A Randomized, Double-blinded, 2-arm Parallel Groups, Single Center Study to Assess Product Use and Adaptation, Safety and Tolerability of P3P, a Novel Nicotine-containing Product, in Adult Healthy Cigarette Smokers Switching to One of Two P3P Variants for One Month
Phase: NA
Conditions: Pharmacokinetics
Sponsor: Philip Morris Products S.A.

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Philip Morris Products S.A. 
Research Study Protocol 
Confidential 
Study P3P-SE-02-RU 
Final 2.0 / 12 June 2019 
Page 2 of 106 
 
 
 
 
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. 
SUMMARY OF CHANGES 
 
 
Version 
Date 
Amendment 
First updated protocol 
Final Version 2.0 
12 June 2019 
Non-substantial 
amendment 
Original protocol 
Final Version 1.0 
23 January 2019 
 
 
The following non-substantial changes were made to the original research study protocol P3P-
SE-02-RU (Final Version 1.0) dated 23 January 2019 generating the updated version (Final 
Version 2.0) dated 12 June 2019. 
Details on the protocol sections changed are provided in the table below. For identification of 
the changes, the previous and the amended texts are provided. The new text has been 
highlighted in bold (e.g. new text) and deleted text has been crossed out (e.g. deleted text). 
Changes from Final 1.0 to Final 2.0 
Section  
Changes 
 
General 
The version number and the revision date were updated.  
A “Summary of changes” section was added.  
Several typing errors were corrected. 
The list of references, abbreviations and table of contents 
were updated. 
7.3.9 
Spirometry 
Old text:  Spirometry predicted values will be standardized 
to the National Health and Nutrition Examination Survey III 
predicted set 
Amended text: Spirometry predicted values will be 
standardized to the National Health and Nutrition 
Examination 
Survey 
III 
predicted 
set 
European 
Community for Coal and Steel (ECCS) reference 
equations as published in the 1993 ERS statement 
Reason to change:  To correct an error in the previous version 
in order to use predicted sets/equations derived from 
European rather than American population. 

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without the written consent of Philip Morris Products S.A. 
7.5.1 
Table 2 
footnote 
Old text:  * Except at Screening where non-fasting glucose 
will be assessed 
Amended text: *Except at Screening where non-fasting 
glucose will can be assessed 
Reason to change:  Specify that at screening collection of 
non-fasting samples for glucose analysis is allowed, although 
this is not a requirement (if subjects have been fasting, 
glucose samples can still be collected and analyzed). 
13.1.1 
Investigator 
Old text:  E-mail: 
 
Amended text:  E-mail: 
 
Reason to change:  To correct a typing error in the 
investigator’s e-mail address. 
Appendix C Table C2 
Old text:  10-9/L  
Amended text:  10-9/L 109/L 
Reason to change:  To correct a typing error in the unit for 
WBC, lymphocytes, neutrophils and platelets. 

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SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Product Name: 
P3P  
Study Title: 
A randomized, double-blinded, 2-arm parallel groups, single center study to assess product 
use and adaptation, safety and tolerability of P3P, a novel nicotine-containing product, in adult 
healthy cigarette smokers switching to one of two P3P variants for one month. 
Study Number: 
P3P-SE-02-RU 
Short Study Title: 
Product use and adaptation, safety and tolerability of P3P in adult healthy smokers switching 
to it. 
Objectives and Endpoints: 
The goal of the proposed research study is to evaluate the adaptation of product use in adult, 
current cigarette smoking subjects between baseline and after 1 month of use of one of two 
P3P variants. The effect of P3P use behavior on nicotine pharmacokinetic (PK) profile, 
acceptability, as well as the safety and tolerability of P3P over a period of 1 month will be 
investigated. In addition, the overall use of tobacco and nicotine containing product use will 
be monitored. 
Primary Objective and Endpoints: 
1. To assess nicotine pharmacokinetics following use of a single P3P-1mg or P3P-2mg 
product on Day 1 and Day 30.  
Endpoints: 
• Plasma nicotine time-concentration profile from prior product use to 4 hours post 
start of product use; 

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• PK parameters: maximum plasma concentration (Cmax); time to maximum 
concentration (tmax); Area under the concentration-time curve from start of product 
use to 4 hours (AUC(0-4h)).  
Secondary Objectives and Endpoints: 
1. To evaluate the pharmacodynamic effects (subjective effects and related behavioral 
assessments) of the two P3P variants. 
Endpoints: 
• Visual Analogue Scale (VAS)-craving assessment in parallel with PK assessment on 
Day 1 and Day 30; 
• Sensory Questionnaire on Day 1 and Day 30; 
• ABOUTTM-Product Experience Questionnaire on Day 1 and Day 30. 
2. To assess product acceptance and puffing/inhalation behavior of both P3P variants  
Endpoints: 
• Product acceptance questionnaire on Day 1 and Day 30; 
• Puffing/inhalation behavior question: 
o Evaluated by site staff on Day 1 and Day 30 
o Answered by subject on Day 2, Day 7, Day 15, Day 22 and Day 29. 
3. To assess nicotine/tobacco product use.  
Endpoints: 
• Number of P3P, cigarettes, e-cigarettes or/and other nicotine/tobacco product use 
from Day 1 to Day 30; 
• Change in the number of cigarettes used throughout the study as compared to the 
reported number at Screening.   
4. To assess safety and tolerability during the study. 
Endpoints: 
• Incidence of adverse events (AEs), serious adverse events (SAEs);  
• Frequency of adverse events (AEs), serious adverse events (SAEs);  
• Incidence of P3P product events including malfunction/misuse;  
• Frequency of P3P product events including malfunction/misuse; 
• Physical examination changes from baseline; 
• Cough assessment changes from baseline (VAS and three Likert scales); 

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Confidential 
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Final 2.0 / 12 June 2019 
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• Electrocardiogram (ECG) changes from baseline (heart rate, PR, QRS, QT, QTcB, 
QTcF intervals); 
• Vital signs changes from baseline (systolic and diastolic blood pressure, pulse rate and 
respiratory rate); 
• Spirometry changes from baseline (FEV1, FEV1 % predicted, FVC, FVC % predicted, 
FEF 25, FEF 25 % predicted, FEF 75, FEF75 % predicted, FEF 25-75, FEF 25-75 % 
predicted, FEV1/FVC); 
• Changes from baseline in clinical chemistry, hematology, and urinalysis safety panel;  
• Concomitant medications. 
5. To assess the exposure to harmful and potentially harmful constituents (HPHCs) in spot 
urine expressed as concentration adjusted for creatinine from Day -1 to Day 30. 
Endpoints: 
• Biomarker of exposure (BoExp) to nicotine: Nicotine equivalents (NEQ); 
• BoExp to NNK: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL);  
• BoExp to Acrylonitrile: 2-cyanoethylmercapturic acid (CEMA).  
6. To assess tobacco and nicotine containing product dependence at Day -1 and at Day 30. 
Endpoint: 
• ABOUTTM-Dependence Questionnaire.  
7. To assess cytochrome P450 2A6 (CYP2A6) enzymatic activity at Day 1 and at Day 30. 
Endpoint: 
• Molar metabolic ratio of trans-3’-hydroxycotinine/cotinine in plasma. 
8. To estimate the amount of powder extracted from P3P used for PK assessment. 
Endpoint: 
• Weight difference of P3P before and after use. 
Additional Study Assessments (for eligibility assessment and baseline characteristics): 
• Serology for human immunodeficiency virus (HIV) 1/2 and hepatitis B and C; 
• Pregnancy test;  
• Urine cotinine test; 
• Urine drug screen (amphetamine type substances, barbiturates, benzodiazepines, 
cannabinoids, cocaine and opiates); 
• Alcohol breath test. 

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Research Study Protocol 
Confidential 
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Final 2.0 / 12 June 2019 
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without the written consent of Philip Morris Products S.A. 
Study Hypothesis: 
The study will be descriptive in nature. However, for the ANOVA tests, the following 
hypothesis will be tested: 
H0: μ1 = μ2 
H1: μ1 ≠ μ2  
where μ1 and μ2 are the means (arithmetic or geometric) for each product variant, respectively. 
Study Design: 
This is a research study of P3P with daily product use of up to 15 P3P products over 1 month 
including 2 occasions of confinement period (3 days at V2 and 2 days at V6). From the start 
of the exposure period onwards, subjects will be instructed to use P3P exclusively. Subjects 
will be randomized to use either P3P-2mg or P3P-1mg. 
A Screening Visit will be conducted within 3 weeks prior to Admission to the investigational 
site (see Figure 1). A demonstration of P3P, without product use, will be done by the 
investigational site staff during the Screening Visit.  
 
Figure 1 Study Flow Chart 
 

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Subjects will return to the investigational site for Admission (Day -1). Subjects should have 
been fasting for at least 6 hours prior to Admission. After confirmation of eligibility, subjects 
will be enrolled. All subjects that are not enrolled will be considered as screen failures. At 
Admission, enrolled subjects will perform a product test using up to 6 P3P products 
(alternating between P3P-1mg and P3P-2mg). In order to continue in the study, each subject 
will need to test at least one product of each P3P variant during the product test. Subjects 
should be abstinent from the use of any tobacco/nicotine containing products for at least 4 
hours prior to product test. After the product test, subjects not willing and/or not ready to use 
P3P will be discontinued from the study. Subjects willing and ready to use P3P during the 
study will be randomized either to P3P-1mg or P3P-2mg in a 1:1 ratio and will start their first 
overnight (confinement) period for pharmacokinetics assessments on Day 1. The subjects and 
the Investigator will be blinded to the randomization arm. 
On Day 1, after at least 10 hour abstinence from any tobacco/nicotine containing products, 
subjects will use a single P3P product, as randomized, for a duration of up to 15 minutes. The 
start of product use will be defined as T0.  
A total of 11 blood samples will be taken for PK parameter estimation. Three blood samples 
will be taken prior to the product use (T0) and 8 aditionnal blood samples will be taken at 
specific timepoints within 4h after the start of product use. 
Pharmacodynamic effects related to craving will be assessed using a VAS scale at different 
time points before, during and after product use. Product evaluation using the ABOUTTM-
product experience questionnaire, the sensory questionnaire and the product acceptance 
questionnaire will be assessed after the end of product use. 
Each P3P used for PK assessment will be weighted before and after product use to estimate 
the amount of nicotine delivered in the aerosol. 
After the end of blood sampling for PK estimation, subjects will stay on-site until the evening 
of Day 2 and will be allowed to use up to 15 P3P products/daily during these two days. Safety 
assessments will be performed both on Day 1 and Day 2. 
Subjects will be instructed to use exclusively P3P for the entire 1-month duration of the 
exposure period (from the end of V2 until discharge at V6). Use of cigarettes and/or other 
tobacco and nicotine containing products during the ambulatory exposure period will not be a 
reason for discontinuing a subject from the study, but should be avoided as much as possible. 
At V2, subjects will be trained on how to record their use of P3P and other tobacco/nicotine 
containing products in a designated website during the entire ambulatory exposure period. 
Subjects will return to the investigational site for weekly visits, V3 (Day 7), V4 (Day 15), V5 
(Day 22) and V6 (Day 29) with a visit time window of ± 2 days each. The visit days and 
windows will be calculated from Day 1. During these visits, product will be resupplied and 
selected safety assessments will be performed. 

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Research Study Protocol 
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without the written consent of Philip Morris Products S.A. 
At V6 subjects will remain at the investigational site for their confinement period for 
pharmacokinetics assessments on the second day of this visit, Day 30. There will be a washout 
of at least 10 hours before T0 to allow adequate background correction of the nicotine plasma 
concentrations. The assessments performed at Day 30 will be the same as those described for 
Day 1. 
After discharge on Day 30 or early termination, subjects will enter a 14-day Safety Follow-
Up Period during which new AE/SAEs will be collected and ongoing AEs/SAEs will be 
followed-up by the site. Any non-serious AE that is ongoing at the time of discharge or early 
discontinuation will be followed-up by the Investigator or designee during Safety Follow-Up 
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) or the subject is lost to follow 
up. At the end of the Safety Follow-Up, all subjects will be contacted via phone in order to 
check the status of the ongoing AEs and also to collect any new AE/SAE experienced by the 
subjects. At the end of the Safety Follow-Up Period, all ongoing non-serious AEs will be 
documented as “ongoing” and no further follow-up information will be sought for them by the 
Investigator or designee. At that point, the Investigator will assess whether the subject should 
be referred to his/her General Practitioner to have their ongoing AEs addressed accordingly. 
All SAEs will be followed up by the Investigator until resolution, stabilization or the 
determination of a plausible explanation for them was found, regardless of the end of the 
Safety Follow-Up Period. 
 
Study Population and Eligibility Criteria: 
Subjects must meet all of the following inclusion criteria to be enrolled into the study: 
1. Subject has signed and dated the ICF and is able to understand the information provided 
in it. 
2. Smoking male or female aged between 21 and 65 years old inclusive. 
3. Subject has been a smoker for at least the last 3 years prior to the Screening Visit and has 
smoked 5 to 15 commercially available cigarettes per day for the last 3 months prior to 
Screening. 
4. Subject has a positive urinary cotinine test (cotinine ≥ 200 ng/mL). 
5. Subject does not plan to quit smoking within 2 months. 
6. Smoking, healthy subject as judged by the Investigator or designee based on available 
assessments from the Screening period (e.g., safety laboratory, spirometry, vital signs, 
physical examination, chest X-ray, ECG and medical history). 
7. Availability for the entire study period and willingness to comply with study procedures, 
including intermittent dietary restrictions. 
8. Ready to switch from smoking cigarettes to using P3P for the duration of the study. 
 

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without the written consent of Philip Morris Products S.A. 
Subjects who meet any of the following exclusion criteria must not be enrolled into the study: 
1. As per the Investigator’s judgment, the subject cannot participate in the study for any 
reason other than medical (e.g., psychological 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. Subject has a clinically relevant disease which requires medication (including but not 
limited to gastrointestinal, renal, hepatic, neurological, hematological, endocrine, 
oncological, urological, immunological, pulmonary, and cardiovascular disease) or any 
other clinically significant medical condition (including safety laboratory), which as per 
the judgment of the Investigator would jeopardize the safety of the subject. 
4. As per the Investigator’s judgment, the subject has medical conditions which require or 
will require in the course of the study, a medical intervention (e.g., start of treatment, 
surgery, hospitalization) which may interfere with the study participation and/or study 
results. 
5. Subject has asthma condition (post-bronchodilator FEV1/FVC < 0.75 and reversibility in 
FEV1 ≥ 12% and > 200 mL from pre- to post-bronchodilator values). 
6. Subject has (FEV1/FVC) < 0.7 and FEV1 < 80% predicted value at post-bronchodilator 
spirometry. 
7. Subject has a history of hypersensitivity to 
 or menthol. 
8. Subject has a contraindication for using salbutamol and/or albuterol as per the summary 
of product characteristics for the given product. 
9. Subject has donated or received whole blood or blood products within 3 months prior to 
Screening Visit. 
10. Subject has a BMI < 18.5 kg/m2 or > 32.0 kg/m2. 
11. Subject has received medication within 14 days or within 5 half-lives of the drug prior to 
Admission (whichever is longer) which has an impact on CYP2A6 activity. 
12. Subject has a positive serology test for HIV 1/2, Hepatitis B, or Hepatitis C. 
13. Subject has a positive alcohol breath test and/or a history of alcohol disorder within the 
past 2 years. 
14. Subject has a positive urine drug test. 
15. Subject or one of their family membersa is a current or former employee in the tobacco 
industry. 
16. Subject or one of their family membersa is an employee of the investigational site or of 
any other parties involved in the study. 
17. Subject has participated in another clinical study within 3 months prior to the Screening 
Visit. 

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18. Subject has been previously screened or enrolled in this study. 
19. For women only: subject is pregnant (does not have negative pregnancy tests at Screening 
Visit and at Admission) or is breastfeeding. 
20. For women of childbearing potential onlyb: subject does not agree to use an acceptable 
method of effective contraception.c 
a As defined by FDA guidance on Human Subject Protection (21 CFR 50.3(l), (m), 50.24(a)(6), (a)(7)(v), b)):  
"Family member” means among other things “parent”, “spouse”, "brothers, sisters, and spouses of brothers and sisters" and 
“any individual related by affinity…whose close association with the subject is equivalent of a family relationship” 
b Women who are not of childbearing potential meet at least one of the following criteria:  
Have undergone hysterectomy or bilateral tubal ligation,  
Have primary ovarian insufficiency, or  
Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no 
alternative pathological or physiological cause). 
c Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with spermicidal 
foam/gel/film/suppository, hormonal contraception, vasectomized partner(s), or true abstinence (periodic abstinence and 
withdrawal are not effective methods) from Screening until the end of the Safety Follow-Up Period.  
Investigational Products 
P3P will be provided by the Sponsor. P3P is a single use product which has two components 
that perform different functions:  
• A Consumable component, which comprises a tube-shaped body and a capsule 
containing the nicotine powder. Once the capsule is activated, i.e. pierced with an 
Accessory component, the user is able to draw on the Consumable so that airflow passes 
through the Consumable and releases the powder from the Capsule. 
• An Accessory component, which is a mechanical unit with a needle to pierce the 
Capsule that enables the release of the powder from the capsule. 
Two product variants (P3P-2mg and P3P-1mg) will be tested in this study. The formulations 
in P3P-2mg and P3P-1mg variants have already been assessed in a short-term 
pharmacokinetics study (ClinTrials.gov: NCT03369340).  
Study Duration: 
The entire study per subject will last 44 to 70 days. This will include a screening period of up 
to 3 weeks prior to Admission (Day -22 to Day -2), the admission day (Day -1),  30-day period 
of  P3P use of up to 15 products per day (Day 1 to Day 30), and a 14-days Safety Follow-Up 
Period. The end of the study (EOS) for a subject is defined as either the Discharge at Day 30, 
or the date of early termination of the subject, plus the 14 days for the Safety Follow-Up 
Period. The end of the whole study corresponds to the individual EOS of the last subject. 
 

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without the written consent of Philip Morris Products S.A. 
Statistical Methods: 
All data will be presented in listings. All endpoints will be summarized with descriptive 
statistics including number of subjects (n), number and percent of subjects with missing data, 
arithmetic means, 95% CIs, and standard deviations, median, first and third quartiles, 
minimum and maximum. Change from baseline will be added to the summary statistics when 
applicable. For log normally distributed endpoints geometric mean, 95% CIs of the geometric 
mean, geometric CV will be presented instead of arithmetic mean, 95% CI, and SD and percent 
change from baseline will be presented instead of change from baseline. Categorical variables 
will be summarized by frequency statistics (number and percentage). For endpoints relating 
to sampling times (e.g., tmax) only median, first and third quartiles, and minimum and 
maximum will be presented. 
Nicotine PK parameters: 
Nicotine PK parameters will be derived from plasma nicotine versus time data. AUC(0-4h) will 
be derived using the trapezoidal rule. To minimize the carry-over effect in the nicotine plasma 
PK parameters due to limited washout periods, background-concentration correction will be 
applied to the nicotine concentration data.  
 Baseline nicotine concentration (C0) will be defined as the last measured concentration prior 
to T0 of each visit. The baseline correction will be implemented by calculating the PK 
parameters using adjusted concentration values as described below (1):  
• Calculate the slope using a linear regression on the log concentration of the 3 pre- T0 
timepoints.  
• If the slope is <= 0, then use the slope to determine to coefficient of elimination λz. 
• If the slope is > 0, then use the average (geometric mean) of the subject’s slopes that 
are <= 0 from the other visits to determine the coefficient of elimination λz. Please note 
if the subject’s slopes are positive for all of the visits, baseline corrected PK parameters 
will not be calculated.  
• Adjust each concentration value post-baseline using the following formula:  
cCt = Ct - C0 * e-λzt. 
Unadjusted PK parameters will also be presented.  
An analysis of variance (ANOVA) will be conducted for Day 1 and Day 30 on background-
corrected AUC(0-4h) and Cmax and geometric least square means and 95% confidence intervals 
for each variant and least square mean ratio and 95% confidence intervals of P3P-2mg:P3P-
1mg ratio will be presented. 
Sample Size: 
A total of 60 subjects will be randomized with a 1:1 randomization ratio (~30 subjects 
randomized to P3P-1mg and ~30 to P3P-2mg). The sample size is empirically based.  

