A Single-center, Randomized, Controlled, Open-label, Cross-over Study in Healthy Subjects to Investigate the Nicotine Pharmacokinetic Profiles of 2 Variants of P4M3 Gen 2.0, an Electronic Nicotine Delivery System, Compared to Cigarettes
Phase: NA
Conditions: Nicotine Vaping, Nicotine, Vaping
Sponsor: Philip Morris Products S.A.

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 1 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
 
 
Clinical Study Protocol 
P4-PK-04-US 
 
Study title: 
A single-center, randomized, controlled, open-label, cross-over 
study in healthy subjects to investigate the nicotine 
pharmacokinetic profiles of 2 variants of P4M3 Gen 2.0, an 
electronic nicotine delivery system, compared to cigarettes  
Study number 
P4-PK-04-US 
Short title 
Nicotine pharmacokinetics of P4M3 Gen 2.0 compared to 
cigarettes 
Product name: 
P4M3 Gen 2.0 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Version: 
Final 
Date: 
14 Oct 2021 
Authors: 
, PhD, Clinical Scientist 
, PhD, Biostatistician 
, MD, Medical Safety Officer 
 
 
 
 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 3 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Name of Product: 
P4M3 Gen 2.0 
Study Title: 
A single-center, randomized, controlled, open-label, cross-over study in healthy subjects to 
investigate the nicotine pharmacokinetic profiles of 2 variants of P4M3 Gen 2.0, an 
electronic nicotine delivery system, compared to cigarettes.  
Study Number: 
P4-PK-04-US 
Short Study Title: 
Nicotine pharmacokinetics of P4M3 Gen 2.0 compared to cigarettes. 
Main Objective and Endpoints: 
 
1. To describe the plasma concentration-time profile of nicotine and derived 
pharmacokinetic (PK) parameters of 2 variants of P4M3 Gen 2.0 and cigarettes from 6 
minutes ad libitum use. 
Endpoints (Day 1 to Day 3) 
• Background-corrected maximum plasma concentration [Cmax] 
• Background-corrected time to the maximum concentration [Tmax] 
• Area under the background-corrected concentration-time curve (AUC) from start of 
product use (T0) to 2 minutes, to 4 minutes, to Tmax, to 10 hours, to time of last 
quantifiable concentration and extrapolated to infinity [AUC0-2min, AUC0-4min, AUC0-
Tmax, AUC0-10h, AUC0-last, AUC0-infinity] 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 4 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
• Maximum ratio of background-corrected concentration over time, from T0 
(excluded) to Tmax (included) [max(Ct/t)t∈]0,Tmax]] 
Secondary Objectives and Endpoints: 
1. To describe pharmacodynamic (PD) effects (subjective effects and related behavioral 
assessments) of 2 variants of P4M3 Gen 2.0 and cigarettes from 6 minutes ad libitum 
use. 
Endpoints (Day 1 to Day 3) 
• Score from cigarette craving by the visual analog sale (VAS)-craving assessment  
• Score from product evaluation by Assessment of Behavioral Outcomes related to 
Tobacco and nicotine products (ABOUT)-Product experience questionnaire 
• Score from product liking by the VAS-liking assessment  
2. To describe human puffing topography (HPT) of 2 variants of P4M3 Gen 2.0 from the 
6 minutes ad libitum use. 
Related Endpoints (Day 1 to Day 3): 
• Per-puff parameters and per-product use experience parameters from the flight 
recorder (FR) puffing topography device for 2 variants of P4M3 Gen 2.0 (Appendix 
D) 
3. To describe the extent of product use from 2 variants of P4M3 Gen 2.0 from the 6 
minutes ad libitum use. 
Related Endpoint (Day 1 to Day 3) 
• Amount of nicotine delivered derived from the weighing of P4M3 Gen 2.0 Cartridge 
before and after use 
4. To evaluate the safety and tolerability during the study 
Related Endpoints (from Enrollment to EOS): 
• Incidence of adverse events (AEs) and serious adverse events (SAEs)  
• Incidence of P4M3 Gen 2.0 product events including malfunction/misuse  
• Changes in physical examination from baseline 
• Changes in electrocardiogram (ECG) from baseline (heart rate, PR, QRS, QT, QTcF 
interval) 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 5 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
• Changes in vital signs from baseline (systolic and diastolic blood pressure, pulse rate 
and respiratory rate) 
• Concomitant medication 
• Changes in standard spirometry from baseline (FEV1, FEV1 % predicted, FVC, FVC 
% predicted, FEV1/FVC) 
• Changes from baseline in clinical chemistry, hematology, and urine analysis safety 
panel (described in Table 3) 
Exploratory Objectives and Endpoints: 
1. To describe the associations between P4M3 Gen 2.0 HPT parameters, PD and PK 
parameters. 
Related Endpoints (Day 1 to Day 3) 
• Score from product liking by the VAS-liking assessment and Cmax, Tmax, and AUC0-
infinity PK endpoints 
• Score from product liking by the VAS-liking assessment and per-product use 
experience parameters from the MDEDR puffing topography device for 2 variants 
of P4M3 Gen 2.0 
Additional Study Assessments (for eligibility assessment and baseline characteristics): 
• Serology for human immunodeficiency virus (HIV) 1/2 and hepatitis B and C  
• Pregnancy test (all females)  
• Urine cotinine test 
• Urine drug test including testing for amphetamine type substances, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates 
• Alcohol breath test 
• Nicotine dependence assessed by Fagerström Test for Nicotine Dependence 
• Cytochrome P450 2A6 (CYP2A6) activity expressed as trans-3'-hydroxycotinine / 
cotinine molar metabolite ratio in plasma 
Study Hypothesis: 
This study is exploratory in nature and there is no pre-specified hypothesis to be tested. 
Study Design: 
This is a single-center, randomized, controlled, open-label, cross-over study in healthy 
subjects to investigate the nicotine pharmacokinetic profiles of 2 variants of P4M3 Gen 2.0, 
an electronic nicotine delivery system (ENDS), compared to cigarettes. In addition, PD 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 6 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
effects (subjective effects and related behavioral assessments) will be evaluated to provide 
further insights on product evaluation. The study will be conducted with 3 periods and 6 
sequences in a cross-over design. 
A Screening Visit will be conducted within 28 days (Day -29 to Day -2) prior to Admission 
(Day -1) to the investigational site (Figure 1). All subjects will undergo a Sars-CoV-2 test 
according to local regulation and investigational site requirements. 
A demonstration of P4M3 Gen 2.0, without product use, will be done by the investigational 
site staff during the Screening Visit. 
 
Figure 1 
Study Design 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 7 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Qualified subjects will return to the investigational site for Day -1. Subjects should have 
fasted for at least 10 hours prior to the safety laboratory assessments. After confirmation of 
eligibility, subjects will be enrolled. All subjects that are not enrolled will be considered as 
screen failures. 
At Day -1, enrolled subjects will perform a product test using P4M3 Gen 2.0 Classic Auburn 
3.5% variant ad libitum for up to 10 minutes. After the product test, subjects not willing 
and/or not ready to use P4M3 Gen 2.0 during the study will be discontinued from the study, 
will enter the 3-day Safety Follow-up and will be replaced. 
Subjects willing and ready to use 2 variants of P4M3 Gen 2.0 during the study after product 
test will start their confinement period of 3 days. The brand of subjects’ cigarettes will be 
recorded.  
36 subjects will be randomized to 1 of 6 possible sequences of product use on Day 1 to Day 
3 (see Figure 1). 
On Day 1 to Day 3, after at least 12 hours of abstinence from any nicotine/tobacco containing 
products (nicotine wash-out), subjects will smoke a cigarette or use a variant of P4M3 
according to randomized product use sequence ad libitum for 6 minutes (± 30 seconds). The 
weight of each P4M3 Gen 2.0 Cartridge will be determined before and after product use to 
estimate the amount of nicotine delivered in the aerosol during the 6 minutes ad libitum use 
period. Subjects will use a single variant of P4M3 Gen 2.0 with the MDEDR puffing 
topography device connected with data recording ad libitum for 6 minutes (± 30 seconds).  
Subjects will complete questionnaires about product evaluation, craving and liking 
assessments.  
The start of product use of the 6 minutes ad libitum use period will be defined as T0. T0 on 
Day 1 to Day 3 should be at approximately the same time in the morning, within a window 
of ± 20 minutes. Venous blood samples will be obtained according to the standard operating 
procedures (SOPs) at the investigational site.  
On Day 1, 15 blood samples will be collected for determination of nicotine concentration at 
the following time points in relation to T0 with a time window as indicated in brackets: 
Prior to T0: 
• T-1: 5 minutes (± 1 minute)  
After T0: 
• T1 after 1 minute (+ 30 seconds) 
• T2 after 2 minutes (+ 1 minute) 
• T3 after 4 minutes (+ 1 minute) 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 8 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
• T4 after 6 minutes (+ 1 minute) 
• T5 after 8 minutes (+ 1 minute) 
• T6 after 10 minutes (+ 1 minute) 
• T7 after 12 minutes (+ 1 minutes) 
• T8 after 15 minutes (± 2 minutes) 
• T9 after 30 minutes (± 2 minutes) 
• T10 after 1 hour (± 5 minutes) 
• T11 after 2 hours (± 5 minutes) 
• T12 after 4 hours (± 5 minutes) 
• T13 after 10 hours (± 5 minutes) 
• T14 after 24 hours (± 10 minutes) (Day 1 and Day 2 only) 
On Day 2, 14 blood samples will be collected for determination of nicotine PK after allocated 
product use at the same time points, except timepoint T-1. The sample T14 after T0 on Day 
1 will also be used to determine the nicotine baseline concentration prior to T0 on Day 2 and 
similarly, T14 after T0 on Day 2 for nicotine baseline concentration prior to T0 on Day 3.  
On Day 3, 13 blood samples will be collected for determination of nicotine PK after allocated 
product use. The sample T14 after T0 on Day 3 will not be collected. 
On Day 1 to Day 3, subjective effects of liking and craving will be assessed using a VAS 
(100 mm going from “strong disliking” to “strong liking” for VAS liking, and from “no 
craving” to “strong craving” for VAS craving) at the following time points in relation to T0 
with a time window as indicated in brackets: 
Prior to T0 (for VAS craving assessment only) 
• T-15: within 15 minutes prior to T0  
After T0: (for VAS craving and VAS liking assessment) 
• T1 after 4 minutes (± 1 minute) 
• T2 after 10 minutes (± 1 minute) 
• T3 after 15 minutes (± 1 minute) 
• T4 after 30 minutes (± 2 minutes) 
• T5 after 1 hour (± 5 minutes) 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 9 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
• T6 after 2 hours (± 5 minutes) 
• T7 after 4 hours (± 5 minutes) 
• T8 after 10 hours (± 5 minutes) 
Additional subjective effects will be assessed on Day 1 to Day 3 by the ABOUT-Product 
experience questionnaire administered within 1 to 2 hours after T0. 
Additional blood samples will be taken for determination of the nicotine concentration to 
evaluate terminal elimination half-life (t1/2z) in relation to T0 from Day 2 at the following 
time points with a time window as indicated in brackets:  
• T1z after 8 hours (± 5 minutes) after T0 from Day 2, 
• T2z after 12 hours (± 5 minutes) after T0 from Day 2, 
• T3z after 16 hours (± 10 minutes) after T0 from Day 2, 
• T4z after 20 hours (± 10 minutes) after T0 from Day 2. 
After enrollment at Day -1, the use of any other tobacco and nicotine containing products 
different from the product assigned for 6 minutes ad libitum use on Day 1 to Day 3, will not 
be allowed. Use of tobacco and nicotine containing products will not be restricted after the 
subject has been discharged from the investigational site on Day 3. 
After discharge at Day 3, the subjects will enter a 3-day Safety Follow-Up Period (FU 
Period) during which AE/SAEs reported by the subjects will be collected and the follow-up 
of AEs/SAEs will be conducted by the study investigational site. 
 
