A Two-arm, Open Label, Prefatory Study to Explore Changes in Nasal Mucociliary Clearance Between Smokers and Never Smokers and to Standardize Nasal Scraping Procedure
Phase: NA
Conditions: Smokers, Never Smokers
Sponsor: Philip Morris Products S.A.

 
 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information 
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without the written consent of Philip Morris Products S.A. 
  
 
Clinical Study Protocol 
 
 
Study title: 
A 2-arm, open label, prefatory study to explore changes in nasal 
mucociliary clearance between smokers and never smokers and 
to standardize nasal scraping procedure. 
Study number 
P1-CMS-01-US 
Short title 
Prefatory study to explore changes in nasal mucociliary 
clearance and to standardize nasal scraping procedure. 
EUDRACT number: 
Not applicable. 
Product name: 
Not applicable 
Sponsor: 
Philip Morris Product S.A. 
PMI Research & Development 
Quai Jeanrenaud 5 
2000 Neuchâtel, Switzerland 
Version number: 
Final 2.0 Amendment 1.0 
Revision date: 
22-May-2017 
Authors: 
 
 
 
 
 

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Clinical Study Protocol 
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without the written consent of Philip Morris Products S.A. 
PROTOCOL REVISION HISTORY 
The following summarizes the updates made from Final Version 1.0 (8-Dec-2016) to Final 
Version 2.0 Amendment 1.0 (22-May-2017) 
 
Synopsis – Study Population and Main Criteria for Inclusion/Exclusion Section 
Inclusion criteria 2. updated from: 
 
Male subject aged ≥25 to ≤40 years 
old.   
 
Rationale for change: Sponsor decision to 
widen the age range of enrolled subjects. 
To: 
 
Male subject aged ≥25 to ≤45 years 
old.   
  
Section 5.1 Selection of Study Population 
 
Inclusion criteria 2. updated from: 
 
Male subject aged ≥25 to ≤40 years 
old.   
 
Rationale for change: Sponsor decision to 
widen the age range of enrolled subjects. 
To: 
 
Male subject aged ≥25 to ≤45 years 
old.   
 
Appendix B – Inclusion and Exclusion Criteria Assessment 
 
Inclusion criteria 2. updated from: 
 
Male subject aged ≥25 to ≤40 years 
old.   
 
Rationale for change: Sponsor decision to 
widen the age range of enrolled subjects. 
To: 
 
Male subject aged ≥25 to ≤45 years 
old.   
 

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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. 
DECLARATION OF INVESTIGATOR 
Study Title: A 2-arm, open label, prefatory study to explore changes in nasal mucociliary 
clearance between smokers and never smokers and to standardize nasal scraping procedure. 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, case report forms (CRFs), and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
Institutional Review Board (IRB). No substantial changes will be made to the study protocol 
without the prior written approval of the Sponsor and the IRB, except where necessary to avert 
an immediate hazard to the subjects. 
I have read the protocol and agree that the study will be conducted in compliance with the 
protocol and in accordance with the principles of the current version of the Declaration of 
Helsinki (Recommendations guiding Medical Doctors in Biomedical Research Involving 
Human Subjects). The conduct of the study will be in accordance with the Notes for Guidance 
on Good Clinical Practice (GCP) (CPMP/ICH/135/95). 
I acknowledge that I am responsible for the overall study conduct. I agree to personally conduct 
or supervise the described clinical study. I agree to ensure that all associates, colleagues and 
employees assisting in the conduct of the study at my site are informed about their obligations. 
Mechanisms are in place to ensure that site staff receive the appropriate information throughout 
the study. 
 
 
 
Neptune, NJ, USA 
Frank Lee, MD, Investigator (Print) 
 
Investigational Site 
 
 
 
 
Frank Lee, MD, Investigator (Signature) 
 
Date 

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are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
SYNOPSIS 
 
Sponsor: 
Philip Morris Product S.A. 
 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Name of Product: 
Not applicable. 
Study Title: 
A 2-arm, open label, prefatory study to explore changes in nasal mucociliary clearance 
between  smokers and never smokers and to standardize nasal scraping procedure 
Study Number: 
P1-CMS-01-US 
Inflamax study code: 15-LE-001-RD 
Study Short Title: 
Prefatory study to explore changes in nasal mucociliary clearance and to standardize nasal 
scraping procedure. 
Study Location: 
             
 
 

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without the written consent of Philip Morris Products S.A. 
 
Objectives and endpoints:  
Primary Objective and Endpoints: 
1. To evaluate the NMC over the course of 12 hours following single use of cigarette 
in smokers.   
 STT value as assessed by STT test at each time point. 
 
2. To compare NMC over the course of 12 hours in smokers following single use 
of cigarette relative to never smokers. 
 STT value as assessed by STT test at each time point. 
 
3. To examine the relationship between plasma nicotine levels and STT value in 
smokers and never smokers. 
 STT value as assed by the STT test and plasma nicotine levels at each time point.
Secondary Objectives and Endpoints: 
1. To standardize nasal scraping procedure using two methods. 
 Collection of nasal epithelium for further histology. 
 Evaluation of RNA quality and quantity. 
 
2. To monitor the safety during the study. 
 Vital signs. 
 Adverse events (AE). 
 Nasal and throat exam. 
 Hematology, clinical chemistry and urine analysis. 
 Brief physical examination. 
 Concomitant medications. 
 

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Additional Study Assessments (for baseline characteristics): 
 Serology for human immunodeficiency virus (HIV) 1/2 and hepatitis B and C. 
 Alcohol breath test. 
 
Evaluation Criterion:  
The evaluation criterion is the time lapse between placing the saccharin and tasting the 
sweetness. These times will be evaluated by the summary statistics described elsewhere. 
Study Hypothesis: 
There are no statistical hypotheses to be tested. 
Study Design: 
This will be a single-center, study in which 14 healthy adult male study participants, 
consisting of 7 cigarette smokers and 7 never smokers as a control group, will be enrolled. 
Study participants will not be replaced after being enrolled. 
The subjects will be divided in two groups: 
Group 1 – 7 cigarette smokers 
Group 2 – 7 never smokers 
This study will have three visits on three separate days as described in Figure 1.  
At Visit 1 (Screening Visit), study participants will undergo the procedures outlined in 
Appendix A to check eligibility criteria, including providing informed consent, undergoing 
a brief physical examination, nasal and throat exam, vital signs, skin prick test (SPT), 
spirometry testing, STT test, exhaled carbon monoxide (eCO) measurements, urine cotinine 
assessment, medical and smoking history and blood and urine collection for medical lab 
exams.  

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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. 
Following Visit 1, study participants who pass all of the inclusion criteria and do not present 
any of the exclusion criteria will be asked to return to the clinic for Visit 2.  
During Visit 2, selected inclusion and exclusion criteria will be reassessed to ensure study 
participants are still eligible for enrollment (Appendix A). All study participants will have 
baseline assessments performed (Appendix A), including STT test.  
Study participants will be confined in the clinic from the beginning of Visit 2 until discharge 
at Visit 3. During this confinement period study participants will abstain from drinking any 
alcohol and any drinks containing caffeine. Standard meals will be served. Drug restrictions 
applicable to study participant exclusion will also be maintained until the end of study 
(EOS). 
No cigarettes are to be smoked from midnight (± 1 hour) between Visit 2 and Visit 3 until 8 
am on the day of Visit 3.  
On the day of Visit 3, at least 8 hours after last cigarette, cigarette smokers, who want to 
smoke, will have a cigarette at 8 am ± 30 minutes and then have the STT test performed 
immediately after smoking (5-10 minutes post T0). T0 will be defined as the start of cigarette 
smoking for smokers. T0 should be the same for all smokers within an acceptable time 
window of 1 hour. Never smokers will also have the STT test performed in the morning  at 
8 am ± 30 minutes (designated T0 ± 30 minutes).  
All study participants (smokers and never smokers) will then have the STT test performed 
at 4h (may be performed until 4h30 min), 8h (may be performed until 8h30 min), and 12h 
(may be performed until 12h30 min) post T0, ensuring at least approximately 4 hours 
between the beginning of each STT test. The participant will be asked to confirm he can no 
longer feel the sweet taste. Study participants will drink a glass of water (approximately 240 
mL) before STT tests are performed. 
Samples for plasma nicotine assessment will be collected at approximately the same time 
points that STT test is performed at T0, 4h (may be performed until 4h30 min), 8h (may be 
performed until 8h30 min), and 12h (may be performed until 12h30 min) post T0.  

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without the written consent of Philip Morris Products S.A. 
Nasal scraping of the inferior turbinate of both nostrils will be performed on all 14 study 
participants at the end of Visit 3, after all other clinic assessments, except the brief physical 
examination which will be done after the nasal scraping:  
 For 4 study participants, nasal scraping (left nostril with method 1, right with method 
2) will be collected and shipped to the appropriate laboratory for further histological 
assessment.  
 For the 10 remaining study participants, 5 will undergo nasal scraping using method 
1, and 5 using method 2. For all 10 study participants, cell sample from one nostril 
will be added into one buffer and cell sample from the other nostril into a second 
buffer. Samples will be collected and shipped to the appropriate laboratory for 
subsequent RNA quantity and quality analysis. 
Full procedure is described in the “Method establishment to obtain human nasal epithelial 
sample using the Rhino-probe”.  
Upon conclusion of all clinic assessments, at the time of discharge on Visit 3, the Principal 
Investigator or designee will perform a brief physical examination on the study participant. 
From the discharge on Visit 3, the study participant will enter a 1-day Safety Follow-Up 
Period during which spontaneously reported new AEs/serious AEs (SAEs) will be recorded, 
and the active follow-up of ongoing AEs/SAEs will be done by the site.  
Any non-serious AE that is ongoing during the Safety Follow-Up Period will be actively 
followed-up by the Principal Investigator or designee during that period until it has been 
resolved, stabilized (i.e., no worsening of the condition), an acceptable explanation has been 
found (e.g., a chronic condition) or lost to follow up. 
At the end of the Safety Follow-Up Period, all ongoing non-serious AEs will be documented as 
“ongoing” and no follow-up information will be sought for on them anymore by the Principal 
Investigator or designee. At that point, the Investigator will assess whether the subject should be 
referred to his/her General Practicioner to have their ongoing AEs addressed accordingly. 

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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. 
All SAEs will be followed up by the Investigator or designee, despite their continuation after the 
end of the Safety Follow-Up Period, until their resolution, stabilization (i.e., no worsening of the 
condition), or an acceptable explanation has been found (e.g., a chronic condition). 
Subjects who are discontinued from the study because of an AE will undergo the early 
termination procedures as soon as practical after the day of discontinuation and will enter 
the period of safety follow-up.  
The end of study for a study participant is defined as the date of discharge on Visit 3 plus 
one day of Safety Follow-Up Period or the date of early termination of the study participant 
plus one day of Safety Follow-Up Period.  
The end of the entire study is defined as the end of the Safety Follow-Up Period of the last 
study participant. 

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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. 
 
 
Figure 1 
Study Flow Chart  
 
 
 
 
 
 

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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. 
 
Study Population and Main Criteria for Inclusion/Exclusion: 
Inclusion criteria:  
1. Informed of the nature of the study and have agreed to and are able to read, review, and 
sign the informed consent form (ICF) prior to Screening. The subject must be willing to 
comply with the study procedures described in the informed consent. The informed 
consent document will be written in English, therefore the volunteer must have the ability 
to read and communicate in English. 
2. Male subject aged ≥25 to ≤45 years old. 
3. BMI between 18.0 kg/m2 to 32.0 kg/m2, inclusive. 
4. Judged by the Principal Investigator or designee to be in good health as documented by 
the medical history, physical examination, vital sign assessments, clinical laboratory 
assessments, and by general observations. 
5. Belong to one of the following two groups: 
a. Non-menthol cigarette smoker (meets all of the following criteria at Visit 1 
and at Visit 2): 
i. A positive urine cotinine test (≥200 ng/mL). 
ii. Smoked at least 20 cigarettes per day for at least the past 5 years.  
iii. eCO levels >10 parts per million (ppm). 
iv. No plans to quit smoking in the next 3 months. 
b. Never smoker (meets all of the following criteria at Visit 1 and at Visit 2): 
i. Subject who has smoked less than 100 cigarettes throughout their 
lifetime and no cigarettes in the past 3 years. 
ii. A negative urine cotinine test (<200 ng/mL). 
iii. eCO levels ≤ 5 ppm. 
6. Completed the Screening process within 30 days prior to Visit 2.  

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without the written consent of Philip Morris Products S.A. 
7. Availability for the entire study period and willingness to comply with study procedures, 
including smoking interruptions, as evidenced by a signed ICF and at Visit 2. 
 
Exclusion criteria: 
1. As per the Principal Investigator or designee’s judgment, the subject cannot participate 
in the study for any reason (e.g., medical, psychiatric, and/or social reason). 
2. Subject is legally incompetent, or physically or mentally incapable of giving consent 
(e.g., emergency situation, under guardianship, prisoners, or subjects who are 
involuntarily incarcerated). 
3. Presence of confounding allergies including allergic rhinitis and non-allergic rhinitis 
during the course of the study based on medical history and SPT. 
4. Clinical significant abnormality on their nasal and throat exam, at the discretion of the 
Principal Investigator or designee at Visit 1 and/or at Visit 2. 
5. Cigarette smoker who smoke/use any tobacco or nicotine products (other than CC), such 
as cigars, pipe, menthol cigarettes or electronic cigarettes in the previous 3 months, as 
self-reported at Visit 1 or Visit 2. 
6. Never smoker who smoke/use any tobacco or nicotine products, such as cigars, pipe, 
menthol cigarettes or electronic cigarettes in the previous 3 years, as self-reported at 
Visit 1 or Visit 2. 
7. Cigarette smokers who state they will be unable to abstain from smoking for up to 24 
hours. 
8. Inability to taste sweet within 60 minutes in the STT test.  
9. Subjects who routinely use or who have used in the previous 4 weeks nasal sprays, 
inhalers or other nasal products, such as nasal irrigation (for example, Neti Pot) prior to 
Visit 1 and/or Visit 2. 
10. Subjects who have taken any of the following medication without the indicated minimum 
washout period: 
 
Table 1 - Prohibited medication. 

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Prohibited Medication 
Restriction period  
(with Principal Investigator 
or designee discretion) 
Short-acting antihistamines including intranasal antihistamines  
3 days before Visit 1 until 
Visit 2 
Long-acting antihistamines (i.e. Loratadine, Desloratadine) 
7 days before Visit 1 until 
Visit 2 
Over-the-counter cough and cold preparations or sleep aids 
containing antihistamines 
3 days before Visit 1 until 
Visit 2 
Leukotriene inhibitors 
14 days before Visit 1 until 
Visit 2 
Oral or intra-articular steroid 
30 days before Visit 1 until 
Visit 2 
Intranasal and inhaled corticosteroids 
14 days before Visit 1 until 
Visit 2 
Use of monoamine oxidase inhibitors 
14 days before Visit 1 until 
Visit 2 
Decongestants  
48 hours before Visit 1until 
Visit 2 
Cromolyn products 
14 days before Visit 1 until 
Visit 2 
Beta-adrenergic blockers (i.e. Acebutolol, Atenolol, etc.) 
14 days before Visit 1 until 
Visit 2 
Anticholinergics 
7 days before Visit 1 until 
Visit 2 
Herbal or natural product remedies for allergy symptoms 
On the day of Visit 1 until 
Visit 2 
Short-Acting Beta Agonists 
6 hours prior to spirometry 
(except as per protocol before 
spirometry) 
Long-Acting Beta Agonists 
3 days before Visit 1 until 
Visit 2 
Phosphodiesterase 5 inhibitors (i.e. Sildenafil, Vardenafil, 
Tadalafil) 
7 days before Visit 1 until 
Visit 2 
Amiloride 
3 days before Visit 1 until 
Visit 2 
Macrolide antibiotics 
7 days before Visit 1 until 

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Visit 2 
Guaifenesin 
3 days before Visit 1 until 
Visit 2 
Mucolytic agents 
14 days before Visit 1  until 
Visit 2 
Topical menthol products 
14 days before Visit 1  until 
Visit 2 
Topical nasal medication 
4 weeks before Visit 1 until 
Visit 2 
Topical ocular medication 
4 weeks before Visit 1 until 
Visit 2 
Any other medication at the Principal Investigator or designee’s 
discretion that might interfere with the endpoints or procedures. 
As per Principal Investigator 
or designee. 
 