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TABLE OF CONTENTS 
SUMMARY OF CHANGES .....................................................................................................2 
SYNOPSIS .................................................................................................................................4 
TABLE OF CONTENTS .........................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................17 
Abbreviations ...................................................................................................................17 
Definitions of Terms ........................................................................................................19 
1 
ETHICS AND REGULATIONS .....................................................................................20 
1.1 
Ethics Committee Approval ...................................................................................20 
1.2 
Ethical Conduct of the Study .................................................................................20 
1.3 
Subject Information and Consent...........................................................................21 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................22 
2 
INTRODUCTION ...........................................................................................................23 
2.1 
Background ............................................................................................................23 
2.2 
Purpose of the Study ..............................................................................................24 
2.3 
Anticipated Benefits and Risks ..............................................................................25 
3 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................27 
3.1 
Primary Objective and Endpoints ..........................................................................27 
3.2 
Secondary Objectives and Endpoints.....................................................................27 
4 
INVESTIGATIONAL PLAN ..........................................................................................29 
4.1 
Overall Study Design and Plan ..............................................................................29 
4.2 
Rationale for Study Design ....................................................................................31 
4.3 
Appropriateness of Measurements .........................................................................33 
4.4 
Study Duration .......................................................................................................33 
5 
STUDY POPULATION ..................................................................................................34 
5.1 
Selection of Study Population ................................................................................34 
5.2 
Discontinuation of Subjects from the Study ..........................................................37 
5.3 
Lost to Follow-Up ..................................................................................................38 
5.4 
Violation of Selection Criteria ...............................................................................38 
6 
INVESTIGATIONAL PRODUCTS ...............................................................................39 
6.1 
Description of Investigational Products .................................................................39 
6.2 
Use of Investigational Products .............................................................................39 
6.3 
Method for Assigning Subjects to Product Variant ...............................................42 
6.4 
Blinding..................................................................................................................42 

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6.5 
Investigational Product Accountability and Compliance ......................................42 
6.6 
Restrictions ............................................................................................................43 
7 
STUDY PROCEDURES .................................................................................................46 
7.1 
Informed Consent...................................................................................................46 
7.2 
Information on the Risk of Smoking, Smoking Cessation Advice and Product 
Debriefing ............................................................................................................46 
7.3 
Clinical Assessments .............................................................................................46 
7.4 
Biomarker Assessment...........................................................................................49 
7.5 
Laboratory Assessments ........................................................................................50 
7.6 
Sample Handling, Storage, and Shipment .............................................................52 
7.7 
Questionnaires........................................................................................................53 
7.8 
Other Study Procedures .........................................................................................56 
8 
ADVERSE EVENTS .......................................................................................................58 
8.1 
Definitions..............................................................................................................58 
8.2 
Collection and Reporting of Adverse Events.........................................................59 
8.3 
Reporting of Serious Adverse Events ....................................................................61 
8.4 
Reporting of Other Events Critical to Safety Evaluations .....................................62 
8.5 
Reporting and Follow–Up of Pregnancies .............................................................63 
8.6 
Adverse Events Leading to Discontinuation..........................................................64 
8.7 
Investigational Product Malfunction and Misuse ..................................................64 
9 
STUDY ACTIVITIES .....................................................................................................65 
9.1 
Screening Visit .......................................................................................................65 
9.2 
Admission Visit .....................................................................................................67 
9.3 
Ambulatory Exposure Period .................................................................................72 
9.4 
Safety Follow-Up Period .......................................................................................76 
9.5 
Early Termination Procedures ...............................................................................76 
10 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................78 
10.1 Monitoring .............................................................................................................78 
10.2 Training of Staff .....................................................................................................78 
10.3 Audits and Inspections ...........................................................................................79 
11 DATA MANAGEMENT ACTIVITIES..........................................................................80 
11.1 Data Capture ..........................................................................................................80 
11.2 Data Handling ........................................................................................................81 
12 PLANNED STATISTICAL METHODS ........................................................................83 

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12.1 General Considerations ..........................................................................................83 
12.2 Determination of Sample Size and Power Consideration ......................................84 
12.3 Analysis Populations ..............................................................................................84 
12.4 Demographics and Baseline Characteristics ..........................................................85 
12.5 Primary Objective and Endpoints ..........................................................................85 
12.6 Secondary Objectives and Endpoints.....................................................................87 
13 ADMINISTRATIVE CONSIDERATIONS ....................................................................89 
13.1 Investigators and Study Administrative Structure .................................................89 
13.2 Subject Confidentiality ..........................................................................................90 
13.3 Access to Source Documentation ..........................................................................90 
13.4 Record Retention ...................................................................................................91 
13.5 Research Study Report ...........................................................................................92 
13.6 Financial Disclosure...............................................................................................92 
13.7 Publication and Disclosure Policy .........................................................................92 
13.8 Insurance ................................................................................................................93 
14 REFERENCE LIST .........................................................................................................94 
15 APPENDICES .................................................................................................................99 
Appendix A – Schedule of Events ...................................................................................99 
Appendix B - Participating Laboratories .......................................................................103 
Appendix C - Laboratory Values ...................................................................................104 
 

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LIST OF IN-TEXT TABLES 
Table 1 
CYP2A6: Substrates, Inhibitors, and Inducers (34)...................................45 
Table 2 
Clinical Laboratory Parameters for Safety Panel.......................................51 
Table 3 
Intensity of Adverse Events .......................................................................60 
Table 4  
Principles for assessing and reporting abnormal laboratory test results ....63 
Table 5 
Time Schedule – Screening Visit [V1] ......................................................65 
Table 6 
Time Schedule – First day of V2 (Day -1) ................................................67 
Table 7 
Time Schedule – Second day of V2 (Day 1) .............................................69 
Table 8  
Time Schedule – Third day of V2 (Day 2) ................................................71 
Table 9 
Time Schedule – V3, V4, V5 .....................................................................72 
Table 10 
Time Schedule – First day of V6 (Day 29) ................................................73 
Table 11 
Time Schedule – Second day of V6 (Day 30) ...........................................74 
Table 12 
Time Schedule – Early Termination ..........................................................77 
Table C1 
Abnormal Laboratory Values Rating: Serum Chemistry Parameters ......104 
Table C2 
Abnormal Laboratory Values Rating: Hematology Parameters ..............105 
Table C3 
Abnormal Laboratory Values Rating: Urine analysis Parameters ...........106 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Flow Chart .........................................................................................7 
Figure 2 
Study Flow Chart .......................................................................................29 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
ABOUT 
Assessment of behavioral outcomes related to tobacco and nicotine products 
AE 
Adverse event 
ANOVA 
Analysis of variance 
AUC(0-4h) 
Area under the concentration-time curve from T0 to 4h after T0 
BMI 
Body mass index 
BoExp 
Biomarker of exposure 
Cmax 
Maximum concentration 
CEMA 
2-cyanoethylmercapturic acid 
CDISC 
Clinical data interchange standards consortium 
CI 
Confidence interval 
CRF 
Case report form 
CRO 
Contract research organization 
CTCAE 
Common terminology criteria for adverse events and common toxicity 
criteria 
CTMS 
Clinical trial management system 
CV 
Coefficient of variation 
CYP2A6 
Cytochrome P450 2A6 
DMP 
Data management plan 
DVP 
Data validation plan 
ECG 
Electrocardiogram 
EOS 
End of study 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good clinical practice 
HIV 
Human immunodeficiency virus 
HPHCs 
Harmful and potentially harmful constituents  
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International council for harmonisation  
IEC 
Independent ethics committee 
IP 
Investigational product 

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LLOQ 
Lower limit of quantification 
λz 
Elimination rate constant 
MedDRA 
Medical dictionary for regulatory activities 
NCP 
Nicotine containing product 
NEQ 
Nicotine equivalents 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic(s) 
PMPSA 
Philip Morris Products S.A. 
RRP 
Reduced risk product 
RSR 
Research study report 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SHM 
Sample handling manual 
SMF 
Study master file 
SMP 
Safety management plan 
SOP 
Standard operating procedure 
T0  
Time point of start of product use 
t1/2z 
Terminal elimination half-life 
tmax 
Time to maximum concentration 
Total NNAL 
Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol 
 
 
ULOQ 
Upper limit of quantification 
VAS 
Visual analogue scale 
WHO 
World health organisation 
 
 
 

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Definitions of Terms 
End of Study 
The end of the study (EOS) for a subject is defined as either the 
Discharge at Day 30, or the date of early termination of the subject, 
plus the Safety Follow-Up Period.  
The end of the whole study corresponds to the individual EOS of 
the last subject. 
Enrollment 
On Admission Visit (Day -1) for eligible subjects after all 
applicable inclusion and exclusion criteria have been satisfactorily 
assessed and met. 
Randomization 
Allocation of the respective product, P3P-1mg or P3P-2mg, after 
product test on Day -1.  
Screen failure 
Subject who signs the ICF but is not enrolled at Admission.  

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1 
ETHICS AND REGULATIONS 
1.1 
Ethics Committee Approval 
Prior to the start of the study, the clinical study protocol, together with its associated documents 
(informed consent form [ICF] including the subject information sheet, subject recruitment 
procedures [e.g., advertisements], written information including questionnaires and 
instructions to be provided to the subjects, Investigator’s brochure [IB], available safety 
information, the Investigator’s curriculum vitae and/or other evidence of qualifications, and 
any other documents requested by the Independent Ethics Committee [IEC]), will be submitted 
for review and approval to the relevant IEC. The IEC shall be appropriately constituted and 
perform its functions in accordance with the International Council for Harmonization (ICH) 
Tripartite Guidance for Good Clinical Practice (GCP) (2) and local requirements, as applicable.  
In accordance with GCP, a written confirmation of the IEC approval should be provided to the 
Sponsor. This should identify the study (Investigator’s name, study number, and title) and the 
documents that have been approved by the IEC, with dates and version numbers, as well as the 
date of approval. The composition of the IEC, including the name and occupation of the 
chairperson, should be supplied to the Sponsor together with a GCP compliance statement.  
The written approval from the IEC will be filed in the Investigator file, and a copy will be filed 
in the study master file (SMF) at the Sponsor or designated organization. No assessment can 
be performed on the subjects before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IEC.  
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the Investigator. All amendments will be submitted 
to the IEC, and substantial amendments will only be implemented after approval by the IEC.  
These requirements for approval should in no way prevent any action from being taken by the 
Investigator or 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 Investigator or designee, 
and is implemented for safety reasons, the Sponsor and the IEC should be informed 
immediately. The Investigator is responsible for local reporting (e.g., to the IEC) of  SAEs that 
occur during the study, according to local regulations.  
Relevant safety information will be submitted to the IEC during the course of the study in 
accordance with national regulations and requirements. Medically qualified study personnel 
will be available during the study.  
1.2 
Ethical Conduct of the Study 
The study will follow the principles as defined in the ICH GCP (2),  in the Declaration of Helsinki 
(3) and other applicable local regulation. The Investigator and any designee agree to conduct the 
clinical study in compliance with the protocol agreed with the Sponsor and approved by the 

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IEC. The Investigator and the Sponsor must sign the protocol (and protocol amendments, if 
applicable) to confirm this agreement. A copy of the Declaration of Helsinki is included in the 
Investigator’s study file. 
1.3 
Subject Information and Consent 
1.3.1 
Informed Consent Form for Study Participation 
Before or at the beginning of the Screening Visit, the 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 Investigator or the designee will answer all 
questions the subject might have to his/her full satisfaction. The subject will have sufficient 
time for consideration of his/her participation in the study and will be notified that he/she is 
free to discontinue his/her participation at any time.  
Once the subject has received all the necessary information, and if he/she agrees to participate, 
this will be documented in the ICF by the date, time and signature of both the subject and the 
Investigator who conducted the informed consent discussion during Screening Visit. No study-
specific procedures will be performed before the ICF has been signed.  
The personally signed and dated original ICF(s) must be kept by the Investigator and filed in 
the Investigator study file at the site or with the subject’s files and a copy must be given to the 
subject.  
Each subject will have to consent that blood samples collected for evaluation of nicotine 
concentrations and CYP2A6 activity as well as urine samples collected for evaluation of 
biomarkers of exposure (BoExp) (i.e. NEQ, NNAL and CEMA) and creatinine will be sent 
abroad for analysis. 
Each subject will also have to consent that blood and urine samples collected for biobanking 
at V2 and V6 will be sent abroad for long-term storage after having received the necessary 
authorization from Russian Authorities. Following completion of this study, biobanking 
samples will be subsequently analyzed. The analytical methods that will be applied include 
biomedical technology including genetic and molecular technology (metabolic, protein, lipid 
and RNA profiling). The subjects will be informed that the analysis of biobanking samples 
does not intend to diagnose any disease. Any results obtained are for research purpose only 
and will not be communicated to the investigator and subjects. The analyses performed will be 
covered by data confidentiality, as for the main analyses described in this protocol. 
The subject will be informed that if he/she withdraws from the study, the data collected until 
the point of withdrawal will be maintained as part of the study data and the samples collected 
prior to withdrawal will be analyzed, unless he/she refuses in writing. The subject will be 
informed that additional data analysis not mentioned in the protocol might be performed with 
the collected data at a later time. Any additional analysis performed will be covered by data 
confidentiality, as for the main analyses described in this protocol.  

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without the written consent of Philip Morris Products S.A. 
1.3.2 
Amendment to the Informed Consent Form  
If a protocol amendment is required, or if any new information regarding the risk profile of the 
investigational product (IP) becomes available, or for any other reason deemed necessary, an 
amendment to the ICF may be required. If a revision of the ICF is necessary, the Investigator 
or designee will, with the support of the Sponsor, ensure that the documents have been 
reviewed and approved by a relevant IEC before subjects are required to re-sign the ICF 
(including date and time). If new and important safety information about the product is 
received, the Sponsor will make every effort to inform current and past study participants as 
appropriate. 
1.4 
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator and designee abide by the principles of the ICH GCP Guideline 
(2). These guidelines apply specifically to pharmaceutical development, but nevertheless 
provide a robust and ethical framework for conducting a clinical study with products such as 
P3P. The study will also be conducted in accordance with the general ethical principles 
outlined in the Declaration of Helsinki (3).  
In addition, the 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 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy 
Cigarette smoking causes pulmonary, cardiovascular and other serious diseases in smokers (4). 
There is no safe cigarette, and the best way for smokers to reduce the adverse health 
consequences of smoking is to quit. Despite the risks which are attributable to smoking, some 
smokers continue smoking. The development of novel tobacco and nicotine containing 
products with the potential to present less risk of harm than cigarettes represents an approach 
to reduce cigarette-related deaths and diseases among smokers who would otherwise continue 
to smoke (5). These products aim to substantially reduce or eliminate the exposure to harmful 
and potentially harmful constituents (HPHCs), with the exception of nicotine, while providing 
acceptable substitutes for cigarettes.  
Several public health agencies have advocated a potential role for such novel products in 
tobacco harm reduction. Public Health England stated “The current best estimate is that e-
cigarettes are around 95% less harmful than smoking” (6) and the Royal College of Physicians 
has recommended “in the interests of public health it is important to promote the use of e-
cigarettes, NRT (nicotine replacement therapy) and other non-tobacco nicotine products as 
widely as possible as a substitute for smoking in the UK” (7). 
In that context, Philip Morris Products S.A. (PMPSA) is developing and scientifically 
substantiating Reduced-Risk Products (RRPs)1  that have the potential to reduce individual 
risk and population harm in comparison to smoking cigarettes. One of these RRPs is P3P.  
2.1.2 
Description of the Product and Scientific Findings 
P3P is a nicotine-containing product (NCP) which generates an inhalable aerosol from 
nicotine-containing powder when air is drawn through it with a sufficient flow rate. By design, 
the P3P aerosol does not contain HPHCs associated with burning/heating tobacco or with 
heating organic carrier compounds such as propylene glycol or glycerol usually found in 
liquids used in e-cigarettes. 
P3P consists of a P3P body in the shape of a cigarette-sized tube which contains a capsule with 
the P3P powder. The capsule is pierced (activated) using a P3P piercing accessory before use. 
The P3P powder is composed of a nicotine-containing powder mixed with menthol flavor 
                                                 
1Reduced-Risk Products (“RRPs”) is the term we use to refer to products that present, are likely to present, or have the 
potential to present less risk of harm to smokers who switch to these products versus continued smoking.  Philip Morris 
Products S.A.I has a range of RRPs in various stages of development, scientific assessment and commercialization.  Because 
Philip Morris Products S.A.’s RRPs do not burn tobacco, they produce far lower quantities of harmful and potentially harmful 
compounds than found in cigarette smoke. 

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particles. The nicotine-containing powder has a particle size that allows deep lung deposition 
whereas the flavor particles have a larger particle size and deposit in the oropharyngeal cavity. 
One P3P product contains 1 or 2 mg of nicotine. 
The ability to regulate smoke and nicotine intake on a puff-by-puff basis has been described to 
occur early in the tobacco-dependence process (8, 9). Changing a current cigarette to a novel 
tobacco /nicotine-containing product requires an adaptation in product use behavior as has 
been described, for example for low-yield cigarettes, electronic cigarettes (e-cigarettes) or a 
novel Tobacco Heating System (10-15). Initial studies with e-cigarettes showed low nicotine 
absorption in smokers (16). Improvements in e-cigarette devices including power settings 
allowed faster and more efficient delivery of nicotine to the users (17). Experienced users of 
e-cigarettes have a high variability in their use behavior reflecting the large variety of e-
cigarette devices, e-liquid nicotine concentrations and flavors (18-20). 
It is expected that subjects in this study will need to adapt their product use behavior to P3P to 
achieve nicotine absorption comparable to smoking cigarettes: P3P does not require heating or 
electronics in its operation, the generation of nicotine-aerosol from nicotine-containing powder 
requires a flow rate that is higher than what has been observed in cigarette smokers (12, 21). 
Non-clinical information on P3P to support this clinical study is presented in the Investigator’s 
brochure (IB) (22). 
One pharmacokinetic clinical study was conducted with P3P in 19 smokers in Switzerland 
(ClinTrials.gov: NCT03369340). In this study, following a single use of four P3P variants, 
nicotine Cmax was 1.1 ng/mL for the 1 mg variant and between 2.1 and 3.1 ng/mL for the 2 mg 
variants and was reached after 15-22.5 minutes (Tmax). Cmax values for P3P were lower 
compared to literature-reported Cmax for cigarettes which ranges between 10-30 ng/mL (23-25) 
or Nicorette® Inhalator, a nicotine replacement therapy, for which Cmax values of 6-8 ng/mL 
have been described (25, 26). Tmax was at a later timepoint for P3P compared to cigarettes for 
which maximal plasma concentration is reached after 5-8 minutes, but earlier compared to 
Nicorette® Inhalator for which Tmax is at 30 minutes. Thus, the observed concentration-time 
profile for P3P is indicative of a partial pulmonary and partial oromucosal absorption compared 
to the pulmonary absorption for cigarettes and the oromucosal absorption of Nicorette® 
inhalator. The adaptation of the product use behavior in these subjects, which were unfamiliar 
with P3P may have been incomplete. The product was generally well tolerated and no safety 
concern was revealed. 
2.2 
Purpose of the Study 
The purpose of the study is to evaluate the adaptation of product use in adult, current cigarette 
smoking subjects between baseline and after 1 month of use of one of two P3P variants.  
The effect of P3P use behavior on nicotine pharmacokinetic (PK) profile, acceptability, as well 
as the safety and tolerability of P3P over a period of 1 month will be investigated. In addition, 
the overall use of tobacco and nicotine containing products will be monitored. 

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without the written consent of Philip Morris Products S.A. 
2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
Information on health risks associated with smoking and smoking cessation advice will be 
provided.  
Any subject who is motivated to quit smoking during the study will be given the opportunity 
to continue his/her smoking cessation attempt and will be referred to appropriate medical 
services for continuing support and counselling at a higher level. The subject will not be 
discontinued from the study, will come to all scheduled visits during which all safety 
assessments will be performed, and his/her financial compensation will not be affected. 
Subjects who decide to quit using tobacco and nicotine containing products will not be 
provided with P3P anymore. 
Subjects who participate in this study will also benefit from repeated and detailed health check-
ups.  
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures 
• 
Risks related to blood sampling (e.g., excessive bleeding, fainting, hematoma, 
paresthesia or infection).  
• 
Risks related to chest X-ray (e.g., a small increase of risk to develop cancer later in life).  
• 
Risk related to spirometry testing procedures (e.g., dizziness or fainting).  
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product  
Although by product design, P3P does not generate toxins and carcinogens as observed with 
cigarette smoking (27), given the current state of knowledge of the product, it has not been 
demonstrated that P3P reduces the risk of developing smoking-related diseases compared to 
cigarettes.  
Due to sensorial and technological differences between P3P and cigarettes, it is expected that 
subjects will adapt their behavior, e.g., by modifying the number, the volume and/or duration 
of puffs, as well as the intensity of inhalation.  
An adult smoker using P3P may experience: 
• Transient nicotine withdrawal symptoms (e.g., urge to smoke, irritability, anxiety feelings, 
restlessness, and difficulty to concentrate) similar to cravings observed during smoking 
cessation; 
• Transient symptoms suggesting mild nicotine overdose such as stimulatory effects on 
sympathetic tone (increased blood pressure, increased heart rate), central nervous system 
(headache, dizziness, tremor, blunting of emotions, and decreased ability to concentrate), 
gastrointestinal system (nausea, hyper-salivation, abdominal pain, vomiting, diarrhea) or 

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respiratory system (cough, increase bronchial secretions, shortness of breath). Individuals 
who experience AEs (suggesting excessive stimulant effects) should be instructed to reduce 
their intensity of product use by decreasing the number of puffs and/or the intensity of 
puffing; 
• Change in smoking habits due to study requirements and related concomitant symptoms, 
e.g., craving. 
All risks related to study procedures or IP will be explained in detail to the subject. Support 
during periods of smoking abstinence will be provided. Further risk mitigation will include:  
• Using commonly accepted research and scientific standards (e.g., blood samples not to 
exceed blood donation standards); 
• Medical assessment of all study subjects with follow-up of those who have experienced 
AE(s)/SAE(s). 
2.3.4 
Unforeseeable Risks 
The possibility of unforeseeable events/risks will be explained in detail to study subjects. 
Subjects will be informed that P3P has not currently been demonstrated to be less harmful than 
cigarettes. Unexpected malfunction of the P3P may lead to unforeseeable risk. Mitigation will 
include close monitoring and medical supervision to detect any unforeseeable risk or safety 
signals at the earliest time possible. 

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3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective and Endpoints 
1. To assess nicotine pharmacokinetics following use of a single P3P-1mg or P3P-2mg product 
on Day 1 and Day 30.  
Endpoints: 
• Plasma nicotine time-concentration profile from prior product use to 4 hours post 
start of product use; 
• PK parameters: maximum plasma concentration (Cmax); time to maximum 
concentration (tmax); Area under the concentration-time curve from start of product 
use to 4 hours (AUC(0-4h)).  
3.2 
Secondary Objectives and Endpoints 
1. To evaluate the pharmacodynamic effects (subjective effects and related behavioral 
assessments) of the two P3P variants. 
Endpoints: 
• Visual Analogue Scale (VAS)-craving assessment in parallel with PK assessment on 
Day 1 and Day 30; 
• Sensory Questionnaire on Day 1 and Day 30; 
• ABOUTTM-Product Experience Questionnaire on Day 1 and Day 30. 
2. To assess product acceptance and puffing/inhalation behavior of both P3P variants  
Endpoints: 
• Product acceptance questionnaire on Day 1 and Day 30; 
• Puffing/inhalation behavior question: 
o Evaluated by site staff on Day 1 and Day 30 
o Answered by subject on Day 2, Day 7, Day 15, Day 22 and Day 29. 
3. To assess nicotine/tobacco product use.  
Endpoints: 
• Number of P3P, cigarettes, e-cigarettes or/and other nicotine/tobacco product use 
from Day 1 to Day 30; 
• Change in the number of cigarettes used throughout the study as compared to the 
reported number at Screening.  

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4. To assess safety and tolerability during the study. 
Endpoints: 
• Incidence of adverse events (AEs), serious adverse events (SAEs);  
• Frequency of adverse events (AEs), serious adverse events (SAEs);  
• Incidence of P3P product events including malfunction/misuse;  
• Frequency of P3P product events including malfunction/misuse; 
• Physical examination changes from baseline; 
• Cough assessment changes from baseline (VAS and three Likert scales) ; 
• Electrocardiogram (ECG) changes from baseline (heart rate, PR, QRS, QT, QTcB, 
QTcF intervals); 
• Vital signs changes from baseline (systolic and diastolic blood pressure, pulse rate and 
respiratory rate); 
• Spirometry changes from baseline (FEV1, FEV1 % predicted, FVC, FVC % predicted, 
FEF 25, FEF 25 % predicted, FEF 75, FEF75 % predicted, FEF 25-75, FEF 25-75 % 
predicted, FEV1/FVC); 
• Changes from baseline in clinical chemistry, hematology, and urinalysis safety panel; 
• Concomitant medications. 
5. To assess the exposure to harmful and potentially harmful constituents (HPHCs) in spot 
urine expressed as concentration adjusted for creatinine from Day -1 to Day 30. 
Endpoints: 
• Biomarker of exposure (BoExp) to nicotine: Nicotine equivalents (NEQ); 
• BoExp to NNK: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL);  
• BoExp to Acrylonitrile: 2-cyanoethylmercapturic acid (CEMA).  
6. To assess tobacco and nicotine containing product dependence at Day -1 and at Day 30. 
Endpoint: 
• ABOUTTM-Dependence Questionnaire.  
7. To assess cytochrome P450 2A6 (CYP2A6) enzymatic activity at Day 1 and at Day 30. 
Endpoint: 
• Molar metabolic ratio of trans-3’-hydroxycotinine/cotinine in plasma. 
8. To estimate the amount of powder extracted from P3P used for PK assessment. 
Endpoint: 
• 
Weight difference of P3P before and after use. 