Study Population and Main Criteria for Inclusion and Exclusion: 
Subjects who meet all the following inclusion criteria will be enrolled into the study: 
1. Subject has signed the ICF and is able to understand the information provided in the 
ICF. 
2. Smoking male or female aged between 24 and 65 years inclusive. 
3. Subject has smoked continuously for at least the last 3 years prior to the Screening 
visit. 
4. Subject has smoked ≥ 10 commercially available cigarettes per day for 4 weeks prior 
to Screening Visit and Admission. Smoking status will be verified based on a urinary 
cotinine test (cotinine ≥ 200 ng/mL). 
5. Subject does not plan to quit smoking cigarettes or using other nicotine or tobacco-
containing products in the next 3 months. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 10 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
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, ECG and medical history). 
7. Subject is available for the entire study period and willing to comply with study 
procedures, including product use assignments and periods of abstinence from any 
nicotine/tobacco containing products. 
 
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, 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 medical condition (including safety laboratory as per CTCAE), 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 donated or received whole blood or blood products within 30 days prior 
to Screening Visit.  
6. BMI < 18.5 kg/m2 or > 35.0 kg/m2.  
7. 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. 
8. Subject has a positive serology test for HIV 1/2, Hepatitis B or Hepatitis C.  
9. Subject has a history of alcohol abuse that could interfere with the subject’s 
participation in study.  
10. Subject has a positive urine drug test. If positive for cannabinoids, inclusion will be 
at the discretion of the Investigator. 
11. Subject has a positive alcohol breath test.  
12. Subject or one of their family members a is a current or former employee of the 
tobacco industry.  
13. Subject or one of their family members a is employee of the investigational site or of 
any other parties involved in the study.  
14. Subject has participated in another clinical study within 30 days prior to the 
Screening Visit.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 11 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
15. Subject has been previously screened or enrolled in this study.  
16. For women only: subject is pregnant (does not have negative pregnancy tests at 
Screening Visit and at Admission) or is breastfeeding.  
17. For women of childbearing potential only b: subject does not agree to use an 
acceptable method of effective contraception. c 
18. Use of estrogen-containing hormonal contraception or hormone replacement 
therapy. 
a. 
As defined by US Food and Drug Administration (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 without estrogens, 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; Dose; and Mode of Administration: 
The 2 variants of P4M3 Gen 2.0 will be provided by the Sponsor. The distribution will be 
controlled by the Investigator or a qualified and appropriately trained designee. 
The following P4M3 Gen 2.0 e-liquid formulations (variants) will be investigated: 
Name 
Name in the study 
Nicotine 
concentration 
e-liquid flavor  
P4M3 Gen 2.0  
Classic Auburn 
CA35 
3.5 % 
Tobacco 
P4M3 Gen 2.0  
Classic Menthol 
CM35 
3.5 % 
Menthol 
 
Subjects’ usual brand of cigarettes will be used as comparator. Subjects’ preferred brand of 
commercially available, regular or mentholated cigarettes will not be provided by the 
Sponsor. All eligible subjects will be asked to purchase their usual brand of cigarettes prior 
to Admission (Day -1). Every subject needs to bring his/her pack of unopened, single-brand 
cigarettes. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 12 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Duration of Study: 
The entire study per subject will last up to 34 days. This will include a screening period of 
up to 28 days prior to Admission (Day -29 to Day -2), 3 days of confinement (after 
enrollment on Day -1 to time of discharge on Day 3, (3 overnight stays), and a 3-day Safety 
Follow-Up (from time of Discharge at Day 3 until Day 6). The end of the study (EOS) for a 
subject is defined as the end of the Safety Follow-up Period. The end of the whole study 
corresponds to the individual EOS of the last subject. 
Statistical Methods: 
Demographics and baseline characteristics will be analyzed on the randomized and PK 
populations. 
PK, PD, HPT and extent of product use endpoints will be analyzed on the randomized and 
the PK population.  
Safety will be analyzed using the safety population.  
Nicotine PK endpoints will be derived from the background-corrected plasma nicotine 
concentrations. Nicotine PK parameters will be derived from background-corrected plasma 
nicotine concentration versus time data using a non-compartmental analysis (NCA) 
technique. 
All data will be presented in listings, ordered by subject, study visit, product and time point, 
unless otherwise specified.  
All endpoints will be summarized with descriptive statistics including number of subjects 
(n), number and percent of subjects with missing data, arithmetic means, and standard 
deviations (mean and SD), median, first and third quartiles, minimum and maximum.  
For log normally distributed endpoints, geometric mean, geometric CV and geometric CI 
will be presented in addition.  
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. 
All analyses and summaries will be performed by product. 
A mixed model analysis of variance (ANOVA) will be conducted on AUC0-2min, AUC0-4min, 
AUC0-Tmax, AUC0-10h, AUC0-last, AUC0-infinity, max(Ct/t)t∈]0,Tmax] and Cmax endpoints in the 
natural logarithmic scale. The results of this analysis will be presented in terms of geometric 
least square mean ratios and 95% confidence intervals (95% CI) for the P4M3 Gen 2.0: 
cigarettes ratio and the ratios of variants of P4M3 Gen 2.0.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 13 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
The analysis of Tmax will be conducted using non-parametric tests and Hodges-Lehmann 
estimates of median difference with its derived 95% CI. 
Sample Size: 
The sample size is empirically based as there are no considerations for statistical hypothesis.  
A total of 36 subjects is expected to be sufficient to obtain a precision of 0.55 or less on the 
P4M3 Gen 2.0 : cigarettes Cmax ratios. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 14 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
TABLE OF CONTENTS 
1 
ETHICS AND REGULATIONS .....................................................................................24 
1.1 
Independent Review Board (IRB) Approval .........................................................24 
1.2 
Ethical Conduct of the Study .................................................................................25 
1.3 
Subject Information and Consent...........................................................................25 
1.3.1 
Informed Consent Form for Study Participation .........................................25 
1.3.2 
Amendment to the Informed Consent Form ................................................25 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................26 
2 
INTRODUCTION ...........................................................................................................27 
2.1 
Background ............................................................................................................27 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy ..........................27 
2.1.2 
Description of the Product and Scientific Findings .....................................28 
2.2 
Purpose of the Study ..............................................................................................29 
2.3 
Anticipated Benefits and Risks ..............................................................................29 
2.3.1 
Anticipated Benefits.....................................................................................29 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures .............................29 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product ....................29 
2.3.4 
Unforeseeable Risks.....................................................................................30 
3 
STUDY OBJECTIVES ....................................................................................................31 
3.1 
Main Objective and Endpoints...............................................................................31 
3.2 
Secondary Objectives and Endpoints.....................................................................31 
3.3 
Exploratory Objectives and Endpoints ..................................................................32 
4 
INVESTIGATIONAL PLAN ..........................................................................................34 
4.1 
Overall Study Design and Plan ..............................................................................34 
4.2 
Rationale for Study Design ....................................................................................38 
4.3 
Appropriateness of Measurements .........................................................................39 
4.4 
Study Duration .......................................................................................................39 
5 
STUDY POPULATION ..................................................................................................40 
5.1 
Selection of Study Population ................................................................................40 
5.1.1 
Inclusion Criteria .........................................................................................40 
5.1.2 
Exclusion Criteria ........................................................................................41 
5.2 
Discontinuation of Subjects from the Study ..........................................................43 
5.3 
Lost to Follow-up ...................................................................................................45 
5.4 
Violation of Eligibility Criteria ..............................................................................45 
6 
INVESTIGATIONAL PRODUCTS ...............................................................................46 
6.1 
Description of Investigational Products .................................................................46 
6.1.1 
Test Product .................................................................................................46 
6.1.2 
Reference Product / Baseline Product..........................................................47 
6.1.3 
Packaging and Labeling ...............................................................................47 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 15 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
6.2 
Use of Investigational Product(s)...........................................................................47 
6.2.1 
Admission (Day -1)......................................................................................48 
6.2.2 
Exposure Period (Day 1 and Day 3) ............................................................48 
6.2.3 
Discharge (Day 3) ........................................................................................48 
6.2.4 
Safety Follow-up Period ..............................................................................48 
6.2.5 
Stopping Rules for Investigational Products................................................48 
6.3 
Method for Assigning Subjects to Product Sequences ..........................................49 
6.4 
Blinding..................................................................................................................49 
6.5 
Investigational Product Accountability and Compliance ......................................49 
6.5.1 
Dispensing Investigational Product .............................................................49 
6.5.2 
Storage and Accountability ..........................................................................49 
6.5.3 
Investigational Product Retention ................................................................50 
6.5.4 
Compliance to Investigational Products ......................................................50 
6.6 
Restrictions ............................................................................................................50 
6.6.1 
Smoking Restrictions ...................................................................................50 
6.6.2 
Dietary Restrictions .....................................................................................50 
6.7 
Concomitant Medication ........................................................................................51 
7 
STUDY PROCEDURES .................................................................................................53 
7.1 
Informed Consent...................................................................................................53 
7.2 
Information on the Risk of Smoking and Smoking Cessation Advice and 
Debriefing on P4M3 Gen 2.0 .................................................................................53 
7.3 
Support during Abstinence from any Tobacco and Nicotine Containing 
Products..................................................................................................................53 
7.4 
Clinical Assessments .............................................................................................54 
7.4.1 
Demographic Data .......................................................................................54 
7.4.2 
Medical History, Concomitant Disease, Prior and Concomitant 
Medication ...................................................................................................54 
7.4.3 
Physical Examination...................................................................................54 
7.4.4 
Body Height and Weight and BMI ..............................................................55 
7.4.5 
Vital Signs ....................................................................................................55 
7.4.6 
Spirometry....................................................................................................55 
7.4.7 
Electrocardiogram ........................................................................................56 
7.5 
Biomarker Assessment...........................................................................................56 
7.5.1 
Biomarkers of Exposure to Nicotine............................................................56 
7.5.2 
CYP2A6 Activity .........................................................................................56 
7.6 
Laboratory Assessments ........................................................................................57 
7.6.1 
Clinical Chemistry, Hematology, and Urine Analysis Safety Panel ...........57 
7.6.2 
Serology .......................................................................................................58 
7.6.3 
Urine Drug Test ...........................................................................................58 
7.6.4 
Urine Cotinine Test ......................................................................................58 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 16 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
7.6.5 
Urine Pregnancy Test ...................................................................................58 
7.6.6 
Alcohol Breath Test .....................................................................................59 
7.7 
Sample Handling, Storage, and Shipment .............................................................59 
7.7.1 
Blood Samples .............................................................................................59 
7.8 
Other Study Procedures .........................................................................................60 
7.8.1 
Demonstration and P4M3 Gen 2.0 Product Test .........................................60 
7.8.2 
Human Puffing Topography ........................................................................60 
7.8.3 
Weighing of P4M3 Gen 2.0 Cartridge .........................................................61 
7.9 
Questionnaires........................................................................................................61 
7.9.1 
Fagerström Test for Nicotine Dependence (FTND, Revised Version)........61 
7.9.2 
Nicotine/Tobacco Product Use History .......................................................61 
7.9.3 
ABOUT-Product Experience Questionnaire ................................................61 
7.9.4 
VAS Craving Assessment ............................................................................62 
7.9.5 
VAS Liking Assessment ..............................................................................62 
8 
ADVERSE EVENTS .......................................................................................................63 
8.1 
Definitions..............................................................................................................63 
8.1.1 
Adverse Events ............................................................................................63 
8.1.2 
Serious Adverse Events ...............................................................................63 
8.1.3 
Conditions Existent Before the Start of the Period of Collection (ICF 
Signature) .....................................................................................................63 
8.2 
Collection and Reporting of Adverse Events.........................................................64 
8.2.1 
Collection of Information ............................................................................64 
8.2.2 
Period of Collection .....................................................................................64 
8.2.3 
Intensity of Adverse Event...........................................................................65 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures ....................................................................................................65 
8.2.5 
Expectedness ................................................................................................65 
8.2.6 
Follow-up of Non-serious and Serious Adverse Events ..............................66 
8.3 
Reporting of Serious Adverse Events ....................................................................66 
8.4 
Reporting of Other Events Critical to Safety Evaluations .....................................67 
8.4.1 
Abnormal Results of Laboratory Tests ........................................................67 
8.4.2 
Reporting other abnormal findings ..............................................................68 
8.5 
Reporting and Follow–Up of Pregnancies .............................................................68 
8.5.1 
Period of Collection and Follow-up .............................................................68 
8.5.2 
Reporting of Pregnancies .............................................................................69 
8.6 
Adverse Events Leading to Discontinuation..........................................................69 
8.7 
Investigational Product Malfunction and Misuse ..................................................69 
9 
STUDY ACTIVITIES .....................................................................................................70 
9.1 
Screening Visit (Day -29 to Day -2) ......................................................................70 
9.2 
Admission (Day -1)................................................................................................73 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 17 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
9.3 
Day 1 ......................................................................................................................75 
9.4 
Day 2 ......................................................................................................................77 
9.5 
Day 3 ......................................................................................................................79 
9.6 
Safety Follow-Up Period .......................................................................................81 
9.7 
Early Termination Procedures ...............................................................................81 
10 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................83 
10.1 
Monitoring .............................................................................................................83 
10.2 
Training of Staff .....................................................................................................83 
10.3 
Audits and Inspections ...........................................................................................84 
11 DATA MANAGEMENT ACTIVITIES..........................................................................85 
11.1 
Data Capture ..........................................................................................................85 
11.1.1 
Case Report Forms and Study Records .......................................................85 
11.1.2 
Protocol Deviations ......................................................................................85 
11.2 
Data Handling ........................................................................................................86 
11.2.1 
Data Verification ..........................................................................................86 
11.2.2 
Coding ..........................................................................................................87 
11.2.3 
Database Lock ..............................................................................................87 
12 PLANNED STATISTICAL METHODS ........................................................................88 
12.1 
General Considerations ..........................................................................................88 
12.1.1 
Stratification Criteria ...................................................................................88 
12.1.2 
Definitions for Statistical Data Analysis......................................................88 
12.1.3 
Descriptive Statistics ....................................................................................88 
12.1.4 
Handling of Missing Values and of Values outside the Detection Limits ...89 
12.1.5 
Significance Level for Inferential Analysis .................................................89 
12.2 
Determination of Sample Size and Power Consideration ......................................89 
12.2.1 
Assumptions .................................................................................................90 
12.2.2 
Method .........................................................................................................90 
12.3 
Analysis Populations ..............................................................................................90 
12.3.1 
Screened Population.....................................................................................91 
12.3.2 
Safety Population .........................................................................................91 
12.3.3 
Randomized Population ...............................................................................91 
12.3.4 
Pharmacokinetics Population .......................................................................91 
12.4 
Demographics and Baseline Characteristics ..........................................................91 
12.5 
Main Objective and Endpoints...............................................................................91 
12.5.1 
Nicotine PK Parameter Analysis Variables .................................................91 
12.5.2 
Baseline Comparability ................................................................................93 
12.5.3 
Descriptive Summary...................................................................................93 
12.5.4 
Inferential Analysis ......................................................................................93 
12.6 
Secondary Objectives and Endpoints.....................................................................94 
12.6.1 
Pharmacodynamic (PD) Endpoints ..............................................................94 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 18 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
12.6.2 
Human Puffing Topography Parameters .....................................................94 
12.6.3 
Extent of Product Use ..................................................................................95 
12.6.4 
Descriptive Summary...................................................................................95 
12.6.5 
Inferential Analysis ......................................................................................95 
12.6.6 
Safety Endpoints ..........................................................................................96 
12.7 
Exploratory Analyses .............................................................................................96 
12.7.1 
Descriptive Summary...................................................................................96 
12.7.2 
Inferential Analysis ......................................................................................96 
13 ADMINISTRATIVE CONSIDERATIONS ....................................................................98 
13.1 
Investigators and Study Administrative Structure .................................................98 
13.1.1 
Investigator ..................................................................................................98 
13.1.2 
Sponsor ........................................................................................................98 
13.1.3 
Other Responsibilities ..................................................................................98 
13.2 
Subject Recruitment ...............................................................................................99 
13.3 
Subject Confidentiality ..........................................................................................99 
13.4 
Access to Source Documentation ........................................................................100 
13.5 
Record Retention .................................................................................................100 
13.6 
Clinical Study Report ...........................................................................................101 
13.7 
Financial Disclosure.............................................................................................102 
13.8 
Publication and Disclosure Policy .......................................................................102 
13.9 
Insurance ..............................................................................................................102 
14 REFERENCE LIST .......................................................................................................103 
 