11. Subjects with evidence of COPD, Global Initiative for Chronic Obstructive Lung 
Disease (GOLD) stage I or greater, and a forced expiratory volume 1 / the forced vital 
capacity ratio (FEV1/FVC ratio) <0.7.  
12. Any condition the Principal Investigator or designee has cause to believe would interfere 
with the procedures for upper or lower airway function. This could include, but is not 
limited to, nasal/septum deviations, or nasal polyps or nasal allergies which will be 
identified by the Principal Investigator or designee. 
13. Upper or lower respiratory diseases in the 4 weeks prior to Visit 2. 
14. History of nasal or sinus surgery in the 5 years prior to Visit 2. 
15. As per the Principal Investigator or designee’s judgment, the subject has medical 
conditions which require or will require in the course of the study, a medical intervention 
(e.g., start of treatment, surgery, hospitalization) which may interfere with the study 
participation and/or study results. 
16. The subject has a positive alcohol test and/or a history of alcohol abuse that could 
interfere with the subject’s participation in study at Visit 1 or Visit 2.  
17. Positive urine drug screen at Visit 1 or Visit 2. 

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18. The subject has positive serology test for human immunodeficiency virus (HIV)1/2, 
Hepatitis B or Hepatitis C. 
19. Subject has donated or been in receipt of whole blood or blood products within 3 months 
prior to Visit 1. 
20. Subject is a current or former employee of the tobacco industry or of their first-degree 
relatives (spouse, legal patner, parent, sibling, and child). 
21. Subject is an employee of the investigational site or any other parties involved in the 
study or of their first-degree relatives (spouse, legal patner, parent, sibling, and child). 
22. Subject has been in receipt of last dose from another clinical study within 3 months prior 
to Visit 1.  
23. Subject has been previously screened in this study. 
 
 
Investigational Product 
Not applicable. 
 
Duration of Study: 
The planned maximum study duration for a single study participant from Screening through 
completion of study will be 33 days. 
The estimated maximum study duration for the whole Study from screening through 
completion will be 35 days. 
 
Statistical Methods 
STT for each time point will be summarized by smoker and never smoker group using the 
descriptive statistics: mean, minimum, maximum, median, quartiles, standard deviation (SD) 
and 95% confidence interval (CI).  

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without the written consent of Philip Morris Products S.A. 
The plasma nicotine levels for each time point will be summarized by smoker and never 
smoker group using the descriptive statistics mean, minimum, maximum, median, quartiles, 
standard deviation (SD) and 95% confidence interval (CI). The relationship between plasma 
nicotine levels and STT at each time point will be evaluated by spearman correlation as well 
as graphical presentation of these endpoints by time point and smoker and never smoker 
group. 
An overall summary of AEs will be presented by smoker and never smoker group showing 
the number of events and percent of study participants who experienced AEs, SAEs, severe 
AEs and AEs leading to study discontinuation. 
RNA concentration will be summarized by method using descriptive statistics: mean, 
minimum, maximum, median, quartiles, standard deviation (SD) and 95% confidence 
interval (CI). 
RNA RIN will be summarized by method using descriptive statistics: mean, minimum, 
maximum, median, quartiles, standard deviation (SD) and 95% confidence interval (CI). 
A summary of AEs by System Organ Class (SOC) and Preferred Term (PT) by smoker and 
never smoker group will be presented. 
Vital signs will be summarized by smoker and never smoker group using descriptive 
statistics: mean, minimum, maximum, median, quartiles, standard deviation (SD) and 95% 
confidence interval (CI). 
Sample Size 
This is an exploratory study. This study will include 14 study participants: 7 cigarette 
smokers and 7 never smokers. No formal powering has occurred. However, with an expected 
standard deviation of 2.5, a difference in STT of 3.75 can be detected.  
 
Human Subject Protection and Institutional Review Board (IRB): 
CHESAPEAKE IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046-3403, USA 

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+1 410.884.2900 
+1 410.884.9190 
 
Safety reporting: 
SAEs are reported from the time the study participants have signed their informed consent 
forms until the end of the study. The Principal Investigator or designee must notify sponsor 
of all SAEs cases to the sponsor representative within 24 hours of first awareness. Expedited 
reporting of SAEs to IRB(s) and/or competent authorities will be done as locally required. 
 
 
 
 
 

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TABLE OF CONTENTS 
 
PROTOCOL AUTHORISATION .............................................................................................2 
DECLARATION OF INVESTIGATOR ...................................................................................4 
SYNOPSIS .................................................................................................................................5 
TABLE OF CONTENTS .........................................................................................................19 
ABBREVIATIONS AND DEFINITIONS OF TERMS .........................................................26 
1 
ETHICS AND REGULATIONS .....................................................................................30 
1.1 
Institutional Review Board (IRB) Approval ..........................................................30 
1.2 
Ethical Conduct of the Study .................................................................................31 
1.3 
Subject Information and Consent...........................................................................31 
1.3.1 
Informed Consent Form for Study Participation .........................................31 
1.3.2 
Amendment to the Informed Consent Form ................................................32 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................32 
2 
INTRODUCTION ...........................................................................................................34 
2.1 
Background ............................................................................................................34 
2.2 
Purpose of the Study ..............................................................................................36 
2.3 
Anticipated Benefits and Risks ..............................................................................37 
2.3.1 
Anticipated Benefits .....................................................................................37 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures .............................37 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product ....................37 
3 
STUDY OBJECTIVES ....................................................................................................38 
3.1 
Primary Objectives and Endpoints .........................................................................38 
3.2 
Secondary Objectives and Endpoints .....................................................................38 
4 
INVESTIGATIONAL PLAN ..........................................................................................40 
4.1 
Overall Study Design and Plan ..............................................................................40 
4.2 
Rationale for Study Design ....................................................................................43 
4.3 
Appropriateness of Measurements .........................................................................44 
4.4 
Study Duration .......................................................................................................45 
5 
STUDY POPULATION ..................................................................................................46 
5.1 
Selection of Study Population ................................................................................46 
5.1.1 
Inclusion Criteria .........................................................................................46 
5.1.2 
Exclusion Criteria ........................................................................................47 
5.2 
Discontinuation of Study participants from the Study ...........................................51 
5.3 
Lost to Follow-up ...................................................................................................52 

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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. 
5.4 
Violation of Selection Criteria ...............................................................................52 
6 
INVESTIGATIONAL PRODUCTS ...............................................................................53 
6.1 
Restrictions ............................................................................................................53 
6.1.1 
Smoking Restrictions ...................................................................................53 
6.1.2 
Dietary Restrictions .....................................................................................53 
6.2 
Concomitant Medication ........................................................................................54 
7 
STUDY PROCEDURES .................................................................................................56 
7.1 
Informed Consent...................................................................................................56 
7.2 
Clinical Assessments .............................................................................................56 
7.2.1 
Demographic Data .......................................................................................57 
7.2.2 
Identification of the Current Cigarette Brand ..............................................57 
7.2.3 
Questions on Smoking History/Habits and Intention to Quit Smoking. ......57 
7.2.4 
Medical History, Concomitant Disease, Previous and Ongoing 
Medications ..................................................................................................58 
7.2.5 
Brief physical examination and nasal and throat exam. ..............................59 
7.2.6 
Body Height and Weight .............................................................................59 
7.2.7 
Vital Signs ....................................................................................................60 
7.2.8 
Other Clinical Assessments .........................................................................60 
7.3 
Laboratory Assessments ........................................................................................66 
7.3.1 
Hematology, clinical chemistry, urine analysis and serology ......................66 
7.4 
Volume of blood sample ........................................................................................67 
8 
ADVERSE EVENTS .......................................................................................................68 
8.1 
Definitions..............................................................................................................68 
8.1.1 
Adverse Events ............................................................................................68 
8.1.2 
Serious Adverse Events ...............................................................................68 
8.2 
Assessment of Adverse Events ..............................................................................69 
8.2.1 
Collection of Information ............................................................................69 
8.2.2 
Period of Collection .....................................................................................70 
8.2.3 
Intensity of Adverse Event ...........................................................................71 
8.2.4 
Relationship to Study Procedures ................................................................72 
8.3 
Reporting of Serious Adverse Events ....................................................................72 
8.4 
Adverse Events Leading to Discontinuation ..........................................................73 
8.5 
Reporting of Other Events Critical to Safety Evaluations .....................................74 
8.5.1 
Abnormal Results of Laboratory Tests ........................................................74 
9 
STUDY ACTIVITIES .....................................................................................................76 

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9.1 
Screening Visit (Day -30 to -1) ..............................................................................76 
9.2 
Confinement Period (Day 1 to Day 2) ...................................................................76 
9.3 
Safety Follow-Up Period .......................................................................................77 
9.4 
Early Termination Procedures ...............................................................................78 
10  QUALITY CONTROL AND QUALITY ASSURANCE ...............................................79 
10.1 
Monitoring .............................................................................................................79 
10.2 
Training of Collaborators .......................................................................................79 
10.3 
Audits and Inspections ...........................................................................................79 
11  DATA MANAGEMENT ACTIVITIES..........................................................................81 
11.1 
Data Capture ..........................................................................................................81 
11.1.1 
Case Report Forms and Study Records .......................................................81 
11.1.2 
Protocol Deviations ......................................................................................82 
11.2 
Data Handling ........................................................................................................82 
11.2.1 
Database Lock ..............................................................................................83 
11.3 
Coding ....................................................................................................................83 
12  PLANNED STATISTICAL METHODS ........................................................................84 
12.1 
General Considerations ..........................................................................................84 
12.1.1 
Handling of Missing Values and of Values outside the Detection Limits ...85 
12.1.2 
Significance Level for Inferential Analysis .................................................85 
12.2 
Determination of Sample Size and Power Consideration ......................................85 
12.3 
Analysis Populations ..............................................................................................86 
12.3.1 
Full Analysis Set (FAS) ...............................................................................86 
12.3.2 
Per Protocol (PP) Population .......................................................................86 
12.3.3 
Safety Population .........................................................................................86 
13  ADMINISTRATIVE CONSIDERATIONS ....................................................................87 
13.1 
Investigator’s and Study Administrative Structure ................................................87 
13.1.1 
Investigator ..................................................................................................87 
13.1.2 
Sponsor ........................................................................................................87 
13.1.3 
Bioanalytical Laboratory .............................................................................87 
13.1.4 
Other Responsibilities ..................................................................................88 
13.2 
Subject Confidentiality ..........................................................................................88 
13.3 
Informed Consent...................................................................................................89 
13.4 
Access to Source Documentation ..........................................................................89 
13.5 
Record Retention ...................................................................................................90 
13.6 
Clinical Study Report (CSR) .................................................................................90 

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13.7 
Financial Disclosure ...............................................................................................90 
13.8 
Publication and Disclosure Policy .........................................................................91 
14  REFERENCE LIST .........................................................................................................92 
15  APPENDICES .................................................................................................................97 
Appendix A - Schedule of Events ......................................................................................98 
Appendix B – Inclusion and Exclusion Criteria Assessment ............................................99 
 
 
 
 
 

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LIST OF IN-TEXT TABLES 
Table 1 - Prohibited medication. ........................................................................................48 
Table 2 - Hematology and clinical chemistry parameters .................................................66 
Table 3 ‐  Principles for assessing and reporting abnormal laboratory test results ............74 
 

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LIST OF IN-TEXT FIGURES 
Figure 1 
Study Flow Chart .......................................................................................43 
 

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LIST OF APPENDICES 
Appendix A 
Schedule of Events .....................................................................................98 
Appendix B 
Inclusion and Exclusion Criteria Assessment ............................................98 

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ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations  
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CF 
Cystic fibrosis 
CFR 
Code of Federal Regulation 
CI 
Confidence interval 
COHb 
Carboxyhemoglobin 
COPD 
Chronic pulmonary obstructive disease 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
CV 
Curriculum vitae 
DMP 
Data management plan 
DNA 
Deoxyribonucleic acid 
eCO 
Exhaled carbon monoxide 
EOS 
End of study 
FAS 
Full analysis set 
FDA 
Food and Drug Administration  
FEV1 
Forced expiratory volume 1 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 

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GGT 
GOLD 
Gamma-glutamyl transferase 
Global Initiative for Chronic Obstructive Lung Disease 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonization  
IRB 
Institutional Review Board 
IU 
International units 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantification 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MDI 
Metered dose inhaler 
MedDRA 
Medical dictionary for regulatory activities 
NMC 
Nasal mucociliary clearance 
PMI 
Philip Morris International 
PP 
Per protocol 
ppm 
PT 
Parts per million 
Preferred term 
QC 
Quality control 
RBC 
Red blood cell 
RNA 
RIN 
Ribonucleic acid 
RNA integrity Number 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SOP 
Standard operating procedure 

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SPT 
Skin prick test 
STT 
Saccharin transit time 
T0 
Time point of first product use during study day 
TLC 
Total lung capacity 
UBC 
United BioSource Corporation 
WBC 
White blood cell 
 

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Explanation of Terms 
The following special terms are used in this protocol:  
Cigarette  
The term ‘cigarette’ refers to commercially available cigarettes 
(manufactured) and excludes cigars, pipes, bidis, and other 
nicotine-containing products. 
End of study (EOS) 
The EOS for a study participant is defined as Discharge on Visit 3 
plus the 1 day for the Safety Follow-up Period or the date of early 
termination of the study participant plus the 1 day for the Safety 
Follow-up Period. The EOS of the entire study is the end of the 
Safety Follow-up Period of the last study participant. 
Screening failure 
All screened study participants that are not enrolled because the 
fail to comply with inclusion/exclusion criteria are considered as 
screen failures.  

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1 
ETHICS AND REGULATIONS 
1.1 
Institutional Review Board (IRB) Approval 
Prior to the start of the study, the clinical study protocol, together with its associated documents 
(Informed Consent Form (ICF), subject information sheet, subject recruitment procedures 
(e.g., advertisements), written information to be provided to the subjects, available safety 
information, the Principal Investigator’s curriculum vitae (CV) and/or other evidence of 
qualifications and any other documents requested by the Institutional Review Board (IRB), 
will be submitted for review and approval to the relevant IRB. The IRB shall be appropriately 
constituted and perform its functions in accordance with the International Conference on 
Harmonization (ICH) Tripartite Guidance for Good Clinical Practices (GCPs) and local 
requirements, as applicable. 
The written approval from the IRB will be filed in the Investigator Site File, and a copy will 
be filed in the study master file at the Sponsor or designated organization. The study must not 
start at a site before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IRB. 
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the Principal Investigator. All amendments will be 
submitted to the IRB, and substantial amendments will only be implemented after approval by 
the IRB. For modifications to the protocol which are administrative in nature, or do not affect 
subject risk, the IRB will be notified in writing by the Principal Investigator or designee with 
a copy provided to the Sponsor. 
These requirements for approval should in no way prevent any action from being taken by the 
Principal Investigator or designee or by the Sponsor in order to eliminate immediate hazards 
to the subjects. If such a change to the protocol is felt to be necessary by the Principal 
Investigator or designee, and is implemented for safety reasons, the Sponsor and the IRB 
should be informed immediately. 
The Principal Investigator is responsible for local reporting (e.g., to the IRB) of SAEs that 
occur during the study, according to local regulations. 
Relevant safety information will be submitted to the IRB during the course of the study in 
accordance with national regulations and requirements. 

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Medically qualified study personnel will be available during the study.  
The following IRB will be used: 
CHESAPEAKE IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046-3403, USA 
+1 410.884.2900 
+1 410.884.9190 
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 (World Medical Association, 2013) and is consistent with ICH/GCPs 
applicable regulatory principles. 
The Principal Investigator or designee agrees to conduct the clinical study in compliance with 
the protocol agreed with the Sponsor and approved by the IRB. The Principal Investigator and 
the Sponsor must sign the protocol (and protocol amendments, if applicable) to confirm this 
agreement.  
 
1.3 
Subject Information and Consent 
1.3.1 
Informed Consent Form for Study Participation 
Before or at Visit 1, the Principal Investigator or designee will ensure that each subject is given 
full and adequate oral and written information about the nature, purpose, possible risks and 
benefits of the study, and the Principal Investigator or the designee will answer all questions 
the subject might have to his full satisfaction. The subject will have sufficient time for 
consideration of his participation in the study and will be notified that he is free to discontinue 
his participation at any time.  

