9 after 60 
min +3 min, T10 after 2 hours +5 min, T11 after 4 hours +5 min, T12 after 6 hours +5 min, T13 after 9 hours +5 min, T14 after 12 
hours +5 min, and T15 after 24 hours +5 min.  
g: COHb blood samples to be taken as follows: 
Single use: A total of 5 blood samples will be taken. The first sample within 15 minutes prior to T0 (start of single product use); thereafter in 
relation to T0 at 15 min +2 min, 60 min +3 min, 4 hours +5 min and 12 hours +5 min 
h: A CO breath test will be conducted once on Day -1 and Day 4. On Day 0, Day 1, Day 2, Day 3, four breath tests will be done per day. On Day 
1 and Day 3, the first test per day will be performed within 15 minutes prior to T0 (T0 = start of first product use) and then around 12:00 pm, 
4:00 pm and 8:00 pm. On the wash-out days (Day 0 and Day 2) it will be conducted around 8:00 am, 12:00 pm, 4:00pm, and 8:00 pm. 
i: QSU–brief will be assessed as follows:  
Single use: The QSU-brief will be completed by the subject himself/herself at single use study days. The first assessment will be done prior to 
T0. All other assessments will be done after T0, at 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours (with an allowed time window of +5 
min each) and 4 hours, 6 hours, 9 hours, 12 hours (with an allowed time window of +10 min each).  

 
 
 
 
 
 
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disclosed without the written consent of Philip Morris Products S.A. 
 
 
 
j: Visual analogue scale, three Likert scales and one open question. Cough questionnaire should be asked on Day 0 between 06:30 and ’09:00, 
on Day 2 24 hours after T0 of Day 1, on Day 4, 24 hours after T0 of Day 3, and on Day 1 and Day 3, prior product use. 
k: All examinations listed at the Day of Discharge should also be conducted in subjects preliminarily terminating the study. 
l: Spontaneous reporting of new AEs/SAEs by the subject and active follow-up of ongoing AEs/SAEs by the site.  

 
 
 
 
 
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Appendix 2 Participating Laboratories 
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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without the written consent of Philip Morris Products S.A. 
 
 
 
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.medicines.org.uk/emc/medicine/20679:  
’Undesirable effects 
Some symptoms may be related to nicotine withdrawal associated with stopping smoking. These can include; 
irritability/aggression, dysphoria/depressed mood, anxiety, restlessness, poor concentration, increased 
appetite/weight gain, urges to smoke (cravings), night-time awakenings/sleep disturbance and decreased heart 
rate. Increased frequency of aphthous ulcer may occur after abstinence from smoking. The causality is unclear.  
Nicorette Nasal Spray may cause adverse reactions similar to those associated with nicotine given by other 
means, including smoking, and these are mainly dose-dependent. At recommended doses Nicorette Nasal Spray 
has not been found to cause any serious adverse effects. Excessive use of Nicorette Nasal Spray by those who 
have not been in the habit of inhaling tobacco smoke could possibly lead to nausea, faintness or headaches.  
During the first 2 days of treatment, nasal irritation as sneezing, running nose, watering eyes, cough was 
reported by nearly all (94%) of the patients. Both the frequency and severity declined with continued use. 
Reported adverse events associated with Nicorette Nasal Spray include: 
Body System 
Incidence* 
Reported adverse event 
Nervous system disorders:  
Common  
Dizziness, headache  
Cardiac disorders:  
Uncommon:  
Palpitations  
  
Very rare:  
Reversible atrial fibrillation  
Respiratory, thoracic and 
mediastinal disorders:  
Common:  
Coughing  
Gastrointestinal disorders:  
Common:  
Gastrointestinal discomfort, nausea, vomiting  
General disorders and 
administration site disorders:  
Very common:  
Epistaxis, running nose, sneezing, watering eyes.  
* Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1 000, < 1/100); rare (>1/10 000, <1/1 000); 
very rare (<1/10 000), including isolated reports.” 