LIST OF IN-TEXT TABLES 
Table 1 
P4M3 Gen 2.0 variants ..............................................................................47 
Table 2 
CYP2A6: Substrates, Inhibitors, and Inducers ..........................................52 
Table 3 
Clinical Laboratory Parameters for Safety Panel .......................................57 
Table 4 
Intensity of Adverse Events .......................................................................65 
Table 5  
Principles for Assessing and Reporting Abnormal Laboratory Test 
Results ........................................................................................................67 
Table 6 
Time Schedule – Screening Visit ...............................................................70 
Table 7 
Time Schedule – Admission (Day -1) .......................................................73 
Table 8 
Time Schedule – Day 1 ..............................................................................75 
Table 9 
Time Schedule – Day 2 ..............................................................................77 
Table 10 
Time Schedule – Discharge (Day 3) ..........................................................79 
Table 11 
Early Termination ......................................................................................82 
 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 19 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ................................................................................................6 
Figure 2 
Study Design ..............................................................................................35 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Events ...................................................................................107 
Appendix B 
Participating Laboratories ........................................................................111 
Appendix C 
Abnormal Laboratory Values Grading ....................................................112 
Appendix D 
Human Puffing Topography Parameters .................................................116 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 20 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
ABOUT 
Assessment of Behavioral OUtcomes related to Tobacco and 
nicotine products 
AE 
Adverse event 
ANOVA 
Analysis of variance 
ANCOVA 
Analysis of covariance 
AUC0-2min 
Area 
under 
the 
background-corrected 
plasma 
nicotine 
concentration-time curve from T0 to 2 minutes after T0 
AUC0-4min 
Area 
under 
the 
background-corrected 
plasma 
nicotine 
concentration-time curve from T0 to 4 minutes after T0 
AUC0-Tmax 
Area 
under 
the 
background-corrected 
plasma 
nicotine 
concentration-time curve from T0 to subject-specific time to 
maximum plasma concentration after T0 
AUC0-10hours 
Area 
under 
the 
background-corrected 
plasma 
nicotine 
concentration-time curve from T0 to 10 hours minutes after T0 
AUC0-last 
Area 
under 
the 
background-corrected 
plasma 
nicotine 
concentration-time curve from T0 to time of last quantifiable 
concentration 
AUC0-infinity 
Area 
under 
the 
background-corrected 
plasma 
nicotine 
concentration-time curve from T0 extrapolated to infinity  
BMI 
Body mass index 
CA35 
P4M3 Gen 2.0 variant Classic Auburn 3.5% nicotine 
CDC 
Centers for disease control and prevention 
CM35 
P4M3 Gen 2.0 variant Classic Menthol 3.5% nicotine 
Cmax 
Background-corrected maximum concentration 
CI 
Confidence interval 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 21 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
CTCAE 
Common terminology criteria for adverse events and common 
toxicity criteria  
CTMS 
Clinical trial management system 
CV (documentation) 
Curriculum vitae 
CV (statistics) 
Coefficient of variation 
CYP2A6 
Cytochrome P450 2A6 
DMP 
Data management plan 
ECG 
Electrocardiogram 
E-cigarette 
Electronic cigarette 
ENDS 
Electronic nicotine delivery system 
EOS 
End of study 
FDA 
US Food and Drug Administration  
FEV1  
Forced expiratory volume in 1 second 
FTND 
Fagerström test for nicotine dependence (revised version) 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
HPHCs 
Harmful and potentially harmful constituents 
HPT 
Human puffing topography  
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International 
Council 
for 
Harmonisation 
of 
Technical 
Requirements for Pharmaceuticals for Human Use 
IP 
Investigational product 
IRB 
Institutional Review Board 
IV 
Intravenous 
LLN 
Lower limit of the normal range 
LLOQ 
Lower limit of quantification 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 22 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
max(Ct/t)t∈]0,Tmax] 
Maximum ratio of background-corrected concentration over time, 
from T0 (excluded) to Tmax (included) [max(Ct/t)t∈]0,Tmax]] 
MDEDR 
Miniaturized detachable external data recorder 
MedDRA 
Medical dictionary for regulatory activities 
NCA 
Non-compartmental analysis 
PD  
Pharmacodynamics 
PK 
Pharmacokinetics 
PMP 
Philip Morris Products S.A. 
QC 
Quality control 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SHM 
Sample handling manual 
SOP 
Standard operating procedure 
T 
Time point  
T0 
Time point of the start of product use 
t½ 
Half-life 
t½z 
Terminal half-life 
Tmax 
Time to background-corrected maximum plasma nicotine 
concentration  
uC 
uncorrected nicotine concentration (at T0: uC0) 
ULN 
Upper limit of the normal range 
ULOQ 
Upper limit of quantification 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 23 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Explanation of Terms 
Alternates 
Subjects who signed the ICF, met the inclusion and exclusion 
criteria, were enrolled but are not randomized due to a sufficient 
number of subjects are already randomized. Alternates will be 
discontinued from the study prior to randomization and will enter 
the 3-day Safety Follow-Up Period. 
End of Study 
The end of the study (EOS) for a subject is defined as the end of 
the Safety Follow-up Period.  
The end of the whole study corresponds to the individual EOS of 
the last subject. 
Cigarette 
The term ‘cigarette’ refers to manufactured and commercially 
available regular or menthol cigarettes and excludes hand-rolled 
cigarettes, cigars, pipes, bidis, and other nicotine-containing 
products. 
Enrollment 
At Admission (Day -1) for eligible subjects after all applicable 
inclusion and exclusion criteria have been satisfactorily assessed 
and met. 
Randomization 
Assignment to the respective sequence of P4M3 Gen 2.0 use and 
cigarette smoking at Admission (Day -1).  
Screen failure 
Subject who signs the ICF but is not enrolled at Admission  
(Day -1). 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 24 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
1 
ETHICS AND REGULATIONS 
1.1 
Independent Review Board (IRB) 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 to be provided to the subjects, 
Investigator’s brochure [IB], available safety information, curriculum vitae of the 
Investigator(s) and designee(s) and/or other evidence of qualifications and any other 
documents requested by an Institutional Review Board [IRB]), will be submitted for review 
and approval to the relevant IRB according to the appropriate provisions found in 21 Code of 
Federal Regulations (CFR) part 50 (“Informed Consent of Human Subjects”) and 21 CFR part 
56 (“Institutional Review Boards”). The IRB shall be appropriately constituted and perform its 
functions in accordance with the International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Guidance for Good Clinical Practice 
(GCP) [1] and local requirements, as applicable. 
In accordance with GCP and 21 CFR part 56, a written confirmation of the IRB approval 
should be provided to the Sponsor. This should identify the study (name of the Investigator(s) 
and designee(s), study number, and title) and the documents that have been approved by the 
IRB, with dates and version numbers, as well as the date of approval. The composition of the 
IRB, including the name and occupation of the chairperson, will be supplied to the Sponsor 
together with a GCP compliance statement. 
The written approval from the IRB will be filed in the Investigator file, and a copy will be filed 
in the study master file at the Sponsor or designated organization. The study must not start at 
a site before the Sponsor has obtained written confirmation of favorable opinion/approval from 
the concerned IRB. 
Any change or addition to this protocol will require a written protocol amendment that must 
be signed by the Sponsor and the Investigator(s). All amendments will be submitted to the IRB, 
and substantial amendments will only be implemented after approval by the IRB. 
These requirements for approval should in no way prevent any action from being taken by the 
Investigator(s) 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(s), and is implemented 
for safety reasons, the Sponsor and the IRB should be informed immediately. The 
Investigator(s) is(are) responsible for local reporting (e.g., to the IRB) of serious adverse events 
(SAEs) that occur during the study, according to local regulations. 
Relevant safety information will be submitted to the IRB during the study in accordance with 
national regulations and requirements. Medically qualified study personnel will be available 
during the study. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 25 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
1.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki [2] and are consistent with the principles of ICH/GCP [1]. 
The Investigator(s) or designee(s) agree(s) to conduct the clinical study in compliance with the 
protocol agreed with the Sponsor and approved by the IRB. The Investigator(s) and the 
Sponsor must sign the protocol (and protocol amendments, if applicable) to confirm this 
agreement. A copy of the Declaration of Helsinki is located in the Investigator’s study file. 
1.3 
Subject Information and Consent 
1.3.1 
Informed Consent Form for Study Participation 
Before or at Screening, 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 and signature of both the subject and the 
Investigator who conducted the informed consent discussion during Screening Visit. Any 
procedures specifically described in and related to the study protocol and study conduct, will 
not be performed before the ICF has been signed. The exact date and time of ICF signature 
will be captured in the volunteers’ registration log.  
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. 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 or in the statistical 
analysis plan (SAP) might be performed with the collected data at a later time. Any additional 
analysis performed will be covered by data confidentiality, as for the main analysis described 
in this protocol. 
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 for any other reason deemed necessary, an 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 26 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
amendment to the ICF may be required. If a revision of the ICF is necessary, the Investigator(s) 
or designee will, with the support of the Sponsor, ensure that the documents have been 
reviewed and approved by a responsible IRB before subjects are required to re-sign the ICF 
(including date and time). If new and important safety information is received, subjects who 
already completed or have been discontinued from the study will be informed by letters, emails 
or phone calls. 
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 
[1]. These guidelines apply specifically to pharmaceutical development, but nevertheless 
provide a robust and ethical framework for conducting a clinical study with products such as 
P4M3 Gen 2.0. The study will also be conducted in accordance with the general ethical 
principles outlined in the Declaration of Helsinki [2]. 
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. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 27 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
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 [3]. 
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 decide to continue smoking. The development of novel tobacco and nicotine 
containing products with the potential to be less harmful than cigarettes represents an approach 
to reduce cigarette-related deaths and diseases among smokers who would have otherwise 
continued smoking [4]. Philip Morris Products S.A. (PMP) is developing such alternative 
products that have the potential to reduce individual risk and population harm in comparison 
to smoking cigarettes. These products aim to substantially reduce or eliminate the exposure to 
harmful and potentially harmful constituents (HPHCs) generated from cigarette smoke, with 
the exception of nicotine, while providing an acceptable substitute for cigarettes. 
One of these products is P4M3 Gen 2.0, which is an electronic nicotine delivery system 
(ENDS) or electronic cigarette (e-cigarette). The liquid used in P4M3 Gen 2.0 is composed of 
propylene glycol, vegetable glycerol, water, nicotine, lactic acid, benzoic acid and flavors.  