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are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
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Once the subject has received all the necessary information, and if he agrees to participate, this 
will be documented in the ICF which includes both the subject information sheet and informed 
consent by the date, and signature of both the subject and the person who conducted the Inform 
Consent discussion during Visit 1. No study-specific procedures will be performed before the 
ICF has been signed and date and time will be recorded. 
The original and completed ICF(s) must be kept by the Principal Investigator and filed in the 
Investigator study file at the site or with the study participant’s files and a copy must be given 
to the study participant. The study participant will be informed that if he discontinues from the 
study, the data collected until the point of discontinuation will be maintained as part of the study 
data and the samples collected prior to discotinuation will be analyzed, unless he refuses it. 
The subject will be informed that any analysis of the data will be covered by data 
confidentiality. 
 
1.3.2 
Amendment to the Informed Consent Form 
If a protocol amendment is required, an amendment may be required to the ICF. If revision of 
the ICF is necessary, the Principal Investigator or designee will, with the support of the 
Sponsor, ensure that the documents have been reviewed and approved by the IRB before study 
participants are required to re-sign and date the ICF.  
 
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 Principal Investigator and designee abide by the principles of the ICH 
guidelines on GCPs. These guidelines apply specifically to pharmaceutical development, but 
nevertheless provide a robust and ethical framework for conducting clinical studies of tobacco 
products. The study will also be conducted in accordance with the general ethical principles 
outlined in the Declaration of Helsinki (World Medical Association, 2013). 

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In addition, the Principal Investigator or designee will carry out the clinical study in accordance 
with applicable national and local laws of the pertinent regulatory authorities. 

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2 
INTRODUCTION 
2.1 
Background 
Tobacco smoke is a complex mixture of chemical compounds that are bound to aerosol 
particles or exist free in a gaseous state. It has been estimated that cigarette smoke has more 
than 6000 chemical compounds from various classes, the majority of which upon combustion 
can transform and have great potential for toxic, harmful, oxidizing, and carcinogenic effects 
(FDA, 2010, 2014). Cigarette smoke has been linked to increased risk of chronic pulmonary 
obstructive disease (COPD), cardiovascular disease, and cancer, which results in more than 
480,000 deaths each year in the United States alone, and 1.2 million deaths annually worldwide 
(CDC, 2015; FDA, 2010). Despite widespread knowledge of the health risk associated with 
cigarette smoking, it is estimated that the prevalence of this habit is in excess of 1 billion people 
worldwide (CDC, 2015).  
Gaseous and particulate constituents of cigarette smoke first interface with the immune system 
at the mucosal surfaces lining the oral cavity, sinuses, and the airways (FDA, 2010; Hecht, 
2003). As the inhaled cigarette smoke moves deeper into the respiratory tract, more soluble 
gases are absorbed and particulates are deposited into the lower airways (Hecht, 2003). The 
carcinogens and toxins produced by cigarette smoke can provoke an array of biological and 
immunological responses in the respiratory tract. With sustained exposure, these inhaled 
constituents can lead to carcinogenesis induction, non-resolving inflammation yet suppressive 
effects on immune cells, mucociliary impairment, and innate and adaptive immune dysfunction 
(Jaspers, 2014; Lee, Taneja, & Vassallo, 2012).  
There are a number of mechanisms involved in protecting the respiratory tract from harmful 
substances such as cigarette smoke. Beating, synchronized cilia function is the first line of 
innate host defense by propelling foreign inhaled substances, microbes, and/or mucus, out of 
the upper airways via nasal mucociliary clearance (NMC) (Fahy & Dickey, 2010; Shah, Ben-
Shahar, Moninger, Kline, & Welsh, 2009). Several factors affect NMC including aging, 
temperature, mucus pH, drugs, smoking, body mass index (BMI), allergic rhinitis, and sinusitis 

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(Baby, Muthu, Johnson, & Kannan, 2014; Özler, Şimşek, Akbay, & Akoğlu, 2014; Ramos et 
al., 2011, Paul 2016, Tamilselvan 2014, Balsamo 2010). A defect or impairment in ciliary 
motility, function, and consequently NMC, can cause increased airway inflammation, lung 
injury, bacterial colonization and eventually airway remodeling (Jain et al. 2012). Patients 
afflicted with diseases including cystic fibrosis (CF) and COPD have been shown to have 
impaired NMC function in their airway (Bhowmik, Chahal, Austin, & Chakravorty; Smaldone 
et al., 1993; Treacy, Tunney, Elborn, & Bradley, 2011). NMC measurement assesses the 
effectiveness of the interaction between cilia and mucus based on the measurement of (1) the 
transport of markers placed on the mucosa and (2) the total nasal clearance time of the 
deposited dose. There are a number of tracer molecules used to measure NMC time including 
saccharin, dye, and vegetable charcoal (Deborah & Prathibha, 2014). NMC strongly correlates 
with ciliary motility and function such that the greater the observed transit time, the further 
that ciliary motility and function is decreased (D. Passàli, Bellussi, & De Seta, 1984; D.  Passàli 
& Bianchini, 1985; D. Passàli, Ferri, Becchini, Passàli, & Bellussi, 1999). Saccharin transit 
time (STT) is an inexpensive, non-invasive reproducible method that has been readily used to 
assess NMC (Stanley et al., 1984; Rutland & Cole, 1981). A positive correlation was observed 
between NMC, as determined by the STT test, and pulmonary clearance, measured by an 
inhaled radiolabelled aerosol (Loebinger, Bilton, & Wilson, 2009; Rutland & Cole, 1981).  
Several authors have reported a decreased NMC in smokers versus non smokers and even 
passive smokers (Stanley et al., 1986, Habesoglu 2012, Utiyama et al., 2016).  Moderate and 
heavy smokers show higher STT results than light smokers and non-smokers (Xavier et al., 
2013). Decreased mucociliary function has been observed in people with moderate and heavy 
cigarette consumption (Proença et al., 2012). Smoking cessation appears to contribute 
favorably to mucociliary clearance (Ramos et al., 2011). 
Proença et al. 2011 have studied the acute and short term effects of smoking on nasal 
mucociliary clearance in current smokers using the STT test immediately after smoking and 8 
hours after the last cigarette. Smokers presented similar STT value immediately after smoking 
(11±6 min; p = 0.87) when compared to STT value in non-smokers’ (10±4 min; mean±standard 
deviation), while the STT value in smokers 8 hours after smoking was significantly longer 

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(16±6 min; p = 0.005 versus non-smokers’ and p = 0.003 versus immediately after smoking), 
(Proença et al., 2011). The alterations of the STT value over time are not fully clear, as was 
demonstrated in the above study where no baseline measurement was reported. Therefore, 
based on this, the need for the present prefatory study and its proposed design is justified. In 
order to better understand the difference in STT over time between smokers and never smokers, 
a never smoker group is added to the study design.  
Additionally, samples from nasal scrapings using two methods will be collected during the 
study from smokers and never smokers. These two methods will be used in this prefatory study 
to identify and standardize the optimal one which results in the highest quantity and quality of 
ribonucleic acid (RNA) for further transcriptomics analysis. The use of multi-omics have been 
used to elucidate mechanistic pathways which are impacted by cigarette smoking. The 
transcriptome of multiple tissues are known to be altered due to cigarette smoke exposure. 
Through targeted transcriptomic analysis from nasal sampling, increased expression and 
identification of antioxidant and xenobiotic genes as well as a wide spectrum of inflammation-
related genes can be characterized. (Martin, Talikka, Hoeng, & Peitsch, 2015; Phillips et al., 
2016; Titz et al., 2016). 
 
2.2 
Purpose of the Study 
This study intends to evaluate the NMC over the course of 12 hours following single use of 
cigarette in smokers, to compare NMC over the course of 12 hours in smokers following single 
use of cigarette relative to never smokers and to examine the relationship between plasma 
nicotine levels and STT value in smokers and never smokers. 
Additionally it also intends to standardize a nasal scraping procedure using two methods with 
a histological assessment of nasal scraping and a RNA quality and quantity evaluation. 
Safety will also be monitored during the study. 
 

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2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
Subjects who participate in this study will benefit from a health check-ups, which may help 
to uncover undiagnosed medical conditions. 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures 
The risk of procedures (e.g., blood samples, nasal scrapes, spirometry) are deemed to be on 
par with procedures routinely performed during normal or extended health examinations by 
the study participant’s health care professional. To monitor study participants for risks 
associated with study procedures after discharge, a follow-up period of 1 day is implemented. 
 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product  
Not applicable.  

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3 
STUDY OBJECTIVES 
3.1 
Primary Objectives and Endpoints 
The primary objectives of this study are: 
1. To evaluate the NMC over the course of 12 hours following single use of cigarette in 
smokers.   
• 
STT value as assessed by STT test at each time point. 
 
2. To compare NMC over the course of 12 hours in smokers following single use of 
cigarette relative to never smokers. 
• 
STT value as assessed by STT test at each time point. 
 
3. To examine the relationship between plasma nicotine levels and STT value in smokers 
and never smokers. 
• 
STT value as assed by the STT test and plasma nicotine levels at each time point. 
 
3.2 
Secondary Objectives and Endpoints 
The secondary objectives of this study are: 
1. To standardize nasal scraping procedure using two methods . 
• 
Collection of nasal epithelium for further histology . 
• 
Evaluation of RNA quality and quantity. 

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2. To monitor the safety during the study. 
• 
Vital signs. 
• 
Adverse events (AE). 
• 
Nasal and throat exam. 
• 
Hematology, clinical chemistry and urine analysis. 
• 
Brief physical examination. 
• 
Concomitant medications. 
 
 
 
 
 
 

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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This will be a single-center study in which 14 healthy adult male study participants, consisting 
of 7 cigarette smokers and 7 never smokers as a control group, will be enrolled. Study 
participants will not be replaced after being enrolled. 
This study will have three visits on three separate days as described in Figure 1.  
At Visit 1 (Screening Visit), study participants will undergo the procedures outlined in 
Appendix A to check eligibility criteria, including providing informed consent, undergoing a 
brief physical examination (including an examination of the head and neck, chest, heart 
(cardiovascular) and abdomen), nasal and throat exam, vital signs, skin prick test (SPT), 
spirometry testing, STT test, exhaled carbon monoxide (eCO) measurements, urine cotinine 
assessment, medical and smoking history and blood and urine collection for medical lab exams.  
Following Visit 1, study participants who pass all of the inclusion criteria and do not present 
any of the exclusion criteria will be asked to return to the clinic for Visit 2.  
During Visit 2, selected inclusion and exclusion criteria will be reassessed to ensure study 
participants are still eligible for enrollment (Appendix A). All study participants will have 
baseline assessments performed (Appendix A), including STT test.  
Study participants will be confined in the clinic from the beginning of Visit 2 until discharge 
at Visit 3. During this confinement period study participants will abstain from drinking any 
alcohol and any drinks containing caffeine.  
Water will be allowed ad libitum except during STT tests. Throughout the study, standardized 
meals and beverages will be served. Meals will be the same in content and quantity during 
each confinement period. No food or drinks will be allowed during STT tests. 
No cigarettes are to be smoked from midnight (± 1 hour) between Visit 2 and Visit 3 until 8 
am on the day of Visit 3. On the day of Visit 3, at least 8 hours after last cigarette, cigarette 
smokers, who want to smoke,  will have a cigarette at 8 am±30 minutes and then have the STT 

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test performed immediately after smoking (5-10 minutes post T0). T0 will be defined as the 
start of cigarette smoking for smokers (time point of first product use during study day). T0 
should be the same for all smokers within an acceptable time window of 1 hour. Never smokers 
will also have the STT test performed in the morning  at 8 am ± 30 minutes (designated T0 ± 
30 minutes). All study participants (smokers and never smokers) will then have the STT test 
performed at 4h (may be performed until 4h30 min), 8h (may be performed until 8h30 min), 
and 12h (may be performed until 12h30 min) post T0, ensuring at least approximately 4 hours 
between the beginning of each STT test. The participant will be asked to confirm he can no 
longer feel the sweet taste. Study participants will drink a glass of water (approximately 240 
mL) before STT tests are performed. 
Samples for plasma nicotine assessment will be collected at approximately the same time 
points that STT test is performed at T0 , 4h (may be performed until 4h30 min), 8h (may be 
performed until 8h30 min), and 12h (may be performed until 12h30 min) post T0.  
Nasal scraping of the inferior turbinate of both nostrils will be performed on all 14 study 
participants at the end of Visit 3, after all other clinic assessments, except the brief physical 
examination which will be done after the nasal scraping:  
 For 4 study participants, the nasal scraping (left nostril with method 1, right with 
method 2) will be performed and samples collected for subsequent histological 
assessment.  
 For the 10 remaining study participants, 5 will undergo nasal scraping using method 1, 
and 5 using method 2. For all 10 study participants, cells from one nostril will be added 
into one buffer, cells from the other nostril into a second buffer. Samples will be 
collected for subsequent RNA quantity and quality analysis. 
Full procedure is described in the “Method establishment to obtain human nasal epithelial 
sample using the Rhino-probe”. 
Upon conclusion of all clinic assessments, at the time of discharge on Visit 3, the Principal 
Investigator or designee will perform a brief physical examination on the study participant. 
From the discharge on Visit 3, the study participant will enter a 1-day Safety Follow-Up Period 
during which spontaneously reported new AEs/serious AEs (SAEs) will be recorded, and the 
active follow-up of ongoing AEs/SAEs will be done by the site.  

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Any non-serious AE that is ongoing during the Safety Follow-Up Period will be actively 
followed-up by the Principal Investigator or designee during that period until it has been 
resolved, stabilized (i.e., no worsening of the condition), an acceptable explanation has been 
found (e.g., a chronic condition) or lost to follow up. 
At the end of the Safety Follow-Up Period, all ongoing non-serious AEs will be documented 
as “ongoing” and no follow-up information will be sought for on them anymore by the 
Principal Investigator or designee. At that point, the Investigator will assess whether the subject 
should be referred to his/her General Practicioner to have their ongoing AEs addressed 
accordingly. 
All SAEs will be followed up by the Investigator or designee, despite their continuation after 
the end of the Safety Follow-Up Period, until their resolution, stabilization (i.e., no worsening 
of the condition), or an acceptable explanation has been found (e.g., a chronic condition). 
Subjects who are discontinued from the study because of an AE will undergo the early 
termination procedures as soon as practical after the day of discontinuation and will enter the 
period of safety follow-up.  
The end of the study for a study participant is defined as the date of discharge on Visit 3 plus 
one day of Safety Follow-Up Period or the date of early termination of the study participant 
plus one day of Safety Follow-Up Period.  
The end of the entire study is defined as the end of the Safety Follow-Up Period of the last 
study participant. 
  

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Figure 1 
Study Flow Chart  
4.2 
Rationale for Study Design  
Several authors have reported a decreased NMC in smokers versus non smokers and even 
passive smokers (Stanley et al., 1986, Habesoglu 2012, Utiyama et al., 2016).  Moderate and 
heavy smokers show higher STT results than light smokers and non-smokers (Xavier et al., 
2013). Decreased mucociliary function was observed in people with moderate and heavy 
cigarette consumption (Proença et al. 2012). Smoking cessation appears to contribute favorably 
to mucociliary clearance (Ramos et al. 2011). 
Proença et al. 2011 have studied the acute and short term effects of smoking on nasal 
mucociliary clearance in current smokers using the STT test immediately after smoking and 8 
hours after the last cigarette.  

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When compared to STT in non-smokers’ (10±4 min; mean±standard deviation), smokers presented 
similar STT immediately after smoking (11±6 min; p = 0.87) and slower STT 8 hours after smoking 
(16±6 min; p = 0.005 versus non-smokers’ and p = 0.003 versus immediately after smoking) 
(Proença et al., 2011). The alterations of the STT values over time is not fully clear as in the 
above study no baseline measurement has been reported and which establishes the need for the 
present prefatory study and justifies its proposed design. In order to better understand the 
difference in STT over time between smokers and never smokers, a never smoker group is 
added to the study design.  
 