 
 
 
 
 
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Appendix 5 
Abnormal Laboratory Values 
ABNORMAL LABORATORY VALUES RATING: SERUM CHEMISTRY PARAMETERS 
Serum Chemistry* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Sodium – Hyponatremia (mmol/l) ** 
(1) 
<LLN - 130 
- 
<130 - 120 
Sodium – Hypernatremia (mmol/l) ** 
(1) 
>ULN - 150 
>150 - 155 
>155 - 160; 
hospitalization 
indicated 
Potassium – Hyperkalaemia 
(mmol/l)**(1) 
>ULN - 5.5 
>5.5 - 6.0 
>6.0 - 7.0; 
hospitalization 
indicated 
Potassium – Hypokalaemia (mmol/l) 
** (1) 
<LLN - 3.0 
<LLN - 3.0; 
symptomatic; 
intervention 
indicated 
<3.0 - 2.5; 
hospitalization 
indicated 
Glucose – Hypoglycaemia ** (1)    
(mg/dL) 
                                                   
(mmol/l)  
<LLN – 55; 
<LLN – 3.0 
<55 – 40; 
<3.0 – 2.2 
<40 – 30; 
<2.2 – 1.7 
Blood Urea Nitrogen (BUN) (mg/dL) 
(2) 
23 – 26 
27 – 31 
>31 
Glucose – Hyperglycaemia: ** 
  
Fasting (1)( (mg/dL) 
                   (mmol/l) 
 
 
>ULN – 160; 
>ULN – 8.9 
 
>160 -250 
> 8.9-13.9 
 
 
>250 – 500; 
>13.9 – 27.8 
Hospitalization 
indicated 
Creatinine increased** (1) 
>1 – 1.5 x 
baseline; 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x 
baseline; 
>1.5 – 3.0 x ULN 
>3.0 x baseline;
>3.0 – 6.0 x ULN
Albumin – Hypoalbuminaemia** 
(1)(g/dL) 
                                                          
(g/l) 
<LLN – 3; 
<LLN - 30 
<3 – 2; 
<30 - 20 
<2; 
<20 

 
 
 
 
 
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Total Protein – Hypoproteinaemia (2) 
(g/dL)
 
5.5 – 6.0 
 
5.0 – 5.4 
 
<5.0 
Alkaline phosphatase increased** (1) 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x 
ULN 
ALT / AST increased** (1) 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x 
ULN 
Gamma-glutamyl transferase (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 ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 ULN 
Cholesterol high** (1)(                            
 
 
 
 
 
 
 
 
 
(mg/dL) 
(mmol/l)
 
>ULN – 300; 
>ULN – 7.75 
 
 
>300-400; 
>7.75-10.34 
 
 
>400-500; 
>10.34-12.92 
Triglycerides - Hypertriglyceridemia 
(1) 
(mg/dL)
(mmol/l)
 
150 – 300; 
1.71 – 3.42 
 
>300 – 500; 
>3.42 – 5.70 
 
>500 – 1000; 
>5.70 – 11.40 
Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; LLN = Lower 
limit of the normal range; ULN = Upper limit of the normal range. 
Data Sources: 
 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, U.S. Department of Health and Human Services, FDA, Center for 
Biologics 
Evaluation 
and 
Research 
- 
Guidance 
for 
Industry. 
 
       (2) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, 
FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
*  Those parameters that are not listed do not have grading categories in either the CTCAE or the 
FDA guidance documents and will therefore be reviewed by the Investigator and only reported as 
an AE if considered to be clinically relevant. 
** Where parameters in this table are listed in both the CTCAE and the FDA guidance documents, 
and each document has different values within each grading category, the grading in CTCAE 
guidance document predominates. 

 
 
 
 
 
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ABNORMAL LABORATORY VALUES RATING: HEMATOLOGY PARAMETERS 
Haematology* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Haemoglobin (Female) – (g/dL) 
(1) 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
change from baseline value – 
(g/dL) (1)
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
Haemoglobin (Male) – (g/dL) (1) 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
change from baseline value – 
(g/dL) (1)
Any decrease – 1.5 
1.6 – 2.0 
2.1 – 5.0 
Haemoglobin increase – (g/dL) (2)
Increase in >0 – 2 
above ULN or 
above baseline if 
baseline is above 
ULN 
Increase in >2 – 4 
above ULN or above 
baseline if baseline 
is above ULN 
Increase in >4 
above ULN or 
above baseline if 
baseline is above 
ULN 
WBC Increase  – (cell/mm3) (1) 
10,800 – 15,000 
15,001 – 20,000 
20,001 – 25,000 
WBC Decrease - (cell/mm3) (2)** 
<LLN – 3000; 
<LLN – 3.0 x 10-9/l 
<3000 - 2000; 
<3.0 – 2.0 x 10-9/l 
<2000 - 1000; 
<2.0 – 1.0 x 10-9/l 
Lymphocytes Increase - 
(cell/mm3) (2) 
- 
>4,000 – 20,000 
>20,000 
Lymphocytes Decrease  - 
(cell/mm3) (2)** 
<LLN – 800; 
<LLN – 0.8 x 10-9/l 
<800 - 500; 
<0.8 – 0.5 x 10-9/l 
<500 - 200; 
<0.5 – 0.2 x 10-9/l 
Neutrophils Decrease  - 
(cell/mm3) (2)** 
<LLN – 1500; 
<LLN – 1.5 x 10-9/l 
<1500 - 1000; 
<1.5 – 1.0 x 10-9/l 
<1000 - 500; 
<1.0 – 0.5 x 10-9/l 
Eosinophils - (cell/mm3) (1) 
650 – 1500 
1501 - 5000 
>5000 
Platelets Decrease - (cell/mm3) 
(2)** 
<LLN – 75,000; 
<LLN – 75.0 x 10-9/l
<75,000 – 50,000; 
<75.0 – 50.0 x 10-9/l 
<50,000 – 25,000; 
<50.0 – 25.0 x 10-9/l
Abbreviations: LLN = Lower limit of the normal range; ULN = Upper limit of the normal range; WBC = 
White blood cell. 
Data Sources: 