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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a randomized, double-blinded, 2-arm parallel groups, single-center study conducted in 
current adult smokers willing to switch from smoking cigarettes to using P3P for 1 month. P3P 
product use will be of up to 15 products per day over 1 month and the study will include 2 
occasions of confinement period (3 days at V2 and 2 days at V6). From the start of the exposure 
period onwards, subjects will be instructed to use P3P exclusively. Subjects will be randomized 
to use either P3P-2mg or P3P-1mg. 
  
 
Figure 2 Study Flow Chart 
 
The Screening Visit (V1 [Day -22 to Day -2]) 
A Screening Visit will be conducted within 3 weeks prior to Admission to the investigational 
site. Eligibility criteria will be verified at the Screening Visit (section 5.1). A demonstration of 
P3P (without product use) will be done by the investigational site staff.  

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The Admission Visit (V2 [Day -1]) 
At V2, subjects will return to the investigational site for Admission (Day -1). Subjects should 
have been fasting for at least 6 hours prior to Admission. After confirmation of eligibility, 
subjects will be enrolled and will undergo baseline assessments. All subjects that are not 
enrolled will be considered as screen failures. At Admission, enrolled subjects will perform a 
product test using up to 6 P3P products (alternating between P3P-1mg and P3P-2mg). In order 
to continue in the study, each subject will need to test at least one product of each P3P variant 
during the product test. Subjects should be abstinent from the use of any tobacco/nicotine 
containing products for at least 4 hours prior to product test. After the product test, subjects 
not willing and/or not ready to use P3P will be discontinued from the study and will undertake 
early termination procedures on the same day (section 9.5) and will enter the 14-day Safety 
Follow-Up Period. Subjects willing and ready to use P3P during the study will be randomized 
either to P3P-1mg or P3P-2mg in a 1:1 ratio and will start their first overnight (confinement) 
period for pharmacokinetics assessments on Day 1. The subjects and the Investigator will be 
blinded to the randomization arm. 
The Exposure Period (V2 [Day 1] to discharge at V6 [Day 30]) 
On Day 1, after at least 10 hour abstinence from any tobacco/nicotine containing products, 
subjects will use a single P3P product, as randomized, for a duration of up to 15 minutes. The 
start of product use (first puff taken) will be defined as T0.  
A total of 11 blood samples will be taken for PK parameter estimation. Three blood sample 
will be taken prior to the product use (T0): 1 hour ± 5 minutes, 30 minutes ± 5 minutes and 5 
minutes ± 2 minutes before T0. Thereafter in relation to T0, blood will be drawn at the following 
time points: after 4 minutes ± 1 minute, after 7 minutes ± 1 minute, after 10 minutes ± 1 minute, 
after 15 minutes ± 2 minutes, after 30 minutes ± 2 minutes, after 1 hour ± 5 minutes, after 2 
hours ± 5 minutes and after 4 hours ± 5 minutes. 
Pharmacodynamic effects related to craving will be assessed using a VAS scale at different 
time points. The first assessment will be done 10 minutes ± 2 minutes prior to T0, all other 
assessments will be done after T0, at 4 minutes ± 2 minutes, 10 minutes ± 2 minutes, at 15 
minutes ± 2 minutes, 30 minutes ± 5 minutes, 1 hour, 2 hours, 4 hours ± 10 minutes each. VAS 
will be assessed immediately after the collection of the time-matching PK samples.  
Product evaluation using the ABOUTTM-Product experience questionnaire, the sensory 
questionnaire and the product acceptance questionnaire will be assessed after the end of 
product use. 
Each P3P used for PK assessment will be weighed before and after product use to estimate the 
amount of powder/nicotine extracted from the product. 
After the end of blood sampling for PK estimation, subjects will stay on-site until the evening 
of Day 2 and will be allowed to use up to 15 P3P products/daily during these two days. Safety 
assessments will be performed both on Day 1 and Day 2. 

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Subjects will be instructed to use exclusively P3P for the entire 1-month duration of the 
exposure period (from the end of V2 until discharge at V6). Use of cigarettes and/or other 
tobacco and nicotine containing products during the ambulatory exposure period will not be a 
reason for discontinuing a subject from the study, but should be avoided as much as possible. 
At V2, subjects will be trained on how to record their use of P3P and other tobacco/nicotine 
containing products in a designated website during the entire period of the study. 
Subjects will return to the investigational site for weekly visits V3 (Day 7), V4 (Day 15), V5 
(Day 22) and V6 (Day 29) with a visit time window of ± 2 days each. The visit days and 
windows will be calculated from Day 1. During these visits product will be resupplied and 
selected safety assessments will be performed. 
At V6 subjects will remain at the investigational site for their confinement period for 
pharmacokinetics assessments on the second day of this visit, Day 30. There will be a washout 
period from any nicotine/tobacco containing products of at least 10 hours before T0 to allow 
adequate background correction of the nicotine plasma concentrations. The assessments 
performed at Day 30 will be the same as those described for Day 1. 
The Safety Follow-Up Period (from Discharge or Early Termination plus 14 days) 
After discharge on Day 30 or early termination, subjects will enter a 14-day Safety Follow-Up 
Period during which new AE/SAEs will be collected and ongoing AEs/SAEs will be followed-
up by the site. At the end of the Safety Follow-Up all subjects will be contacted via phone in 
order to check the status of the ongoing AEs and also to collect any new AEs experienced by 
the subjects. Subjects should be contacted 14-days after Day 30. In case they cannot be reached 
two additional attempts at the next 2 consecutive days will be made. If the subjects cannot be 
reached after the three attempts they will be declared lost to follow-up. Phone calls should be 
recorded in the source documents. Any non-serious AE that is ongoing at the time of discharge 
or early discontinuation or previously reported during the Safety Follow-Up will be followed-
up by the Investigator or designee during Safety Follow-Up 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) or the subject is 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 further 
follow-up information will be sought for them by the Investigator or designee. At that point, 
the Investigator will assess whether the subject should be referred to his/her General 
Practitioner to have their ongoing AEs addressed accordingly. All SAEs will be followed up 
by the Investigator until resolution, stabilization or the determination of a plausible explanation 
for them was found, regardless of the end of the Safety Follow-Up Period. 
4.2 
Rationale for Study Design 
The minimum age of 21 years old in the inclusion criteria was selected based on the legal age 
of smoking in Russia which is 18 years old and to account for the 3 years of smoking history. 

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In a previous study conducted with P3P (ClinTrials.gov: NCT03369340), the pharmacokinetic 
profiles of nicotine following a single use of P3P were indicative of a partial pulmonary and 
partial oromucosal absorption with lower plasma nicotine levels compared to published data 
for single cigarette smoking (23, 24). It is well established that changing a current cigarette to 
a novel tobacco /nicotine-containing product requires an adaptation in product use behavior as 
has been described for low-yield cigarettes, e-cigarettes or a novel Tobacco Heating System 
(10-15). The changes in product use behaviour over time (e.g. potential changes in 
puffing/inhalation process) may result in changes in the nicotine PK profiles in particular in 
the absorption phase. For this reason, nicotine PK profiles and parameters following a single 
product use will be assessed at the beginning of the exposure period (Day 1) and at the end of 
the exposure period following adaptation to product use (Day 30). Sampling timepoints for 
determination of nicotine concentrations were selected to ensure reliable estimation of PK 
parameters.  
Plasma nicotine presents a biphasic profile, with a typical rapid initial disposition half-life 
(t1/2α) of 1.35 hours, followed by a slower terminal elimination half-life (t1/2z) of 17 hours (28). 
To ensure a full nicotine washout between each product use, a separation of 3 days would have 
been required (~ 5 x elimination t1/2z). Based on nicotine population PK modeling, it was 
estimated that subjects’ nicotine has entered in the terminal elimination phase with 
concentrations decreasing according to the terminal elimination rate constant (λz) after 8 to 10 
hours post administration. As a consequence, a minimum of 10 hours have been established in 
this study design before the start of product use for PK assessment to ensure appropriate 
washout of nicotine. Background-concentration correction will be applied to adjust for any 
residual carry-over effects as detailed in section 12.5.1.  
In addition to the nicotine PK assessment in plasma, exposure to nicotine during the 
ambulatory exposure period will be assessed by measuring urinary concentrations of nicotine 
equivalents (NEQ) in spot urine adjusted for creatinine. During cigarette smoking, on average 
98% of the nicotine dose can be accounted for in the urine. NEQ, which is the molar sum of 
nicotine and five of it’s phase I and phase II metabolites in urine, represents more than 90% of 
the total dose recovered in urine (29). 
Biomarkers of exposure to HPHCs found in tobacco and cigarette smoke will be measured 
during the study to detect reduction in the levels of these BoExp. Changes in levels of the 
tobacco-specific BoExp, total NNAL (30), and the BoExp to acrylonitrile, CEMA (31) which 
are predominantly formed during combustion of tobacco will be measured in spot urine 
adjusted for creatinine. Adjustment for creatinine will be performed to normalize for volume 
of urine excretion. As P3P is a nicotine containing product and the aerosol generated by P3P 
does not generate by design HPHCs other than nicotine, the levels of CEMA and total NNAL 
may be further used to detect cigarette use in addition to P3P use during the ambulatory 
exposure period and used as a chemical verification of the self-reporting. 
The activity of CYP2A6 will be measured. CYP2A6 activity drives the metabolism of nicotine 
to cotinine and subsequent metabolites. Nicotine metabolism by CYP2A6 varies between 

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individuals of the same ethnicity/race and across ethnicity/race due to genetic variations. These 
genetic differences could be associated with reduced/increased nicotine metabolism (25). 
4.3 
Appropriateness of Measurements 
All bioanalytical assays and laboratory assessments performed in the study will be carried out 
using appropriate and validated methods. Questionnaires used in this study, except product 
acceptance, craving VAS and cough assessment questionnaires, are available as 
validated/previously published or adapted versions of validated questionnaires. Of note, 
questionnaires used to assess global dependence and product experience are part of the 
ABOUT™ (Assessment of Behavioral OUtcomes related to Tobacco and nicotine products) 
Toolbox, an initiative resulting from a collaborative effort to develop fit-for-purpose 
measurement instruments (i.e., concept-driven instruments providing interpretable outcomes 
for the purpose intended) to enhance the scientific framework of harm reduction (32). 
4.4 
Study Duration 
The entire study per subject will last 44 to 70 days. This will include a screening period of up 
to 3 weeks prior to Admission (Day -22 to Day -2), the admission day, 30-day period of P3P 
use of up to 15 products per day (Day 1 to Day 30), and a 14-days Safety Follow-Up Period. 
The end of the study (EOS) for a subject is defined as either the Discharge at Day 30, or the 
date of early termination of the subject, plus the 14 days for the Safety Follow-Up Period. The 
end of the whole study corresponds to the individual EOS of the last subject. 

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5 
STUDY POPULATION 
5.1 
Selection of Study Population 
Sixty female or male healthy adult subjects who have smoked between 5 and 15 cigarettes per 
day for the last 3 months prior to Screening will be randomized in this study. Each 
randomization group (P3P-1mg, P3P-2mg) will be stratified on sex distribution to ensure that 
at least 40% of each sex is randomized in each exposure group. 
5.1.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be enrolled into the study: 
Inclusion Criteria 
Rationale 
Screening  
Admission 
(Day -1)  
1. Subject has signed and dated the ICF and is able 
to understand the information provided in it. 
Administrative 
X 
 
2. Subject is male or female aged between 21 and 
65 years old inclusive. 
Safety 
X 
 
3. Subject has been a smoker for at least the last 3 
years prior to the Screening visit and has 
smoked 5 to 15 commercially available 
cigarettes per day over the last 3 months prior to 
Screening. 
Effect 
X 
 
4. Subject has a positive urinary cotinine test 
(cotinine ≥ 200 ng/mL). 
Effect  
X 
X 
5. Subject does not plan to quit smoking in the next 
2 months. 
Safety 
X 
X 
6. Smoking, healthy subject as judged by the 
Investigator or designee based on available 
assessments from the Screening period (e.g., 
safety laboratory, spirometry, vital signs, 
physical examination, chest X-ray, ECG and 
medical history). 
Safety 
X 
 
7. Availability for the entire study period and 
willingness to comply with study procedures, 
including intermittent dietary restrictions. 
Effect 
X 
X 
8. Ready to switch from smoking cigarettes to 
using P3P for the duration of the study.  
Effect 
X 
 

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5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the study: 
Exclusion Criteria 
Rationale 
Screening  Admission 
(Day -1)  
1. As per the Investigator’s judgment, the subject 
cannot participate in the study for any reason 
other than medical (e.g., psychological, social 
reason).  
Safety  
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). 
Administrative 
X 
 
3. Subject has a clinically relevant disease which 
requires medication (including but not limited 
to gastrointestinal, renal, hepatic, neurological, 
hematological, 
endocrine, 
oncological, 
urological, immunological, pulmonary, and 
cardiovascular disease) or any other medical 
condition (including safety laboratory as per 
CTCAE), which as per the judgment of the 
Investigator would jeopardize the safety of the 
subject.  
Safety 
X 
 
4. As per the Investigator’s judgment, the subject 
has medical conditions which require or will 
require in the course of the study, a medical 
intervention (e.g., start of treatment, surgery, 
hospitalization) which may interfere with the 
study participation and/or study results.  
Effect  
X 
 
5. Subject 
has 
asthma 
condition 
(post-
bronchodilator 
FEV1/FVC 
< 
0.75 
and 
reversibility in FEV1 ≥ 12% and > 200 mL from 
pre- to post-bronchodilator values). 
Safety 
X 
 
6. Subject has (FEV1/FVC) < 0.7 and FEV1 < 80% 
predicted 
value 
at 
post-bronchodilator 
spirometry. 
Safety 
X 
 
7. Subject has a history of hypersensitivity to 
 or menthol. 
Safety 
X 
 

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Exclusion Criteria 
Rationale 
Screening  Admission 
(Day -1)  
8. Subject has a contraindication for using 
salbutamol and/or albuterol as per the 
summary of product characteristics for the 
given product 
Safety 
X 
 
9. Subject has donated or received whole blood or 
blood products within 3 months prior to 
Screening Visit.  
Safety 
X 
 
10. BMI < 18.5 kg/m2 or ≥ 32.0 kg/m2.  
Safety 
X 
 
11. Subject has received medication within 14 days 
or within 5 half-lives of the drug prior to 
Admission (whichever is longer) which has an 
impact on CYP2A6 activity. 
Effect 
 
X 
12. Subject has a positive serology test for HIV 1/2, 
Hepatitis B, or Hepatitis C.  
Safety 
X 
 
13. The subject has a positive alcohol breath test 
and/or had a history of alcohol disorder within 
the past 2 years.  
Administrative 
X 
X 
14. The subject has a positive urine drug test.  
Administrative 
X 
X 
15. Subject or one of their family membersa is a 
current or former employee of the tobacco 
industry.  
Administrative 
X 
 
16. Subject or one of their family membersa is 
employee of the investigational site or of any 
other parties involved in the study.  
Administrative 
X 
 
17. The Subject has participated in another clinical 
study within 3 months prior to the Screening 
Visit.  
Safety 
X 
 
18. Subject has been previously screened or 
enrolled in this study.  
Administrative 
X 
 
19. Subject is pregnant (does not have negative 
pregnancy tests at Screening Visit and at 
Admission) or is breastfeeding.  
Safety  
X 
X 

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Exclusion Criteria 
Rationale 
Screening  Admission 
(Day -1)  
20. For women of childbearing potential onlyb: 
subject does not agree to use an acceptable 
method of effective contraception.c 
Safety  
X 
 
a. 
As defined by FDA guidance on Human Subject Protection (21 CFR 50.3(l), (m), 50.24(a)(6), (a)(7)(v), b)): "Family 
member” means among other things “parent”, “spouse”, "brothers, sisters, and spouses of brothers and sisters" and “any 
individual related by affinity…whose close association with the subject is equivalent of a family relationship” 
b. 
Women who are not of childbearing potential meet at least one of the following criteria:  
Have undergone hysterectomy or bilateral tubal ligation,  
Have primary ovarian insufficiency, or  
Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no 
alternative pathological or physiological cause). 
c. 
Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with spermicidal 
foam/gel/film/suppository, hormonal contraception, vasectomized partner(s), or true abstinence (periodic abstinence and 
withdrawal are not effective methods) from Screening until the end of the Safety Follow-Up Period.  
 
5.2 
Discontinuation of Subjects from the Study 
Discontinued subjects will include both subjects who withdraw from the study (subject’s 
decision) or subjects who are discontinued from the study by the decision of the Investigator. 
A subject can only be discontinued from the study after enrollment.  
Subjects will be informed that they are free to withdraw from the study at any time. Subjects 
will be questioned for the reason for withdrawal from the study, although they are not obliged 
to disclose it. If the subject withdraws from the study, he/she will be asked to confirm that 
he/she agrees to undertake the early termination procedures for safety assessments, and this 
information will be fully documented by Investigator. 
The subject will be informed that if he/she withdraws from the study, the data collected until 
the point of withdrawal will be maintained as part of the study data. The samples collected 
prior to withdrawal will be analyzed, even after his/her withdrawal unless the subject confirms 
his/her disagreement to the site staff and the disagreement is documented. 
When a subject is discontinued from the study, all early termination procedures (section 9.5) 
will be performed unless the subject refuses to perform the assessments. Early termination 
procedures are to be performed only for subjects who have been exposed to P3P. Early 
termination visit should be performed within 7 days from the date of discontinuation. After the 
date of termination, the subject will enter into the 14-day Safety Follow-Up Period. This 
applies to all subjects independent of the reason of discontinuation (for example, withdrawal 
of consent, or at the Investigator’s decision etc). 
Subjects must be discontinued from the study for any of the following reasons:  
• Withdrawal of informed consent. 

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• Any AE/SAE or condition (including clinically significant changes in a laboratory 
parameter), which at the discretion of the Investigator no longer justifies the subject’s 
participation in this study. 
• Positive pregnancy test (section 8.5). 
• The Sponsor or Investigator terminates the study or the study terminates at a particular 
investigational site. If the Sponsor or the Investigator decides to prematurely terminate the 
study, the subject will be promptly informed. The head of the investigational site should 
report the fact and the reason in writing to the IEC. 
• Discontinuation is considered to be in the best interest of the subject or the other subjects 
as judged by the Investigator.  
• Subject is not willing to use P3P after the product test at Admission. In such a situation, 
the subject will be discontinued immediately after the product test. 
Subjects may be discontinued from the study for the following reason:  
• Non-compliance with the study procedures based on the judgment of the Investigator. 
Use of any tobacco and nicotine containing product other than P3P during the ambulatory 
exposure period will not lead to the discontinuation of the subject from the study. However, 
the subjects will be instructed to use exclusively P3P (up to 15 products daily) during this 
period. Until randomization subjects can be replaced, however subjects that discontinue the 
study after randomization will not be replaced. 
5.3 
Lost to Follow-Up 
Reasonable number of attempts (at least three attempts on three different days) to contact the 
subject (including written correspondence and phone calls) should be done and documented in 
the source documents by the site. When the Investigator or designee(s) declare(s) a subject is 
lost to follow-up, the lost to follow-up date will be recorded. The date of lost to follow up 
corresponds to the date of the end of study of the subject.  
If the investigational site has lost track of the subject but the subject has reached the maximum 
number of study days (70 days), then the Investigator or designee(s) will declare the subject 
lost to follow-up at this date. 
5.4 
Violation of Selection Criteria 
Any subjects who do not meet the entry criteria after signing the ICF and prior to Enrollment 
at Admission will be considered as screen failures and will be replaced by other subjects. Re-
screening of subjects will not be permitted.  
Any violation of selection criteria detected after enrollment have to be reported within 24 hours 
after awareness to the Clinical Research Associate (Monitor). 

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6 
INVESTIGATIONAL PRODUCTS 
6.1 
Description of Investigational Products 
6.1.1 
Investigational Products 
P3P is a novel type of nicotine-containing product (NCP) which generates an inhalable aerosol 
from nicotine-containing powder when air is drawn through it. P3P does not contain tobacco 
and does not require heating and/or electronics for its operation. 
It is a single use product which has two components that perform different functions:  
• A consumable component, which comprises a tube-shaped body and a capsule 
containing the P3P powder. Once the capsule is activated, i.e. pierced with an accessory 
component, the user is able to draw on the consumable so that airflow passes through 
the consumable and releases the powder from the capsule. 
• An accessory component, which is a mechanical unit with a needle to pierce the capsule 
that enables the release of the powder from the capsule. Each capsule should be pierced 
immediately before product use. 
The P3P powder is composed of a nicotine-containing powder mixed with menthol flavor 
particles. The nicotine-containing powder has a particle size that allows deep lung deposition 
whereas the flavor particles have a larger particle size and deposit in the oropharyngeal cavity. 
One P3P product contains 1 (P3P-1mg) or 2 mg (P3P-2mg) of nicotine. 
P3P will be provided by the Sponsor and its distribution by site will be controlled by a qualified 
and appropriately trained designee as specified in the IP handling manual.  
6.1.2 
Packaging and Labeling 
Five P3P consumables will be packed in a pouch. Four pouches (or 20 Consumables) and one 
accessory will be packed in a pack. Six packs will be packed in a carton. Each 
carton/pack/pouch will be labelled with the necessary information according to local regulatory 
requirements, and blinding requirements. The contents of each label will be specified in the IP 
handling manual.  
6.2 
Use of Investigational Products  
Subjects can use up to 15 P3P products daily during the exposure period, except during the PK 
assessments and wash-out hours preceeding those assessments, as described below. Subjects 
will never be forced to use P3P and will be free to stop using P3P at any time during the study.  