E-cigarettes have the potential to benefit adult smokers who are not pregnant if used as a 
complete substitute for combustible tobacco containing products such as cigarettes. However, 
in some particular conditions of e-cigarettes use, harm has been recently reported. In a recent 
investigation, the Centers for Disease Control and Prevention (CDC) have analyzed national 
data on e-cigarette, or vaping, product use-associated lung injury. CDC and FDA recommend 
that people should not use Tetrahydrocannabinol (THC)-containing e-cigarette, or vaping, 
products, particularly from informal sources like friends, family, or in-person or online sellers. 
Vitamin E acetate should not be added to e-cigarette, or vaping, products, or any other 
substances not intended by the manufacturer.  
CDC, FDA, and state health authorities have made progress in identifying substances of 
concern in e-cigarettes or vaping products. However, there are many different substances and 
product sources that remain under investigation, and there may be more than one cause.  
Given that context, when developing new products such as P4M3 Gen 2.0, appropriate 
assessment including comprehensive understanding of product characterization, its safety, and 
related impact of product use in humans is critical. P4M3 Gen 2.0 is a closed e-cigarette with 
a Cartridge that cannot be refilled and for which the e-liquid does not contain THC or Vitamin 
E acetate (section 2.1.2). 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 28 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
2.1.2 
Description of the Product and Scientific Findings 
P4M3 Gen 2.0 is an Electronic Nicotine Delivery System (ENDS) that produces an aerosol 
through vaporization of an e-liquid. The e-liquid is composed of propylene glycol (PG), 
vegetable glycerol (VG), water, nicotine, lactic acid, benzoic acid and flavors. P4M3 Gen 2.0 
is a closed e-cigarette composed of a Battery unit containing all the electronics with a 
rechargeable battery and a disposable, replaceable Cartridge containing the e-liquid and the 
heating element. The P4M3 Gen 2.0 Cartridge is not refillable. 
The aerosol production (heating cycle) is triggered by a pressure sensor in the Battery unit 
when a puff is detected. The e-liquid aerosol is produced by a heater of a fine mesh of stainless-
steel wires heated by an electric current. 
The aerosol generated by P4M3 Gen 2.0 is free from the majority of HPHCs associated with 
heating or burning tobacco, except nicotine. P4M3 Gen 2.0 does not contain tobacco and there 
is no combustion during use. 
The non-clinical assessment is described in the Investigator’s Brochure and supports the 
clinical assessment of P4M3 Gen 2.0 [5]. P4M3 Gen 2.0 has not been tested in humans before. 
In 2016, FDA finalized a rule extending its Center for Tobacco products’ (CTP's) regulatory 
authority to cover all tobacco products, including ENDS that meet the definition of a tobacco 
product. FDA regulates the manufacture, import, packaging, labeling, advertising, promotion, 
sale, and distribution of ENDS, including components and parts of ENDS. 
When assessing ENDS use, significant inter-subject variability has been described for human 
puffing topography (HPT) parameters, especially puff duration, puff frequency, and flow rate 
[6]. Experienced e-cigarette users may extract more nicotine by puffing with a low flow rate 
and long duration puffs in comparison to cigarette smokers. E-cigarette design features also 
affect nicotine exposure; increasing the battery voltage output and e-liquid nicotine 
concentration increases the nicotine delivery [7]. Differences in puffing behavior (such as puff 
duration or depth of inhalation) resulted in a faster absorption rate and a higher amount of 
nicotine absorption in experienced e-cigarette users as compared to naïve e-cigarette users 
when using the same e-cigarette [8]. Battery output, type of wicks, ventilation holes, and other 
mechanical characteristics of each individual e-cigarette product determine how much aerosol 
and nicotine is released. More effective and appealing e-cigarette products to provide satisfying 
alternatives to smoking has led to e-liquids containing ‘nicotine salts’. Nicotine salts are 
formed by the reaction of nicotine with a suitable acid and are less volatile than freebase 
nicotine [9]. As a result, a greater fraction of the nicotine in the salt form is expected to remain 
in inhaled aerosol droplets until the aerosol reaches the alveoli for pulmonary absorption. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 29 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
2.2 
Purpose of the Study 
The purpose of the study is to evaluate the nicotine pharmacokinetics (PK) profiles of 2 
variants of P4M3 Gen 2.0 versus cigarettes following a 6 minutes ad libitum use period. In 
addition, pharmacodynamic effects (PD), including subjective effects and related behavioral 
assessments, as well as human puffing topography (HPT) will be evaluated, to provide further 
insights on P4M3 Gen 2.0 product acceptance and product use. Safety will be assessed 
throughout the study. 
The aim is to evaluate if P4M3 Gen 2.0 can provide an acceptable alternative to smoking 
cigarettes in terms of both, nicotine delivery and sensorial satisfaction for smokers who would 
otherwise continue smoking cigarettes. 
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. Subjects who are motivated to quit smoking or using other nicotine/tobacco-
containing products during the study will be given the opportunity to continue their smoking 
cessation attempt and will be referred to appropriate stop smoking services for continuing 
support and counselling at a higher level. 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 
The risk of scheduled procedures in the present study (e.g., blood samples) are deemed to be 
on par with procedures routinely performed during normal or extended health examinations by 
the subject’s healthcare professional. The total volume of blood to be drawn is approximately 
300 mL and does not exceed the levels for a standard blood donation. The risks related to blood 
sampling include for example: excessive bleeding, fainting, hematoma, paresthesia or 
infection, and those related to the total amount of blood taken over a period of time such as 
weakness, dizziness or anemia. 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product  
By product design, the aerosol generated by P4M3 Gen 2.0 is free from the majority of HPHCs 
associated with heating or burning tobacco, except nicotine. However, given the current state 
of knowledge about the product, it has not yet been demonstrated that P4M3 Gen 2.0 or other 
e-cigarettes reduce the risk of developing smoking-related diseases compared to cigarettes.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 30 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Due to sensorial and technological differences between P4M3 Gen 2.0 and cigarettes, it is 
possible 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.  
The confinement setting may also have an influence on puffing behavior and nicotine uptake. 
An adult smoker using P4M3 Gen 2.0 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 (tremor, blunting of emotions, and decreased ability to concentrate), gastric acid 
secretion, and vomiting. Individuals who experience adverse events (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 
Support during periods of abstinence from any tobacco and nicotine containing products 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 supervision of all study subjects with follow-up of those who have experienced 
AEs/serious adverse events (SAEs)  
2.3.4 
Unforeseeable Risks 
The possibility of unforeseeable events/risks will be explained in detail to study subjects. 
Unexpected malfunction of the P4M3 Gen 2.0 may lead to unforeseeable risk. Risk mitigation 
strategies will include close monitoring and medical supervision to detect any unforeseeable 
risk or safety signals at the earliest time possible. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 31 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
3 
STUDY OBJECTIVES 
3.1 
Main Objective and Endpoints 
The main objective of this study is: 
1. To describe the plasma concentration-time profile of nicotine and derived PK parameters 
of 2 variants of P4M3 Gen 2.0 and cigarettes from 6 minutes ad libitum use. 
Endpoints (Day 1 to Day 3): 
• Background-corrected maximum plasma concentration [Cmax] 
• Background-corrected time to the maximum concentration [Tmax] 
• Area under the background-corrected concentration-time curve (AUC) from start of 
product use (T0) to 2 minutes, to 4 minutes, to Tmax, to 10 hours, to time of last 
quantifiable concentration and extrapolated to infinity [AUC0-2min, AUC0-4min, AUC0-
Tmax, AUC0-10h, AUC0-last, AUC0-infinity] 
• Maximum ratio of background-corrected concentration over time, from T0 (excluded) 
to Tmax (included) [max(Ct/t)t∈]0,Tmax]] 
3.2 
Secondary Objectives and Endpoints 
The secondary objectives of this study are: 
1. To describe pharmacodynamic (PD) effects (subjective effects and related behavioral 
assessments) of 2 variants of P4M3 Gen 2.0 and cigarettes from 6 minutes ad libitum use. 
Endpoints (Day 1 to Day 3) 
• Scores from cigarette craving by the visual analog sale (VAS)-craving assessment  
• Score from product evaluation by ABOUT-Product experience questionnaire 
• Score from product liking by the VAS-liking assessment 
2. To describe human puffing topography (HPT) of 2 variants of P4M3 Gen 2.0 and 
cigarettes from the 6 minutes ad libitum use. 
Related Endpoints (Day 1 to Day 3): 
• Per-puff parameters and per-product use experience parameters from the flight recorder 
(FR) puffing topography device for 2 variants of P4M3 Gen 2.0 (Appendix D)  
3. To describe the extent of product use from 2 variants of P4M3 Gen 2.0 from the 6 
minutes ad libitum use. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 32 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Related Endpoint (Day 1 to Day 3) 
• Amount of nicotine delivered derived from the weighing of P4M3 Gen 2.0 Cartridge 
before and after use 
4. To evaluate the safety and tolerability during the study 
Related Endpoints (from Enrollment to EOS): 
• Incidence of adverse events (AEs) and serious adverse events (SAEs)  
• Incidence of P4M3 Gen 2.0 product events including malfunction/misuse  
• Changes in physical examination from baseline 
• Changes in electrocardiogram (ECG) from baseline (Heart rate, PR, QRS, QT, QTcF 
interval) 
• Changes in vital signs from baseline (systolic and diastolic blood pressure, pulse rate 
and respiratory rate) 
• Concomitant medication 
• Changes in standard spirometry from baseline (FEV1, FEV1 % predicted, FVC, FVC 
% predicted, FEV1/FVC) 
• Changes from baseline in clinical chemistry, hematology, and urine analysis safety 
panel (described in Table 3) 
3.3 
Exploratory Objectives and Endpoints 
1. To describe the associations between P4M3 Gen 2.0 HPT parameters, PD and PK 
endpoints. 
Related Endpoints (Day 1 to Day 3) 
• Product liking by the VAS-liking assessment and Cmax, Tmax, and AUC0-infinity PK 
endpoints 
• Product liking by the VAS-liking assessment and per-product use experience 
parameters from the MDEDR puffing topography device for 2 variants of P4M3 Gen 
2.0 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 33 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Additional Study Assessments (for eligibility assessment and baseline characteristics): 
• Serology for human immunodeficiency virus (HIV) 1/2 and hepatitis B and C  
• Pregnancy test (all females)  
• Urine cotinine test 
• Urine drug test including testing for amphetamine type substances, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates 
• Alcohol breath test 
• Nicotine dependence assessed by Fagerström Test for Nicotine Dependence 
• Cytochrome P450 2A6 (CYP2A6) activity expressed as trans-3'-hydroxycotinine / 
cotinine molar metabolite ratio in plasma 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 34 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a single-center, randomized, controlled, open-label, cross-over study in healthy subjects 
to investigate the nicotine pharmacokinetic profiles of two variants of P4M3 Gen 2.0 an 
electronic nicotine delivery system (ENDS), compared to cigarettes. In addition, PD effects 
(subjective effects and related behavioral assessments) will be evaluated to provide further 
insights on product evaluation. The study will be conducted with 3 periods and in a 6 sequence-
cross-over design. 
A Screening Visit will be conducted within 28 days (Day -29 to Day -2) prior to Admission 
(Day -1) to the investigational site (Figure 2). A demonstration of P4M3 Gen 2.0, without 
product use, will be done by the investigational site staff during the Screening Visit. A 
sufficient number of subjects will be screened to ensure that 36 subjects will be randomized 
into the study.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 35 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
 