 
 
 
 
 
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(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. 

 
 
 
 
 
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ABNORMAL LABORATORY VALUES RATING: URINALYSIS PARAMETERS 
Urine* 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Protein ** (1) 
1+ proteinuria; 
urinary protein <1.0 
g/24 hours 
2+ proteinuria; 
urinary protein 1.0-
3.4 g/24 hours 
Urinary protein ≥3.5 
g/24 hours 
Glucose (2) 
Trace 
1+ 
2+ 
Blood – Haematuria ** (1) 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; urinary 
catheter or bladder 
irrigation indicated; 
limiting instrumental 
ADL 
Gross haematuria; 
transfusion, IV 
medications or 
hospitalization 
indicated; elective 
endoscopic, radiologic 
or operative 
intervention indicated; 
limiting self-care ADL 
Abbreviations: ADL = Activities of daily living; IV = Intravenous. 
Data Sources: 
 
(1) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
   (2) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, 
FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
*  Those parameters that are not listed do not have grading categories in either the CTCAE or the 
FDA guidance documents and will therefore be reviewed by the Investigator and only reported as 
an AE if considered to be clinically relevant. 
**  Where parameters in this table are listed in both the CTCAE and the FDA guidance documents, 
and each document has different values within each grading category, the grading in CTCAE 
guidance document predominates. 
 
 
 
 

 
 
 
 
 
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Appendix 6 Investigational Micro+TM Smokerlyzer® 
The Micro+™ Smokerlyzer® carbon monoxide (CO) monitor is the new-and-improved 
version of the revolutionary Micro™ Smokerlyzer®. The Micro™ Smokerlyzer® is a 
longstanding benchmark device used in clinical studies and research. 
The Micro+™ is the most comprehensive CO monitor available. It analyses breath CO levels 
in adults and adolescents up to 250 ppm, and automatically converts CO readings of pregnant 
women to foetal %COHb. 
Micro+ Features 
• Analyses COHb and CO levels in a single breath. 
• Options for testing adults, adolescents and pregnant women. 
• Instant conversion to foetal %COHb at the touch of a button. 
• Clinically proven stop smoking help. 
• Easy-to-use colour touch screen instantly displays the exact result. 
• On-screen instructions with audio prompts. 
• Store up to 100 readings and view them as a table or a graph. 
• Improved electrochemical sensor and anti-humidity filter. 
• Antibacterial filter and one-way valve for optimal infection control. 
• Auto-zero and adjustable breath hold countdown. 
• Built-in maintenance reminders. 
• Minimal hydrogen cross-sensitivity. 
Operation 
The Micro+ analyses the amount of CO in a single exhaled breath. It uses this reading to 
automatically calculate the percentage of COHb in the blood. Carrying out a test: simply 
press the button to switch the monitor on, then follow the instructions on the touch screen 
display. Exhale into the monitor through the Flatpak™ mouthpiece and the result is displayed 
instantly in exact parts per million (ppm) for CO, and as a percentage for COHb (%COHb). 

 
 
 
 
 
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The numbers are displayed either in green, amber or red (a familiar ‘traffic light’ system) to 
represent the level of CO. 
Instrument cleansing wipes 
Instrument cleansing wipes specific to the instrument are provided. 
Calibration 
Calibration gas 
Calibration gas is supplied by Bedfont in lightweight disposable cylinders. Calibration of the 
Micro+™ should be carried out with Bedfont's 50 ppm CO in air calibration gas. No 
specialist technical knowledge or skills are required and Bedfont provides comprehensive 
calibration kits for ultimate ease of use. Calibration should be carried out at least every 
6 months. A calibration reminder will appear automatically when calibration is due.