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6.2.1 
Admission (Day -1 – V2) 
After enrollment, subjects will be required to perform product test by using up to 6 P3P 
products (alternating between P3P-1mg and P3P-2mg). In order to continue in the study, each 
subject will need to test at least one product of each P3P variant during the product test. Product 
test must be performed after the subjects have abstained from the use of any tobacco/nicotine 
containing products for at least 4 hours (4h wash-out period prior to product test). The product 
test period should be organized in a dedicated supervised area (i.e. not a dedicated cigarette 
smoking area). Subjects will be instructed on how to activate and use P3Pas specified in the 
P3P user guide. . They will be asked to puff with sufficient intensity to trigger the spinning of 
the capsule. The subject should hear the sound of the capsule spin and/or feel the vibration of 
the product induced by the spinning. Product test should end at least 10 hours prior to the start 
of product use for PK assessment on Day 1 (section 6.2.2) 
After the product test, subjects not willing and/or unable to use P3P will be discontinued from 
the study and will enter a 14-day Safety Follow-Up Period. 
At Day -1, after check-in on site, subjects will not be allowed to smoke cigarettes and/or use 
any other tobacco/nicotine containing products with the exception of P3P which can only be 
used during the product test period. 
6.2.2 
Product use during confinement (V2, V6) 
During the investigational period subjects will be requested to attend two on-site  visits with 
overnight stays (with a confinement of 3-days at V2 and 2-days at V6). At the beginning of 
these visits, subjects will be asked to give their cigarettes and used/unused P3P products to the 
site staff. 
Smoking cigarettes and/or use any tobacco/nicotine containing products other than P3P will 
not be allowed on site during the visits. On the first day of V6 (Day 29), subjects will be 
allowed to use P3P until the evening which will be subsequently followed by a wash-out period 
of at least 10 hours prior to the PK assessments which will be done on the second day of the 
visits. P3P use on the first day of V2 will only be allowed during the product test period (section 
6.2.1). P3P will be dispensed by the site staff on a product by product basis during the 
timeframe allowed by the protocol. The distribution should be recorded at site logs by site staff 
and the use of any product during the confinement days should be also recorded in the product 
use diary which is completed by the subject. The time of the use of the last tobacco/nicotine 
containing product, prior to the start of the wash-out period should be recorded.  
In the morning of the second day of V2 (Day 1) and V6 (Day 30), following at least 10 hours 
of abstinence from any tobacco and nicotine containing products, subjects will use a single 
P3P product with no restrictions on the number of puffs or puffing frequency (ad libitum use) 
for a duration of up to 15 minutes. The start of product use (first puff) will be considered as 
T0. The start and stop time of product use will be recorded. At V2 (Day 1), after the end of the 
blood sampling for PK assessments (4h after T0) subjects will be allowed to restart the use of 

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P3P. Subjects will remain on-site until the evening of Day 2 and will be allowed to use up to 
15 P3P products/day on Day 1 and Day 2. During this time, subjects will not be allowed to 
smoke cigarettes and/or use any other tobacco/nicotine containing products with the exception 
of P3P. 
6.2.3 
Ambulatory Exposure Period (Discharge at V2 until start of V6) 
Subjects will be instructed to use P3P exclusively (using up to 15 products daily) from 
discharge at V2 until check-in at V6. Use of cigarettes and/or other tobacco and nicotine 
containing products during the ambulatory Exposure Period will not be a reason for 
discontinuing a subject from the study, but should be avoided as much as possible. During the 
entire exposure period, subjects will report their daily consumption in a product use diary 
(section 7.8.1) 
6.2.4 
Safety Follow-Up Period 
Use of the investigational product will not be permitted during the Safety Follow-Up Period. 
Subjects will be allowed to use their own cigarettes. 
6.2.5 
Stopping Rules for Investigational Product  
For safety purposes, use of P3P should be temporarily reduced (decreasing number or/and 
intensity of puffs) or stopped in the event of any signs suggesting nicotine overexposure, e.g., 
gastrointestinal disturbance (nausea, vomiting, diarrhea, stomach or abdominal pain), cold 
sweats, headache, dizziness and breathing problems, or any other reasons at the discretion of 
the Investigator.  Signs suggesting respiratory disturbance  (e.g., wheezing, dyspnoea, chest 
tightness) which may be related to P3P powder inhalation could also be taken in consideration 
for P3P reduced use or P3P stopping. 
6.2.6 
Stopping Rules for the Study  
The study may be stopped if the subjects are placed at risk because of clinically significant 
findings or SAEs that, for example:  
• are assessed as causally related to P3P 
• are not considered to be consistent with continuation of the study 
• are not consistent with the information provided in Section 6.5 of the current P3P 
Investigator’s Brochure.  
The Sponsor, Investigator, and/or Ethics Committee(s) reserve the right to terminate or 
suspend the study at any time; however this should be discussed between the relevant parties 
beforehand and the reason for such decision recorded. Should this occur, all data available will 
also be recorded in the case report forms (CRFs). 

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The Investigator should notify the EC in writing of the study’s completion or early termination. 
In the event that the study is terminated early, every effort should be made by the Investigator, 
investigational site personnel, and Sponsor to follow AEs and SAEs for all subjects until the 
end of the 14-Day Safety Follow-Up Period. 
6.3 
Method for Assigning Subjects to Product Variant 
At Day -1 after product test subjects who confirmed their willingness to continue in the study 
will be randomized using an interactive web response system (IWRS). Subjects will be 
randomized to one of the two arms: P3P-1mg or P3P-2mg in a 1:1 ratio. 
Each randomization group (P3P-1mg, P3P-2mg) will be stratified on sex distribution to ensure 
that at least 40% of each sex is randomized in each group. 
6.4 
Blinding 
This is a double-blinded study. Neither the site staff (except designated unblinded site staff if 
applicable) nor the subject will be informed about the product variant the subjects have been 
randomized to. PMPSA and CRO personnel will not be blinded to the randomization arm. 
Blinding process will be described in more details in the IP handling manual.  
6.5 
Investigational Product Accountability and Compliance 
6.5.1 
Dispensing Investigational Products  
Product test at the investigational site: Product test will be performed using up to 6 P3P 
products(alternating between P3P-1mg and P3P-2mg). In order to continue in the study, each 
subject will need to test at least one product of each P3P variant during the product test. 
Distribution of the P3P product will be done by site staff on a product by product basis for each 
use. The distribution should be recorded at site logs by site staff.  Used P3P consumables will 
be returned to the site staff at the end of each use. 
Products for PK assessment and on-site use during confinement: The single P3P products used 
for PK assessment (second day of V2 and V6) will be provided to the subject by the site staff 
shortly before product use, after the product has been weighed, and will be returned to the site 
staff immediately after use, for after-use weighing (section 7.8.2). The products used for PK 
assessment will be activated (pierced) by the site staff immediately before product use.  
All other products used during the confinement period will be dispensed by site staff on a 
product by product bases during the timeframe allowed by the protocol and will be activated 
by the subjects themselves.  
Products for ambulatory exposure period: Starting from V2, prior to the Check-out of each 
visit, subjects will be provided with a sufficient number of P3P packs to cover their needs until 
the next visit. In the situation in which site staff judges that a re-supply is needed, optional 

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extra visits may be accommodated. At the visits during the ambulatory period, subjects will be 
asked to return all used and unused P3P packs and consumables. At V6, unused products 
should be returned at the beginning of the visit.  
6.5.2 
Storage and Accountability 
The Investigator or designee will be responsible for the storage and accountability of P3P on site, 
in accordance with the Sponsor’s requirements. The subject should be instructed to follow the 
storage and handling requirements of P3P as specified in the User guide.  
The P3P components will be stored in a secured storage place at the investigational site with 
access limited to the authorized personnel only and according to the blinding requirements 
specified in the IP handling manual. Full accountability of the distributed products will be 
ensured by recording the timing and quantities of distributed products at each visit in appropriate 
logs by the designated site staff. Products used for product test, products dispensed during V2 
and V6 and products used for PK will also be registered in an appropriate log. 
6.5.3 
Investigational Products Retention  
Used and unused P3P products remaining on site will be destroyed or returned to the Sponsor 
upon study completion and as agreed with the Sponsor.  
6.5.4 
Compliance to Investigational Products  
From Check-out at V2 until Discharge at V6, P3P product use compliance will be based on the 
daily self-reporting by the subjects in the product use diary (section 7.8.1). BoExp (Total 
NNAL and CEMA) may be used as additional tools for verifying cigarette smoking in addition 
to P3P use during analyses. 
6.6 
Restrictions 
6.6.1 
Smoking and Product Use Restrictions 
During the Screening period, subjects will be allowed to smoke according to their smoking 
habits except during the procedures of the Screening Visit (section 9.1). At Day -1 of V2, after 
check-in on site, smoking cigarettes and/or use any other tobacco/nicotine containing products 
will not be allowed. P3P use will be allowed only during the product test period.  
From Day 1 until the end of the exposure period (Day 30) subjects will be instructed to 
exclusively use P3P. During the ambulatory visits, P3P use will be allowed except during 
procedures and at the discretion of the investigational site. In general, the performance of 
scheduled procedures has priority over the wish of a subject to use P3P. Use of cigarettes will 
not be allowed on site during the study visits. 

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An abstinence period from any tobacco/nicotine containing products of at least 10 hours must 
be respected before product use for PK assessment at Day 1 and Day 30 and during the blood 
sampling for nicotine measurement. 
During the overnight on-site visits (V2 and V6) P3P will be dispensed by the site staff on a 
product by product basis during the timeframe allowed by the protocol. Dispensing will be 
recorded in an appropriate log (section 6.5) 
6.6.2 
Dietary Restrictions 
During the overnight on-site visits: V2 and V6, a standard diet will be designed for the whole 
confinement period. For each meal, the caloric and fat content should be controlled in order to 
avoid a “high-fat” diet. The FDA guidance on food-effect studies for bioequivalency testing 
identifies a “high-fat” diet as a diet which contains “approximately 50 percent of total caloric 
content of the meal [from fat] and is high in calories (approximately 800 to 1000 calories) 
(33).” Subjects are not allowed to bring their own food or beverages to the investigational site. 
Meals will be served according to the schedules provided in section 9. During these visits, 
consumption of water is allowed as desired. Consumption of quinine-containing drinks (e.g., 
tonic water) is not allowed. Subjects should be instructed to refrain from ingesting foods or 
beverages containing grapefruit or seville-type (bitter) oranges and marmalade within 7 days 
prior to the PK assessment days (Day 1 and Day 30). The same menu and meal schedule will 
be administered uniformly for all subjects.  
There will be no dietary restrictions during the ambulatory exposure period.  
Fasting state has to be observed for at least 6 hours prior to safety laboratory and biobanking 
blood draws at V2, V4 (safety laboratory only) and V6. 
6.6.3 
Concomitant Medication 
All medication taken within 4 weeks prior to the ICF signature will be considered prior 
medication. All medication taken from Screening Visit to end of the Safety Follow-Up Period 
will be considered concomitant medication. No concomitant medication should be taken by 
the subjects from Screening until the end of the ambulatory exposure period without informing 
the Investigator or designee. 
CYP2A6 is involved in nicotine metabolism. To be eligible for the study any medication with 
impact on CYP2A6 metabolism including, but not limited to medication listed in Table 1, must 
have been discontinued at least 14 days prior to Admission or for at least 5 half-lives 
(whichever is longer). It is at the discretion of the Investigator to assess if a termination of such 
medication is medically justified and safe for the subject. In addition, any medication with 
impact on CYP2A6 activity must be avoided at least 14 days prior to the PK assessment at Day 
1 and Day 30 or for at least 5 half-lives of the drug (whichever is longer). Prior to database 
lock, concomitant medication will be reviewed according to their potential impact on CYP2A6 
activity and assessed for their potential impact on the study results.  

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Table 1 
CYP2A6: Substrates, Inhibitors, and Inducers (34) 
Inhibitor 
Drug Class 
Amiodarone 
Antiarrhythmic agent, Class III 
Desipramine 
Antidepressant 
Isoniazid 
Anti-bacterial drug  
Ketoconazole 
Anti-fungal medication  
Letrozole 
Anti-estrogen drug 
Methoxsalen 
Systemic psoralens  
Miconazole 
Anti-fungal medication  
Tranylcypromine 
Antidepressant 
Inducer 
Drug Class 
Amobarbital 
Barbiturate 
Pentobarbital 
Barbiturates 
Phenobarbital 
Barbiturates/anticonvulsants 
Rifampin 
Antimycobacterials 
Secobarbital 
Barbiturates 
Substrate 
Drug Class 
Dexmedetomidine 
α2-Adrenoceptor, sedative 
Ifosfamide 
Anti-cancer, alkylating agents 
 
Use of any other concomitant medication will be evaluated on a case by case basis by the 
Investigator. The Investigator is responsible for the medical care including medication of the 
subjects during their participation in the study. Any decisions regarding the prescription of 
medications will be made in the best interest of the subject. Any concomitant medications used 
will be fully documented (for details see section 7.3.4).  

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7 
STUDY PROCEDURES 
Site personnel performing or recording study assessments must have the appropriate and fully 
documented training. An overview of all study assessments is shown in the schedule of events 
(Appendix A). Appropriate medical advice will be provided to the subject in case of any 
medical findings requiring health care. Site personnel will adhere to the site’s standard 
operating procedures (SOPs) for study related procedures.  
7.1 
Informed Consent 
Prior to any study assessment being performed, subjects will be asked to provide their written 
consent to participate in the study (section 1.3). Study assessments must only start after the 
time of ICF signature by the subject. 
7.2 
Information on the Risk of Smoking, Smoking Cessation Advice and 
Product Debriefing 
At V1, V2 and V6 all subjects will receive 1) information on the risks of smoking, 2) smoking 
cessation advice, and 3) debriefing on P3P.  
The information on the risk of smoking and advice on smoking cessation will take the form of 
a brief interview according to the WHO recommendations (35). The debriefing of subjects on 
P3P will address any intended or unintended beliefs that participants may have about P3P. The 
goal of the debriefing is to help ensure that subjects enter and exit the study with an accurate 
understanding of the product risks, including an understanding that P3P has not currently been 
demonstrated to be less harmful than cigarettes.  
Details of the sessions will be recorded in the source document file. This information will be 
given to the subjects on an individual basis during a face-to-face meeting between the subject 
and the Investigator or designee or may be given in a group session. 
7.3 
Clinical Assessments 
7.3.1 
Demographic Data  
Sex, date of birth and race will be recorded for each subject at V1. 
7.3.2 
Tobacco and Nicotine Containing Products Use History and Habits 
At V1, subjects will answer questions about their tobacco and nicotine containing products use 
history and habits. This self-reported daily consumption of cigarettes at V1 will be reviewed 
by the Investigator and used to assess eligibility for the study.  

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At V1 and V2 the subject will also be asked if he/she is planning to quit smoking in the next 2 
months i.e. before completion of the study and the answer should be documented on source 
documents. Only subjects not planning to quit will be considered for participation in the study.  
Furthermore, subjects will be asked if they are ready to switch from cigarette smoking to use 
of P3P for the duration of the study. Only subjects prepared and able to comply with this 
requirement will be considered for participation in the study. 
7.3.3 
P3P demonstration and P3P Test 
All subjects will have a demonstration of P3P (without product use) at V1. 
At V2, after enrollment, and after at least 4h of abstinece from the use of any tobacco/nicotine 
containing products, subjects will be required to perform a product test using up to 6 P3P 
products (alternating between P3P-1mg and P3P-2mg). Each subject will need to test at least 
one product of each P3P variant during the product test. They will be instructed to use the 
product as described in section 6.2.1.  
After the product test, subjects not willing and/or unable to use P3P will be discontinued from 
the study and will enter a 14-day Safety Follow-Up Period. 
7.3.4 
Medical History, Concomitant Disease, Previous and Concomitant 
Medications 
Relevant medical history and any concomitant disease will be documented at V1. Medical 
history is defined as any condition that started and ended prior to the ICF signature at V1. A 
concomitant disease is defined as any condition that is either detected or is still ongoing at the 
time of ICF signature. The final status of any concomitant disease (i.e stop date or ongoing) 
should be verified at each visit. 
Any medication taken within 4 weeks prior to V1 and any concomitant medication will be 
documented. Any medication started prior to V1 and still being taken by the subject will be 
considered concomitant medication. Medication initiated after V1 will also be referred to as 
concomitant medication. The definition of concomitant medication applies to both prescription 
and over-the-counter products.  
Records of medication taken should include the drug name (preferably both generic and trade 
name), route of administration (e.g., oral, intravenous), dose and frequency (expressed in 
metric units, for example, mg, mL, or IU), indication, and the start and, if applicable, the stop 
date (day, month, and year). Therapy changes (including changes of regimen) during the study 
have to be documented.  
7.3.5 
Physical Examination 
Physical examination will be conducted at V1, V2 (at admission and prior to discharge) and 
V3-V6. 

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A full physical examination will include review of general appearance, skin, head, eyes, ears, 
nose and throat, thyroid gland, chest, lungs, back, abdomen, dentition, cardiovascular, 
gastrointestinal, musculoskeletal and neurological systems. 
The physical examination is to be conducted by the Investigator or designated fully trained 
representative and assessed as normal,  abnormal - not clinically significant or abnormal – 
clinically significant. 
7.3.6 
Body Height and Weight 
Body height and weight will be recorded at V1 and BMI will be calculated using the following 
formula:  
BMI = weight in kilograms
height in meters2
= 𝑘𝑘𝑘𝑘
𝑚𝑚2 
The BMI will be used to assess eligibility for enrollment. 
At V2 and V6 only body weight will be recorded. 
7.3.7 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, respiratory rate and pulse rate) will be 
recorded at each visit from V1 to V6. At V2 (Day -1, Day 1 and Day 2) and V6 (Day 30) vital 
signs are to be checked prior to any product use and at the end of the day/at discharge. 
All parameters will be recorded in supine position after subject has rested for at least 5 minutes. 
The subject should have abstained from smoking or using P3P for at least 15 minutes prior to 
measurement. 
7.3.8 
Electrocardiogram 
A standard 12-lead ECG will be recorded after subject has rested for at least 10 minutes in 
supine position at each visit from V1 to V6. The following parameters will be documented: 
heart rate, PR interval, QRS interval, QT interval, and QTc interval corrected according to 
Bazett’s formula and Fridericia’s formula. Any print-outs of ECGs on thermo-sensitive paper 
must be photocopied and stapled together for inclusion in the source documents. 
7.3.9 
Spirometry 
Spirometry will be performed in accordance with the 2005 guideline of the American Thoracic 
Society (ATS)/European Respiratory Society (ERS) Joint Task Force on the standardization 
of spirometry (36). Spirometry predicted values will be standardized to the European 
Community for Coal and Steel (ECCS) reference equations as published in the 1993 ERS 
statement (37).   

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Assessed parameters will include: FEV1, FEV1 % predicted, FVC, FVC % predicted, FEF 25, 
FEF 25 % predicted, FEF 75, FEF75 % predicted, FEF 25-75, FEF 25-75 % predicted, 
FEV1/FVC. The ratio FEV1/FVC will be calculated from the highest acceptable FEV1 and the 
highest acceptable FVC respectively. 
Spirometry without (pre-) and with (post-) bronchodilator will be performed at Screening (V1). 
The pre- and post-bronchodilator spirometry will be used for assessment of eligibility to the 
study. All post-bronchodilator spirometry testing will be performed 15-30 minutes post 
administration of around 400 μg of salbutamol/albuterol (usually equivalent to 4 puffs 
assuming 100 μg/puff). The time of salbutamol/albuterol inhalation and time of spirometry 
assessment will be recorded in the source document.  
Spirometry without bronchodilator will be performed at V2: Day -1 before and after product 
test, Day 1 and Day 2 before product exposure and at the end of the daily product exposure; 
V3; V4; V5; V6: Day 29 at arrival on site and Day 30 prior to discharge.  
All personnel performing spirometry testing should have the appropriate training and quality 
control measures should be put into place and be properly documented. The testing will be 
performed in sitting position after resting for at least 15 minutes and at least 1 hour after having 
stopped using cigarettes or P3P. Spirometry should be performed after assessment of vital signs 
and ECG. 
7.3.10 
Chest X-ray  
During V1 a chest X-ray (anterior-posterior and left lateral views) will be assessed to exclude 
subjects with relevant pulmonary diseases. Subjects will be referred to a radiology facility for 
this procedure. No new examination is required if the subject can present at V1, a chest X-ray 
not older than 6 months with anterior-posterior and left lateral views. Available chest computed 
tomography (CT) or chest magnetic resonance imaging (MRI) results, or radiologist report 
from an equivalent radiological assessment, not older than 6 months can be accepted by 
Investigator for this purpose instead of chest X-ray. All reports have to be interpreted by a 
radiologist. 
7.4 
Biomarker Assessment 
7.4.1 
Biomarkers of Exposure to Nicotine 
7.4.1.1 
Nicotine in plasma 
For PK analysis of plasma nicotine levels, venous blood samples will be obtained at Day 1 
(V2) and Day 30 (V6) according to the investigational site standard operating procedures 
(SOPs). A total of 11 blood samples will be taken. Three samples will be taken prior to product 
use (T0): 1 hour ± 5 minutes, 30 minutes ± 5 minutes and 5 minutes ± 2 minutes  before T0. 
Thereafter in relation to T0, blood will be drawn at the following time points: after 4 minutes 
± 1 minute, after 7 minutes ± 1 minute, after 10 minutes ± 1 minute, after 15 minutes ± 2 

Philip Morris Products S.A. 
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without the written consent of Philip Morris Products S.A. 
minutes, after 30 minutes ± 2 minutes, after 1 hour ± 5 minutes, after 2 hours ± 5 minutes and 
after 4 hours ± 5 minutes. The actual collection time of each blood sample must be recorded 
on the CRF. 
Since the test for nicotine concentration is highly sensitive, precautions should be taken during 
blood sampling and processing to prevent the contamination of samples with environmental 
nicotine. Detailed procedures for handling of samples are described in the separate sample 
handling manual (SHM)/lab manual. 
7.4.1.2 
Nicotine Equivalents in Urine 
Nicotine Equivalents (NEQ): molar sum of nicotine, cotinine, trans-3′-hydroxycotinine, 
nicotine-N-glucuronide, cotinine-N-glucuronide and trans-3′-hydroxycotinine-O-glucuronide 
will be measured in spot urine at Admission (Day -1; V2), and V3-V6. The results will be 
normalized to urine creatinine and expressed as concentration adjusted for creatinine. 
7.4.2 
Other Biomarkers of Exposure in Urine 
At V2-V6, total NNAL and CEMA will be measured in spot urine. The results will be 
normalized to creatinine and expressed as concentration adjusted to creatinine. 
7.4.3 
Creatinine in urine 
Creatinine will be measured in spot urine for normalization of urinary BoExp. 
7.4.4 
CYP2A6 Activity  
CYP2A6 activity will be assessed on Day 1 (V2) and Day 30 (V6) prior to P3P use. CYP2A6 
activity drives the metabolism of nicotine to cotinine and subsequent metabolites. In this study 
the CYP2A6 activity will be measured in plasma using the metabolic molar ratio of trans-3’-
hydroxycotinine/cotinine. 
7.5 
Laboratory Assessments 
7.5.1 
Clinical Chemistry, Hematology, and Urine Analysis Safety Panel  
A blood sample for hematology and clinical chemistry analysis will be taken from each subject 
at V1, V2, V4 and V6. Subjects should be fasting for at least 6 hours prior to sampling, except 
at V1 and early termination where non-fasting samples can be used. Tests will be conducted at 
a local laboratory (Appendix B). If during screening period a blood sample is not suitable for 
analysis (e.g. blood clotting) a re-test shoud be performed for the specific parameters which 
are not available. A urine sample will also be collected from each subject for urine analysis. 
Parameters to be tested are listed in Table 2. 
 