Figure 2 
Study Design 
Qualified subjects will return to the investigational site for Day -1. Subjects should have fasted 
for at least 10 hours prior to the safety laboratory assessments. After confirmation of eligibility, 
subjects will be enrolled. All subjects that are not enrolled will be considered as screen failures. 
On Day -1, enrolled subjects will perform a product test using P4M3 Gen 2.0 Classic Auburn 
3.5% (CA35) variant ad libitum for up to 10 minutes. After the product test, subjects not willing 
and/or not ready to use P4M3 Gen 2.0 during the study will be discontinued from the study, 
will enter the 3-day Safety Follow-up and will be replaced.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 36 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Subjects willing and ready to use 2 variants of P4M3 Gen 2.0 during the study after product 
test will start their confinement period of 3 days. The brand of subjects’ cigarettes will be 
recorded.  
36 subjects will be randomized to 1 of 6 possible sequences of product use on Day 1 to Day 3 
(see Figure 2). 
On Day 1 to Day 3, after at least 12 hours of abstinence from any nicotine/tobacco containing 
products (nicotine wash-out), subjects will smoke a cigarette or use a variant of P4M3 
according to randomized product use sequence ad libitum for 6 minutes (± 30 seconds). The 
weight of each P4M3 Gen 2.0 Cartridge will be determined before and after product use to 
estimate the amount of nicotine delivered in the aerosol during the 6 minutes ad libitum use 
period. Subjects will use a variant of P4M3 Gen 2.0 with the MDEDR puffing topography 
device connected with data recording ad libitum for 6 minutes (± 30 seconds).  
Subjects will complete questionnaires about product evaluation, craving and liking 
assessments.  
The start of product use of the 6 minutes ad libitum use period will be defined as T0. T0 on Day 
1 to Day 3 should be at approximately the same time in the morning, within a window of ± 20 
minutes. Venous blood samples will be obtained according to the standard operating 
procedures (SOPs) at the investigational site.  
On Day 1, 15 blood samples will be collected for determination of nicotine concentration at 
the following time points in relation to T0 with a time window as indicated in brackets: 
Prior to T0: 
• T-1: 5 minutes (± 1 minute) 
After T0: 
• T1 after 1 minute (+ 30 seconds) 
• T2 after 2 minutes (+ 1 minute) 
• T3 after 4 minutes (+ 1 minute) 
• T4 after 6 minutes (+ 1 minute) 
• T5 after 8 minutes (+ 1 minute) 
• T6 after 10 minutes (+ 1 minute) 
• T7 after 12 minutes (+ 1 minute) 
• T8 after 15 minutes (± 2 minutes) 
• T9 after 30 minutes (± 2 minutes) 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 37 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
• T10 after 1 hour (± 5 minutes) 
• T11 after 2 hours (± 5 minutes) 
• T12 after 4 hours (± 5 minutes) 
• T13 after 10 hours (± 5 minutes) 
• T14 after 24 hours (± 10 minutes) (Day 1 and Day 2 only) 
On Day 2, 14 blood samples will be collected for determination of nicotine PK after allocated 
product use at the same time points, except timepoint T-1. The sample T14 after T0 on Day 1 
will also be used to determine the nicotine baseline concentration prior to T0 on Day 2 and 
similarly, T14 after T0 on Day 2 for nicotine baseline concentration prior to T0 on Day 3.  
On Day 3, 13 blood samples will be collected for determination of nicotine PK after allocated 
product use. The sample T14 after T0 on Day 3 will not be collected. 
On Day 1 to Day 3, subjective effects of liking and craving will be assessed using a VAS (100 
mm going from “strong disliking” to “strong liking” for VAS liking, and from “no craving” to 
“strong craving” for VAS craving) at the following time points in relation to T0: 
Prior to T0 (for VAS craving assessment only) 
• T-15: within 15 minutes prior to T0 with a time window as indicated in brackets 
After T0: (for VAS craving and VAS liking assessment) 
• T1 after 4 minutes (± 1 minute) 
• T2 after 10 minutes (± 1 minute) 
• T3 after 15 minutes (± 1 minute) 
• T4 after 30 minutes (± 2 minutes) 
• T5 after 1 hour (± 5 minutes) 
• T6 after 2 hours (± 5 minutes) 
• T7 after 4 hours (± 5 minutes) 
• T8 after 10 hours (± 5 minutes) 
Additional subjective effects will be assessed on Day 1 to Day 3 by the ABOUT-Product 
experience questionnaire administered within 1 to 2 hours after T0. 
On Day 2 and 3, additional blood samples will be taken for determination of the nicotine 
concentration to evaluate terminal elimination half-life (t1/2z) in relation to T0 from Day 2 at 
the following time points with a time window as indicated in brackets:  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 38 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
• T1z after 8 hours (± 5 minutes) after T0 from Day 2 
• T2z after 12 hours (± 5 minutes) after T0 from Day 2, 
• T3z after 16 hours (± 10 minutes) after T0 from Day 2, 
• T4z after 20 hours (± 10 minutes) after T0 from Day 2 
After enrollment at Admission, the use of any other tobacco and nicotine containing products 
different from the product assigned for 6 minutes ad libitum use on Day 1 to Day 3, will not 
be allowed. Use of tobacco and nicotine containing products will not be restricted after the 
subject has been discharged from the investigational site on Day 3. 
After discharge at Day 3, the subjects will enter a 3-day Safety Follow-Up Period (FU Period) 
during which AE/SAEs reported by the subjects will be collected and the follow-up of 
AEs/SAEs ongoing at discharge will be conducted by the investigational site (section 8.2.6).  
Subjects who will be discontinued from the study before enrolment will be replaced. After 
enrollment but before randomization, subjects who will be discontinued from the study will 
enter the 3-day Safety Follow-Up Period and will be replaced. However, subjects that are 
discontinued after randomization will not be replaced. 
4.2 
Rationale for Study Design  
The minimum age of 24 years old in the inclusion criteria was selected based on the legal age 
of smoking in the United States of America of 21 years; and to account for the 3 years of 
smoking history. 
The goal of this study is to evaluate the nicotine absorption profiles and related PK parameters 
from two variants P4M3 Gen 2.0 (CA35 and CM35) with 3.5% nicotine compared to 
cigarettes. 
The 6 minutes ad libitum use allow appropriate comparisons between different products and 
smoking a cigarette similar to published data [10-13]. The ad libitum use will also allow to 
explore effects of product liking on PK parameters.  
Sampling time points for determination of nicotine concentrations were selected to ensure 
reliable estimation of PK parameters. In particular, frequent sampling during the first 15 
minutes from T0 will be performed in order to reliably assess Tmax, which is expected to be 
comparable to what was observed previously (Tmax range: 7 to 10 minutes after fixed puffing 
regimen) with P4M3 Gen 1.0, an earlier developmental version [5] and for cigarettes (Tmax 
range: ~10 minutes) [14] and which is compatible with absorption by the pulmonary route.  
Comparing early AUC values AUC0-2min, AUC0-4min, AUC0-Tmax, and the maximum ratio 
max(Ct/t)t∈]0,Tmax] of the 2 variants P4M3 Gen 2.0 and cigarettes may provide insight into the 
efficiency of nicotine absorption rate into the blood.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 39 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
The PK of 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 hours 
[15]. To ensure a complete nicotine washout between each product use, 3 days without product 
use (cigarette or P4M3 Gen 2.0) would have been required (~ 5 x terminal elimination t1/2z). 
Based on nicotine population PK modeling, it was estimated that nicotine enters in the terminal 
elimination phase with concentrations decreasing with a terminal elimination rate constant (λz) 
8 to 10 hours post administration. As a consequence, a minimum of 12 hours has been 
established in this study design prior to T0 on Day 1 and approximately 24 hours prior to T0 on 
Day 2 and Day 3. Background-concentration correction will be applied to adjust for carry-over 
effects with adjustment of baseline values to the estimated t1/2z (or λz) which will be derived 
from additional blood sampling on Day 2 and Day 3 for each subject.  
The use of estrogen contraceptive is known to accelerate nicotine clearance by 20% to 30% 
compared to women who do not take estrogen contraceptive [16]. Therefore, for the purpose 
of this study, use of hormonal contraception containing estrogens is prohibited. This also 
applies to hormone replacement therapy.  
The activity of CYP2A6 will be measured as this enzyme drives the metabolism of nicotine 
into cotinine and subsequent metabolites. Nicotine metabolism by CYP2A6 varies between 
individuals of the same ethnicity/race and across ethnicity/race due to genetic variations. These 
genetic differences could be associated with reduced/increased nicotine metabolism [14]. 
4.3 
Appropriateness of Measurements 
All laboratory measures utilized for this study are validated and are appropriate for the study 
assessments. FTND [17, 18] and ABOUT-Product experience questionnaires [19] used in this 
study are validated and previously published or adapted versions of validated questionnaires.  
4.4 
Study Duration 
The entire study per subject will last up to 34 days. This will include a screening period of up 
to 28 days prior to Admission (Day -29 to Day -2), 3 days of confinement (after enrollment on 
Day -1 to time of discharge on Day 3, 3 overnight stays), and a 3-day Safety Follow-Up (from 
time of Discharge at Day 3 until Day 6). The end of the study (EOS) for a subject is defined as 
either the Discharge at Day 3, or the date of early termination of the subject, plus 3 days for 
the Safety Follow-up Period. The end of the whole study corresponds to the individual EOS of 
the last subject. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 40 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
5 
STUDY POPULATION 
All subjects will undergo a Sars-CoV-2 test according to local regulation and investigational 
site requirements. 
36 subjects will be randomized to one of six possible product use sequences at Day 1.  
The study population will be stratified by sex. Each sex will have a quota applied to ensure 
they represent at least 40% of the total randomized subjects.  
In addition, at least 15% subjects of Black, Asian, American Indian or Alaska native, Native 
Hawaiian, other Pacific Islander race will be randomized to account for the US American 
smoking population. The randomization of subjects by ethnicity will not be enforced by 
stratification. 
5.1 
Selection of Study Population 
5.1.1 
Inclusion Criteria 
Subjects who meet all the following inclusion criteria can be enrolled into the study: 
Inclusion Criteria 
Screening  
Admission (Day -1) 
1. Subject has signed the ICF and is able to 
understand the information provided in the ICF. 
X 
 