Additionally, samples from nasal scrapings using two methods will be collected during the 
study from smokers and never smokers. These two methods will be used in this prefatory study 
to identify and standardize the optimal one which results in the highest quantity and quality of 
ribonucleic acid (RNA) for further transcriptomics analysis. The use of multi-omics have been 
used to elucidate mechanistic pathways which are impacted by cigarette smoking. The 
transcriptome of multiple tissues are known to be altered due to cigarette smoke exposure. 
Through targeted transcriptomic analysis from nasal sampling, increased expression and 
identification of antioxidant and xenobiotic genes as well as a wide spectrum of inflammation-
related genes can be characterized. (Martin, Talikka, Hoeng, & Peitsch, 2015; Phillips et al., 
2016; Titz et al., 2016). 
It was decided to focus the present study on a male population only to minimize the variability 
between genders. 
4.3 
Appropriateness of Measurements 
STT measurements are an easy and effective method to measure NMC (Rutland and Cole 
1981), whereby a 1-2 mm particle of saccharin is placed on the inferior nasal turbinate, 1 cm 
from the anterior end. The study participant will remain sitting for the duration of the test 
without speaking or engaging in any other activities that would disrupt the evaluation. The 
study participant will report when saccharin can be tasted and the time elapsed will be recorded 
and used as a measure of NMC (Rutland and Cole 1981). NMC strongly correlates with ciliary 
motility and function such that the greater the observed transit time, the further that ciliary 
motility and function is decreased (D. Passàli, Bellussi, & De Seta, 1984; D.  Passàli & 
Bianchini, 1985; D. Passàli, Ferri, Becchini, Passàli, & Bellussi, 1999). The STT test has been 

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considered a “gold-standard” procedure for assessing NMC function as it permits large-scale 
assessment outside of specialized respiratory centres. 
All laboratory measures utilized for this study are validated and are appropriate for the study 
assessments. 
Since the test for nicotine concentration is highly sensitive, all study personnel who will be 
collecting blood must be non-smokers. 
4.4 
Study Duration 
The planned maximum study duration for a single study participant from Screening through 
completion of study will be 33 days. 
The estimated maximum study duration for the whole Study from screening through 
completion will be 35 days. 
 
 

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5 
STUDY POPULATION 
This study will enroll 14 study participants: 7 cigarette smokers and 7 never smokers. 
The subjects will be divided in two groups: 
Group 1 – 7 cigarette smokers 
Group 2 – 7 never smokers 
5.1 
Selection of Study Population 
An overview of the timing for assessment of each inclusion and exclusion criteria can be found 
in the Appendix B – Inclusion and Exclusion Criteria Assessment 
5.1.1 
Inclusion Criteria 
Subjects who meet all the following inclusion criteria can be enrolled into the study: 
1. Informed of the nature of the study and have agreed to and are able to read, review, and 
sign the informed consent form (ICF) prior to Screening. The subject must be willing to 
comply with the study procedures described in the informed consent. The informed consent 
document will be written in English, therefore the volunteer must have the ability to read 
and communicate in English. 
2. Male subject aged ≥25 to ≤45 years old. 
3. BMI between 18.0 kg/m2 to 32.0 kg/m2, inclusive. 
4. Judged by the Principal Investigator or designee to be in good health as documented by the 
medical history, physical examination, vital sign assessments, clinical laboratory 
assessments, and by general observations.  
5. Belong to one of the following two groups: 
a. Non-menthol cigarette smoker (meets all of the following criteria at Visit 1 and 
at Visit 2): 

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i. A positive urine cotinine test (≥200ng/mL). 
ii. Smoked at least 20 cigarettes per day for at least the past 5 years.  
iii. eCO levels >10 parts per million (ppm). 
iv. No plans to quit smoking in the next 3 months. 
b. Never smoker (meets all of the following criteria at Visit 1 and at Visit 2): 
i. Subject who has smoked less than 100 cigarettes throughout their 
lifetime and no cigarettes in the past 3 years. 
ii. A negative urine cotinine test (<200 ng/mL). 
iii. eCO levels ≤ 5 ppm. 
6. Completed the Screening process within 30 days prior to Visit 2.  
7. Availability for the entire study period and willingness to comply with study procedures, 
including smoking interruptions, as evidenced by a signed ICF and at Visit 2. 
 
5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the 
study: 
1. As per the Principal Investigator or designee’s judgment, the subject cannot participate in 
the study for any reason (e.g., medical, psychiatric, and/or social reason). 
2. Subject is legally incompetent, or physically or mentally incapable of giving consent (e.g., 
emergency situation, under guardianship, prisoners, or subjects who are involuntarily 
incarcerated). 
3. Presence of confounding allergies including allergic rhinitis and non-allergic rhinitis 
during the course of the study based on medical history and SPT. 
4. Clinical significant abnormality on their nasal and throat exam, at the discretion of the 
Principal Investigator or designee at Visit 1 and/or at Visit 2. 

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5. Cigarette smoker who smoke/use any tobacco or nicotine products, such as cigars, pipe, 
menthol cigarettes or electronic cigarettes in the previous 3 months, as self-reported at Visit 
1 or Visit 2. 
6. Never smoker who smoke/use any tobacco or nicotine products, such as cigars, pipe, 
menthol cigarettes or electronic cigarettes in the previous 3 years, as self-reported at Visit 
1 or Visit 2. 
7. Cigarette smokers who state they will be unable to abstain from smoking for up to 24 hours. 
8. Inability to taste sweet within 60 minutes in the STT test. 
9. Subjects who routinely use or who have used in the previous 4 weeks nasal sprays, inhalers 
or other nasal products, such as nasal irrigation (for example, Neti Pot) prior to Visit 1 
and/or Visit 2. 
10. Subjects who have taken any of the following medication without the indicated minimum 
washout period: 
Table 1 - Prohibited medication. 
Prohibited Medication 
Restriction period  
(with Principal Investigator 
or designee discretion) 
Short-acting antihistamines including intranasal antihistamines  
3 days before Visit 1 until 
Visit 2 
Long-acting antihistamines (i.e. Loratadine, Desloratadine) 
7 days before Visit 1 until 
Visit 2 
Over-the-counter cough and cold preparations or sleep aids 
containing antihistamines 
3 days before Visit 1 until 
Visit 2 
Leukotriene inhibitors 
14 days before Visit 1 until 
Visit 2 
Oral or intra-articular steroid 
30 days before Visit 1 until 
Visit 2 
Intranasal and inhaled corticosteroids 
14 days before Visit 1 until 
Visit 2 
Use of monoamine oxidase inhibitors 
14 days before Visit 1 until 
Visit 2 
Decongestants  
48 hours before Visit 1 until 
Visit 2 

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Cromolyn products 
14 days before Visit 1 until 
Visit 2 
Beta-adrenergic blockers (i.e. Acebutolol, Atenolol, etc.) 
14 days before Visit 1 until 
Visit 2 
Anticholinergics 
7 days before Visit 1 until Visit 
2 
Herbal or natural product remedies for allergy symptoms 
On the day of Visit 1 until 
Visit 2 
Short-Acting Beta Agonists 
6 hours prior to spirometry 
(except as per protocol before 
spirometry) 
Long-Acting Beta Agonists 
3 days before Visit 1 until Visit 
2 
Phosphodiesterase 5 inhibitors (i.e. Sildenafil, Vardenafil, 
Tadalafil) 
7 days before Visit 1 until Visit 
2 
Amiloride 
3 days before Visit 1 until Visit 
2 
Macrolide antibiotics 
7 days before Visit 1 until Visit 
2 
Guaifenesin 
3 days before Visit 1 until Visit 
2 
Mucolytic agents 
14 days before Visit 1  until 
Visit 2 
Topical menthol products 
14 days before Visit 1  until 
Visit 2 
Topical nasal medication 
4 weeks before Visit 1 until 
Visit 2 
Topical ocular medication 
4 weeks before Visit 1 until 
Visit 2 
Any other medication at the Principal Investigator or designee’s 
discretion that might interfere with the endpoints or procedures. 
As per Principal Investigator 
or designee. 
 
11. Subjects with evidence of COPD, Global Initiative for Chronic Obstructive Lung Disease 
GOLD stage I or greater, and a forced expiratory volume 1 / the forced vital capacity 
ratio (FEV1/FVC ratio) <0.7.  

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12. Any condition the Principal Investigator or designee has cause to believe would interfere 
with the procedures for upper or lower airway function. This could include, but is not 
limited to, nasal/septum deviations, or nasal polyps or nasal allergies which will be 
identified by the Principal Investigator or designee. 
13. Upper or lower respiratory diseases in the 4 weeks prior to Visit 2. 
14. History of nasal or sinus surgery in the 5 years prior to Visit 2. 
15. As per the Principal Investigator or designee’s judgment, the subject has medical 
conditions which require or will require in the course of the study, a medical intervention 
(e.g., start of treatment, surgery, hospitalization) which may interfere with the study 
participation and/or study results. 
16. The subject has a positive alcohol test and/or a history of alcohol abuse that could interfere 
with the subject’s participation in study at Visit 1 or Visit 2.  
17. Positive urine drug screen at Visit 1 or Visit 2. 
18. The subject has positive serology test for human immunodeficiency virus (HIV)1/2, 
Hepatitis B or Hepatitis C. 
19. Subject has donated or been in receipt of whole blood or blood products within 3 months 
prior to Visit 1. 
20. Subject is a current or former employee of the tobacco industry or of their first-degree 
relatives (spouse, legal partner, parent, sibling, and child). 
21. Subject is an employee of the investigational site or any other parties involved in the study 
or of their first-degree relatives (spouse, legal partner, parent, sibling, and child). 
22. Subject has been in receipt of last dose from another clinical study within 3 months prior 
to Visit 1.  
23. Subject has been previously screened in this study. 
 

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5.2 
Discontinuation of Study participants from the Study 
Discontinued study participants will include both study participants who withdraw from the 
study (study participant’s decision) or study participants who are removed from the study by 
the Principal Investigator. A study participant can only be discontinued from the study after 
enrollment. 
Study participants will be informed that they are free to withdraw from the study at any time. 
Study participants should be questioned for the reason of premature withdrawal from the study, 
although they are not obliged to disclose it. This needs to be fully documented in the source 
document and case report form (CRF). 
If the study participant withdraws his consent for the study, the Principal Investigator or 
designee needs to document if: 
 The study participants agrees that the data can be used until the time of withdrawal. 
 The study participant agrees to have his samples collected until the time of 
withdrawal to be analyzed. 
This information needs to be fully documented in the source document and CRF.  
When a study participant is discontinued from the study, he will be asked to perform the 
examination procedure planned in Section 9.4 as soon as possible after the time of 
discontinuation, unless the study participant is not willing to perform any additional 
assessment.  
Study participants discontinued from the study cannot re-enter the study. 
Study participants must be discontinued from the study for any of the following reasons: 
 Withdrawal of informed consent. 
 Any AE or condition (including clinically relevant changes in a laboratory parameter) 
which at the discretion of the Principal Investigator no longer justifies the study 
participant’s participation in this study. 
 The Sponsor or the Principal Investigator terminates the study. If the Sponsor or the 
Principal Investigator decides to prematurely terminate the study, the study participant 

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will be promptly informed. The Principal Investigator should report the fact and the 
reason of termination in writing to the IRB. 
 Discontinuation is considered to be in the best interest for the study participant himself 
or for other study participants participating to the study. 
Study participants may be discontinued from the study for any of the following reasons: 
 Non-compliance to the study procedures based on the judgment of the Principal 
Investigator. 
Study participants discontinued prematurely after enrollment will not be replaced and will not 
be allowed to re-enter the study. All study participant discontinuations must be documented 
properly in the source document and in the CRF. 
 
5.3 
Lost to Follow-up 
Not applicable. 
 
5.4 
Violation of Selection Criteria 
Study participants who are eligible at Screening (Visit 1), but who do not meet the entry criteria 
at Visit 2, will be considered as a screen failure until enrollment is completed.  
If a violation of selection criteria after enrollment is detected, the study participant may be 
discontinued from the study at the discretion of the Principal Investigator or designee. If study 
participants are not yet enrolled, they can be replaced. If study participants are enrolled, and 
the Principal Investigator decides that they should be discontinued from the study, they will 
not be replaced. 
 

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6 
INVESTIGATIONAL PRODUCTS 
Not applicable.  
 
6.1 
Restrictions 
6.1.1 
 Smoking Restrictions 
Study participants will be allowed to use their own brand of cigarettes.  
After enrollment, and between Visit 2 and Visit 3, the smokers group (group 1) will abstain 
from smoking for a period of 8 hours. At Visit 3, after the 8 hour smoking abstinence period, 
the smokers will smoke 1 single cigarette. 
The subjects enrolled in the never smokers group (group 2) will not be allowed to smoke during 
the entire study duration.  
For both groups 1 and 2, there will be no smoking restriction after the discharge at Visit 3 and 
during the 1 day follow-up period.  
 
6.1.2 
Dietary Restrictions 
Study participants are not allowed to bring their own food or beverages to the investigational 
site. No food or drinks will be allowed during the conduct of the STT test except for the 
required glass of water (approximately 240 mL) before conducting the STT tests. Meals will 
be served according to the schedules provided in Section 9. Additional light snacks, fruits, and 
raw vegetables may be distributed to the study participants (except during STT tests). 
Consumption of water is allowed as desired (except during STT tests as described above). 
 

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6.2 
Concomitant Medication 
Prohibited medication is described under exclusion criteria 10 (Table 1, depicted below). 
Table 1 - Prohibited medication. 
Prohibited Medication 
Restriction period  
(with Principal Investigator 
or designee discretion) 
Short-acting antihistamines including intranasal antihistamines  
3 days before Visit 1 until 
Visit 2 
Long-acting antihistamines (i.e. Loratadine, Desloratadine) 
7 days before Visit 1 until 
Visit 2 
Over-the-counter cough and cold preparations or sleep aids 
containing antihistamines 
3 days before Visit 1 until 
Visit 2 
Leukotriene inhibitors 
14 days before Visit 1 until 
Visit 2 
Oral or intra-articular steroid 
30 days before Visit 1 until 
Visit 2 
Intranasal and inhaled corticosteroids 
14 days before Visit 1 until 
Visit 2 
Use of monoamine oxidase inhibitors 
14 days before Visit 1 until 
Visit 2 
Decongestants  
48 hours before Visit until 
Visit 2 
Cromolyn products 
14 days before Visit 1 until 
Visit 2 
Beta-adrenergic blockers (i.e. Acebutolol, Atenolol, etc.) 
14 days before Visit until Visit 
2 
Anticholinergics 
7 days before Visit 1 until Visit 
2 
Herbal or natural product remedies for allergy symptoms 
On the day of Visit 1 until 
Visit 2 
Short-Acting Beta Agonists 
6 hours prior to spirometry 
(except as per protocol before 
spirometry) 

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Long-Acting Beta Agonists 
3 days before Visit 1 until Visit 
2 
Phosphodiesterase 5 inhibitors (i.e. Sildenafil, Vardenafil, 
Tadalafil) 
7 days before Visit 1 until Visit 
2 
Amiloride 
3 days before Visit 1 until Visit 
2 
Macrolide antibiotics 
7 days before Visit 1 until Visit 
2 
Guaifenesin 
3 days before Visit 1 until Visit 
2 
Mucolytic agents 
14 days before Visit 1  until 
Visit 2 
Topical menthol products 
14 days before Visit 1  until 
Visit 2 
Topical nasal medication 
4 weeks before Visit 1 until 
Visit 2 
Topical ocular medication 
4 weeks before Visit 1 until 
Visit 2 
Any other medication at the Principal Investigator or designee’s 
discretion that might interfere with the endpoints or procedures. 
As per Principal Investigator 
or designee. 
Note: drugs included in the list above cannot be used during the study, from enrollment until 
discharge on Visit 3. In case the subjects use any of the above mentioned drugs, that use will 
be recorded in the eCRF and the Principal Investigator will decide on the subject permanence 
on the study.  

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7 
STUDY PROCEDURES 
Personnel performing study assessments must have the appropriate training and full 
documentation. An overview of all study assessments is shown in the Schedule of Events 
(Appendix A). In this section, only the expected/planned timepoints for the various 
assessments are described. As not all study participants can undergo a procedure at the same 
time, adequate time windows are given for each study procedure and each timepoint (Section 
9). Site personnel will adhere to the internal SOPs for all activities. Appropriate medical advice 
will be provided to the study participant in case of any medical findings requiring health care. 
 