 

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Research Study Protocol 
Confidential 
Study P3P-SE-02-RU 
Final 2.0 / 12 June 2019 
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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. 
7.5.5 
Alcohol Breath Test 
An alcohol breath test will be performed using an alcometer device at V1 and V2. In case of a 
positive alcohol test, a retest will not be allowed in order to evaluate eligibility. In case of an 
inconclusive test, a retest can be performed but this needs to be done immediately after the 
inconclusive test. 
7.5.6 
Urine Pregnancy Test 
A urine pregnancy test will be performed for all female subjects at V1, V2, V4 and V6. Subjects 
with a positive urine pregnancy test or unclear results (from two repetitions) at V1 or V2 will 
not be enrolled and will be considered as screen failures. In case of any positive pregnancy 
test, the Investigator or designee will inform the subject about the risks associated with 
smoking during pregnancy. 
All pregnancies detected during the study must be reported and handled as described in 
section 8.5. Pregnancies detected after enrollment will lead to discontinuation from the study 
(section 5.2). 
7.6 
Sample Handling, Storage, and Shipment 
Urine drug screen, breath alcohol screen, urine pregnancy tests and urine cotinine tests will be 
done by the site personnel at the site. All other blood and urine samples will be managed by 
the laboratory designated in Appendix B. 
Detailed procedures for handling of samples are described in the separate sample handling 
manual (SHM). Safety laboratory samples will be destroyed as per laboratory local regulations. 
All other samples (except biobanking samples) will be destroyed post database lock or post 
finalization of the bioanalytical reports, whichever occurs last. The facility/-ies at which the 
samples are stored will be informed in writing by the Sponsor when destruction of the samples 
shall be performed. 
7.6.1 
Blood Samples  
Blood samples will be drawn by qualified and trained site personnel. Since the test for nicotine 
concentration is highly sensitive, precautions should be taken during blood sampling and 
processing to prevent the contamination of samples with environmental nicotine. Subjects should 
be in a seated position during blood collection.  
In total, around 238 mL of blood will be drawn for this study including samples for 
determination of nicotine concentrations (around 99 mL), CYP2A6 activity (8 mL), serology 
(5mL), safety (around 80 mL) and biobanking (about 46 mL). This calculation is based on an 
individual volume of each sample of 4.5 mL for nicotine PK (of which 4 mL is needed for 
nicotine dosing and 0.5 mL for cannula rincing of saline solution), 4 mL for CYP2A6 analysis, 
5 mL for serology, 20 mL for safety laboratory assessments and 23 mL for biobanking (5 mL 
for transcriptomic and 6 mL for each of the following: proteomic, lipidomic and 

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without the written consent of Philip Morris Products S.A. 
metabolomics). The total volume of blood drawn will not exceed the levels for a standard blood 
donation.  
More details on the procedures for collection, labeling, handling and shipment of samples are 
described in the SHM/ lab manual. 
7.6.2 
Spot Urine Samples 
Spot urine samples will be used for the urine drug screen, urine cotinine screen, urine 
pregnancy test, safety urinalysis, BoExp (NEQ, Total NNAL and CEMA) and creatinine 
analysis and for biobanking samples.  
Spot urine for BoExp will be collected from V2-V6. Baseline values of BoExp will be assessed 
at V2 (Day -1) when spot urine should be collected prior to product test. At V6 (Day 29) spot 
urine should be collected before the start of the wash-out period.  
Spot urine for biobanking will be collected at V2 (Day 1) and V6 (Day 30. 
For spot urine collected for BoExp and biobanking, the time of collection as well as the total 
volume collected should be recorded. 
7.6.3 
Biobanking 
Samples of urine and whole blood/plasma will be collected at V2 and V6 for biobanking and 
subsequent transcriptomic, proteomic, lipidomic and metabolomic profiling as follows:  
• 
Samples will be collected from spot urine for lipidomic profiling (2 tubes of 2 mL each 
per timepoint), for metabolomic profiling (4 tubes of 10 mL each per timepoint) and for 
proteomic profiling (4 tubes of 10 mL each per timepoint).  
• 
Whole blood for transcriptomic (RNA) profiling (2 tubes of 2.5 mL each per time point), 
plasma for proteomic profiling (6 mL of whole blood at each time point to obtain and store 
4 x 0.5 mL of plasma), plasma for lipidomic profiling (6 mL of whole blood at each time 
point to obtain and store 2 x 1 mL of plasma), and plasma for metabolomic profiling (6 
mL of whole blood at each time point to obtain and store 4 x 0.5 mL of plasma) will also 
be collected.  
All samples intended for biobanking will be kept frozen and will be shipped to a central storage 
facility or a bioanalytical laboratory according to the laboratory manual. Analysis of the 
biobanking samples will not be part of the research study report and will be reported separately. 
After the final RSR is signed, samples will be stored for a maximum of 10 years. 
7.7 
Questionnaires 
The subject questionnaires will be completed by the subjects directly. All subject-reported 
outcome data as well as instructions will be provided in the subject’s local language. 

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Symptoms or worsening of symptoms as documented on any of the questionnaires do not need 
to be documented as AEs because the questionnaires will be analyzed as part of the report. 
However, it is at the discretion of the Investigator to document such symptoms also as AEs. 
The main source for AE collection will be the face-to-face interview between the subject and 
investigational site staff using, open, non-directive questions (see section 8.2.1). 
7.7.1 
ABOUTTM-Dependence 
Global dependence on tobacco and nicotine-containing products will be assessed via a subject 
self-reported outcome measure at V2, and at V6 using the ABOUT™-Dependence 
Questionnaire (32, 38). The questionnaire includes two multi-items scales (attitudinal and 
behavioral) complemented by one single item assessment on urgency to use (i.e., time to first 
product use in the day).  
Subjects will be asked to assess the questionnaire on a 5 point scale ranging: 
• from “not at all” to “extremely” for the attitudinal scale; 
• from “never” to “all the time” for the behavioral scale; 
• from “0 to 5 minutes” to “more than 3 hours” for the urgency to use. 
7.7.2 
ABOUTTM-Product Experience 
Product Experience  will be assessed via a subject self-reported outcome measure at V2 and 
V6 within 60 minutes after the P3P product use for PK assessment, using the ABOUT™-
Product Experience Questionnaire, also part of the ABOUT™ Toolbox (32, 39).  
The questionnaire consists of three multi-item scales and two single-item scales, arising from 
an adaptation and rewording of the modified cigarette evaluation questionnaire (mCEQ) (40) 
to RRPs and the Product Evaluation Scale (41). 
The questionnaire assesses the degree to which subjects experience the reinforcing effects of 
P3P use by measuring: 
• 
Product satisfaction (satisfying, tastes good, enjoy the product). 
• 
Psychological rewards (calms down, more awake, less irritable, helps concentrate, 
reduces hunger). 
• 
Aversion (dizziness, nausea). 
• 
Enjoyment of respiratory tract sensations (single-item assessment). 
• 
Craving reduction (single-item assessment). 
Subjects will be asked to assess the 12 items of the questionnaire on a 7-point scale, ranging 
from “not at all” to “extremely”. 

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without the written consent of Philip Morris Products S.A. 
7.7.3 
Sensory Questionnaire 
A sensory questionnaire will be completed by each subject at V2 and V6 within 60 minutes 
after the P3P product use for PK assessment (adapted from (42)). The sensory questionnaire 
assesses the subject’s opinion on the following sensory parameters: 
• 
Puff information i.e., how they liked the puffs, harshness of puffs, and similarity to own 
brand; 
• 
Strength of puffs on tongue, nose, mouth, windpipe, and chest. 
Subjects will be asked to assess the 8 items of the questionnaire on a 7-point scale, ranging 
from “not at all” to “extremely”. 
7.7.4 
Product Acceptance Questionnaire  
In the context of tobacco harm reduction, alternative sources of nicotine offered need to be 
acceptable to smokers as substitutes for cigarettes (43).  
At V2 and V6, subjects will complete the product acceptance questionnaire. This questionnaire 
will be used to assess product characteristics of P3P relevant to determine subjects’ 
acceptability of the product. Subjects will be asked to rate P3P in terms of sensory attributes,  
ease of use and occasions of use.  
A baseline version of the product acceptance questionnaire consisting of 5 questions will be 
answered at V2, while a 6-questions version containing an additional question asking about 
occasions of P3P use will be answered at V6. 
7.7.5 
Visual Analogue Scale for Craving 
A VAS-craving assessment will be used to assess the level of craving of the subject based on 
their response to the question, “How strong is your craving for cigarettes?” on a scale of 0 (no 
craving) to 10 (strong craving) (44). 
The VAS craving will be completed multiple times by the subject in relation to the P3P product 
used for PK assessment at V2 and V6. The first assessment will be done 10 minutes ± 2 minutes 
prior to T0. Thereafter in relation to T0, the assessment is to be performed at 4 minutes ± 2 
minutes, at 10 minutes ± 2 minutes, at 15 minutes ± 2 minutes, 30 minutes ± 5 minutes, 1 hour 
± 10 minutes, 2 hours ± 10 minutes and 4 hours ± 10 minutes. VAS will be assessed 
immediately after the collection of the time-matching PK samples. 
7.7.6 
Cough Assessment 
At V2-V6, subjects will be asked if they have experienced a regular need to cough, e.g., 
whether they have coughed several times in the previous 24 hours prior to assessment. If the 
answer is ‘yes’, they will be asked to complete a cough assessment questionnaire (which 
includes a VAS and three Likert scales). 

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The VAS will assess how bothersome cough is to the subject, on a 10 cm scale ranging from 
‘not bothering me at all’ to ‘extremely bothersome’. 
Furthermore, subjects will be asked to assess the intensity and frequency of cough and the 
amount of sputum production on Likert scales: 
• 
The intensity of cough will be assessed on a 5-point Likert scale ranging from 1 to 5: 
1 = very mild; 2 = mild; 3 = moderate; 4 = severe; 5 = very severe. 
• 
The frequency of cough will be assessed on a 5-point Likert scale ranging from 1 to 5: 
1 = rarely; 2 = sometimes; 3 = fairly often; 4 = often; 5 = almost always. 
• 
The amount of sputum production will be assessed on a 4-point Likert scale ranging 
from 0 to 3: 
0 = no sputum; 1 = a moderate amount of sputum; 2 = a larger amount of sputum; 3 = a 
very large amount of sputum. 
7.8 
Other Study Procedures 
7.8.1 
Product Use Diary 
Subjects will enter the number of P3P consumables used per day, the number of cigarettes used 
per day, or/and other tobacco and nicotine containing products used per day in a product use 
diary from Day 1 (V2) until the Discharge at V6 (including during the visits). At V2, before 
they start using it, subjects will be trained on how to log into the designated website and 
complete the product use diary by site staff. For subjects who decide to quit using all tobacco 
and nicotine containing products the product use will no longer be captured. 
Site staff should train the subject on the correct use of the subject diary and perform regular 
checks to ensure that the subject completes the diary in the frequency and the way required.   
7.8.2 
Puffing/inhalation behavior question 
At V2 (Day 1) and V6 (Day 30), during the use of P3P for PK assessment the site staff will be 
asked to observe the puffing/inhalation behaviour of the subjects and answer a question related 
to it. The staff will evaluate if the subject is using P3P by:  
- 
puffing and holding the aerosol in the mouth for a short time and then inhaling (i.e. like 
a cigarette); 
- 
puffing and immediately inhaling (without holding the aerosol in the mouth); or 
- 
puffing and immediately exhaling, without inhalation; 
At V2 (Day 2), V3, V4, V5, V6 (Day 29), the subjects will also answer the same question about 
their own puffing/inhalation behaviour. 

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without the written consent of Philip Morris Products S.A. 
The Sponsor will provide training to the site staff prior to the study initiation related to the 
correct evaluation of this assessment. Subjects will also be trained on the correct evaluation of 
their puffing/inhalation behavior 
7.8.3 
Weighing of P3P Products 
At V2 and V6, P3P used for PK assessment should be weighed before product use and as early 
as possible (but within maximum 1 hour) after the end of product use. The balance precision 
needed for product weighing is at milligram (mg) level. The pre- and post- product use weight 
and time of weighing will be recorded in the CRF. 

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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 
An adverse event is defined as any health-related event which is adverse or unfavorable and 
which either starts after ICF signature or represents a worsening of a health–related condition 
that existed at the time of that signature. Careful medical judgment is required to establish 
whether a clinical finding (including an abnormal laboratory result) is a true AE or just a 
manifestation of a preexisting health–related condition. An AE may or may not have a causal 
relationship with the study procedures or with the use of investigational product. 
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,  
• is a congenital anomaly/birth defect, or 
• 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 Investigator’s 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. 
8.1.3 
Conditions Existent Before the Start of the Period of Collection (ICF 
Signature) 
Clinical conditions that existed before the start of the period of collection of AEs and still 
ongoing at V1 (concomitant disease), and whose severity or frequency remained unchanged 
after that point, should not be considered AEs and should not be captured as such. This includes 
medical therapies or surgical interventions that had been planned before the start of the period 
of collection regardless of involving admissions to hospital, if the medical condition to be 
addressed did not get worse after the start of the collection period. Otherwise, any medical 
condition that existed before the start of the period of collection and still ongoing at V1 

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without the written consent of Philip Morris Products S.A. 
(concomitant disease) and whose severity or frequency increased after that point is to be 
captured as an AE or SAE, depending on the seriousness criteria met.  
8.2 
Collection and Reporting of Adverse Events 
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 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 
investigator(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 an AE/SAE should 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. 
8.2.2 
Period of Collection 
AEs (including SAEs) will be collected from the time of ICF signature until the EOS. 
Any AEs which occur during the screening period will be captured by the study site staff and 
assessed by the Investigator or designee(s) in order to establish relationship to study 
procedures.  
During a 14-day Safety Follow-Up Period new AEs/SAEs will be recorded and ongoing 
AEs/SAEs will be followed-up by the study site. In general, AEs will be followed-up until 
resolved, stabilized (i.e., no worsening of the event), or a plausible explanation for the event 
has been found and until the end of the study. At the end of the Safety Follow-Up all subjects 
will be contacted via phone in order to check the status of the ongoing AEs and also to collect 
any new AEs/SAEs experienced by the subjects. Subjects should be contacted 14-days after 
Day 30. In case they cannot be reached two additional attempts at the next 2 consecutive days 
will be made. If the subjects cannot be reached after the three attempts they will be declared 

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lost to follow-up. Phone calls should be recorded in the source documents. Any AEs or SAEs 
that are ongoing at the end of the Safety Follow-Up Period will be managed as described in 
section 8.2.6. 
SAEs spontaneously reported to the Investigator after the end of the Safety Follow-Up Period 
and considered related to the investigational product must also be reported to the sponsor.  
8.2.3 
Intensity of Adverse Event 
The Investigator must assess the intensity of each reported AE according to the following 
grading scale: 
Table 3 
Intensity of Adverse Events 
Mild: 
Easily tolerated, not interfering with normal everyday activities 
Moderate: 
Interferes with normal everyday activities, but the subject is still able to function 
Severe: 
Incapacitating and requiring medical intervention 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures 
The Investigator must assess the causal relationship between the exposure to the IP and each 
of the reported AEs, using the classification system and the criteria described below. The same 
assessment must be made separately to assess the causal relationship between the study 
procedures and each of the reported AEs:  
Not related: The temporal relationship of the adverse event to IP administration or study 
procedure(s) makes a causal relationship unlikely, or concomitant medication, 
therapeutic interventions, or underlying conditions provide a sufficient 
explanation for the observed event.  
Related: 
The temporal relationship of the adverse event to IP or study procedure(s) 
makes a causal relationship possible, and concomitant medication, therapeutic 
interventions, or underlying conditions do not provide a sufficient explanation 
for the observed event.  
8.2.5 
Expectedness 
Any AE assessed as related to the IP will be assessed for its expectedness. An AE will be 
regarded as “unexpected” if its nature or severity is not consistent with information already 
recorded about the IP P3P in section 6.5 of the current Investigator’s Brochure (22).  
8.2.6 
Follow-up of Non-serious and Serious Adverse Events 
Any non-serious AE that is ongoing at the time of Discharge or early termination will be 
followed-up by the Investigator during the Safety Follow-Up Period until it has been resolved, 

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stabilized (i.e., no worsening of the condition), or an acceptable explanation has been found 
(e.g., a chronic condition). The follow-up of the ongoing non-serious AEs will be done via a 
phone call performed at the end of the Safety Follow-Up Period. 
At the end of the Safety Follow-Up Period, all ongoing non-serious AEs will be documented 
as “ongoing” and no further follow-up information will be sought on them by the Investigator. 
At that point, the Investigator will assess whether the subject should be referred to his/her 
General Practitioner to have their ongoing AEs addressed accordingly.  
All SAE 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). 
8.3 
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 
, as described in the respective safety management 
plan (SMP). 
SAEs considered related to the IP and observed by, or reported to, any of the parties involved 
in this study (including the Investigational site personnel) after the period of collection must 
also be reported by that party within 24 hours of first awareness to 
 
for safety surveillance purposes.  
All the SAE report forms must be sent as an attachment to an e-mail message to 
 
 and the Sponsor: 
 
 
E-mail: 
 
 Fax number: 
+41 
 
Address: 
 
 
 
Switzerland 
Sponsor: 
E-mail: 
 
Phone: 
+ 41 
 
Address: 
Philip Morris Products S.A. 
R&D Innovation Cube 
5, Quai Jeanrenaud 
2000 Neuchâtel 
Switzerland 

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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 on a new SAE 
report form, marked as a follow-up report and submitted to 
 and the 
Sponsor according to the same timelines as described above. The follow-up SAE report form 
must include the minimum information required for form completion and only changed/new 
information needs to be specified. Information provided in the follow-up SAE report form 
supersedes any information that was initially reported.  
The SAE report form to be used in this study is provided as a separate document. All SAEs 
will also be recorded on the relevant CRF page, in addition to the SAE report form. 
The Investigator or designee is responsible for submitting the relevant reports of SAEs that 
occur during the study to the local IEC, according to local regulations and in accordance with 
the respective safety management plan (SMP).  
8.4 
Reporting of Other Events Critical to Safety Evaluations 
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator and assessed for clinical significance according to its severity. 
The severity of abnormal laboratory test result must be assessed using CTCAE version 4.03 
grading scales (Appendix C). 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 4: 

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Table 4  
Principles for assessing and reporting abnormal laboratory test 
results 
Grading 
Clinically significant? Is it a grade increase 
from previous results 
in study?§ 
Report? 
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. 
 
In general, laboratory values will be recorded as “increased <lab parameter>” or “decreased 
<lab parameter>” to ensure consistency of recording/coding.  
8.4.2 
Reporting other abnormal findings 
The other abnormal findings discovered during different clinical assessments (e.g., ECG, 
spirometry, physical examination, vital signs, body weight) should be evaluated for the clinical 
significance by the Investigator/designee based on his/her medical judgement. All abnormal 
clinically significant test results or clinical examination findings should be reported as AEs 
and handled according to the directions from section 8.2. 
8.5 
Reporting and Follow–Up of Pregnancies 
8.5.1 
Period of Collection and Follow-up 
Pregnancies detected between the time of signature of the ICF and first exposure to the IP will 
be considered a reason for screen failure. No pregnancy form will be filled in that case, 
however the diagnosed pregnancy must be captured in the screen failure page of the CRF. 
Any pregnancy that was potentially associated with exposure to the IP, including pregnancies 
spontaneously reported to the Investigator after the EOS must be reported by the Investigator 
and followed-up until the pregnancy outcome is reached (e.g., normal delivery, spontaneous 
abortion, voluntary termination) and also until 8 weeks after delivery. Potential association 
with the exposure to the IP is defined as exposure to IP during or after the calculated conception 
date. 

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Any pregnancy complication, adverse pregnancy outcome or maternal complications will be 
recorded as an AE accordingly. 
8.5.2 
Reporting of Pregnancies 
A dedicated pregnancy form will be used to report reportable cases of pregnancy. 
The procedure to report a pregnancy and provide any additional/follow-up information to 
 
 and Sponsor is the same and performed within the same timelines as the 
one described for an SAE (section 8.3). 
The Investigator is responsible for informing the corresponding IEC of any pregnancy case 
that was reported during the study, as determined by local regulations. 
8.6 
Adverse Events Leading to Discontinuation 
Subjects who are discontinued from the study because of an AE will undergo the early 
termination procedures (section 9.5), as soon as practical after discontinuation and will enter 
the 14-day Safety Follow-Up Period. In general, AEs will be followed-up until resolved, 
stabilized (i.e., no worsening of the event), or a plausible explanation has been found and until 
the end of the study.  
Any AEs or SAEs that are ongoing at the end of the Safety Follow-Up Period will be managed 
as described in section 8.2.6. 
8.7 
Investigational Product Malfunction and Misuse 
Any occurrence of P3P events, including malfunction or misuse (use not in accordance with 
its instruction) by a subject will be documented by the Investigator using a Product Issue Log. 
Information regarding product events should be actively collected during the study visits. 
Investigational product misuse may result in use-related hazards (section 2.3.4). 
Furthermore, any malfunction or misuse of P3P that leads to an AE/SAE will follow the same 
processes as described above. 
 

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9 
STUDY ACTIVITIES 
A detailed schedule of all study activities and assessments is provided in Appendix A. 
Measurements not conducted at the exact time point indicated, but conducted within the given 
time window (if applicable), do not constitute a protocol deviation but an accepted variability 
for the given time point.  
In general, if no start time for the procedure is provided, then the procedure can be performed 
at any time during the day. 
9.1 
Screening Visit 
The Screening Visit (V1) will be performed within 3 weeks prior to enrollment at V2. First, 
the ICF along with study information should be given to the subject. Prior to being asked to 
sign the consent form, subjects will be given time to review the study information and ask any 
questions. When/if the ICF is signed, dated and timed, the other screening procedures can be 
performed in the order deemed most practical. While it is recommended to complete as many 
screening procedures as possible in one day, it is permissible to complete those over more than 
one day. Smoking is allowed at the Screening Visit at the discretion of the investigational site. 
Screening activities are listed in Table 5. 
Table 5 
Time Schedule – Screening Visit [V1] 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V1 
 
Prior to any 
other procedure 
 
Collection of signed informed 
consent 
 
During the visit 
 
Information on risks of smoking, 
smoking cessation advice and 
product debrief 
 
 
 
Tobacco and nicotine containing 
products use history and habits 
 
 
 
Demographic data 
 
 
 
Medical history/ concomitant 
disease 
 
 
 
Prior (within 4 weeks prior to V1) 
and concomitant medication 
 
 
 
Physical examination 
 
 
 
Body height, weight and 
calculated BMI 
 

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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V1 
 
 
 
Vital signs  
At least 5 min in supine position 
prior to measurement. At least 15 
minutes smoking abstinence 
prior to measurement. 
 
 
ECG 
After resting for at least 10 min in 
supine position prior to recording 
 
 
Chest X-ray 
If not performed within 6 Months 
prior to V1. 
 
 
Spirometry (pre-bronchodilator 
and then post-bronchodilator) 
Has to be done at least 1 hour 
after smoking. After resting in 
sitting position for at least 15 
minutes prior to testing. To be 
done after vital signs and ECG. 
Post-bronchodilator spirometry to 
be performed 15-30 minutes post 
administration of salbutamol 
 
 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
 
 
 
Collection of spot urine for: 
- 
Urine analysis safety panel 
- 
Urine drug screen 
- 
Urine cotinine screen 
- 
Urine pregnancy test (all 
female subjects) 
 
 
 
Serology 
HIV 1/2, Hepatitis B and C. 
 
 
Alcohol breath test 
 
 
 
Review of inclusion/exclusion 
criteria based on all relevant 
assessments 
Includes readiness to comply 
with study procedures and 
willingness to use P3P during the 
study; no intention to quit 
smoking in the next 2 months. 
 
 
P3P demonstration 
Without product use. 
 
 
AE/SAE recording 
If the Screening Visit is performed 
on two separate days the AE/SAE 
questions will be asked again. 
Abbreviations: AE = Adverse event; BMI = Body mass index; ECG = Electrocardiogram; HIV = Human immunodeficiency 
virus; SAE = Serious adverse event. 