2. Smoking male or female aged between 24 and 
65 years inclusive. 
X 
 
3. Subject has smoked continuously for at least the 
last 3 years prior to the Screening visit. 
X 
 
4. Subjects has smoked ≥ 10 commercially 
available cigarettes per day for 4 weeks prior to 
Screening Visit and Admission. Smoking status 
will be verified based on a urinary cotinine test 
(cotinine ≥ 200 ng/mL). 
X 
X 
5. Subject does not plan to quit smoking cigarettes 
or using other nicotine or tobacco-containing 
products in the next 3 months. 
X 
X 
6. Smoking, healthy subject as judged by the 
Investigator or designee based on available 
X 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 41 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Inclusion Criteria 
Screening  
Admission (Day -1) 
assessments from the Screening period (e.g., 
safety laboratory, spirometry, vital signs, 
physical examination, ECG, and medical 
history). 
7. Subject is available for the entire study period 
and willing to comply with study procedures, 
including product use assignments, and periods 
of abstinence from any nicotine/tobacco 
containing products. 
X 
X 
5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the study: 
Exclusion Criteria 
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). 
X 
 
2. Subject is legally incompetent, or physically or 
mentally incapable of giving consent (e.g., 
emergency 
situation, 
under 
guardianship, 
prisoners, or subjects who are involuntarily 
incarcerated). 
X 
 
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. 
X 
 
4. As per the Investigator’s judgment, the subject 
has medical conditions which require or will 
X 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 42 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Exclusion Criteria 
Screening  
Admission (Day -1) 
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 donated or received whole blood or 
blood products within 3 months prior to 
Screening Visit. 
X 
 
6. BMI < 18.5 kg/m2 or > 35.0 kg/m2. 
X 
 
7. 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. 
 
X 
8. Subject has a positive serology test for HIV 1/2, 
Hepatitis B or Hepatitis C. 
X 
 
9. Subject has a history of alcohol abuse that could 
interfere with the subject’s participation in 
study. 
X 
 
10. Subject has a positive urine drug test. If positive 
for cannabinoids, inclusion will be at the 
discretion of the Investigator. 
X 
X 
11. Subject has a positive alcohol breath test. 
X 
X 
12. Subject or one of their family membersa is a 
current or former employee of the tobacco 
industry. 
X 
 
13. Subject or one of their family membersa is 
employee of the investigational site or of any 
other parties involved in the study. 
X 
 
14. Subject has participated in another clinical 
study within 30 days prior to the Screening 
Visit. 
X 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 43 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Exclusion Criteria 
Screening  
Admission (Day -1) 
15. Subject has been previously screened or 
enrolled in this study. 
X 
 
16. For women only: subject is pregnant (does not 
have negative pregnancy tests at Screening 
Visit and at Admission) or is breastfeeding. 
X 
X 
17. For women of childbearing potential onlyb: 
subject does not agree to use an acceptable 
method of effective contraception c. 
X 
X 
18. Use 
of 
estrogen-containing 
hormonal 
contraception or hormone replacement therapy. 
X 
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 without estrogens, 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) and 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 a 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 the Investigator. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 44 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
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 the subject disagrees in writing.  
When a subject is discontinued from the study, all early termination procedures (section 9.7) 
will be performed unless the subject refuses to perform the assessments or the procedures have 
already been performed during the study day. Early termination procedures are to be performed 
only for subjects who have been exposed to P4M3 Gen 2.0. After the date of termination, the 
subject will enter into the 3-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. 
• Any AE/SAE or condition (including clinically significant changes in a laboratory 
parameter), which at the discretion of the Investigator is not compatible with the 
subject’s continued participation in this study. 
• Positive pregnancy test (section 8.5). 
• The Sponsor the study. If the Sponsor decides to prematurely terminate the study, the 
subject will be promptly informed by the Investigator. The Investigator should report 
the fact and the reason in writing to the IRB. 
• 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 and/or ready to use P4M3 Gen 2.0 after the product test at 
Admission (Day -1). In such a situation, the subject will be discontinued after the 
product test and will enter the 3-day Safety Follow-up. 
• Subject uses any tobacco or nicotine containing product different from the assigned 
product during confinement. 
Subjects may be discontinued from the study for the following reasons:  
• Non-compliance to the study procedures based on the judgment of the Investigator. 
• A sufficient number of subjects are already randomized to the study sequences (section 
5.2). In this case, additional subjects (alternates) will be discontinued prior to 
randomization.  
• Violations of eligibility criteria have been determined (section 5.4). 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 45 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Subjects who will be discontinued from the study before enrolment will be replaced. After 
enrollment but before randomization, subjects who will be discontinued from the study will 
enter the 3-day Safety Follow-Up Period and will be replaced. However, subjects that are 
discontinued after randomization will not be replaced. 
5.3 
Lost to Follow-up 
A reasonable number of attempts to contact the subject should be done and documented in the 
source documents by the site. When the Investigator declares a subject as 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 lost contact to the subject but the subject has reached the maximum 
number of study days (34 days), then the Investigator or designee(s) will declare the subject 
lost to follow-up at this date. 
5.4 
Violation of Eligibility Criteria 
Detected violations of eligibility criteria post enrollment may require subjects to be 
discontinued from the study based on a case-by-case decision of the Investigator. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 46 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
6 
INVESTIGATIONAL PRODUCTS 
6.1 
Description of Investigational Products 
P4M3 Gen 2.0 will be provided by the Sponsor.  
The distribution and return of investigational products will be controlled by qualified and 
appropriately trained investigational site staff. 
6.1.1 
Test Product 
P4M3 Gen 2.0 is an ENDS or electronic cigarette (e-cigarette), which produces an aerosol 
through vaporization of an e-liquid. P4M3 Gen 2.0 is composed of a Battery unit containing 
all the control electronics with the rechargeable battery and a disposable Cartridge containing 
the e-liquid and the heating element. The Battery unit comprises several functions. The device 
provides electrical power when required, which is activated by puff detection. The device has 
a “dry mesh detection” function to prevent overheating when the liquid on heater is not 
sufficient.  
The Battery unit is charged via a USB port. The Battery unit also features a tactile function 
that will operate when the unit is turned on and off and when a puff is taken. 
The Battery unit is controlled through a single multi-function button used for switching on and 
off and allowing the modification of both the haptic (vibration) and the power level. 
The Cartridge consists of a reservoir for storing the e-liquid, which also acts as the mouthpiece 
and includes the air flow channels to carry the aerosol from the heater to the user. The Cartridge 
contains the e-liquid, the mesh heater sub-assembly and the porous materials for liquid 
retention and transport from the reservoir to the heater. The Cartridge is disposed of when the 
e-liquid in the reservoir is depleted.  
The P4M3 Gen 2.0 e-liquid formulations are composed of propylene glycol (PG), vegetable 
glycerin (VG), water, tobacco-derived nicotine, lactic acid, benzoic acid and could differ in 
flavors and nicotine concentrations. The following P4M3 Gen 2.0 e-liquid formulations 
(variants) will be investigated in this study (Table 1).  
 