7.1 
Informed Consent 
Prior any study assessments is performed, the subject will be asked to provide his written 
consent to participate to the study (ICF/subject information sheet for study participation) 
(Section 1.3). All assessments must start after the time of ICF signature by the subject for study 
participation. 
7.2 
Clinical Assessments 
Any clinically relevant medical condition detected at Visit 1 has to be documented as a 
concomitant disease. This also applies to clinically relevant findings in laboratory values and 
vital signs detected at Visit 1. Any untoward medical occurrence in a study participant detected 
during the study which was not present at Visit 1 must be documented as an AE. Worsening 
of a pre-existing condition from Visit 1 onwards will also be documented as an AE. If a 
clinically relevant finding is detected at Visit 1, the Principal Investigator or designee will need 
to check if the inclusion criterion No. 4 is still fulfilled. 
The results of the clinical assessments described in this section will be recorded in the CRF. 
Any abnormalities or deviations outside the normal ranges for any clinical testing (laboratory 
tests, etc.) can be repeated at the discretion of the Principal Investigator or designee and judged 
to be not clinically significant for study participation. Any abnormalities or deviations outside 

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the normal range for vital signs can be repeated by clinical staff and judged by the Principal 
Investigator or designee to be not clinically significant for study participation. 
 
7.2.1 
Demographic Data 
See Appendix A - Schedule of Events for the timepoints of assessment. Demographic data 
(sex, age, and ethnicity) will be recorded. 
7.2.2 
Identification of the Current Cigarette Brand 
Information on the current cigarette brand will be collected in the smoking history. 
7.2.3 
Questions on Smoking History/Habits and Intention to Quit Smoking.  
Study participants will be asked the following questions about their smoking history and habits:  
1. Have you ever smoked 100 cigarettes or more in your life) (yes/no) 
If answer is Yes, move to question 2. If answer is No, move to question 8. 
2. What brand of cigarettes do you smoke (free text) 
3. Are you planning to quit smoking in the next 3 months? (yes/no) 
4. Have you smoked at least 20 cigarettes per day for at least the past 5 consecutive years? 
(yes/no) 
5. How many years have you smoked cigarettes in your entire life? (numeric response, 2 
digits) 
a. On average, how many cigarettes per day have you smoked during these 
years? (numeric response, 2 digits) 
6. When you smoke cigarettes, do you mostly exhale smoke through the nose? (yes/no) 
7. Have you used any of the following tobacco/nicotine containing products over the last 
3 months? 
 
Yes 
No 
a. E-cigarette 
 
 
b. Cigar 
 
 

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c. Pipe or Hookah 
 
 
d. Snuff or chewing tobacco 
 
 
a. Nicotine products to help you quit smoking (patch, 
gum, …) 
 
 
a. Other 
 
 
 
8. Have you smoked any cigarettes in the past 3 years? (yes/no) 
9. Have you used any of the following tobacco/nicotine containing products over the last 
3 years? 
 
Yes 
No 
a. E-cigarette 
 
 
b. Cigar 
 
 
c. Pipe or Hookah 
 
 
d. Snuff or chewing tobacco 
 
 
a. Nicotine products to help you quit smoking (patch, 
gum, …) 
 
 
a. Other 
 
 
 
This self-reported cigarette daily consumption will be used to assess eligibility. 
7.2.4 
Medical History, Concomitant Disease, Previous and Ongoing Medications 
Relevant medical history will be documented at the Screening Visit. Medical history is defined 
as any condition that started and ended prior to the Screening Visit. Any concomitant disease 
will be documented at the Screening Visit. A concomitant disease is defined as any condition 
that started before and was going on at the time of ICF signature.  
All medication taken 30 days prior to Visit 1 and all concomitant medication taken during the 
study will be documented in the source documentation and recorded in the CRF. Medication 
which was started prior to Visit 1 and which is still being taken by the study participant during 
the study as well as medication that is initiated after Visit 1 will be considered as a concomitant 

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medication. Medication initiated after Visit 1 is also referred to as concomitant medication. 
This applies to both prescription and over-the-counter products. 
Records of medication taken include the drug name (preferably both generic and trade name), 
route of administration (e.g., oral, intravenous), total daily dose/unit (e.g., expressed in mg, 
mL or international units, IU), indication, the start and if applicable, the stop date (day, month 
and year). Any therapy changes (including changes of regimen) during the study have to be 
documented. Any concomitant medication that is still being taken by the study participant at 
the EOS will be recorded in the CRF. 
 
7.2.5 
Brief physical examination and nasal and throat exam. 
See Appendix A - Schedule of Events for the timepoints of assessment. A brief physical 
examination (including an examination of the head and neck, chest, heart (cardiovascular) and 
abdomen), and a nasal and throat exam, will be performed at Screening and at study discharge 
or at early termination. Additional physical examinations may be performed throughout the 
study as judged by the Principal Investigator or designee. 
 
7.2.6 
Body Height and Weight  
See Appendix A - Schedule of Events for the timepoints of assessment. Body weight and height 
will be measured.  
Body mass index (BMI) will be calculated from the body weight and height using the following 
formula: 
BMI =  
weight in kilograms 
————————     ( kg/m² ) 
height in meters² 
 
At Visit 1, BMI will be calculated from the height and weight recorded at Visit 1.  

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7.2.7 
Vital Signs 
See Appendix A - Schedule of Events for the timepoints of assessment. Systolic and diastolic 
blood pressure, pulse rate and respiratory rate will be measured at each visit. All measurements 
will be made according to the latest version of SOP titled Vital Signs Measurement.  
 
7.2.8 
Other Clinical Assessments 
7.2.8.1 
Spirometry post-bronchodilator 
See Appendix A - Schedule of Events for the timepoints of assessment. 
Spirometry post-bronchodilator testing is mandatory during the screening for all study 
participants.  
Spirometry post-bronchodilator testing will be performed in accordance with the latest version 
of SOP titled Spirometry, latest version of SOP titled Reversibility testing and also according 
to the American Thoracic Society (ATS) recommendations. (Miller et al., 2005) 
Bronchodilator Dosing 
1. Bronchodilator dosing should be performed after baseline spirometry has been 
completed following latest version of SOP and also according to the ATS 
recommendations. (Miller et al., 2005) 
2. The chosen bronchodilator will be Salbutamol and the selected dose will be 90 µg by 
using a metered dose inhaler (MDI). The MDI should be primed according to the 
manufacturer’s instructions. 

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3. Four separate doses (one puff) of the inhaled bronchodilator will be administered by 
MDI in one long, slow breath to total lung capacity (TLC).  
4. The doses should occur approximately 30 seconds apart using a spacer.  
5. Each inhaled dose of the inhaled bronchodilator should be held by the study participant 
for 5-10 seconds. 
10 to 15 minutes after the inhaled bronchodilator is given, spirometry maneuvers should be 
initiated following latest version of SOP CO-038 and also according to the ATS 
recommendations. (Miller et al., 2005).  
The doses, the number of sprays administered and the interval period between administration 
of the bronchodilator and the assessment, will be recorded on dedicated log.  
7.2.8.2 
Drug screening  and alcohol breath test 
See Appendix A - Schedule of Events for the timepoints of assessment. All study participants 
will undergo a drug screen and an alcohol breathalyzer test on Visit 1 and Visit 2.  
7.2.8.3 
Exhaled carbon monoxide (eCO) 
See Appendix A - Schedule of Events for the timepoints of assessment. An eCO measurement 
will be performed using a carbon monoxide breath monitor on Visit 1 and Visit 2. For this 
procedure, study participants must first inhale fully and exhale steadily into the carbon 
monoxide breath monitor for at least 10 seconds. 
7.2.8.4 
Skin prick test (SPT) 
See Appendix A - Schedule of Events for the timepoints of assessment. SPT will be carried 
out according to applicable SOP using the Test Applicator Application and a standard panel of 
allergens, including seasonal allergens such as major trees, grass, ragweed and perennial 
allergens including cat, dog and dust mite will be tested. 

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7.2.8.5 
Urine cotinine  
See Appendix A - Schedule of Events for the timepoints of assessment. A urine cotinine 
screen will be performed on Visit 1 and Visit 2. 
7.2.8.6 
Plasma nicotine samples 
See Appendix A - Schedule of Events for the timepoints of assessment.  
a) Sample collection 
 1 x 7 mL of blood will be collected at each time point in pre-chilled K3EDTA 
vacutainers.  
 Samples will be sequentially collected by direct venipuncture or catheter and 
processed in a timely manner as per appropriate Analytical Method Information 
Sheet (AMIS).  
 The labels for all biological sample collection and storage containers will contain, 
at a minimum: 
– Subject number 
– Study number 
– Collection date  
– Scheduled collection time (study hour) 
b) Sample processing 
 Samples will be cooled in an ice bath or cooling device until processed by 
centrifuging at approximately 3000 rpm (+/- 50 rpm) at 4C (± 4C) for 15 minutes 
and then placed into an ice bath or cooling device. Samples that are disturbed during 
the sampling process will be re-spun under the same conditions in an attempt to 
obtain the maximum amount of plasma from each sample.  
 The time between blood collection and placement in the centrifuge will not exceed 
30 minutes (+/- 15 mins). 

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 Plasma will be evenly divided and transferred into duplicate 5 mL polypropylene 
tubes and maintained in the ice bath or cooling device. 
 A minimum of 1.5 mL of plasma is required for each aliquot. 
 Samples will then be stored at approximately -20C (±10C) until shipment to the 
bioanalytical laboratory. 
 The time between the start of centrifugation and placement in freezer will not 
exceed 1 hour (+/- 15 mins). 
 In cases where the volume of plasma harvested from the blood sample is not 
sufficient to meet the minimum volume requirement as indicated by the 
bioanalytical facility, the first polypropylene tube will be filled to meet the 
minimum volume requirement, and any remaining plasma will be transferred to the 
second polypropylene tube. 
c) Sample shipment 
 The clinical staff will inventory the samples for Group 1 (smokers) and Group 2 
(never smokers) which are to be shipped to the bioanalytical laboratory. Each 
shipment will contain a complete set of samples for each group. The complete set 
of samples for Group 1 and 2 will be sent first. The second set of samples for Group 
1 and 2 will not be shipped until the status of the first shipment is determined. The 
inventory record will accompany the plasma samples as per SOPs. 
 The samples will be packed in ample dry ice within a Styrofoam container to ensure 
the samples will remain frozen for at least 72 hours and shipped via express delivery 
to the bioanalytical facility. Temperature during shipment is recommended to be 
monitored, using appropriate devices for the shipment. Written notification of 
sample shipment will be communicated to the bioanalytical facility and Sponsor. 
The samples will be tracked to ensure arrival in a safe and timely manner. 
 The shipment will be accompanied by logs identifying the: 
study number, protocol number, number of subjects, number of samples included 
in the shipment and sample collection log sheets. 

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– Documentation noting the conditions of the samples upon arrival at the 
bioanalytical laboratory and whether the amount of dry ice remaining is 
adequate or inadequate will be returned to the clinic. 
– Temperature during shipment is recommended to be monitored, using 
appropriate devices for the shipment. 
 The samples will be shipped to: 
 
  
 
Tel: 
 
Fax: 
 
Email: 
 
 
  
  
 
d) Bioanalytical sample analysis 
 The Nicotine plasma concentrations will be measured using validated LC/MS/MS 
bioanalytical method and according to the Sannova Analytical Inc’s Standard 
Operating Procedures and FDA guidelines and applicable regulatory requirements. 
7.2.8.7 
Saccharin transit time test 
See Appendix A - Schedule of Events for the timepoints of assessment. NMC rate will be 
assessed using saccharin transit time. Before performing the test, each study study participant 
will spend approximately 15 minutes acclimatizing to the environment of the clinic. A 1-2 mm 
particle of saccharin will be placed under direct vision, approximately 1 cm behind the anterior 
end of the inferior turbinate. The position of the study participant’s head should be flexed 
approximately 10° by visual assessment. The study participant will be instructed not to sniff, 
sneeze, cough, eat or drink and instructed to remain in a seated position for the duration of the 
test. If possible, the study participant will also be instructed not to speak or engage in any other 
activities that would disrupt the evaluation. The saccharin transit time will be determined as 

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the elapsed time in minutes and seconds from placement of the saccharin until the time the 
study participant perceives a sweet taste.  
In case there is no response, the test will be terminated after 60 minutes. The study participant 
will then have a direct application of saccharin on their tongue to ensure that they can taste the 
saccharin. 
 
7.2.8.8 
Nasal scraping, sical assessment and biological specimen collections for further 
analysis 
See Appendix A - Schedule of Events for the timepoints of assessment.  
Nasal scraping of the inferior turbinate of both nostrils will be performed on all 14 study 
participants as described in the separate document “Method establishment to obtain human nasal 
epithelial sample using the Rhino-probe”.  
For 4 study participants, nasal scraping (left nostril with method 1, right with method 2) will 
be performed and cell samples will be collected, processed, appropriately labeled and shipped 
by the study site as per the “Method establishment to obtain human nasal epithelial sample 
using the Rhino-probe” to the appropriate laboratory for further histological assessment.  
For the 10 remaining study participants, 5 will undergo nasal scraping using method 1, and 5 
using method 2. For all 10 study participants, cell sample from one nostril will be added into 
one buffer and cell sample from the other nostril into a second buffer. Samples will be 
collected, processed, appropriately labeled and shipped by the study site as per the “Method 
establishment to obtain human nasal epithelial sample using the Rhino-probe” to the 
appropriate laboratory for subsequent RNA quantity and quality analysis. 
RNA quantity and quality will be assessed  as per the Sponsor internal laboratory SOPs. RNA 
from the nasal sample will be extracted. Then a quantification step will occur using a Nanodrop 
1000 instrument (TermoFisher scientific). 
The quality will be assessed by using a  Bioanlayzer 2100 (Agilent Technologies): the 
Bioanalyzer delivers a mark from 1 to 10 (10 is the best) to give an idea of the quality and 
integrity of the RNA (RIN value stands for RNA integrity Number).  
 

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7.3 
Laboratory Assessments 
7.3.1 
Hematology, clinical chemistry, urine analysis and serology 
For hematology, clinical chemistry and virology, up to 22.5 mL of blood per assessment will 
be needed. The following parameters will be measured: 
The blood samples will be sent to LabCorp Raritan for analysis.  
A labeling system will be devised such that each sample is distinguishable from all others. 
Each collection label will contain the following information: 1) study protocol number, 2) 
sample type, 3) study participant number, and 4) date and time of collection. 
 
Table 2 - Hematology and clinical chemistry parameters  
Hematology 
Clinical Chemistry 
 Hematocrit 
 Hemoglobin 
 Mean corpuscular hemoglobin (MCH) 
 Mean corpuscular hemoglobin concentration (MCHC) 
 Mean corpuscular volume (MCV) 
 Platelet count 
 Red blood cell (RBC) count  
 White blood cell (WBC) count 
 Differential WBC count:  
 
Neutrophils 
 
Basophils  
 
Eosinophils  
 
Lymphocytes 
 
Monocytes 
 
 Albumin 
 Total protein 
 Alkaline phosphatase (AP) 
 Alanine aminotransferase (ALT) 
 Aspartate aminotransferase (AST) 
 Blood urea nitrogen (BUN) 
 Creatinine 
 Fasting Glucose 
 Fibrinogen 
 Gamma-glutamyl transferase (GGT) 
 Lactate dehydrogenase (LDH) 
 Potassium  
 Sodium 
 Total and direct bilirubin 
 Total cholesterol 
 Triglycerides 
 

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The following parameters will be analyzed semi-quantitatively in urine: 
 pH 
 Bilirubin 
 Glucose 
 Nitrite 
 Red blood cell traces 
 Protein 
 Specific gravity 
 
A test for Hepatitis B surface antigen, hepatitis C virus and human immunodeficiency virus 
(anti-HIV1/2) will be done at Visit 1. 
 
7.4 
Volume of blood sample 
After enrollment, a total of four (4) blood samples (28 mL total volume) will be collected for 
nicotine analysis.  
A total of 50.5 mL of blood will be collected for each subject. 