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9.2 
Admission Visit  
Visit 2 will consist of 3 consecutive days (Day -1, Day 1 and Day 2) with on-site overnight 
period. Admission, enrollment, product test and randomization will take place at the first day 
of the visit (Day -1) while nicotine PK will be assessed on the second day of the visit (Day 1), 
after an overnight nicotine abstinence period of at least 10 hours. Following the PK 
assessments, subjects will remain on-site and will be allowed to use up to 15 P3P products 
daily on Day 1 and Day 2. The assessments performed at the first day of V2 (Day -1) are listed 
in Table 6; the assessments performed at the second day of V2 (Day 1) are listed in Table 7 
and the assessments performed at the third day of V2 (Day 2) are listed in Table 8. 
Table 6 
Time Schedule – First day of V2 (Day -1) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day -1 
 
Before enrollment 
 
Concomitant medication 
 
 
 
Collection of spot urine for: 
- 
Urine drug screen 
- 
Urine cotinine screen 
- 
Pregnancy test (all 
female subjects) 
 
 
 
Alcohol breath test 
 
 
 
Review of Inclusion criteria 4, 
5 and 7 and exclusion criteria  
11, 13, 14 and 19 
 
Before enrollment 
 
Information on risks of 
smoking, smoking cessation 
advice and product debrief 
 
Enrollment 
 
Enrollment 
 
After enrollment, 
before product test 
 
Clinical laboratory 
parameters (hematology, 
clinical chemistry) 
After at least 6 hours of fasting.  
 
 
Collection of spot urine for: 
- 
Urinalysis safety panel 
- 
BoExp and creatinine 
 
 
 
Physical examination 
 
 
 
Vital signs  
At least 5 min in supine position 
prior to measurement. At least 15 
minutes smoking abstinence 
prior to measurement. 

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ECG 
After resting for at least 10 min in 
supine position prior to recording. 
 
 
Body weight 
 
 
 
Cough assessment 
VAS and Likert  
 
 
Spirometry (without 
bronchodilator) 
Has to be done at least 1 hour 
after smoking. After resting in 
sitting position for at least 15 
minutes. To be done after vital 
signs and ECG. 
Product test 
 
Alternate use of P3P-1mg and 
P3P-2mg with up to 6 products 
in total 
A wash-out period from any 
tobacco/nicotine containing 
products of at least 4 h prior to 
product test must be respected 
After product test 
 
Collection of used and unused 
products 
 
After product test 
and before 
randomization 
 
Confirmation that subject is 
willing to use P3P during the 
study 
 
 
 
Randomization 
 
 
 
Vital signs 
At least 5 min in supine position 
prior to measurement. At least 15 
min after P3P use.  
 
 
Spirometry 
To be done at least 1 hour after 
P3P use. After resting in sitting 
position for at least 15 minutes. 
 
 
Dinner 
 
Evening 
 
Start of at least 10h nicotine 
wash-out period 
 
During the visit, 
after enrollment 
 
Provide access and training for 
filling in questionnaires and 
product use diary 
 
During the visit, 
after enrollment 
 
ABOUTTM-Dependence 
questionnaire 
 
During the visit, 
after enrollment 
 
Concomitant disease status 
check 
Provide stop date if available 
Ongoing 
 
AE/SAE recording 
 
During product 
test 
 
Product events 
malfunctions/misuse 
 
Abbreviations: ABOUT = Assessment of behavioral outcomes related to tobacco and nicotine products; AE = Adverse event; 
BoExp = Biomarkers of Exposure; ECG = Electrocardiogram; SAE = Serious adverse event; VAS = Visual analogue scale 

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Table 7 
Time Schedule – Second day of V2 (Day 1) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of Procedure 
 
Day 1 
 
Prior to product use 
 
Blood sampling for CYP2A6 
assessment 
 
Prior to 
breakfast/snack 
 
Blood sampling for 
biobanking 
After at least 6 hours of fasting 
 
 
Collection of spot urine for 
biobanking 
 
At least 1h prior to 
start of product use 
 
Light snack 
e.g. biscuit, zwieback, fruit 
After biobanking blood sampling  
Prior to product use 
 
Vital signs 
At least 5 min in supine position 
prior to measurement. 
Prior to product use 
 
Spirometry 
After resting in sitting position 
for at least 15 minutes. To be 
done after vital signs. 
Prior to product use 
(within 2 hours) 
 
Weighing of product 
 
Prior to product use 
 
Blood sampling for baseline 
nicotine level  
Prior to T0 blood will be drawn at 
the following timepoints: 
1 hour ± 5 min before T0,  
30 min ± 5 min before T0, 
5 min ± 2 min before T0 
10 ± 2 min prior to T0 
 
VAS-craving: baseline 
 
Just before T0 
 
Piercing of P3P capsule by 
site staff 
 
Start of product use 
= T0 
 
Product use  
Single product for a duration of 
up to 15 minutes.  
During/after product 
use 
 
Blood sampling for nicotine 
PK assessment 
Post T0, blood will be drawn at 
the following time points:  
4 minutes ± 1 minute after T0, 
7 minutes ± 1 minute after T0,  
10 minutes ± 1 minute after T0,  
15 minutes ± 2 minutes after T0,  
30 minutes ± 2 minutes after T0, 
1 hour ± 5 minutes after T0, 
2 hours ± 5 minutes after T0, 
4 hours ± 5 minutes after T0. 

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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of Procedure 
 
Day 1 
 
During/after product 
use 
 
VAS-craving 
 
Post T0, craving will be assessed 
at the following time points: 
4 minutes (± 2 minutes) 
10 minutes (± 2 minutes) 
15 minutes (± 2 minutes) 
30 minutes (± 5 minutes) 
1 hour (± 10 minutes) 
2 hours (± 10 minutes) 
4 hours (± 10 minutes) 
During product use 
 
Puffing/inhalation behavior 
question 
Assessment performed by site 
staff. 
Within 60 min after 
product use 
 
Collection and weighing of 
used product 
 
Within 60 min after 
product use 
 
Questionnaires: 
- 
ABOUT TM-product 
experience 
- 
Product acceptance 
- 
Sensory 
- 
Cough assessment 
 
 
 
 
VAS and Likert 
1 to 2 hours after T0 
 
Breakfast 
 
After the last blood 
collection for PK until 
10:00 PM 
 
On-site P3P use 
Up to 14 P3P (15 in total 
including the one used for PK) 
During the on-site 
product use period 
 
Lunch and dinner 
 
After the end of daily 
product use 
 
Vital signs 
At least 5 min in supine position 
prior to measurement. At least 
15 min after P3P use, 
After the end of daily 
product use 
 
ECG 
After resting for at least 10 min 
in supine position. 
1h after the end of 
daily product use 
 
Spirometry 
To be done at least 1 hour after 
P3P use. After resting in sitting 
position for at least 15 minutes. 
To be done after vital signs and 
ECG. 
Ongoing 
 
AE/SAE, concomitant 
medication recording 
 

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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of Procedure 
 
Day 1 
 
Ongoing 
 
Product events 
malfunctions/misuse 
 
Abbreviations: ABOUT = Assessment of behavioral outcomes related to tobacco and nicotine products; AE = Adverse event; 
ECG = Electrocardiogram; min = minutes; PK = Pharmacokinetic; SAE = Serious adverse event; VAS = Visual analogue 
scale 
Table 8  
Time Schedule – Third day of V2 (Day 2) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of Procedure 
 
Day 2 
 
Prior to product use 
 
Vital signs 
At least 5 min in supine position 
prior to measurement. 
Prior to product use 
 
Spirometry 
After resting in sitting position 
for at least 15 minutes. To be 
done after vital signs. 
6:30 AM - Discharge 
 
On-site P3P use 
Up to 15 P3P  
During the visit 
 
Puffing/inhalation behavior 
question 
Answered by subjects. 
Shortly before discharge
 
Vital signs 
At least 5 min in supine position 
prior to measurement. At least 
15 min after P3P use. 
Shortly before discharge
 
Physical examination 
 
Shortly before discharge
 
ECG 
After resting for at least 10 min 
in supine position. 
Shortly before discharge
 
Spirometry 
To be done at least 1 hour after 
P3P use. After resting in sitting 
position for at least 15 minutes. 
Done after vital signs and ECG. 
At the end of the visit 
 
Dispensing of P3P for 
ambulatory use 
 
After 6:30 PM 
 
Discharge 
 
Ongoing 
 
AE/SAE, concomitant 
medication recording 
 
Ongoing 
 
Product events 
malfunctions/misuse 
 
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; SAE = Serious adverse event 

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9.3 
Ambulatory Exposure Period 
From check-out on V2 onwards, subject will use P3P up to 15 products daily in an ambulatory 
setting for 1 month. Subjects will come to the investigational site for weekly visits V3 (Day 
7), V4 (Day 15), V5 (Day 22) and V6 (Day 29) with a visit time window of ± 2 days each. V6 
will be a 2-day visit ie. subjects will remain on-site overnight and nicotine PK assessments will 
be performed on the second day of the visit, Day 30.  
The study activities performed at V3-V5 are listed in Table 9.  
Table 9 
Time Schedule – V3, V4, V5  
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of Procedure 
 
 
 
Beginning of the visit 
 
Return of used and unused 
P3P consumables 
 
Beginning of the visit 
 
Collection of spot urine for : 
- 
Pregnancy test (all 
female subjects) 
- 
Urinalysis safety panel 
- 
BoExp and creatinine 
Pregnancy test and urinalysis 
safety panel only at V4. 
 
 
During the visit 
 
AE/SAE, concomitant 
medication recording 
 
During the visit 
 
Product events 
malfunctions/misuse 
 
During the visit 
 
Cough assessment  
VAS and Likert. 
During the visit 
 
Puffing/inhalation behavior 
question 
Answered by subjects. 
During the visit 
√ 
Clinical laboratory 
parameters (hematology, 
clinical chemistry) 
Only at V4. 
After at least 6 hours of fasting. 
During the visit 
 
Vital signs 
After resting for at least 5 min in 
supine position. At least 15 min 
after P3P use 
During the visit 
 
ECG 
After resting for at least 10 min in 
supine position. 
During the visit 
 
Physical examination 
 
During the visit 
 
Spirometry (without 
bronchodilator) 
After resting in sitting position 
for at least 15 minutes. At least 

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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of Procedure 
 
 
 
1h after P3P use. To be done 
after vital signs and ECG. 
During the visit 
 
Concomitant disease status 
check 
Provide stop date if available 
At the end of the visit 
 
Dispensing of P3P  
 
Abbreviations: AE = Adverse event; BoExp = Biomarkers of Exposure; ECG = Electrocardiogram; SAE = Serious adverse 
event 
 
The study activities performed on Day 29 (the first day of V6) are shown in Table 10.  
Table 10 
Time Schedule – First day of V6 (Day 29)  
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 29 
 
Beginning of the 
visit 
 
Return of used and unused 
P3P consumables 
 
Before start of 
nicotine wash-out 
 
Collection of spot urine for: 
- 
Pregnancy test (all 
female subjects) 
- 
BoExp and creatinine 
 
 
 
Vital signs  
At least 5 min in supine position 
prior to measurement. At least 15 
min after P3P use 
 
 
Spirometry 
After resting in sitting position for 
at least 15 minutes. At least 1h 
after P3P use.To be done after 
vital signs. 
 
 
Cough assessment 
VAS and Likert.  
 
 
Puffing/inhalation behavior 
question 
Answered by subjects. 
 
 
Dinner 
 
Evening 
 
Start of at least 10h nicotine 
wash-out period 
 

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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
Day 29 
 
During the visit 
 
Information on risks of 
smoking, smoking cessation 
advice and product debrief 
 
During the visit 
 
Concomitant disease status 
check 
Provide stop date if available or 
indicate as ongoing 
During the visit 
 
AE/SAE, concomitant 
medication recording 
 
During the visit 
 
Product events 
malfunctions/misuse 
 
Abbreviations: AE = Adverse event; BoExp = Biomarkers of Exposure; SAE = Serious adverse event; VAS = Visual analogue 
scale 
The study activities performed on Day 30 (the second day of V6) are shown in Table 11. 
Table 11 
Time Schedule – Second day of V6 (Day 30) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of Procedure 
 
Day 30 
 
Prior to product use 
 
Blood sampling for 
CYP2A6 assessment 
 
Prior to breakfast/snack 
 
Blood sampling for 
biobanking 
After at least 6 hours of fasting. 
Prior to breakfast/snack 
 
Clinical laboratory 
parameters (hematology, 
clinical chemistry) 
After at least 6 hours of fasting.  
 
 
Collection of spot urine for: 
- 
Urinalysis safety panel 
- 
Biobanking 
 
At least 1h prior to 
start of product use 
 
Light snack 
e.g. biscuit, zwieback, fruit 
After biobanking blood sampling  
Prior to product use 
 
Vital signs 
At least 5 min in supine 
position prior to measurement.  
Prior to product use 
(within 2 hours) 
 
Weighing of product 
 
Prior to product use 
 
Blood sampling for 
baseline nicotine level  
Prior to T0 blood will be drawn 
at the following timepoints: 

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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of Procedure 
 
Day 30 
 
1 hour ± 5 min before T0,  
30 min ± 5 min before T0, 
5 min ± 2 min before T0. 
10 ± 2 min prior to T0 
 
VAS-craving: baseline 
 
Just before T0 
 
Piercing of P3P capsule 
 
Start of product use = 
T0 
 
Product use  
Single product for a duration of 
up to 15 minutes.  
During/after product 
use 
 
Blood sampling for nicotine 
PK assessment 
Post T0, blood will be drawn at 
the following time points:  
4 minutes ± 1 minute after T0, 
7 minutes ± 1 minute after T0,  
10 minutes ± 1 minute after T0,  
15 minutes ± 2 minutes after T0,  
30 minutes ± 2 minutes after T0, 
1 hour ± 5 minutes after T0, 
2 hours ± 5 minutes after T0, 
4 hours ± 5 minutes after T0. 
During/after product 
use 
 
VAS-craving 
 
Post T0, craving will be assessed 
at the following time points: 
4 minutes (± 2 minutes) 
10 minutes (± 2 minutes) 
15 minutes (± 2 minutes) 
30 minutes (± 5 minutes) 
1 hour (± 10 minutes) 
2 hours (± 10 minutes) 
4 hours (± 10 minutes) 
During product use 
 
Puffing/inhalation behavior 
question 
Assessment performed by site 
staff. 
Within 60 min after 
product use 
 
Collection and weighing of 
used product 
 
Within 60 min after 
product use 
 
Questionnaires: 
- 
ABOUTTM-product 
experience 
- 
Product acceptance 
- 
Sensory 
- 
ABOUTTM-dependence 
 
1 to 2 hours after T0 
 
Breakfast 
 

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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of Procedure 
 
Day 30 
 
Shortly before discharge
 
Vital signs 
At least 5 min in supine position 
prior to measurement. At least 
15 min after P3P use 
 
 
ECG 
After resting for at least 10 min 
in supine position prior to 
recording. 
 
 
Physical examination 
 
 
 
Body Weight 
 
 
 
Spirometry 
After resting in sitting position 
for at least 15 minutes. At least 
1 h after P3P use. To be done 
after vital signs and ECG 
During the visit 
 
AE/SAE, concomitant 
medication recording 
 
During the visit 
 
Product events 
malfunctions/misuse 
 
Abbreviations: ABOUT = Assessment of behavioral outcomes related to tobacco and nicotine products; AE = Adverse event; 
ECG = Electrocardiogram; min = minutes; PK = Pharmacokinetic; SAE = Serious adverse event; VAS = Visual analogue 
scale 
9.4 
Safety Follow-Up Period 
After Discharge on Day 30 or at the time of early discontinuation all enrolled subjects will 
enter a 14-day Safety Follow-Up Period during which new AE/ will be collected and ongoing 
AEs/SAEs will be followed-up by the site. The follow-up of ongoing AEs/SAEs will be 
conducted by the study investigational site as described in sections 8.2.2 and 8.2.6. 
9.5 
Early Termination Procedures 
If a subject is discontinued from the study, all early termination procedures listed below are 
performed unless the subject refuses to perform the assessments.  

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Table 12 
Time Schedule – Early Termination 
Blood Sample 
Procedures 
Additional Information 
 
Return of used and unused P3P 
consumables 
 
 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
May be done in non-fasting state. 
 
Urine analysis safety panel 
 
 
Urine pregnancy test (all female subjects)  
 
Vital signs (blood pressure, pulse rate, 
respiratory rate) 
At least 5 min in supine position prior 
to measurement. At least 15 min 
after P3P use 
 
ECG  
After resting for at least 10 min in 
supine position prior to recording. 
 
Spirometry 
After resting in sitting position for at 
least 15 minutes. At least 1 h after 
P3P use. To be done after vital signs 
and ECG. 
 
Physical examination 
 
 
Information on risks of smoking, 
smoking cessation advice  
 
 
Concomitant disease status check 
Provide stop date if available or note 
ongoing if ongoing at early termination 
 
AE/SAE, concomitant medication 
recording 
 
 
Product events malfunctions/misuse 
 
 
Discharge 
 
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; SAE = Serious adverse event 
If a subject withdraws from the study or is discontinued during a planned visit, assessments 
required as per protocol for early termination that have been already performed during the 
planned visit should not be conducted again. 

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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
A Clinical Research Associate (“Monitor”) of the contract research organization (CRO) will 
be responsible for the monitoring of the study. Monitoring will be performed according to the 
CRO’s SOPs and as per monitoring plan agreed with the Sponsor. 
An Investigator’s meeting will be held prior to the site initiation visit. During this meeting, the 
general training of the study procedures and specific training on selected procedures will be 
completed and documented.  
Subsequent to the Investigator’s meeting, and before the first subject is screened into the study, 
the site initiation visit will be conducted by the Monitor and, if necessary, together with the 
Sponsor or its authorized representative. The purpose of the site initiation visit is described in 
the monitoring plan. 
During the study, the Monitor will have regular contact with the investigational site, including 
routine monitoring visits. The frequency and purpose of the monitoring visits will be defined 
in the monitoring plan agreed with the Sponsor.  
The Investigator or designee shall permit the Monitor to review study data as frequently as 
deemed necessary to ensure that data are being recorded in an adequate manner and that 
protocol adherence is satisfactory.  
The Investigator or designee shall access medical records for the Monitor so that entries in the 
CRFs may be verified. The Investigator and designees, as part of their responsibilities, is 
expected to ensure that the study adheres to GCP requirements. 
The Investigator, or a designated member of the Investigator’s staff, must be available during 
the monitoring visit to review the data and resolve any queries and to allow direct access to the 
subject’s records for source data verification. 
The Monitor and the Sponsor’s personnel will be available between visits, should the 
Investigator or other staff at the investigational site need information and/or advice.  
Communication by telephone, mail and e-mail may be used as needed to supplement 
investigational site visits. The Investigator and study personnel will cooperate with the 
Monitor, provide all appropriate documentation and will be available to discuss the study.  
10.2 Training of Staff 
A formal meeting (Investigator’s meeting) will be conducted prior to site initiation. During this 
meeting, the Sponsor or its authorized representative will discuss the requirements of the 
clinical study protocol and related documents and will also provide training to the relevant 
systems and other study-specific procedures. The activities of this meeting will be described 
in the monitoring plan.  

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Further to the Investigator’s meeting, the Investigator or designee will ensure that appropriate 
training relevant to the study is regularly provided to all staff involved in the study, and that 
any new information relevant to the performance of this study is forwarded in a timely manner 
to the staff. The Investigator or designee will maintain a record of all individuals involved in 
the study.  
The Monitor will also train the site staff on study procedures during the site initiation visit, and 
this training will be documented. 
10.3 Audits and Inspections 
Good Clinical Practice regulations require independent inspections of clinical program 
activities. Such inspections may be performed at any time before, during and/or after the study.  
Authorized representatives of the Sponsor, regulatory agencies and/or IEC may perform audits 
or inspections, including source data verification. The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted and data was recorded, analyzed and 
accurately reported according to the protocol, ICH GCP guidelines and any applicable 
regulatory requirements. The Investigator or designee will contact the Sponsor or the 
authorized representative immediately if contacted by a regulatory agency about an inspection 
at their investigational site.  
The Investigator and study staff are responsible for maintaining a comprehensive and accurate 
filing system of all study-related documentation that will be suitable for inspection at any time 
by the Sponsor, its authorized representative and/or regulatory agencies. By signing this 
protocol, the Investigator or designee understands and agrees to provide access to the necessary 
documentation and files. 

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11 DATA MANAGEMENT ACTIVITIES 
All data management activities will be described in detail in the data management plan (DMP) 
and referenced documents. The electronic systems used to collect subject data, CRF and 
electronic patient reported outcome (ePRO), will be FDA 21 CFR Part 11 compliant. 
11.1 Data Capture 
11.1.1 
Case Report Forms and Study Records 
With the exception of the subject-reported outcome data, all results from the clinical 
assessments will be recorded in the source documents by the Investigator or their authorized 
designee(s) and then captured in the CRFs at the investigational site. The subject 
questionnaires and the daily product use (P3P, cigarettes, e-cigarettes or other) will be entered 
by the subject directly in a diary. Trained study personnel will be responsible for capturing the 
data from the observations, tests and assessments specified in the protocol in the source 
documents and then transferring the data into the CRF, in accordance with the CRF Completion 
Guidelines.  
The Investigator has ultimate responsibility for the collection and reporting of all data related 
to the clinical study and ensuring that the data are accurate, authentic/original, legible, timely 
(contemporaneous), enduring and available when required. The CRF must be signed by the 
Investigator to attest that the data contained in the CRF are true and accurate. Any corrections 
made to source documents must be clearly recorded, without obscuring the original values and 
be accompanied by the date of change, reason for change and identification of the person 
making the change. The CRF for each subject will be checked against the source documents at 
the investigational site by the Monitor. Instances of missing or unclear data will be discussed 
with the Investigator for resolution. All subject reported outcome questionnaires including 
instructions will be provided in the subject’s local language, and transcribed in the CRF in 
English. A CRF will be generated for all subjects who have signed the ICF. 
11.1.2 
Protocol Deviations 
Protocol deviations are defined as any deviations from the procedures defined in this 
document, including but not limited to, 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.  
Protocol deviations will be entered into the clinical trial management system (CTMS) or other 
approved format. The data collected in the CRF will be used to assess protocol deviations from 
the data programmatically. Protocol deviations will be reconciled prior to closing the study 
and locking the clinical database.  