 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 47 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Table 1 
P4M3 Gen 2.0 variants 
Name 
Name in the 
study 
Nicotine 
concentration 
e-liquid flavor  
P4M3 Gen 2.0  
Classic Auburn 
CA35 
3.5 % 
Tobacco 
P4M3 Gen 2.0  
Classic Menthol 
CM35 
3.5 % 
Menthol 
 
The non-clinical assessment is described in the Investigator’s brochure and supports the 
clinical assessment of P4M3 Gen 2.0 [5].  
6.1.2 
Reference Product / Baseline Product 
Subjects’ preferred brand of commercially available, regular or mentholated cigarettes will not 
be provided by the Sponsor.  
All eligible subjects will be asked to purchase their usual brand of cigarettes prior to Admission 
(Day -1). Every subject needs to bring his/her pack of unopened, single-brand cigarettes. 
6.1.3 
Packaging and Labeling 
At Admission (Day -1), all study subjects will provide one sealed pack of cigarettes to the 
investigational site staff. The cigarette pack provided by the subject should not be opened and 
the cellophane should be intact.  
Each pack of cigarettes provided by the subject will be labeled to identify to which subject the 
cigarettes belong to. The investigational site staff will return all unused products to the subjects 
at Discharge or Early termination. 
For P4M3 Gen 2.0, packs of P4M3 Gen 2.0 Cartridges will be printed with the necessary 
information including, but not limited to, product code and expiry date. 
6.2 
Use of Investigational Product(s) 
Subjects will not be forced to smoke cigarettes or use P4M3 Gen 2.0 and will be free to stop 
smoking/using tobacco/nicotine-containing products at any time of the study.  
During the screening period, subjects will be allowed to smoke and use tobacco/nicotine-
containing products according to their product use habits except during the procedures of the 
Screening Visit (section 9.1). 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 48 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
6.2.1 
Admission (Day -1)  
After enrollment in the study, subjects will be provided with information on the risks of 
smoking, advice on smoking cessation and briefing on P4M3 Gen 2.0 and will perform a 
product test with P4M3 Gen 2.0 (with CA35 only) for a maximum of 10 minutes. After the 
product test, subjects willing and ready to use P4M3 Gen 2.0 during the study will be required 
to abstain from any nicotine/tobacco containing product use until the first product use on 
Day 1. 
6.2.2 
Exposure Period (Day 1 and Day 3)  
On Day 1 to Day 3, after at least 12 hours of abstinence from any tobacco/nicotine containing 
products, subjects will start using their allocated product ad libitum for 6 minutes ± 30 seconds 
(section 4.1). 
For P4M3 Gen 2.0 use, subjects will be provided with a new P4M3 Gen 2.0 Cartridge (CA35 
or CM35 depending on product assignment) and a fully charged P4M3 Gen 2.0 Battery unit 
with the MDEDR puffing topography device connected. 
For cigarette smoking, subjects will smoke one cigarette ad libitum for 6 minutes ± 30 seconds. 
6.2.3 
Discharge (Day 3)  
After Discharge, subjects will be free to use any nicotine/tobacco products according to their 
usual habits.  
6.2.4 
Safety Follow-up Period  
During the 3-day safety follow-up period, subjects will be free to use any nicotine/tobacco 
containing products according to their usual habits. 
6.2.5 
Stopping Rules for Investigational Products  
For safety purposes, using P4M3 Gen 2.0 or smoking cigarettes should be temporarily stopped 
in the event of any signs suggesting nicotine overexposure, e.g., gastrointestinal disturbance 
(nausea, vomiting, diarrhea, stomach or abdominal pain), cold sweats, headache, dizziness and 
breathing problems, or any reasons at the discretion of the Investigator.  
For subjects who are discontinued, the reason for discontinuation should be documented in the 
source documents and in the CRF and subjects will undertake early termination procedures 
(section 9.7), unless they disagree or certain procedures have already been performed (section 
5.2). 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 49 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
6.3 
Method for Assigning Subjects to Product Sequences 
On Day -1, the subjects will be randomized to one of the six sequences of the 3-period cross-
over design (section 4.1) by means of a permuted-block schema. Details about the 
randomization process will be included in the Data Management Plan (DMP). 
The following quotas will be applied on the total number of randomized subjects: 
• At least 40% of each sex will be represented 
• At least 15% of Black, Asian, American Indian or Alaska native, Native Hawaiian, 
and other Pacific Islander race will be represented 
If a sufficient number of subjects are already randomized to the study sequences, any additional 
subjects (alternates) will be discontinued from the study prior to randomization and will enter 
the 3-day Safety Follow-Up Period (section 5.2). 
Block size and other randomization details will be available in the randomization plan. The 
randomization scheme will be generated by an independent statistician and neither the Sponsor 
staff, nor Investigator or study subjects will have access to the randomization scheme during 
study conduct. 
6.4 
Blinding 
This is an open-label study. Therefore, the subjects, the Investigator, the PMP and CRO 
personnel will be unblinded to the subject’s sequence and product use. 
6.5 
Investigational Product Accountability and Compliance 
6.5.1 
Dispensing Investigational Product 
From Day -1 until Day 3, P4M3 Gen 2.0, comprising of a fully charged Battery unit with a full 
Cartridge, and cigarettes will be dispensed by the investigational site staff, as per the study 
design. For each product use, subjects will receive a full Cartridge.  
Each dispensing of investigational products to the subject will be recorded in a log.  
6.5.2 
Storage and Accountability  
P4M3 Gen 2.0 components and cigarettes will be stored in a secured storage place at the 
investigational site with access limited to the authorized personnel only. The distribution and 
return of investigational products will be controlled by qualified and appropriately trained 
investigational site staff. Subjects will return P4M3 Gen 2.0, comprising of the P4M3 Gen 2.0 
Battery unit and the P4M3 Gen 2.0 Cartridge, immediately after the 6 minutes ad libitum use 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 50 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
to the investigational site staff for accountability and P4M3 Gen 2.0 Cartridge weighing 
(section 7.8.3).  
Smoked cigarettes will be documented and cigarette butts will be collected by investigational 
site staff. 
6.5.3 
Investigational Product Retention 
Used and unused P4M3 Gen 2.0 Battery units and P4M3 Gen 2.0 Cartridges will be destroyed 
or returned to the Sponsor upon study completion. Smoked cigarette butts will be destroyed 
upon study completion. 
6.5.4 
Compliance to Investigational Products 
Compliance will be ensured by strict distribution and collection of any used and unused P4M3 
Gen 2.0, comprising of the P4M3 Gen 2.0 Battery unit and the P4M3 Gen 2.0 Cartridge, and 
cigarettes / cigarette butts by designated investigational site staff. 
6.6 
Restrictions 
6.6.1 
 Smoking Restrictions 
During the Screening period, subjects will be allowed to use any nicotine/tobacco-containing 
products according to their usual habits except during the procedures of the Screening Visit 
(section 9.1). Spirometry assessments at Screening and at Day -1 will be performed 1 hour 
after stopping smoking (section 9.1 and 9.2). 
From Admission (Day -1) to Discharge (Day 3) or early termination, use of any 
nicotine/tobacco containing products, except use as per study design of the allocated product 
will not be permitted.  
A nicotine washout period of at least 12 hours should be respected before product use at Day 
1 to Day 3. 
6.6.2 
Dietary Restrictions 
A standard diet will be designed for the whole confinement period. For each meal, the caloric 
and fat content should be controlled to avoid a “high-fat” diet. The FDA guidance on food-
effect studies for bioequivalence 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) [20].”  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 51 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Subjects are not allowed to bring their own food or beverages to the investigational site. Meals 
will be served as described in section 9. Additional light snacks, fruits, and raw vegetables can 
be distributed to the subjects without restrictions at any time during confinement (except during 
product use periods) if they comply with the standard diet. Consumption of water is allowed 
as desired. Consumption of quinine-containing drinks (e.g., tonic water) is not allowed. 
Subjects should refrain from ingesting foods or beverages containing grapefruit or Seville-type 
(sour) oranges and marmalade from 7 days prior to Day -1 and throughout the study. The same 
menu and meal schedule will be administered uniformly for all subjects. Subjects should have 
fasted (black coffee or tea without sugar is possible) for at least 6 hours prior to safety 
laboratory assessments at Day -1 and on Day 3. 
Subjects should refrain from strenuous and/or unaccustomed exercise throughout the entire 
course of the study. 
6.7 
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.  
Only progesterone-containing hormonal contraception will be allowed. Hormonal 
contraception containing estrogens or hormone replacement therapy will be prohibited and 
subjects will be excluded based on eligibility criteria. 
Any medication with an impact on the CYP2A6 metabolism [21] (used as prescription and 
over-the-counter products), including, but not limited to medications listed in Table 2, must be 
avoided as CYP2A6 is involved in the nicotine metabolism. To be eligible for the study, any 
medication with impact on CYP2A6 metabolism must have been discontinued at least 14 days 
prior to Day -1 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, they should not be used during the entire study until the time of Discharge 
or early termination. Prior to database lock, concomitant medication will be reviewed for their 
potential impact on CYP2A6 activity and the study results. 
 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 52 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Table 2 
CYP2A6: Substrates, Inhibitors, and Inducers 
Inhibitors  
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 
Inducers  
Drug Class 
Amobarbital 
Barbiturate 
Pentobarbital 
Barbiturates 
Phenobarbital 
Barbiturates/anticonvulsants 
Rifampin 
Antimycobacterials 
Secobarbital 
Barbiturates 
Substrates  
Drug Class 
Dexmedetomidine 
α2-Adrenoceptor, sedative 
Ifosfamide 
Anti-cancer, alkylating agents 
 