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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. 
8 
ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
For the purpose of this study an AE is defined as any untoward medical occurrence that may present 
itself during the conduct of a study and which may or may not have a causal relationship with the 
study procedures. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease.  
8.1.2 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an AE 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. 
• 
Is an important medical event. 
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. 
"Life-threatening" means that the subject was at immediate risk of death from the event. It 
might have caused death if it had occurred in a more serious form. 

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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. 
8.2 
Assessment of Adverse Events 
The Principal Investigator or designee is responsible for obtaining, assessing and documenting 
all AEs during the study.   
Any exacerbation/worsening of an AE or pre-existing condition shall be evaluated and 
recorded. 
AEs will be coded at the end of the study in the latest Medical Dictionary for Regulatory 
Activities (MedDRA) version, preferred term, available at the time of adverse events coding. 
 
8.2.1 
Collection of Information 
Any non-serious AE occurrence during the study must be documented in the subject’s medical 
records in accordance with the Principal Investigator’s normal clinical practice and on the AE 
page of the CRF. SAEs that occur during the study must be documented in the subject’s 
medical record, on the AE CRF, and on the SAE form. 
AEs should be collected mainly via face-to-face interview with the subject through 
spontaneous reporting or by the use of consistent, open, non-directive questions from the PI(s) 
or designee(s) (e.g., “Have you had any health problems since you were last asked? or “How 
have you been feeling since you were last asked?”). Information recorded will include: 
verbatim description of the AE/SAE, start and stop dates, seriousness, severity (intensity), 
action taken (e.g., whether or not the AE/SAE led to the subject’s discontinuation from the 
study), and outcome (e.g., resolved, stabilized). Information to be recorded about a SAE should 
also include, whenever possible, onset and resolution dates and times, circumstances leading 
up to the event, clinical elements such as clinical course, specific vital signs and test results 
that may explain the pathophysiology of the event, as well as alternative explanations to its 
occurrence. 
Whenever a medically meaningful diagnosis is available to comprise a set of reported signs 
and/or symptoms, it should be preferentially provided as the AE or SAE term, rather than the 
individual signs and/or symptoms. Otherwise, each one of those signs and/or symptoms should 
be reported separately as event terms. 

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The following details will be recorded for AEs: 
 Description of event/symptom 
 Onset date and time of event 
 End date and time of event 
 Severity/intensity rated as follows: 
Mild: 
Awareness of symptoms but easily tolerated, no disruption of 
normal activities. 
Moderate: 
Discomfort enough to cause interference with usual activity. 
Severe: 
Incapacitating with inability to work or do usual activity. 
 Any other action taken (such as concomitant medication, non-drug therapy, both, 
or none) 
 Outcome of AE noted as follows:  
 Fatal 
 Not recovered/not resolved 
 Recovered/resolved 
 Recovered/resolved with sequelae 
 Recovering/resolving 
 Unknown 
8.2.2 
Period of Collection 
Starting from the time when consent was obtained, the PI or designee will record all adverse 
events observed, queried, or spontaneously reported by the study participants. An adverse 
event query will be performed as scheduled as per Principal Investigator or designee’s direction 
at the screening visit and throughout the confinement period and prior to being released from 

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confinement. Study participants will be asked non-leading questions such as “How do you feel 
now?”, “How have you felt since last asked?”, or “Have you taken any medication since last 
asked?” If the presence of any symptom(s), adverse event(s), and/or concomitant medication 
is recorded, the clinical staff may advise the study participants to remain at the clinic site for 
safety reasons until the Principal Investigator or designee decides it is safe for the study 
participants to leave. If the study participant decides to leave despite the advice of the Principal 
Investigator or designee, he/she will be asked to sign a waiver. 
Any non-serious AE that is ongoing during the Safety Follow-Up Period will be actively 
followed-up by the Principal Investigator or designee during that period until it has been 
resolved, stabilized (i.e., no worsening of the condition), or an acceptable explanation has been 
found (e.g., a chronic condition).  
At the end of the Safety Follow-Up Period, all ongoing non-serious AEs will be documented 
as “ongoing” and no follow-up information will be sought for on them anymore by the 
Principal Investigator or designee. At that point, the Investigator will assess whether the subject 
should be referred to his/her General Practicioner to have their ongoing AEs addressed 
accordingly. 
All SAEs will be followed up by the Investigator or designee, despite their continuation after 
the end of the Safety Follow-Up Period, until their resolution, stabilization (i.e., no worsening 
of the condition), or an acceptable explanation has been found (e.g., a chronic condition). 
 
8.2.3 
Intensity of Adverse Event 
Mild: 
Awareness of symptoms but easily tolerated, no disruption of 
normal activities. 
Moderate: 
Discomfort enough to cause interference with usual activity. 
Severe: 
Incapacitating with inability to work or do usual activity. 
Change in severity (intensity) needs to be documented. 

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without the written consent of Philip Morris Products S.A. 
8.2.4 
Relationship to Study Procedures 
This study will not involve administration of any investigational product and therefore, the 
Principal Investigator or designee will make a determination of the relationship of the AE to 
study procedures (not related, related) according to the following guidelines: 
 
 
 
Related: 
 
This relationship suggests a probable temporal sequence of 
the event with study procedure(s) exists. Based upon the 
Principal Investigator, the association of the event with the 
study procedure(s) seems probable and the event is unlikely 
to be attributed to concurrent diseases or other drugs or 
chemicals. 
This relationship suggests a reasonable temporal sequence 
of the event with study procedure(s) exists. Based upon the 
Principal Investigator’s clinical experience, the association 
of the event seems possible. 
Not Related: 
The event has been judged by the Investigator to have no 
relationship to study procedure(s). 
 
8.3 
Reporting of Serious Adverse Events 
Any SAE observed during the period of collection by any of the parties involved in this study 
(including the Investigational site personnel) must be reported by that party within 24 hours of 
first awareness to the sponsor representative. The Sponsor representative will be notified in 
writing (SAE report form) within 24 hours of when a SAE is first recognized or reported by 
contacting: 

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Sponsor representative contacts: 
Company: United BioSource Corporation (UBC) Pharmacovigilance 
Fax: 
 
Email: 
  
 
Subsequently, a summary of the SAE will be sent to the sponsor representative within three 
working days of the original notification. 
The IRB will be notified in writing (e.g., facsimile) within 24 hours (1 working day) of when 
a reportable SAE is first recognized or reported. In addition, a copy of the written confirmation 
or summary of the SAE, as submitted to the sponsor representative, will also be submitted to 
the IRB within 3 working days of when the reportable SAE is first recognized or reported. The 
IRB’s serious and unexpected adverse experience submission form will be completed and 
submitted with the copy of the written confirmation or summary of the SAE. 
As further information regarding an already reported SAE becomes available to any of the 
parties involved in this study, such follow-up information should be reported to the sponsor 
representative and if applicable to the IRB, according to the same timelines described above.  
8.4 
Adverse Events Leading to Discontinuation 
Study participants will be advised they are free to withdraw from the study at any time. Over 
the course of the study, the Investigator and/or the Sponsor may discontinue participation of 
any study participant from the study in the case of unnecessary risk, adverse events, or 
noncompliance. When a study participant withdraws or is discontinued from the study, all 
safety data normally required at the end of the study will be obtained, if possible. 
Subjects who are discontinued from the study because of an AE will undergo the early 
termination procedures as soon as practical after the day of discontinuation and will enter the 
period of safety follow-up. Any AEs or SAEs that are ongoing at the end of the Safety Follow-
up Period will be managed as described in section 8.2.2. 
If, in the opinion of the Investigator, Sponsor, or the IRB, the incidence and severity of AE(s) 
outweighs the benefit of continuing the study, the study may be terminated. In the event this 
course of action is to be pursued, the Investigator will make every attempt to communicate 

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with the Sponsor prior to the decision to develop a complete plan of action and to assess 
outcomes. 
8.5 
 Reporting of Other Events Critical to Safety Evaluations 
8.5.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator and assessed for clinical significance according to its severity. 
The severity of abnormal laboratory test result must be assessed using CTCAE 4.03 grading 
scales. Whenever that grading scheme is not available for the laboratory result of concern, the 
Investigator should assess the severity and the clinical significance of that result using his/her 
medical judgment. 
Abnormal laboratory test results detected at the screening visit whose CTCAE grades are 2 
or higher or still are CTCAE grade 1 and deemed clinically significant are usually 
concomitant disease or a manifestation of one and must be recorded accordingly.  However, 
in some instances, they may be assessed as AEs (and therefore must be handled according to 
the directions in section 8.2) or as manifestations of already reported AEs. This decision will 
require a careful assessment of the abnormal result within the clinical context on a case-by-
case basis and will depend on the Investigator's medical judgment. 
 
Abnormal laboratory test results detected after the screening visit whose CTCAE grades are 
2 or higher or still are CTCAE grade 1 and deemed clinically significant must be either 
recorded as AEs (and handled according to the directions in section 8.2) or linked to a 
concomitant disease or still to an already reported AE.  
The principles for assessing and reporting abnormal laboratory test results, emerging after the 
screening visit, using CTCAE 4.03 grading scales are set up in Table 2: 
Table 3 
 Principles for assessing and reporting abnormal laboratory test results 
Grading 
Clinically 
significant? 
Is it a grade increase 
from previous 
results in study?§ 
Report? 

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Grade 1 
No 
Not applicable 
No 
Grade 1 
Yes 
No 
No* 
Grade 1 
Yes 
Yes 
Yes, as AE or linked 
to an already 
reported AE 
Grade 2 or higher 
No/Yes 
No 
No* 
Grade 2 or higher 
No/Yes 
Yes 
Yes, as AE or linked 
to an already 
reported AE 
* in this situation, this abnormal lab test result is either a manifestation of a concomitant disease or of an already 
reported AE. 
§ grade increase in this context means the value is higher  than the one from the screening visit. 
 
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, the Investigator may consider 
them to be of clinical significance and, if they are, must report them as AEs. 
In general, laboratory values will be recorded as “increased <lab parameter>” or “decreased 
<lab parameter>” to ensure consistency of recording/coding. 

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without the written consent of Philip Morris Products S.A. 
9 
STUDY ACTIVITIES 
9.1 
Screening Visit (Day -30 to -1) 
At Visit 1 (Screening Visit), study participants will undergo the procedures outlined in 
Appendix A to check eligibility criteria, including providing informed consent, undergoing a 
brief physical examination, nasal and throat exam, vital signs, skin prick test (SPT), spirometry 
testing, STT test, exhaled carbon monoxide (eCO) measurements, urine cotinine assessment, 
medical and smoking history and blood and urine collection for medical lab exams. 
Following Visit 1, study participants who pass all of the inclusion criteria and do not present 
any of the exclusion criteria will be asked to return to the clinic for Visit 2. 
9.2 
Confinement Period (Day 1 to Day 2)  
During Visit 2, selected inclusion and exclusion criteria will be reassessed to ensure study 
participants are still eligible for enrollment (Appendix B – Inclusion and Exclusion Criteria 
Assessment). All study participants will have baseline assessments performed (Appendix A), 
including STT test.  
Study participants will be confined in the clinic from the beginning of Visit 2 until discharge 
at Visit 3. During this confinement period study participants will abstain from drinking any 
alcohol and any drinks containing caffeine. Standard meals will be served. Drug restrictions 
applicable to study participant exclusion will also be maintained until the end of the study. 
No cigarettes are to be smoked from midnight (± 1 hour) between Visit 2 and Visit 3 until 8 
am on the day of Visit 3. On the day of Visit 3, at least 8 hours after last cigarette, CC smokers, 
who want to smoke, will have a cigarette at 8 am±30 minutes and then have the STT test 
performed immediately after smoking (5-10 minutes post T0). T0 will be defined as the start of 
cigarette smoking for smokers. T0 should be the same for all smokers within an acceptable 
time window of 1 hour. Never smokers will also have the STT test performed in the morning  
at 8 am ± 30 minutes (designated T0 ± 30 minutes). All study participants (smokers and never 
smokers) will then have the STT test performed at 4h (may be performed until 4h30 min), 8h 
(may be performed until 8h30 min), and 12h (may be performed until 12h30 min) post T0, 
ensuring at least approximately 4 hours between the beginning of each STT test. The 

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participant will be asked to confirm he/she can no longer feel the sweet taste. Study participants 
will drink a glass of water (approximately 240 mL) before STT tests are performed. 
Samples for plasma nicotine assessment will be collected at approximately the same time 
points that STT test is performed at T0, 4h (may be performed until 4h30 min), 8h (may be 
performed until 8h30 min), and 12h (may be performed until 12h30 min) post T0.  
Nasal scraping of the inferior turbinate of both nostrils will be performed on all 14 study 
participants at the end of Visit 3, after all other clinic assessments, following the “Method 
establishment to obtain human nasal epithelial sample using the Rhino-probe”. 
Full procedure will be described in the “Method establishment to obtain human nasal epithelial 
sample using the Rhino-probe”. Upon conclusion of all clinic assessments, at the time of 
Discharge on Visit 3, the Principal Investigator or designee will perform a brief physical 
examination on the study participant. 
9.3 
Safety Follow-Up Period    
From the Discharge on Visit 3, the study participant will enter a 1-day Safety Follow-Up Period 
during which spontaneously reported new AEs/serious AE (SAE)s will be recorded, and the active 
follow-up of ongoing AEs/SAEs will be done by the site with a phone call to the study participant. 
Any non-serious AE that is ongoing during the Safety Follow-Up Period will be actively 
followed-up by the Principal Investigator or designee during that period until it has been 
resolved, stabilized (i.e., no worsening of the condition), or an acceptable explanation has been 
found (e.g., a chronic condition).  
At the end of the Safety Follow-Up Period, all ongoing non-serious AEs will be documented 
as “ongoing” and no follow-up information will be sought for on them anymore by the 
Principal Investigator or designee. At that point, the Investigator will assess whether the subject 
should be referred to his/her General Practicioner to have their ongoing AEs addressed 
accordingly. 
All SAEs will be followed up by the Investigator or designee, despite their continuation after 
the end of the Safety Follow-Up Period, until their resolution, stabilization (i.e., no worsening 
of the condition), or an acceptable explanation has been found (e.g., a chronic condition).  

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The end of the study for a study participant is defined as the date of Discharge on Visit 3 plus 
one day of Safety Follow-Up Period or the date of early termination of the study participant 
plus one day of Safety Follow-Up Period. 
The end of the entire study is defined as the end of the Safety Follow-Up Period of the last 
study participant. 
9.4 
Early Termination Procedures 
If a study participant is discontinued from the study prematurely the following assessments 
will be performed (unless the subject refuses to do so):  
 Adverse event recording 
 Hematology 
 Clinical chemistry 
 Urine analysis 
 Vital signs 
 Brief physical examination.  
 

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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
The CRO (Clinical Research Organization) will designate a “Monitor” who will be responsible 
for the monitoring of the study. Monitoring will be performed according to CRO’s SOPs and 
as per the agreed Monitoring Plan with the Sponsor. 
The Monitor will be responsible for monitoring the study to assess compliance with the 
protocol, adherence to regulatory requirements, the protection of the rights and well-being of 
the study participants and the accuracy and completeness of reported study data recorded on 
the source documentation. 
The Principal Investigator shall access source data for the Monitor in order that entries in the 
CRFs may be verified. The Principal Investigator, as part of his/her responsibilities, is expected 
to ensure that the study adheres to GCP requirements. 
 
10.2 Training of Collaborators 
A pre-study meeting will be conducted before site initiation. The Sponsor or its authorized 
representative will discuss the requirements of the Clinical Study Protocol and related 
documents and will also provide training to the relevant systems and other study-specific 
procedures. The activities of this meeting will be described in the monitoring plan. 
Site staff will follow all applicable SOPs for which they will have receive proper training and 
comply with all applicable requirements and regulations. 
 
10.3 Audits and Inspections 
Inflamax Research, Inc. will implement and maintain quality control (QC) procedures to 
ensure that the study is conducted, and that the data are generated, documented, and reported 

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in compliance with the protocol, ICH-GCP, Inflamax Research SOPs, and applicable 
regulatory documents. 
The Sponsor may conduct monitoring and/or audit visits at Inflamax Research, Inc. to verify 
adherence to the study protocol, the protection of the rights and well-being of the study 
participants and the accuracy and completeness of reported study data recorded on the source 
documentation. 