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Information from the source documents will represent the primary source of protocol 
deviations. Information following investigational site monitoring and other manual reviews 
will be documented in the investigational site visit reports, follow-up letters, audit 
documentation, or other manual review and will be recorded and tracked in the CTMS or other 
approved format. Telecommunications and other verbal communications regarding deviations 
will be considered and handled as important communication, documented and tracked as 
protocol deviations, as necessary.  
Individual entries for protocol deviations that are recorded in the CTMS, or other approved 
format, following investigational site monitoring and other manual reviews, will be reviewed 
against the individual data points in the CRF database. The overall procedure for managing 
protocol deviations are defined in the SOPs and study specific procedures of the CRO. All 
deviations will be reviewed, as determined at study start, to identify trends to improve 
monitoring and/or potential impact on the statistical analysis. 
11.2 Data Handling 
All study data will be managed by the data management team at the CRO responsible for this 
study. The overall procedures for quality assurance of clinical study data are described in the 
SOPs of the CRO. The CRO will prepare the DMP that will be approved by the Sponsor, prior 
to the start of the study. This document will describe, in detail, the procedures and processes 
related to data management.  
Data of all subjects that sign the ICF will be captured and stored in the study database. For 
Screen Failures the following information should be captured: date/time of ICF signature, date 
of birth, sex, race, AEs, concomitant medication given for treatment of AEs, date and reason 
for screen failure. 
All data collected during the study is property of the Sponsor, irrespective of the location of 
the database and the CRO. 
Additional details are covered in the DMP. 
11.2.1 
Data Verification 
The data will be verified as defined in the DMP and data validation plan (DVP). Discrepancy 
will be generated electronically, and queries will be issued to the investigational site, as 
necessary.  
Data queries will be raised for discrepant or missing data. All changes to data will be captured 
in the database with a comprehensive audit trail. 

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11.2.2 
Coding 
Adverse events, concomitant diseases, medical/surgical history, prior/concomitant medication 
will be classified according to the terminology of the latest version of the following 
dictionaries, at time of coding the first entry: 
Adverse 
events, 
concomitant 
disease, medical/surgical history:  
Medical Dictionary for Regulatory Activities 
(MedDRA®) 
Prior/concomitant medications:  
WHO Drug Dictionary Enhanced and Anatomical 
Therapeutic and Chemical classification system 
11.2.3 
Database Lock 
When all outstanding data management issues have been resolved and quality review and 
cleaning activities are complete, the database or selected data is/are declared soft-locked. 
Access to change data in the soft-locked database or to change selected data at this time is 
limited.  
After data review by the Sponsor, resolution of all raised queries and quality control 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.  
The study database will be transformed into a Clinical Data Interchange Standards Consortium 
(CDISC) compliant format and transferred to the Sponsor as specified in the DMP and defined 
in the data transfer agreement. The clinical data will adhere to the CDISC Study Data 
Tabulation Model Data Structure Specifications. 

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12 PLANNED STATISTICAL METHODS 
12.1 General Considerations 
Full details of the statistical analysis will be given in the statistical analysis plan (SAP). The 
following statistical analyses will not be performed prior to the finalization of the SAP. Any 
changes to the planned statistical methods from the SAP will be documented in the research 
study report (RSR). The statistical evaluation will be performed using SAS®, version 9.2 or 
later. 
12.1.1 
Stratification Criteria 
The sample randomization will enforce at least 40% of each sex in each product variant. 
Analyses stratified by sex will be detailed in the SAP.  
12.1.2 
Definitions for Statistical Data Analysis 
For plasma nicotine time-concentration and VAS-craving, baseline will be defined as the last 
measurement prior to product use for PK assessment (prior to T0) 
For the changes from baseline in PK parameters, PD parameters, CYP2A6 and product 
acceptance, described in sections 3.1 and 3.2, Day 1 value will be considered as the baseline. 
For BoExp and safety parameters the last assessments prior to product test will be considered 
as baseline. 
12.1.3 
Descriptive Statistics 
All data will be presented in listings.  
All endpoints will be summarized with descriptive statistics including number of subjects (n), 
number and percent of subjects with missing data, arithmetic means, 95% confidence intervals 
of the mean, and standard deviations (mean and SD), median, first and third quartiles, 
minimum and maximum. Change from baseline will be added to the summary statistics when 
applicable. 
For log-normally distributed endpoints geometric mean, 95% confidence intervals of the 
geometric mean, geometric CV will be presented instead of arithmetic mean, 95% confidence 
intervals of the mean, and SD and percent change from baseline will be presented instead of 
change from baseline. 
Categorical variables will be summarized by frequency statistics (number and percentage).  
For endpoints relating to sampling times (e.g., tmax) only median, first and third quartiles, and 
minimum and maximum will be presented. 

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12.1.4 
Handling of Missing Values and of Values outside the Detection Limits  
In general, missing data will not be imputed.  
For questionnaire data total scores and domain or subscale scores a certain degree of 
imputation may occur by averaging across individual item scores. Further details will be 
provided in the SAP. 
For biological measurements, values below the lower limit of quantification (LLOQ) will be 
imputed using 0.5 x lower limit of quantification. For values above the upper limit of 
quantification (ULOQ), i.e., preceded by a “>”, for example “>xx,” the numerical xx will be 
used for calculation and reporting in summary tables. The number and percent of values below 
LLOQ or above ULOQ will be presented in each summary table. 
12.1.5 
Significance Level for Inferential Analysis 
Not applicable. 
12.2 Determination of Sample Size and Power Consideration 
A total of 60 subjects will be enrolled randomized with a 1:1 randomization ratio (~30 subjects 
randomized to P3P-1mg and ~30 to P3P-2mg). The sample size is empirically based.  
12.3 Analysis Populations 
Pharmacokinetic, pharmacodynamics, product acceptance, puffing/inhalation behavior 
endpoints will be analyzed using the PK population by actual product exposure and overall. 
Nicotine/tobacco containing product use, tobacco and nicotine containing product dependence, 
and CYP2A6 activity will be analyzed using the randomized population by actual product 
exposure and overall. Exposure to harmful and potentially harmful constituents will be 
analyzed using the randomized population. Safety will be analyzed using the safety population 
by actual product exposure and overall.  
Actual product use exposure categories will be further defined in the SAP. Additional 
populations for sensitivity analysis could be defined in the SAP. 
12.3.1 
Safety Population 
The safety set population, consists of all the subjects who give informed consent, have at least 
one exposure to P3P (including the product test at Admission [Day -1]) and have at least one 
safety assessment. 
12.3.2 
Randomized population  
The randomized population is a subset of the safety population and consists of all randomized 
subjects who had at least one post-randomization P3P use experience and have at least one 
valid non-safety assessment. 

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12.3.3 
Pharmacokinetic Population 
The PK population is a subset of the randomized population and consists of all subjects who 
completed at least one of the single use of P3P for PK assessment, and for whom at least one 
primary nicotine PK parameter can be derived. Only subjects without major protocol 
deviations, as defined in the SAP, which have an impact on evaluability of the primary 
objective will be included in the PK population. 
Additional analysis sets may be defined in the SAP. 
12.4 Demographics and Baseline Characteristics 
Demographic information and baseline characteristics will be summarized for the safety 
population, randomized population, and PK population.  
Summaries will include sex, age, height, weight and BMI, smoking history, ABOUT 
Dependence Questionnaire, CYP2A6 activity and other endpoints that are only captured prior 
to product use.  
These data will be summarized as described in section 12.1.3. 
12.5 Primary Objective and Endpoints 
12.5.1 
Primary Endpoint Analysis Variables 
PK endpoints are listed in section 3.1. 
Nicotine PK parameters will be derived from plasma nicotine concentration versus time data. 
AUC(0-4h) will be derived using the trapezoidal method.  
To minimize the carry-over effect in the nicotine plasma PK parameters due to limited washout 
periods (see section 4.2), background-concentration correction will be applied to the nicotine 
concentration data.  
Baseline nicotine concentration (C0) will be defined as the last measured concentration prior 
to T0 of each visit. The baseline correction will be implemented by calculating the PK 
parameters using adjusted concentration values as described below (1):  
• Calculate the slope using a linear regression on the log concentration of the 3 pre- T0 
timepoints.  
• If the slope is <= 0, then use the slope to determine the elimination rate constant λz. 
• If the slope is > 0, then use the average (geometric mean) of the subject’s slopes that 
are <= 0 from the other visits to determine λz. If the subject’s slopes are positive for all 
of the visits, baseline corrected PK parameters will not be calculated.  
• Adjust each concentration value post-baseline using the following formula:  

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without the written consent of Philip Morris Products S.A. 
cCt = Ct - C0 * e-λzt. 
cCt is the corrected concentration at each time point, Ct is the concentration at each time point, C0 
is the pre-use baseline nicotine concentration, λz is the elimination rate constant and t is the actual 
time. 
The following PK parameters will be derived from nicotine levels adjusted for baseline: 
cCmax 
Background-corrected maximum observed plasma concentration. cCmax will be 
reported as long as there is at least one quantifiable concentration post-exposure 
ctmax 
Time to maximum concentration cCmax  
cAUC (0-4h)  Background-corrected area under the plasma concentration-time curve from 
start of product use (T0) to 4 hour 
Unadjusted PK parameters will also be presented.   
More details on nicotine PK parameter derivations will be provided in the SAP. 
12.5.2 
Baseline Comparability 
Not applicable. 
12.5.3 
Statistical Analysis  
PK parameters will be summarized as described in section 12.1.3. 
Nicotine PK profiles will be summarized and plotted over time for each visit. 
An analysis of variance (ANOVA) will be conducted for Day 1 and Day 30 on background-
corrected AUC(0-4h) and background-corrected Cmax endpoints in the natural logarithmic scale. 
The model will include sex as a covariate. The results of this analysis for each of cAUC(0-4h) 
and cCmax will be presented as geometric least square means and 95% confidence intervals for 
each variant and least square mean ratio and 95% confidence intervals of P3P-2mg:P3P-1mg 
ratio. 
For the ANOVA tests, the following hypothesis will be tested: 
H0: μ1 = μ2 
H1: μ1 ≠ μ2  
where μ1 and μ2 are the means (arithmetic or geometric) for each product variant, respectively. 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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without the written consent of Philip Morris Products S.A. 
12.6 Secondary Objectives and Endpoints 
12.6.1 
Secondary Endpoint Analysis Variables 
12.6.1.1 PD endpoints  
PD endpoints are listed in section 3.2. 
VAS craving score and changes from baseline will be summarized by timepoint. In addition, 
AUCVAS will be derived by P3P variant: AUCVAS (0-4h). 
Sensory Questionnaire and ABOUT Product Experience Questionnaire will be described as 
detailed in section 12.1.3. Further details on the summary statistics of these questionnaires will 
be provided in the SAP.  
12.6.1.2 
Product Acceptance 
Product acceptance questionnaire will be described as detailed in section 12.1.3. Further details 
on the summary statistics of this questionnaire will be provided in the SAP. 
12.6.1.3 
Product Use  
Nicotine/tobacco containing product use will be derived from product use diary. Some further 
exploration based on BoExp levels could be added in the SAP. Product use and product use 
will be described as detailed in section 12.1.3. 
12.6.1.4 
Biomarkers of Exposure 
Biomarkers of Exposure (NEQ, total NNAL, and CEMA) will be described as detailed in 
section 12.1.3. 
12.6.1.5 
CYP2A6 
CYP2A6 will be described as detailed in section 12.1.3. 
12.6.1.6 
ABOUT Dependence 
Product Dependence Questionnaire will be described as detailed in section 12.1.3. Further 
details on the summary statistics of this questionnaire will be provided in the SAP. 
12.6.1.7 
Product weighing 
Amount of powder extracted from P3P during the PK assessment will be described as detailed 
in section 12.1.3. Further details will be provided in the SAP. 

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without the written consent of Philip Morris Products S.A. 
12.6.2 
Statistical Analysis 
An analysis of variance (ANOVA) will be conducted for Day 1 and Day 30 on VAS-craving 
endpoints in the linear scale following the same approach described in section 12.5.3 
presenting LS Means and LS mean differences. Additional statistical analysis of secondary 
endpoints may be defined in the SAP. 
12.6.3 
Safety Endpoints 
In general, all safety data will be listed and tabulated as described in section 12.1.3.  
AE data will serve for the primary assessment of safety. Other safety variables monitored in 
this study include: incidence and frequency of P3P product events including 
malfunction/misuse; respiratory symptoms (cough assessment VAS and Likert scales); vital 
signs; spirometry; ECG data; clinical chemistry, hematology, and urine analysis safety panel; 
physical examination; concomitant medications.  
The number and percentage of subjects with AEs, SAEs, and product events will be tabulated 
by system organ class and preferred term. Summaries will also be presented for AEs leading 
to discontinuation, AEs leading to death, AEs by relatedness to product exposure (with and 
without laboratory related AEs), AEs by severity, and laboratory AEs. Tabulations will be 
performed for both the number of subjects experiencing an event and the number of events. 
Summary tables showing actual values and change from baseline of clinical findings will be 
provided for spirometry, ECGs, vital signs, and laboratory parameter. Descriptive statistics 
will be summarized by product variant and change from baseline will be presented for 
laboratory parameters, ECG, respiratory symptoms, and vital signs. Shift tables will be 
provided for selected laboratory, spirometry, and ECG data. 
12.6.4 
Exploratory Analyses 
There are no planned exploratory analyses. 

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without the written consent of Philip Morris Products S.A. 
13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Investigators and Study Administrative Structure 
13.1.1 
Investigator 
Investigator: 
Vasilyuk Vasily Bogdanovich, MD 
LLC Scientific Research Center Eco-Safety 
 
Russia 
Phone: +7 
  
E-mail: 
  
13.1.2 
Sponsor 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5, 
2000 Neuchâtel, 
Switzerland. 
Phone: +41 (0) 58 242 2111 
Fax: +41 (0) 58 242 2811 
, PhD 
Clinical Scientist 
Phone: +41 
  
E-mail: 
pmi.com 
 
, 
MEng, MSc 
Study Statistician 
Phone : +41
 
E-mail : 
.pmi.com 
, MD 
Medical Safety Officer 
Phone : +41
 
Email1 : 
pmi.com 
E-mail2 :
pmi.com 
, PhD 
Clinical Study Manager 
Phone : +41 
 
E-mail :
pmi.com 
13.1.3 
Other Responsibilities 
CRO 
 
 
  
  
  

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without the written consent of Philip Morris Products S.A. 
All duties and responsibilities transferred by the Sponsor to the above listed CROs will be 
defined in the agreement signed between the relevant two parties. 
Any SAEs or pregnancies will be handled by the Investigator, study monitor (or Sponsor), as 
per the instructions listed in section 8.3. 
Details of the laboratories conducting the clinical safety laboratory services, bioanalyses and 
storage for biobanking samples are shown in Appendix B. 
13.2 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects' state of 
health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subject in writing and signed by the subject, in compliance with all local and 
national data protection and privacy legislation. 
The names of the subjects participating in this study will be kept confidential. Subjects will be 
identifiable by the Sponsor (or Sponsor’s authorized representative) on CRFs and other 
documents by their subject (or randomization) number/code, sex and age, but not by name, 
initial, or any other details relating to identifiable person (e.g., address, social security number, 
medical chart number, etc.). The assignment of a subject number/code for subject identification 
will be based on the appropriate data protection rules. 
Any documents that allow full identification of the subject (e.g., the subject’s signed ICF) must 
be maintained in confidence by the Investigator. If any document relating to this study shows 
a subject’s name or any other details relating to an identifiable person (e.g., address, social 
security number, medical chart number, etc.), the name or other identifiable details must be 
obscured before a copy of that document is supplied to the Sponsor or the Sponsor’s authorized 
representative. 
13.3 Access to Source Documentation 
Subjects will be informed that, during the course of the study, the Sponsor, any authorized 
representatives of the Sponsor, IEC or regulatory authorities may inspect their medical records 
and source documentation to verify the information collected and ensure that all personal 
information made available for inspection is handled in the strictest confidence and in 
accordance with national and local data protection and privacy legislation. 
The Investigator and all investigational site staff involved with the study must permit direct 
access to source data/documents for study related monitoring, audits, IEC review and 
regulatory inspection(s). 

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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. 
13.4 Record Retention 
All records of data, source data and source documents (original records or certified copies), in 
any form (including, but not limited to, written, electronic, magnetic, optical records and scans, 
X-rays and ECGs) that describe or record the methods, conduct, and/or results of the study, the 
factors affecting the study and the actions taken will be maintained by the investigational site 
for the study, as required by ICH GCP (2) and any other applicable local or national 
regulations. For X-rays, at least the radiologist’s assessment is required as source document. 
If the actual image is available, it can be stored on CD as well. 
Essential study documents/records, which individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced, are described in section 8 of the 
ICH GCP Guideline (2). 
Essential documents must be retained by the Investigator for a minimum of:  
• At least 15 years after completion or discontinuation of the study.  
However, these documents should be retained for a longer period if required by the applicable 
regulatory requirements or by agreement with the Sponsor.  
Examples of essential records/documents include, but are not limited to:  
• Signed informed consent documents for all subjects and master ICF.  
• Subject identification code list, Screening log and Enrollment log (if applicable).  
• Record of all communications between the Investigator and the IEC, composition of the 
IEC.  
• Record of all communications/contact between the Investigator, the Sponsor, and its 
authorized representatives.  
• List of sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in the 
study, CVs, and their signatures. 
• CRFs, study specific questionnaires (and associated data/scoring), subject diaries. 
• AE reports and details of follow-up investigations, details of concomitant medication. 
• All other source documents (e.g., chest X-rays, ECGs, consultation reports, physical 
examination and laboratory records) or any electronically captured study source data. 
• Clinical laboratory reports, laboratory normal ranges. 
• Original medical/hospital records, if applicable (the medical files of study subjects must be 
retained in accordance with local legislation and in accordance with the maximum period 
of time permitted by the hospital or study site). 

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without the written consent of Philip Morris Products S.A. 
• Record of any body fluids or tissue samples collected and retained. 
• IP Accountability Logs, dispensing records. 
• Information regarding subjects’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the Investigator/study site as to when these 
documents no longer need to be retained. 
The Investigator/study site must take measures to prevent accidental or premature destruction 
of these documents. 
If an Investigator wishes to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. The Investigator must obtain written 
approval from the Sponsor before destruction of any records. Normally, these records will be 
held in the Investigator’s archives. If an Investigator is unable to meet this obligation, they 
must ask the Sponsor for permission to make alternative arrangements. Details of these 
arrangements must be documented. 
The Sponsor will maintain documentation relating to the study as long as the IP is on the market, 
and three years after its discontinuation or for 15 years after the RSR has been finalized, 
whichever is longer. 
13.5 Research Study Report 
The Sponsor must ensure that a RSR for this study is prepared regardless of whether the study 
is completed or prematurely terminated.  
The RSR will be written based on standards of the ICH Guideline for the “Structure and 
Content of Clinical Study Reports”(45). In certain circumstances, an abbreviated RSR may be 
acceptable. Submission of the RSR to the IEC will be complied with as requested by local 
requirements. 
13.6 Financial Disclosure 
Investigators and any designees are required to provide financial disclosure information to the 
Sponsor. In addition, the Investigators and designees must provide the Sponsor with 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. 
13.7 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 study 
for the Sponsor. Disclosure of the content of this document is allowed only to study personnel, 
IEC, or duly authorized representatives of regulatory agencies for this purpose under 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. 
condition that confidentiality is maintained. The contents of this document may not be used in 
any other 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 must be given to the Sponsor prior to any such disclosure.  
The Sponsor plans to disclose details of the study protocol on a web-based, publicly available, 
clinical trial register database (e.g., ClinicalTrials.gov). 
13.8 Insurance 
The Sponsor is responsible for AEs and health damage of the subjects that are associated with 
the investigational products which are used during the study, except for AEs and health damage 
of the subjects caused by a negligent or an intentional misconduct and/or significant deviation 
to the protocol of the Investigator or the clinical investigational site or the subjects. The 
Sponsor has taken out insurance to cover any bodily injury and property damage caused by the 
operations carried out by the insured. 

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without the written consent of Philip Morris Products S.A. 
14 REFERENCE LIST 
1. Kraiczi H, Hansson A, Perfekt R. Single-dose pharmacokinetics of nicotine when given 
with a novel mouth spray for nicotine replacement therapy. Nicotine Tob Res. 
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2. ICH E6 (R2). Integrated addendum to ICH E6 (R1): guideline for good clinical practice - 
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3. World Medical Association (WMA). Declaration of Helsinki - Ethical principles for 
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4. U.S. Department of Health and Human Services. The health consequences of smoking - 50 
years of progress: a report of the Surgeon General. 2014. 
5. WHO Study Group, Ashley DL, Ayo-Yusuf OA, Boobis AR, da Costa e Silva VL, 
Djordjevic MV, et al. WHO study group on tobacco product regulation - Report on the 
scientific basis of tobacco product regulations: fifth report of a WHO study group. 2015. 
6. McNeill A, Brose LS, Calder R, Bauld L, Robson D. Evidence review of e-cigarettes and 
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7. Royal College of Physicians. Nicotine without smoke: tobacco harm reduction. A report 
by the Tobacco Advisory Group of the Royal College of Physicians. London: RCP. 2016. 
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10. Farsalinos KE, Spyrou A, Stefopoulos C, Tsimopoulou K, Kourkoveli P, Tsiapras D, et al. 
Nicotine absorption from electronic cigarette use: comparison between experienced consumers 
(vapers) and naive users (smokers). Sci Rep. 2015;5:1-8. Epub 2015/06/18. doi: 
10.1038/srep11269. PubMed PMID: 26082330; PubMed Central PMCID: PMCPmc4469966. 