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11 DATA MANAGEMENT ACTIVITIES 
All Data Management activities will be described in detail in the Data Management Plan 
(DMP) and documents specified therein. The electronic systems used to collect subject data 
will be Food and Drug Administration (FDA) 21 Code of Federal Regulation (CFR) Part 11 
compliant. 
11.1 Data Capture 
11.1.1 
Case Report Forms and Study Records 
With the exception of electronic source data, all results from the clinical assessments will be 
recorded in the source data file by the Principal Investigator or designee, and then captured in 
the electronic CRFs at the study site. Trained study personnel will be responsible for capturing 
the data from the observations, tests and assessments, specified in the protocol, in the source 
documents and transferring the data to the eCRF according to the eCRF Completion 
Guidelines. 
The PI has the ultimate responsibility for the collection and reporting of all data related to the 
clinical study and ensuring that the data are accurate, authentic/original, legible, timely 
(contemporaneous), enduring and available when required. The eCRF must be signed by the 
PI to attest that the data contained in the eCRF are true and accurate. Any corrections made to 
source documents must be recorded, without obscuring the original values, and must be 
accompanied by the date of change, reason for change and identification of the person making 
the change. Any change to the eCRF data will be recorded in the system’s audit trail.  The 
eCRF data will be verified against the source documents at the study site by the Monitor as 
described in the monitoring plan. Instances of missing or unclear data will be discussed with 
the PI or delegate for resolution. All questionnaires will be administered to the study participant 
in their local language.  
 

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11.1.2 
Protocol Deviations 
Protocol deviations are defined as deviations from the study procedures as defined in this 
document, including but not limited to, as any violation of inclusion/exclusion criteria, 
assessments not performed or performed outside the scheduled time windows, or use of drugs 
that are known to affect study endpoints. 
All protocol deviations will be entered into the electronic data capture system (EDC) or other 
approved format. 
Information from the source documents will represent the primary source of protocol 
deviations. Information following site monitoring and other manual reviews will be 
documented in the site visit reports, follow-up letters, audit documentation, or other manual 
review and will be recorded and tracked in the EDC 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. 
The overall procedure for managing protocol deviations is described in the SOPs and/or 
agreed upon procedure of the clinical site(s). 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 Data 
Management Team at the CRO will prepare a Data Management Plan (DMP). This document 
will describe, in details, the Data Management-related procedures and processes.  The overall 
procedures for quality assurance of clinical study data are described in the SOPs of the CRO 
Data Management Team and/or Data Management Plan (DMP).  
Data of all study participants enrolled, including screening failures and AE during the study 
(from the time of Informed Consent to the end of the safety follow-up period) will be captured 
in the source documents. All enrolled subjects will be entered in the study database (eCRF). 

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All data collected during the study is declared property of the Sponsor, irrespective of the 
location of the database and the Data Management CRO. 
11.2.1 
Database Lock 
The database will be soft-locked after all source data verification (SDV) has been completed,all 
SDV queries are resolved, all outstanding Data Management issues have been resolved and all 
validation, quality review and cleaning activities are complete.  
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. 
11.3 Coding 
Adverse Events will be coded in the Medical Dictionary for Regulated Activities (MedDRA) 
and prior and concomitant medications will be coded in the World Health Organization (WHO) 
Drug dictionary as described in the study specific Data Management Plan (DMP).  
 

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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. 
12 PLANNED STATISTICAL METHODS 
12.1 General Considerations 
Full details of the statistical analysis will be given in a Statistical Analysis Plan (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. 
STT for each time point will be summarized by smoker and never smoker group using the 
descriptive statistics: mean, minimum, maximum, median, quartiles, standard deviation (SD) 
and 95% confidence interval (CI).  
The plasma nicotine levels for each time point will be summarized by smoker and never 
smoker group using the descriptive statistics mean, minimum, maximum, median, quartiles, 
standard deviation (SD) and 95% confidence interval (CI).. The relationship between plasma 
nicotine levels and STT at each time point will be evaluated by spearman correlation as well 
as graphical presentation of these endpoints by time point and smoker and never smoker group. 
An overall summary of AEs will be presented by smoker and never smoker group showing the 
number of events and percent of study participants who experienced AEs, SAEs, severe AEs 
and AEs leading to study discontinuation. 
RNA concentration will be summarized by method using descriptive statistics: mean, 
minimum, maximum, median, quartiles, standard deviation (SD) and 95% confidence interval 
(CI).. 
RNA RIN will be summarized by method using descriptive statistics: mean, minimum, 
maximum, median, quartiles, standard deviation (SD) and 95% confidence interval (CI). 
A summary of AEs by System Organ Class (SOC) and Preferred Term (PT) by smoker and 
never smoker group will be presented. 
Vital signs will be summarized by smoker and never smoker group using descriptive statistics: 
mean, minimum, maximum, median, quartiles, standard deviation (SD) and 95% confidence 
interval (CI).. 

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are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
12.1.1 
Handling of Missing Values and of Values outside the Detection Limits 
Missing STT values for a time point will be treated as missing. When STT detection takes 
longer than 1 hour, the STT will be considered as 1 hour. 
Regarding plasma nicotine samples:  
 Missing sampling time: if the time of collection for a sample is unknown, that 
individual data point will be treated as missing data for descriptive statistics. 
 Missing concentration data: missing concentration data will be treated as missing and 
replaced with a “.” in the concentration dataset.  No values will be imputed. 
 Concentration data below lower limit of quantification (LLOQ): in the calculation of 
descriptive statistics for concentration data at each sampling time point, all LLOQ 
values will be treated as zero for time zero and as 1/2 LLOQ for the remaining time  
12.1.2 
Significance Level for Inferential Analysis 
This study has no formal pre-specified hypotheses associated with the study objectives. 
However, 95% CI will accompany all effect estimates.  
 
12.2 Determination of Sample Size and Power Consideration 
This is an exploratory study. This study will include 14 study participants: 7 cigarette smokers 
and 7 never smokers. No formal powering has occurred. However, with an expected standard 
deviation of 2.5 minutes, a difference in STT of 3.75 minutes can be detected. 
 

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are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
12.3 Analysis Populations 
12.3.1 
Full Analysis Set (FAS) 
All study participants who have at least one evaluable STT test at Visit 3 will be included in 
FAS population. 
12.3.2 
Per Protocol (PP) Population 
All study participants in Full Analysis Set who have no major protocol deviation will be 
included in the PP population. 
12.3.3 
Safety Population 
All enrolled subjects will be included in safety population. 
 
 

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13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Investigator’s and Study Administrative Structure 
13.1.1 
Investigator 
Investigator: 
Dr Frank Lee, MD 
Tel: +1 
 
Fax.: +1 
 
E-mail: 
 
 
 
13.1.2 
Sponsor 
Sponsor: 
Philip Morris Product S.A. 
PMI Research & Development 
Quai Jeanrenaud 5 
2000 Neuchâtel, Switzerland  
Tel: +41 (58) 242 2111 
Fax: +41 (58) 242 2811 
 
13.1.3 
Bioanalytical Laboratory 
Bioanalytical Lab 
 
  
 
 

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are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
Tel: +
 
Fax: +
 
 
13.1.4 
Other Responsibilities 
Any SAEs will be handled by: 
Company: United BioSource Corporation (UBC) Safety 
Address: 
 
Phone: 
  
Fax: 
 
Email: 
 
 
13.2 Subject Confidentiality 
Privacy and confidentiality will be maintained and governed by company procedures in 
compliance with the applicable federal and/or state laws as well as the Health Insurance 
Portability and Accountability Act (HIPAA), as applicable. Personal and medical information 
will not be released unless required by law. 
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 Principal Investigator or 
designee. 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. 
 

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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. 
13.3 Informed Consent 
In accordance with 21 CFR 50, the informed consent process shall be documented by the use 
of a written ICF approved by the IRB. The ICF will be signed by the subject prior to any 
protocol-specific procedures being performed. 
The Principal Investigator will explain the purpose of the study. All procedures and risks must 
be explained to all potential study participants in a form understandable to them and each 
individual must be provided with the opportunity to ask questions. The potential study 
participants will be informed that participation is voluntary and that they can withdraw from 
the study at any time. 
The ICF will contain all of the elements required by ICH guidelines for GCP and any additional 
elements required by local regulations. 
A copy of the signed ICF and any other written information will be provided to the study 
participant prior to study participation. The original signed ICFs will be maintained at study 
site. 
 
13.4 Access to Source Documentation 
Study participants will be informed that, during the course of the clinical study, the Sponsor, 
any authorized representatives of the Sponsor, IRB or regulatory authorities may inspect their 
medical records to verify the information collected and ensure that all personal information 
made available for inspection is handled in the strictest confidence and in accordance with 
national and local data protection and privacy legislation. 
The Principal Investigator and all study site staff involved with the study must permit direct 
access to source data/documents for study related monitoring, audits, IRB review and 
regulatory inspection(s). 
 

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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. 
13.5 Record Retention 
The Principal Investigator will maintain drug records, source documents, and signed study 
participant consent documents for at least 25 years unless instructed in writing by the Sponsor 
that records may be forwarded to the Sponsor. In accordance with Federal Regulations and 
ICH-GCP guidelines, these records will be available for inspection and copying if requested 
by a properly authorized regulatory agent. 
 
13.6 Clinical Study Report (CSR) 
A CSR for this study will be prepared regardless of whether the study is completed or 
prematurely terminated. 
The CSR will be written based on standards of the ICH Guideline for the Structure and Content 
of Clinical Study Reports. In certain circumstances, an abbreviated CSR may be acceptable. 
Submission of the CSR to the IRB will be complied with as requested by local requirements. 
The results of the additional variables for analysis, including the histological assessment of the 
nasal epithelium, will be presented in reports separate from the study CSR. 
 
13.7 Financial Disclosure 
Principal Investigators are required to provide financial disclosure information to the Sponsor. 
In addition, the Principal Investigators must provide to the Sponsor a commitment to promptly 
update this information if any relevant changes occur during the course of the investigation 
and for one year following the completion of the study. 
 

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are hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
13.8 Publication and Disclosure Policy 
This document contains information that is confidential and proprietary to the Sponsor. This 
information is being provided solely for the purpose of evaluation and/or conducting this 
clinical study for the Sponsor. Disclosure of the content of this document is allowed only to 
qualified study staff personnel (all individuals who are qualified by education, training and 
experience to perform his or her respective task(s) as assigned and delegated by the Principal 
Investigator), IRB, or duly authorized representatives of regulatory agencies for this purpose 
under the condition that confidentiality is maintained. The content of this document may not 
be used in any other clinical study, disclosed to any other person or entity without the prior 
written permission of the Sponsor. The foregoing shall not apply to disclosure required by any 
regulations; however, prompt notice will be given to the Sponsor prior to any such disclosure. 
The Sponsor plans to disclose details of the study protocol on a web-based, publicly available, 
clinical trial register database (e.g., ClinicalTrials.gov). 
 

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14 REFERENCE LIST 
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nasal mucociliary clearance: A comparative analysis using saccharin test. Lung India, 31(1), 
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33. doi: 10.1183/09059180.00003510. 
Benowitz, N. L., Hukkanen, J., & Jacob, P. (2009). Nicotine Chemistry, Metabolism, Kinetics 
and Biomarkers. Handbook of experimental pharmacology (192), 29-60. doi:10.1007/978-3-
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Bhowmik, A., Chahal, K., Austin, G., & Chakravorty, I. Improving mucociliary clearance in 
chronic 
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Deborah, S., & Prathibha, K. (2014). Measurement of Nasal Mucociliary Clearance. Clinical 
Research in Pulmonology, 2(2), 1019.  
Fahy, J. V., & Dickey, B. F. (2010). Airway Mucus Function and Dysfunction. The New 
England journal of medicine, 363(23), 2233-2247. doi:10.1056/NEJMra0910061 
FDA, U. (2010). How tobacco smoke causes disease: the biology and behavioral basis for 
smoking-attributable disease: a report of the Surgeon General US Department of Health and 
Human Services, Centers for Disease Control and Prevention, National Center for Chronic 
Disease Prevention and Health Promotion, Office on Smoking and Health    
FDA, U. (2014). The health consequences of smoking-50 years of progress: a report of the 
Surgeon General.  
Habesoglu M, Demir K, Yumusakhuylu AC, Yilmaz AS, Oysu C. Does passive smoking have 
an effect on nasal mucociliary clearance? Otolaryngol Head Neck Surg. 2012 Jul;147(1):152-
6. doi: 10.1177/0194599812439004. Epub 2012 Feb 29. Review. PubMed PMID: 22383459. 
Hecht, S. S. (2003). Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat 
Rev Cancer, 3(10), 733-744.  Retrieved from http://dx.doi.org/10.1038/nrc1190 

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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. 
Jain R, Javidan-Nejad C, Alexander-Brett J, Horani A, Cabellon MC, Walter MJ,  Brody SL. 
Sensory functions of motile cilia and implication for bronchiectasis. Front Biosci (Schol Ed). 
2012 Jan 1;4:1088-98. Review. PubMed PMID: 22202111; PubMed Central PMCID: 
PMC3841983. 
Jaspers, I. (2014). Cigarette Smoke Effects on Innate Immune Mechanisms in the Nasal 
Mucosa. Potential Effects on the Microbiome. Annals of the American Thoracic Society, 
11(Supplement 1), S38-S42. doi:10.1513/AnnalsATS.201306-154MG 
Lee, J., Taneja, V., & Vassallo, R. (2012). Cigarette Smoking and Inflammation: Cellular and 
Molecular 
Mechanisms. 
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of 
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91(2), 
142-149. 
doi:10.1177/0022034511421200 
Loebinger, M. R., Bilton, D., & Wilson, R. (2009). Upper airway • 2: Bronchiectasis, cystic 
fibrosis 
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sinusitis. 
Thorax, 
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Martin, F., Talikka, M., Hoeng, J., & Peitsch, M. C. (2015). Identification of gene expression 
signature for cigarette smoke exposure response--from man to mouse. Hum Exp Toxicol, 
34(12), 1200-1211. doi:10.1177/0960327115600364 
Miller, M.R., Hankinson, J., Brusasco, V., Burgos, F., Casaburi, R., Coates, A., Crapo, R., 
Enright, P., Van Der Gritenm C. P. M., Gustafsson, P., Jensen, R., Johnson, D. C.,  Macintyre, 
N., McKay, R., Navajas, D., Pedersen, O. F., Pellegrino, R., Viegi, G., Wanger, J. (2005) 
Standardization of spirometry. Eur Respir J, 26:319–338. doi: 10.1183/09031936.05.00034805  
Özler, G. S., Şimşek, G. Ö., Akbay, E., & Akoğlu, E. (2014). The Effect of Passive and Active 
Smoking on Nasal Mucociliary Clerarance Time. Journal of Clinical and Analytical Medicine, 
7(2), 149-151.  
Passàli, D., & Bianchini, C. M. (1985). Normal values of mucociliary transport time in young 
subjects. Int J Pediatr Otorhinolaryngol, 9(2), 151-156.  
Passàli, D., Bellussi, L., & De Seta, E. (1984). Experiences in the Determination of Nasal 
Mucociliary 
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Passàli, D., Ferri, R., Becchini, G., Passàli, C. G., & Bellussi, L. (1999). Alterations of nasal 
mucociliary transport in patients with hypertrophy of the inferior turbinates, deviations of the 

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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. 
nasal septum and chronic sinusitis. European Archives of Oto-Rhino-Laryngology, 256(7), 
335-337. doi:10.1007/s004050050158 
Paul P, Akbar MS, Arumugam B, Subramanyam L. A study of body mass index and nasal 
mucociliary clearance in healthy South Indian adult volunteers. Int J Res Med Sci. 2016; 4(7): 
2902-2908. doi:10.18203/2320-6012.ijrms20161974. 
Phillips, B., Veljkovic, E., Boue, S., Schlage, W. K., Vuillaume, G., Martin, F., Hoeng, J. 
(2016). An 8-Month Systems Toxicology Inhalation/Cessation Study in Apoe-/- Mice to 
Investigate Cardiovascular and Respiratory Exposure Effects of a Candidate Modified Risk 
Tobacco Product, THS 2.2, Compared With Conventional Cigarettes. Toxicol Sci, 149(2), 411-
432. doi:10.1093/toxsci/kfv243 
Poirier, M. C. (1997). DNA adducts as exposure biomarkers and indicators of cancer risk. 
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1470061/pdf/envhper00329-0209.pdf 
Proença M, Fagundes Xavier R, Ramos D, Cavalheri V, Pitta F, Cipulo Ramos EM.  
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Port Pneumol. 2011 Jul-Aug;17(4):172-6. doi: 10.1016/j.rppneu.2010.12.001. Epub 2011 Apr 
20. Portuguese. PubMed PMID: 21549667. 
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EM. Mucociliary clearance and its relation with the level of physical activity in daily life in 
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22608005. 
Ramos, E. M. C., De Toledo, A. C., Xavier, R. F., Fosco, L. C., Vieira, R. P., Ramos, D., & 
Jardim, J. R. (2011). Reversibility of impaired nasal mucociliary clearance in smokers 
following a smoking cessation programme. Respirology, 16(5), 849-855. doi:10.1111/j.1440-
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Rutland, J., & Cole, P. J. (1981). Nasal mucociliary clearance and ciliary beat frequency in 
cystic fibrosis compared with sinusitis and bronchiectasis. Thorax, 36(9), 654-658.  Retrieved 
from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC471692/ 

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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. 
Scherer, G. (2006). Carboxyhemoglobin and thiocyanate as biomarkers of exposure to carbon 
monoxide and hydrogen cyanide in tobacco smoke. Experimental and Toxicologic Pathology, 
58(2–3), 101-124. doi:http://dx.doi.org/10.1016/j.etp.2006.07.001 
Shah, A. S., Ben-Shahar, Y., Moninger, T. O., Kline, J. N., & Welsh, M. J. (2009). Motile Cilia 
of Human Airway Epithelia Are Chemosensory. Science (New York, N.Y.), 325(5944), 1131-
1134. doi:10.1126/science.1173869 
Smaldone, G. C., Foster, W. M., O'Riordan, T. G., Messina, M. S., Perry, R. J., & Langenback, 
E. G. (1993). Regional Impairment of Mucociliary Clearance in Chronic Obstructive 
Pulmonary Disease. Chest, 103(5), 1390-1396. doi:http://dx.doi.org/10.1378/chest.103.5.1390 
Stanley P, MacWilliam L, Greenstone M, Mackay I, Cole P. Efficacy of a saccharin test for 
screening to detect abnormal mucociliary clearance. Br J Dis Chest. 1984 Jan;78(1):62-5. 
PubMed PMID: 6691910. 
Stanley PJ, Wilson R, Greenstone MA, MacWilliam L, Cole PJ. Effect of cigarette smoking 
on nasal mucociliary clearance and ciliary beat frequency. Thorax. 1986;41(7):519-523. 
Tamilselvan K, Latha R, Nirmala N, Susiganeshkumar E, Thananjayam A. Does body mass 
index influence mucociliary clearance? Int J Med Res Health Sci., Volume 2015; 4(1): 178–
182. DOI: 10.5958/2319-5886.2015.00028.4 
Titz, B., Boue, S., Phillips, B., Talikka, M., Vihervaara, T., Schneider, T., Hoeng, J. (2016). 
Effects of Cigarette Smoke, Cessation, and Switching to Two Heat-Not-Burn Tobacco 
Products on Lung Lipid Metabolism in C57BL/6 and Apoe-/- Mice-An Integrative Systems 
Toxicology Analysis. Toxicol Sci, 149(2), 441-457. doi:10.1093/toxsci/kfv244 
Treacy, K., Tunney, M., Elborn, J. S., & Bradley, J. M. (2011). Mucociliary clearance in cystic 
fibrosis: physiology and pharmacological treatments. Paediatrics and Child Health, 21(9), 425-
430. doi:http://dx.doi.org/10.1016/j.paed.2011.05.011 
Utiyama DM, Yoshida CT, Goto DM, de Santana Carvalho T, de Paula Santos U, Koczulla 
AR, Saldiva PH, Nakagawa NK. The effects of smoking and smoking cessation on nasal 
mucociliary clearance, mucus properties and inflammation. Clinics (Sao Paulo). 2016 
Jul;71(6):344-50. doi: 10.6061/clinics/2016(06)10. PubMed PMID: 27438569; PubMed 
Central PMCID: PMC4930664 
Xavier RF, Ramos D, Ito JT, Rodrigues FM, Bertolini GN, Macchione M, de Toledo AC, 
Ramos EM. Effects of cigarette smoking intensity on the mucociliary clearance of active 

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smokers. Respiration. 2013;86(6):479-85. doi: 10.1159/000348398. Epub 2013 Apr 19. 
PubMed PMID: 23615315 
Weitkunat, R., Coggins, C., Sponsiello-Wang, Z., et al. (2014). Assessment of Cigarette 
Smoking in Epidemiologic Studies. Beiträge zur Tabakforschung / Contributions to Tobacco 
Research, 25(7), pp. 638-648. Retrieved 21 Oct. 2016, from doi:10.2478/cttr-2013-0940 
World Medical Association Declaration of Helsinki - Ethical Principles for Medical Research 
Involving Human Subjects. 64th WMA General Assembly, Fortaleza, Brazil, October 2013 

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15 APPENDICES 
 

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Appendix A - Schedule of Events 
  
Visit 1 
Visit 2 
Visit 3 
Follow-Up 
 
Study day 
D-30 to D-1 
D1 
D2 
D3 
Informed consent 
1 
  
  
 
Review study procedures 
1 
1 
1 
 
Assessment/review of inclusion/exclusion criteria 
1 
1 
 
Demographics  
1 
  
  
 
Body height, weight and derived BMI 
1 
 
 
 
Medical history and concomitant disease 
1 
  
  
 
Hematology, clinical chemistry, urine analysis 
1 
  
1 (at discharge) 
 
Smoking history 
1 
1  
  
 
Readiness to comply to study procedures, incl. smoking 
interruptions 
1 
1 
 
 
Prior and concomitant medication assessment 
1 
1 
 1 
 
Vital signs 
1 
1 
1 
 
Nasal and throat exam 
1 
1 
 
 
Brief physical exam 
1 
  
 1 (at discharge) 
 
Spirometry post-bronchodilator 
1 
 
 
 
Serology for HIV, hepatitis B and C  
1 
 
 
 
Alcohol breath test 
1 
1  
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P1-CMS-01-US 
Final 2.0 Amendment 1.0, 22-May-2017 
Page 99 of 106 
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Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, and the legal protections 
provided to such trade secrets and confidential information are hereby claimed under the provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
  
Visit 1 
Visit 2 
Visit 3 
Follow-Up 
 
Drug screening 
1 
1  
 
Exhaled carbon monoxide 
1 
1 
 
 
Skin Prick Test 
1 
  
  
 
Urine Cotinine 
1 
1 
 
Enrolled 
1 
  
 
Plasma nicotine sampling 
 
 
1a 
 
Saccharin transit time test 
 1 
1 
1a 
 
Nasal scraping 
  
 
1b,c 
 
Discharge from Study 
 
 
1d 
 
Adverse event recording 
 1 
1 
1 
1 
a At time: T0 (post-cigarette), 4h (may be performed until 4h30 min), 8h (may be performed until 8h30 min), and 12h (may be performed until 12h30 min) 
post-T0. For the never smokers equivalent time points will be used. 
b After the last STT test and collection of sample for plasma nicotine. 
c Collection of samples for subsequent histological assessment and evaluation of RNA quantity and quality. 
d Upon completion of all study assessments. 
 
 
Appendix B – Inclusion and Exclusion Criteria Assessment 
 

Philip Morris Products SA 
Clinical Study Protocol 
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P1-CMS-01-US 
Final 2.0 Amendment 1.0, 22-May-2017 
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disclosed without the written consent of Philip Morris Products S.A. 
Inclusion Criteria 
Visit 1 
(Screening) 
Visit 2 
(Enrollment) 
1. Informed of the nature of the study and have agreed to and are able to read, review, and sign 
the informed consent form (ICF) prior to Screening. The subject must be willing to comply 
with the study procedures described in the informed consent. The informed consent document 
will be written in English, therefore the volunteer must have the ability to read and 
communicate in English. 
X 
 
2. Male subject aged ≥25 to ≤45 years old. 
X 
 
3. BMI between 18.0 kg/m2 to 32.0 kg/m2, inclusive. 
X 
 
4. Judged by the Principal Investigator or designee to be in good health as documented by the 
medical history, physical examination, vital sign assessments, clinical laboratory assessments, 
and by general observations. 
X 
X 
5. Belong to one of the following two groups: 
a. Non-menthol cigarette smoker (meets all of the following criteria at Visit 1 and at 
Visit 2): 
i. A positive urine cotinine test (≥200 ng/mL). 
ii. Smoked at least 20 cigarettes per day for at least the past 5 years.  
iii. eCO levels >10 parts per million (ppm). 
X 
X 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P1-CMS-01-US 
Final 2.0 Amendment 1.0, 22-May-2017 
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Related to PMI_RD_WKI_000759 
 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, and the legal protections 
provided to such trade secrets and confidential information are hereby claimed under the provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
iv. No plans to quit smoking in the next 3 months. 
b. Never smoker (meets all of the following criteria at Visit 1 and at Visit 2): 
i. Subject who has smoked less than 100 cigarettes throughout their lifetime 
and no cigarettes in the past 3 years. 
ii. A negative urine cotinine test (<200 ng/mL). 
iii. eCO levels ≤ 5 ppm. 
 
6. Completed the Screening process within 30 days prior to Visit 2.  
 
X 
7. Availability for the entire study period and willingness to comply with study procedures, 
including smoking interruptions, as evidenced by a signed ICF and at Visit 2. 
X 
X 
Exclusion Criteria 
Visit 1 
(Screening) 
Visit 2 
(Enrollment) 
1. As per the Principal Investigator or designee’s judgment, the subject cannot participate in the 
study for any reason (e.g., medical, psychiatric, and/or social reason). 
X 
 
2. Subject is legally incompetent, or physically or mentally incapable of giving consent (e.g., 
emergency situation, under guardianship, prisoners, or subjects who are involuntarily 
incarcerated). 
X 
 

Philip Morris Products SA 
Clinical Study Protocol 
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P1-CMS-01-US 
Final 2.0 Amendment 1.0, 22-May-2017 
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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. 
3. Presence of confounding allergies including allergic rhinitis and non-allergic rhinitis during the 
course of the study based on medical history and SPT. 
X 
X 
4. Clinical significant abnormality on their nasal and throat exam, at the discretion of the Principal 
Investigator or designee at Visit 1 and/or at Visit 2. 
X 
X 
5. Cigarette smoker who smoke/use any tobacco or nicotine products (other than CC), such as 
cigars, pipe, menthol cigarettes or electronic cigarettes in the previous 3 months, as self-
reported at Visit 1 or Visit 2. 
X 
X 
6. Never smoker who smoke/use any tobacco or nicotine products, such as cigars, pipe, menthol 
cigarettes or electronic cigarettes in the previous 3 years, as self-reported at Visit 1 or Visit 2. 
X 
X 
7. Cigarette smokers who state they will be unable to abstain from smoking for up to 24 hours. 
X 
X 
8.  
Inability to taste sweet within 60 minutes in the STT test.  
X 
 
9. Subjects who routinely use or who have used in the previous 4 weeks nasal sprays, inhalers or 
other nasal products, such as nasal irrigation (for example, Neti Pot) prior to Visit 1 and/or Visit 
2. 
X 
X 
10. Subjects who have taken any of the following medication without the indicated minimum 
washout period: 
Prohibited Medication 
Restriction period  
(with Principal Investigator or 
designee discretion) 
X 
X 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P1-CMS-01-US 
Final 2.0 Amendment 1.0, 22-May-2017 
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disclosed without the written consent of Philip Morris Products S.A. 
Short-acting antihistamines including intranasal antihistamines  
3 days before Visit 1 until Visit 
2 
Long-acting antihistamines (i.e. Loratadine, Desloratadine) 
7 days before Visit 1 until Visit 
2 
Over-the-counter cough and cold preparations or sleep aids 
containing antihistamines 
3 days before Visit 1 until Visit 
2 
Leukotriene inhibitors 
14 days before Visit 1 until Visit 
2 
Oral or intra-articular steroid 
30 days before Visit 1 until Visit 
2 
Intranasal and inhaled corticosteroids 
14 days before Visit 1 until Visit 
2 
Use of monoamine oxidase inhibitors 
14 days before Visit 1 until Visit 
2 
Decongestants  
48 hours before Visit 1until 
Visit 2 
Cromolyn products 
14 days before Visit 1 until Visit 
2 
Beta-adrenergic blockers (i.e. Acebutolol, Atenolol, etc.) 
14 days before Visit 1 until Visit 
2 
Anticholinergics 
7 days before Visit 1 until Visit 
2 
Herbal or natural product remedies for allergy symptoms 
On the day of Visit 1 until Visit 
2 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P1-CMS-01-US 
Final 2.0 Amendment 1.0, 22-May-2017 
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Confidentiality Statement 
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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. 
Short-Acting Beta Agonists 
6 hours prior to spirometry 
(except as per protocol before 
spirometry) 
Long-Acting Beta Agonists 
3 days before Visit 1 until Visit 
2 
Phosphodiesterase 5 inhibitors (i.e. Sildenafil, Vardenafil, Tadalafil) 
7 days before Visit 1 until Visit 
2 
Amiloride 
3 days before Visit 1 until Visit 
2 
Macrolide antibiotics 
7 days before Visit 1 until Visit 
2 
Guaifenesin 
3 days before Visit 1 until Visit 
2 
Mucolytic agents 
14 days before Visit 1  until 
Visit 2 
Topical menthol products 
14 days before Visit 1  until 
Visit 2 
Topical nasal medication 
4 weeks before Visit 1 until 
Visit 2 
Topical ocular medication 
4 weeks before Visit 1 until 
Visit 2 
Any other medication at the Principal Investigator or designee’s 
discretion that might interfere with the endpoints or procedures. 
As per Principal Investigator or 
designee. 
 

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Clinical Study Protocol 
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P1-CMS-01-US 
Final 2.0 Amendment 1.0, 22-May-2017 
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disclosed without the written consent of Philip Morris Products S.A. 
11. Subjects with evidence of COPD, Global Initiative for Chronic Obstructive Lung Disease 
(GOLD) stage I or greater, and a forced expiratory volume 1 / the forced vital capacity ratio 
(FEV1/FVC ratio) <0.7. 
X 
 
12. Any condition the Principal Investigator or designee has cause to believe would interfere with 
the procedures for upper or lower airway function. This could include, but is not limited to, 
nasal/septum deviations, or nasal polyps or nasal allergies which will be identified by the 
Principal Investigator or designee. 
X 
X 
13. Upper or lower respiratory diseases in the 4 weeks prior to Visit 2. 
X 
X 
14. History of nasal or sinus surgery in the 5 years prior to Visit 2. 
 
X 
15. As per the Principal Investigator or designee’s judgment, the subject has medical conditions 
which require or will require in the course of the study, a medical intervention (e.g., start of 
treatment, surgery, hospitalization) which may interfere with the study participation and/or 
study results. 
X 
 
16. The subject has a positive alcohol test and/or a history of alcohol abuse that could interfere with 
the subject’s participation in study at Visit 1 or Visit 2. 
X 
X 
17. Positive urine drug screen at Visit 1 or Visit 2. 
X 
X 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P1-CMS-01-US 
Final 2.0 Amendment 1.0, 22-May-2017 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, and the legal protections 
provided to such trade secrets and confidential information are hereby claimed under the provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A. 
18. The subject has positive serology test for human immunodeficiency virus (HIV)1/2, Hepatitis 
B or Hepatitis C. 
 
X 
19. Subject has donated or been in receipt of whole blood or blood products within 3 months prior 
to Visit 1. 
X 
 
20. Subject is a current or former employee of the tobacco industry or of their first-degree relatives 
(spouse, legal patner, parent, sibling, and child). 
X 
 
21. Subject is an employee of the investigational site or any other parties involved in the study or 
of their first-degree relatives (spouse, legal patner, parent, sibling, and child). 
X 
 
22. Subject has been in receipt of last dose from another clinical study within 3 months prior to 
Visit 1.  
X 
 
23. Subject has been previously screened in this study. 
X