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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. 
11. Spindle TR, Breland AB, Karaoghlanian NV, Shihadeh AL, Eissenberg T. Preliminary 
results of an examination of electronic cigarette user puff topography: the effect of a 
mouthpiece-based topography measurement device on plasma nicotine and subjective effects. 
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PMID: 25239957; PubMed Central PMCID: PMCPmc4838000. 
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switched from tobacco to electronic cigarettes. Addict Behav. 2015;48:1-4. Epub 2015/05/02. 
doi: 10.1016/j.addbeh.2015.04.003. PubMed PMID: 25930009; PubMed Central PMCID: 
PMCPMC4457608. 
13. Hammond D, Fong GT, Cummings KM, Hyland A. Smoking topography, brand switching, 
and nicotine delivery: results from an in vivo study. Cancer Epidemiol Biomarkers Prev. 
2005;14(6):1370-5. Epub 2005/06/09. doi: 10.1158/1055-9965.epi-04-0498. PubMed PMID: 
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14. Ludicke F, Picavet P, Baker G, Haziza C, Poux V, Lama N, et al. Effects of switching to 
the Menthol Tobacco Heating System 2.2, smoking abstinence, or continued cigarette smoking 
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sequential confinement and ambulatory settings (Part 2). Nicotine Tob Res. 2018;20(2):173-
82. Epub 2017/02/09. doi: 10.1093/ntr/ntx028. PubMed PMID: 28177498; PubMed Central 
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15. Farsalinos KE, Romagna G, Tsiapras D, Kyrzopoulos S, Voudris V. Evaluation of 
electronic cigarette use (vaping) topography and estimation of liquid consumption: 
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18. Robinson RJ, Hensel EC, Morabito PN, Roundtree KA. Electronic cigarette topography in 
the natural environment. PLoS ONE. 2015;10(6):e0129296. Epub 2015/06/09. doi: 

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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. 
10.1371/journal.pone.0129296. PubMed PMID: 26053075; PubMed Central PMCID: 
PMCPmc4460076. 
19. Robinson RJ, Hensel EC, Al-Olayan AA, Nonnemaker JM, Lee YO. Effect of e-liquid 
flavor on electronic cigarette topography and consumption behavior in a 2-week natural 
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PMCPmc5931659. 
20. Farsalinos K, Poulas K, Voudris V. Changes in puffing topography and nicotine 
consumption depending on the power setting of electronic cigarettes. Nicotine Tob Res. 
2018;20(8):993-7. Epub 2017/10/24. doi: 10.1093/ntr/ntx219. PubMed PMID: 29059377. 
21. Ross KC, Dempsey DA, St Helen G, Delucchi K, Benowitz NL. The influence of puff 
characteristics, nicotine dependence, and rate of nicotine metabolism on daily nicotine 
exposure in African American smokers. Cancer Epidemiol Biomarkers Prev. 2016;25(6):936-
43. Epub 2016/04/01. doi: 10.1158/1055-9965.epi-15-1034. PubMed PMID: 27030603; 
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Edition 1. 2017. 
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pharmacokinetics of nicotine following single and ad Libitum use of a tobacco heating system 
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pharmacokinetic profiles of the Tobacco Heating System 2.2, cigarettes and nicotine gum in 
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of nicotine pharmacokinetics and subjective effects following use of a novel nicotine delivery 
system. Nicotine Tob Res. Accepted article 2017. 
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approaches to smoking (NICE public health guidance 45). 2013; Available from: 

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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. 
http://www.nice.org.uk/guidance/ph45/resources/guidance-tobacco-harmreduction-
approaches-to-smoking-pdf (Accessed on 11 August 2014). 
28. Marchand M, Brossard P, Merdjan H, Lama N, Weitkunat R, Ludicke F. Nicotine 
population pharmacokinetics in healthy adult smokers: a retrospective analysis. Eur J Drug 
Metab Pharmacokinet. 2017. Epub 2017/03/12. doi: 10.1007/s13318-017-0405-2. PubMed 
PMID: 28283988. 
29. Benowitz NL, Jacob P, 3rd, Fong I, Gupta S. Nicotine metabolic profile in man: 
comparison of cigarette smoking and transdermal nicotine. J Pharmacol Exp Ther. 
1994;268(1):296-303. Epub 1994/01/01. PubMed PMID: 8301571. 
30. Hecht SS, Carmella SG, Murphy SE, Riley WT, Le C, Luo X, et al. Similar exposure to a 
tobacco-specific carcinogen in smokeless tobacco users and cigarette smokers. Cancer 
Epidemiol Biomarkers Prev. 2007;16(8):1567-72. Epub 2007/08/09. doi: 10.1158/1055-
9965.epi-07-0227. PubMed PMID: 17684130. 
31. Minet E, Cheung F, Errington G, Sterz K, Scherer G. Urinary excretion of the acrylonitrile 
metabolite 2-cyanoethylmercapturic acid is correlated with a variety of biomarkers of tobacco 
smoke exposure and consumption. Biomarkers. 2011;16(1):89-96. Epub 2010/11/27. doi: 
10.3109/1354750x.2010.533287. PubMed PMID: 21108560; PubMed Central PMCID: 
PMC3026342. 
32. Chrea C, Spies E, Afolalu E, Mainy N, Gallot S, Binggeli P, et al. Assessing consumer 
responses to reduced risk products: experience at Philip Morris International in developing fit-
for-purpose self-report instruments. 2018; Poster presented at the Fifth Global Forum on 
Nicotine, Warsaw, Poland. Available from: https://gfn.net.co/posters-2018/566-assessing-
consumer-responses-to-reduced-risk-products-experience-at-philip-morris-international-in-
developing-fit-for-purpose-self-report-instruments (Accessed on 20 August 2018). 
33. FDA (Food and Drug Administration). Food-effect bioavailability and fed bioequivalence 
studies. 2002. 
34. American Pharmacists Association. Cytochrome P450 enzymes: substrates, inhibitors, and 
inducers.  Drug information handbook. 23rd ed2014. p. 2316-24. 
35. Raw M, Anderson P, Batra A, Dubois G, Harrington P, Hirsch A, et al. WHO Europe 
evidence based recommendations on the treatment of tobacco dependence. Tob Control. 
2002;11(1):44-6. PubMed PMID: 11891367. 
36. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. Epub 2005/08/02. doi: 
10.1183/09031936.05.00034805. PubMed PMID: 16055882. 

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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. 
37. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes 
and forced ventilatory flows. Eur Respir J. 1993;6 Suppl 16:5-40. Epub 1993/03/01. doi: 
10.1183/09041950.005s1693. PubMed PMID: 24576915. 
38. Chrea C, Salzberger T, Abetz-Webb L, Afolalu E, Cano S, Rose J, et al. Development of a 
tobacco and nicotine products dependence instrument. 2018; Poster presented at the Society 
for Research on Nicotine and Tobacco Annual Meeting, Baltimore, MD, USA. Available from: 
https://www.pmiscience.com/library/publication/development-of-a-tobacco-and-nicotine-
products-dependence-instrument (Accessed on 16 April 2018). 
39. Salzberger T, Cano S, Mainy N, Chrea C, Vandyke S, Haziza C, et al. Psychometric 
evaluation of the mCEQ applied to cigarettes and heat-notburn products in the US and Japan. 
2018; Poster presented at the Society for Research on Nicotine and Tobacco Annual Meeting, 
Baltimore, 
MD, 
USA. 
Available 
from: 
https://www.pmiscience.com/library/publication/psychometric-evaluation-of-the-mceq-
applied-to-cigarettes-and-heat-notburn-products-in-the-us-and-japan (Accessed on 16 April 
2018). 
40. Cappelleri JC, Bushmakin AG, Baker CL, Merikle E, Olufade AO, Gilbert DG. 
Confirmatory factor analyses and reliability of the modified cigarette evaluation questionnaire. 
Addict Behav. 2007;32:912–23. doi: 10.1016/j.addbeh.2006.06.028. 
41. Hatsukami DK, Zhang Y, O'Connor RJ, Severson HH. Subjective responses to oral tobacco 
products: scale validation. Nicotine Tob Res. 2013;15(7):1259-64. Epub 2012/12/15. doi: 
10.1093/ntr/nts265. PubMed PMID: 23239843; PubMed Central PMCID: PMCPmc3682844. 
42. Rose JE, Turner JE, Murugesan T, Behm FM, Laugesen M. Pulmonary delivery of nicotine 
pyruvate: sensory and pharmacokinetic characteristics. Exp Clin Psychopharmacol. 
2010;18(5):385-94. doi: 10.1037/a0020834. PubMed PMID: 20939642. 
43. Royal College of Physicians. Harm reduction in nicotine addiction: helping people who 
can’t quit. A report by the Tobacco Advisory Group of the Royal College of Physicians. 
London: RCP. 2007. 
44. Moyses C, Hearn A, Redfern A. Evaluation of a novel nicotine inhaler device: part 2-effect 
on craving and smoking urges. Nicotine Tob Res. 2015;17(1):26-33. Epub 2014/08/02. doi: 
10.1093/ntr/ntu122. PubMed PMID: 25082830; PubMed Central PMCID: PMCPmc4282120. 
45. ICH E3. Structure and content of clinical study reports - Guideline. 1995; Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_G
uideline.pdf (Accessed on 17 July 2014). 
 

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consent of Philip Morris Products S.A. 
15 APPENDICES 
Appendix A – Schedule of Events 
 
Screening 
Admission 
Product use period (up to 15 products/day) 
Discharge 
Early 
termination 
Safety Follow-
Up 
Visit 
1 
2 
3 
4 
5 
6 
 
 
Study day 
-22 to -2 
-1 
1 
2 
7 
±2d 
15 
±2d 
22  
±2d 
29 
±2d 
30 
±2d 
 
+14 days 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
Information on the risks of smoking/ 
smoking cessation advice and 
debriefing on P3P 
● 
● 
 
 
 
 
 
● 
 
● 
 
Inclusion/exclusion criteria a 
● 
● 
 
 
 
 
 
 
 
 
 
Tobacco and nicotine containing 
products use history and habits  
● 
 
 
 
 
 
 
 
 
 
 
P3P demonstration 
● 
 
 
 
 
 
 
 
 
 
 
Demographics 
● 
 
 
 
 
 
 
 
 
 
 
Medical history/concomitant diseases 
● 
 
 
 
 
 
 
 
 
 
 
Chest X-ray b 
● 
 
 
 
 
 
 
 
 
 
 
B: HIV, Hepatitis B and C 
● 
 
 
 
 
 
 
 
 
 
 
U: Drug screen 
● 
● 
 
 
 
 
 
 
 
 
 
U: Cotinine test 
● 
● 
 
 
 
 
 
 
 
 
 
U: Pregnancy test 
● 
● 
 
 
 
● 
 
● 
 
● 
 
Alcohol breath test 
● 
● 
 
 
 
 
 
 
 
 
 
Vital signs c 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Physical examination  
● 
● 
 
● 
● 
● 
● 
 
● 
● 
 
Body height, weight and BMI d 
● 
● 
 
 
 
 
 
 
● 
 
 
Spirometry e 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Prior/concomitant medication 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
●f 

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consent of Philip Morris Products S.A. 
 
Screening 
Admission 
Product use period (up to 15 products/day) 
Discharge 
Early 
termination 
Safety Follow-
Up 
Visit 
1 
2 
3 
4 
5 
6 
 
 
Study day 
-22 to -2 
-1 
1 
2 
7 
±2d 
15 
±2d 
22  
±2d 
29 
±2d 
30 
±2d 
 
+14 days 
B/U: Hematology, clinical chemistry, 
urinalysis safety panel 
● 
● 
 
 
 
● 
 
 
● 
● 
 
ECG 
● 
● 
● 
● 
● 
● 
● 
 
● 
● 
 
Enrollment 
 
● 
 
 
 
 
 
 
 
 
 
P3P product test g 
 
● 
 
 
 
 
 
 
 
 
 
Willing to continue to use P3P for 1 
Month (confirmation after product 
test) 
 
● 
 
 
 
 
 
 
 
 
 
Randomization 
 
● 
 
 
 
 
 
 
 
 
 
B: CYP2A6 activity h 
 
 
● 
 
 
 
 
 
● 
 
 
Overnight nicotine wash-out period i 
 
● 
 
 
 
 
 
● 
 
 
 
P3P single product use for PK 
assessment j 
 
 
● 
 
 
 
 
 
● 
 
 
Weighing of P3P k 
 
 
● 
 
 
 
 
 
● 
 
 
Collection of used and unused P3P l 
 
 
 
 
● 
● 
● 
● 
 
● 
 
On-site product use (up to 15 P3P) 
 
 
● 
● 
 
 
 
 
 
 
 
P3P resupply 
 
 
 
● 
● 
● 
● 
 
 
 
 
B: nicotine in plasma m 
 
 
● 
 
 
 
 
 
● 
 
 
U: BoExp n 
 
● 
 
 
● 
● 
● 
● 
 
 
 
B/U: Biobanking 
 
 
● 
 
 
 
 
 
● 
 
 
Product use diary o 
 
 
● 
● 
● 
● 
● 
● 
● 
 
 
ABOUTTM-Dependence 
Questionnaire 
 
● 
 
 
 
 
 
 
● 
 
 
ABOUTTM-Product Experience 
 
 
● 
 
 
 
 
 
● 
 
 
Product acceptance 
 
 
● 
 
 
 
 
 
● 
 
 

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consent of Philip Morris Products S.A. 
 
Screening 
Admission 
Product use period (up to 15 products/day) 
Discharge 
Early 
termination 
Safety Follow-
Up 
Visit 
1 
2 
3 
4 
5 
6 
 
 
Study day 
-22 to -2 
-1 
1 
2 
7 
±2d 
15 
±2d 
22  
±2d 
29 
±2d 
30 
±2d 
 
+14 days 
Sensory Questionnaire 
 
 
● 
 
 
 
 
 
● 
 
 
VAS Craving p 
 
 
● 
 
 
 
 
 
● 
 
 
Puffing/inhalation behavior question 
(assessed by site staff) 
 
 
● 
 
 
 
 
 
● 
 
 
Puffing/inhalation behavior question 
(assessed by subject) 
 
 
 
● 
● 
● 
● 
● 
 
 
 
Cough assessment (VAS, Likert 
scale) 
 
● 
● 
 
● 
● 
● 
● 
 
 
 
AE/SAE reporting 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● q 
Concomitant disease status 
 
● 
 
 
● 
● 
● 
● 
 
● 
 
P3P product event reporting 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Abbreviations: ABOUT = Assessment of Behavioral Outcomes related to Tobacco and nicotine products; AE = Adverse event; B = Blood sample; BMI = Body mass index; BoExp = Biomarkers 
of Exposure; ECG = Electrocardiogram; PK = Pharmacokinetics; SAE = Serious adverse event; U = Urine sample; VAS = Visual analog scale 
a. 
Prior to enrollment, at Day -1 the following eligibility criteria will be re-checked: Inclusion criteria: smoking status confirmed by urine cotinine, subject is not planning to quit smoking 
within 2 months, subject is available for the entire study period and is willing to comply with the study procedures. Exclusion criteria: urine pregnancy test (all females), urine drug 
screen and alcohol breath test. The following eligibility criteria will only be checked at Day -1: Exclusion criteria: subject has received medication which has an impact on CYP2A6 
activity within 14 days or within 5 half-lives of the drug prior to Day -1 (whichever is longer) 
b. 
Pre-study chest X-ray (with anterior-posterior and left lateral views). Available chest computed tomography (CT) or chest magnetic resonance imaging (MRI) results, or radiologist 
report from an equivalent radiological assessment within 6 months prior to Screening. 
c. 
Systolic and diastolic blood pressure, pulse rate, and respiratory rate. At V2 (Day -1, Day 1 and Day 2) and V6 (Day 30) vital signs are to be checked prior to any product use and at the 
end of the day/at discharge.  
d. 
Subjects with a BMI < 18.5 kg/m2 or BMI ≥ 32 kg/m2 will be excluded. At V2 and V6 weight only will be recorded. 
e. 
Spirometry with and without bronchodilator performed at Screening. Spirometry without bronchodilator performed at the remaining visits. At Day -1, spirometry will be performed 
before and after product test. At Day 1 and Day 2 spirometry will  be performed before product use and at the end of the daily product use. 
f. 
Only medication used for treatment of an AE/SAEs 
g. 
P3P product test using up to 6 P3P products (both P3P-1mg and P3P-2mg) will be conducted at Day -1 after enrollment. A wash-out period from any tobacco/nicotine containing products 
of at least 4 h prior to product test is needed. 

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h. 
Sample taken in the morning prior to product use. 
i. 
Starting on the first day of each confinement period, subjects will abstain from tobacco/nicotine containing products for at least 10 h prior to P3P use for PK assessment on the second 
confinement day. 
j. 
Use of a single product with puffing depending on the subjects preference (ad libitum use) for a duration of up to 15 minutes. 
k. 
Each P3P used for PK assessment should be weighed prior to product use and within 1h after the end of the use. 
l. 
On Day 29 collection of unused P3P should occur right before the start of the 10h wash-out period. 
m. A total of 11 blood samples will be taken for PK parameter estimation at Day 1 and Day 30. Three blood samples will be taken prior to the start of product use (T0) 1 hour ± 5 minutes, 
30 minutes ± 5 minutes and 5 minutes ± 2 minutes before T0. Thereafter in relation to T0, blood will be drawn at the following time points: after 4 minutes ± 1 minute, after 7 minutes ± 
1 minute, after 10 minutes ± 1 minute, after 15 minutes ± 2 minutes, after 30 minutes ± 2 minutes, after 1 hour ± 5 minutes, after 2 hours ± 5 minutes and after 4 hours ± 5 minutes.  
n. 
NEQ, NNAL and CEMA will be analyzed in spot urine and adjusted for creatinine.  
o. 
Daily during the exposure period. Use of P3P and any other tobacco and nicotine containing products will be captured in a diary starting from Check-out of Day 1 until Discharge at Day 
30. 
p. 
First assessment to be done 10 ± 2 minutes prior to T0. Thereafter, in relation to T0, assessment is to be performed at 4 minutes ± 2 minutes, 10 minutes ± 2 minutes, 15 minutes ± 2 
minutes, 30 minutes ± 5 minutes, 1 hour, 2 hour and 4 hours ± 10 minutes each. 
q. 
At the end of Safety FU (end of V6 + 14 days) the site will call all subjects to collect new AEs/SAEs and to follow-up ongoing AEs/SAEs. If the subject is not responding at the initial 
call, 2 additional attempts on the next consecutive days will be made in order to reach the subject

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without the written consent of Philip Morris Products S.A. 
Appendix B - Participating Laboratories 
 
Bioanalytical laboratory (plasma nicotine and CYP2A6 analysis; urinary BoExp and 
creatinine): 
 
 
 
  
  
  
 
Clinical Safety Laboratory (Hematology, Clinical Chemistry and Urine Analysis): 
  
 
Russia  
 
  
 
 
Russia  
 
Samples shipment:  
 
  
 
Russia   
 
Biobanking of samples: 
  
 
  
Germany 

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Appendix C - Laboratory Values 
Table C1 
Abnormal Laboratory Values Rating: Serum Chemistry Parameters 
Serum Chemistry 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
 (Grade 4) 
Sodium – Hyponatremia (mmol/L) a 
<LLN - 130 
- 
<130 - 120 
<120 
Sodium – Hypernatremia (mmol/L) a 
>ULN - 150 
>150 - 155 
>155 - 160; 
hospitalization 
indicated 
>160 
Potassium – Hyperkalemia (mmol/L) a 
>ULN - 5.5 
>5.5 - 6.0 
>6.0 -7.0; 
hospitalization 
indicated 
>7.0 
Potassium – Hypokalemia (mmol/L) a 
<LLN - 3.0 
<LLN - 3.0; 
symptomatic; 
intervention 
indicated 
<3.0 - 2.5; 
hospitalization 
indicated 
<2.5 
Glucose – Hypoglycemia a 
(mg/dL) 
(mmol/L)  
<LLN – 55; 
<LLN – 3.0 
<55 – 40; 
<3.0 – 2.2 
<40 – 30; 
<2.2 – 1.7 
<30; 
<1.7 
Glucose – Hyperglycemia: a 
Fasting (mg/dL) 
(mmol/L) 
 
>ULN-160; 
>ULN-8.9 
 
>160-250; 
>8.9-13.9 
 
>250-500; 
>13.9-27.8; 
hospitalization 
indicated 
 
>500; 
>27.8 
Creatinine increased a 
>1 – 1.5 x 
Baseline; 
>ULN – 1.5 x 
ULN 
>1.5 – 3.0 x 
Baseline; 
>1.5 – 3.0 x 
ULN 
>3.0 x Baseline; 
>3.0 – 6.0 x 
ULN 
>6.0 x ULN 
Albumin - Hypoalbuminemia a 
(g/dL) 
(g/L) 
<LLN – 3; 
<LLN - 30 
<3 – 2; 
<30 - 20 
<2; 
<20 
 
- 
- 
Alkaline phosphatase increased a 
>ULN – 2.5 x 
ULN 
>2.5 – 5.0 x 
ULN 
>5.0 – 20.0 x 
ULN 
>20.0 x ULN 
ALT / AST increased a 
>ULN – 3.0 x 
ULN 
>3.0 – 5.0 x 
ULN 
>5.0 – 20.0 x 
ULN 
>20.0 x ULN 
Gamma-glutamyl transferase (GGT) 
increased a 
>ULN – 2.5 x 
ULN 
>2.5 – 5.0 x 
ULN 
>5.0 – 20.0 x 
ULN 
>20.0 x ULN 
Blood bilirubin increased  
(total and direct) a 
>ULN – 1.5 x 
ULN 
>1.5 – 3.0 x 
ULN 
>3.0 – 10.0 x 
ULN 
>10.0 x ULN 
Cholesterol high a 
(mg/dL) 
 
>ULN - 300; 
 
>300-400; 
 
>400-500; 
 
>500; 

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Serum Chemistry 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
 (Grade 4) 
(mmol/L) 
>ULN - 7.75 
>7.75-10.34 
>10.34-12.92 
>12.92 
Triglycerides - Hypertriglyceridemia a 
(mg/dL) 
(mmol/L) 
150 – 300; 
1.71 – 3.42 
>300 – 500; 
>3.42 – 5.70 
>500 – 1000; 
>5.70 – 11.40 
 
>1000; 
>11.4  
Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; BUN = Blood urea nitrogen; 
GGT = Gamma-glutamyl transferase; LLN = Lower limit of the normal range; ULN = Upper limit of the normal range. 
Data Sources: 
a 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, 
FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
 
Table C2 
Abnormal Laboratory Values Rating: Hematology Parameters 
Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
 (Grade 4) 
Anemia (Hemoglobin) a 
(g/dL) 
(mmol) 
(g/L) 
 
<LLN-10.0 
<LLN-6.2 
< LLN-100 
 
<10-8.0 
<6.2-4.9 
< 100-80 
 
<8.0 
<4.9 
<80 
Transfusion 
indicated 
 
Life 
threateming 
consequences; 
urgent 
intervention 
indicated 
Hemoglobin increase a – 
(g/dL) 
Increase in >0 – 
2 above ULN or 
above Baseline 
if Baseline is 
above ULN 
Increase in >2 – 4 
above ULN or 
above Baseline if 
Baseline is above 
ULN 
Increase in >4 
above ULN or 
above Baseline if 
Baseline is above 
ULN 
- 
WBC Decrease a - 
(cell/mm3)  
(109/L) 
 
<LLN – 3000; 
<LLN – 3.0 
 
<3000 - 2000; 
<3.0 – 2.0  
 
<2000 - 1000; 
<2.0 – 1.0  
 
<1000; 
<1.0  
Lymphocytes increase a 
(cell/mm3)  
 
- 
 
>4,000 – 20,000 
 
>20,000 
 
- 
Lymphocytes decrease a 
(cell/mm3)  
(109/L) 
 
<LLN – 800; 
<LLN – 0.8 
 
<800 - 500; 
<0.8 – 0.5 
 
<500 - 200; 
<0.5 – 0.2 
 
<200; 
<0.2 
Neutrophils Decrease a 
(cell/mm3)  
(109/L) 
 
<LLN – 1500; 
<LLN – 1.5 
 
<1500 - 1000; 
<1.5 – 1.0 
 
<1000 - 500; 
<1.0 – 0.5 
 
<500; 
<0.5 
Platelets decrease a 
 
 
 
 

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Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
 (Grade 4) 
(cell/mm3)  
(109/L) 
<LLN – 75,000; 
<LLN – 75.0 
<75,000 – 50,000; 
<75.0 – 50.0 
<50,000 – 25,000; 
<50.0 – 25.0 
<25,000; 
<25.0 
Abbreviations: LLN = Lower limit of the normal range; ULN = Upper limit of the normal range; WBC = White blood cell. 
Data Source: 
a 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human 
Services, FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
 
 
Table C3 
Abnormal Laboratory Values Rating: Urine analysis Parameters 
Urine 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-Threatening 
(Grade 4) 
Protein a 
1+ proteinuria; 
urinary protein <1.0 
g/24 hours 
2+ proteinuria; 
urinary protein 1.0-
3.4 g/24 hours 
Urinary protein ≥3.5 
g/24 hours 
- 
Data Source: 
a 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human 
Services, FDA, Center for Biologics Evaluation and Research - Guidance for Industry.