Use of over-the-counter medication will be restricted from Admission (Day -1) to Discharge 
or early termination, although exceptions may be made on a case-by-case basis at the discretion 
of the Investigator. 
Use of any other concomitant medication will be evaluated on a case-by-case basis by the 
Investigator. Any concomitant medication used will be fully documented (section 7.4.2). 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 53 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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 
STUDY PROCEDURES 
Investigational site staff performing or recording study assessments must have the appropriate 
and fully documented training. An overview of study assessments and time points 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 
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 and Smoking Cessation 
Advice and Debriefing on P4M3 Gen 2.0  
At the Screening Visit, before enrollment at Day -1 and at Discharge (Day 3), subjects will 
receive 1) information on the risks of smoking, 2) smoking cessation advice, and 3) debriefing 
on P4M3 Gen 2.0 as described in the Schedule of events (Appendix A).  
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 [22]. The debriefing of subjects on 
P4M3 Gen 2.0 will address any intended or unintended beliefs that subjects may have about 
P4M3 Gen 2.0. The goal of the debriefing is to help ensure that subjects enter and exit the 
study with an accurate understanding of the product risks.  
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 may be given in a group session. 
7.3 
Support during Abstinence from any Tobacco and Nicotine 
Containing Products  
Subjects will be offered support during periods of abstinence from any nicotine/tobacco 
containing products during the study from Day -1 to Discharge by the Investigator and/or 
investigational site staff as per Schedule of events. Support resources will include counselling 
and assistance, entertainment, monitoring of the subject’s behavior, AEs, and the subject’s 
mood, clinical tests e.g., vital signs, physical examination. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 54 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
7.4 
Clinical Assessments 
7.4.1 
Demographic Data 
Sex, date of birth, race and ethnicity will be recorded for each subject as described in the 
Schedule of events. 
7.4.2 
Medical History, Concomitant Disease, Prior and Concomitant Medication 
Relevant medical history or any concomitant disease will be documented at the Screening 
Visit. Medical history is defined as any condition that started and ended prior to the ICF 
signature at the Screening Visit. 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. 
Prior medication taken within 4 weeks prior to the Screening Visit and any concomitant 
medication will be documented. Any medication started prior to the Screening Visit and still 
being taken by the subject will be considered concomitant medication. Medication initiated 
after the Screening Visit will also be referred to as concomitant medication. The definition of 
concomitant medication applies to both prescribed 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. If a concomitant medication is still being taken by the subject at the 
end of the study, this will be recorded in the CRF. 
7.4.3 
Physical Examination 
Physical examinations will be conducted as described in the Schedule of events. 
A physical examination will include review of general appearance, hair and skin, head, eyes, 
ears, nose and throat, neck, thyroid gland, chest, lungs, back, abdomen, dentition, 
gastrointestinal, cardiovascular, musculoskeletal, and neurological systems. The physical 
examination is to be conducted by the Investigator or designated fully trained representative. 
For those results outside of the normal range, the Investigator will determine appropriate 
follow-up including reporting of any AEs. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 55 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
7.4.4 
Body Height and Weight and BMI 
Body height and weight will be recorded at the Screening Visit and body-mass-index (BMI) 
will be calculated using the following formula:  
BMI = weight in kilograms
height in meters2
= 𝑘𝑔
𝑚2 
The BMI will be used to assess eligibility for enrollment. 
7.4.5 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, respiratory rate and pulse rate) will be 
measured as described in the Schedule of events. On Day 1 to Day 3, vital signs will be assessed 
prior to T0. 
All parameters will be recorded in supine position after the subject has rested for at least 5 
minutes. Subjects should have abstained from using any nicotine/tobacco containing products 
for at least 15 minutes prior to Vital signs assessment. 
The Investigator will define Vital sign ranges to determine normal or abnormal results. For 
those results outside of the normal range, the Investigator will determine appropriate follow-
up including reporting of any AEs. 
7.4.6 
Spirometry 
Spirometry without bronchodilator will be performed at the Screening Visit, Day -1 and at 
Discharge (Day 3) or early termination in accordance with the 2005 guideline of the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) Joint Task Force on the 
standardization of spirometry [23, 24]. Spirometry predicted values will be standardized to the 
National Health and Nutrition Examination Survey III predicted set [25].  
Assessed parameters will include: FEV1, FEV1 % predicted, FVC, FVC % predicted and 
FEV1/FVC. 
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 at rest for at least 15 minutes and at least 1 hour after smoking 
cigarettes (Screening Visit). 
The Investigator will define Spirometry ranges to determine normal or abnormal results. For 
those results outside of the normal range, the Investigator will determine appropriate follow-
up including reporting of any AEs. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 56 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Any printouts of Spirometry on thermo-sensitive paper must be photocopied and stapled 
together for inclusion in the source documents. 
7.4.7 
 Electrocardiogram 
At the Screening Visit, Day -1 and at Discharge (Day 3) or early termination, a standard 12-
lead ECG will be recorded after the subject has rested for at least 10 minutes in supine position 
as described in the Schedule of events.  
All ECGs will be reviewed on an ongoing basis by the Investigator or designee. The following 
parameters will be documented: heart rate, PR interval, QRS interval, QT interval, and QTc 
interval corrected according to Fridericia’s formula.  
The Investigator will define ECG ranges to determine normal or abnormal results. For those 
results outside of the normal range, the Investigator will determine appropriate follow-up 
including reporting of any AEs.  
Any printouts of ECGs on thermo-sensitive paper must be photocopied and stapled together 
for inclusion in the source documents. 
7.5 
Biomarker Assessment  
All bioanalytical assays and laboratory assessments will be carried out using validated 
methods. The bioanalytical methods used will be documented in the respective bioanalytical 
plans/reports. A list of laboratories is provided in Appendix B. 
7.5.1 
Biomarkers of Exposure to Nicotine 
On Day 1 to Day 3, venous blood samples will be collected to evaluate nicotine plasma PK 
profile and at Day 2 and Day 3 additional samples will be collected for determination of 
terminal elimination half-life as described in the Schedule of events.  
The time of collection of each blood sample must be recorded on the CRF. 
7.5.2 
CYP2A6 Activity  
CYP2A6 activity drives the metabolism of nicotine to cotinine and subsequent metabolites. 
CYP2A6 activity will be measured in plasma using the metabolic molar ratio of trans-3’-
hydroxycotinine/cotinine. 
On Day -1, one blood sample will be collected for determination of CYP2A6 activity (cotinine 
and trans-3’-hydroxy-cotinine) prior to the P4M3 Gen 2.0 product test as described in the 
Schedule of events. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 57 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
The time of collection of the blood sample must be recorded on the CRF. 
7.6 
Laboratory Assessments 
7.6.1 
Clinical Chemistry, Hematology, and Urine Analysis Safety Panel 
Hematology and clinical chemistry analysis will be assessed as per Schedule of events. 
Subjects should have fasted for at least 10 hours prior to safety laboratory assessments, except 
at Screening and early termination where non-fasting samples can be used. Tests will be 
conducted at a local laboratory (Appendix B). If during the screening period a blood sample is 
not suitable for analysis (e.g., blood clotting) a re-test should be performed for the specific 
parameters which are not available. Safety urine analysis will be assessed at Screening, 
Admission and at Discharge or at early termination.  
Parameters to be tested are listed in Table 3. 
Table 3 
Clinical Laboratory Parameters for Safety Panel 
Hematology 
Clinical Chemistry 
Urine analysis 
• 
Hematocrit 
• 
Hemoglobin 
• 
Mean corpuscular hemoglobin 
• 
Mean corpuscular hemoglobin 
 
concentration 
• 
Mean corpuscular volume 
• 
Platelet count 
• 
Red blood cell count 
• 
White blood (WBC) cell count 
• 
Differential WBC count: 
- 
Neutrophils 
- 
Basophils 
- 
Eosinophils 
- 
Lymphocytes 
- 
Monocytes 
• 
Albumin 
• 
Total protein 
• 
Alkaline phosphatase 
• 
Alanine aminotransferase 
• 
Aspartate aminotransferase 
• 
Blood urea nitrogen 
• 
Creatinine 
• 
Gamma-glutamyl transferase 
• 
Glucose 
• 
Lactate dehydrogenase 
• 
Potassium 
• 
Sodium 
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Total cholesterol 
• 
Triglycerides 
• 
pH 
• 
Bilirubin 
• 
Glucose 
• 
Nitrite 
• 
Red blood cell traces 
• 
Protein 
• 
Specific gravity 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 58 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
7.6.2 
Serology 
Tests for hepatitis B (HbsAg), hepatitis C (HCV antibody) virus and human immunodeficiency 
virus (anti-HIV1/2) will be performed at the Screening Visit.  
. 
In case of positive results, the subject will be referred to appropriate medical care. 
7.6.3 
Urine Drug Test 
A urine drug screen including testing for alcohol will be performed at the site at the Screening 
Visit and at Day -1. The urine will be screened for:  
• amphetamine type substances,  
• barbiturates,  
• benzodiazepines,  
• cannabinoids,  
• cocaine,  
• opiates, and 
In case of a positive urine drug test, a re-test will not be allowed in order to evaluate eligibility. 
In case of an inconclusive test, a re-test can be performed but this needs to be done immediately 
after the inconclusive test. If positive for cannabinoids, a cannabis intoxication evaluation will 
be performed at Screening and at Admission and inclusion will be at the discretion of the 
Investigator. 
7.6.4 
Urine Cotinine Test  
A urine cotinine test will be performed to confirm the nicotine/tobacco use status as described 
in the Schedule of events. 
The test must detect cotinine with a threshold of ≥ 200 ng/mL. In case of a negative cotinine 
test, a re-test will not be allowed in order to evaluate eligibility. In case of an inconclusive test, 
a re-test can be performed but this needs to be done immediately after the inconclusive test. 
7.6.5 
Urine Pregnancy Test  
A urine pregnancy test will be performed for all female subjects as per Schedule of events. 
Subjects with a positive urine pregnancy test or unclear results (from two repetitions) before 
enrollment will be considered as screen failures. In case of any positive pregnancy test, the 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 59 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Investigator or designee will inform the subject about the risks associated with smoking during 
pregnancy and subjects will be referred to health care facility/health care provider for 
pregnancy follow-up. 
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). 
7.6.6 
Alcohol Breath Test 
An alcohol breath test will be performed in all subject as described in the Schedule of events. 
7.7 
Sample Handling, Storage, and Shipment 
Urine drug test including testing for alcohol, 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 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. 
7.7.1 
Blood Samples  
Blood samples will be drawn by qualified and trained site personnel and according to the 
standard operating procedures (SOPs) at the investigational site. 
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.  
In total, approximately 300 mL of blood will be collected for this study including samples for 
determination of plasma nicotine concentrations (approximately 230 mL), CYP2A6 activity (5 
mL), serology (5 mL) and safety laboratory (approximately 60 mL). This calculation is based 
on an individual volume of each sample of 5.0 mL for nicotine PK, 5.0 mL for CYP2A6 
analysis, 5 mL for serology, 20 mL per safety laboratory assessments. The total volume of 
blood drawn will not exceed the levels for a standard blood donation.  
Details on the procedures for collection, labeling, handling and shipment of samples are 
described in the SHM/ laboratory manual. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 60 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
7.8 
Other Study Procedures  
7.8.1 
Demonstration and P4M3 Gen 2.0 Product Test  
All subjects will have a demonstration of P4M3 Gen 2.0 by the investigational site staff at the 
Screening Visit without product use.  
At Admission (Day -1), after enrollment, investigational site staff will inform subjects on 
product use and subjects will have a product test with P4M3 Gen 2.0 with CA35 Cartridge ad 
libitum for up to 10 minutes.  
7.8.2 
Human Puffing Topography 
Human puffing topography (HPT) involves the measurement of each subject’s unique way of 
using P4M3 Gen 2.0 or smoking cigarettes.  
The MDEDR puffing topography device measures and records the flow rate and other per-puff 
parameters listed in Appendix D. From the per-puff parameters, per-product experience 
parameters, representing average or total values per product, will be derived (Appendix D). 
The MDEDR puffing topography device will be used with the P4M3 Gen 2.0 on Day 1 to Day 
3 with data recording during 6 minutes (±30 seconds) ad libitum use as described in the 
Schedule of events. Data will be not be collected during cigarette smoking. 
The P4M3 Gen 2.0 device is equipped with a pressure sensor, which measures the pressure at 
the Cartridge level. When a puff is drawn, the P4M3 Gen 2.0 calculates the difference of 
pressure between the atmospheric pressure and the pressure measured at the Cartridge level. 
The aerosol production (heating cycle) is then triggered based on the difference of pressure 
values calculated by the device. The MDEDR puffing topography device is mechanically 
attached to the Battery unit of P4M3 Gen 2.0 and electronically connected to its USB port. The 
MDEDR puffing topography device works as a data logger. Once connected to the P4M3 Gen 
2.0 device, the MDEDR puffing topography device is able to record HPT data. Any 
malfunction of the MDEDR puffing topography device will be documented in the appropriate 
log.  
One MDEDR puffing topography device will be assigned at Day -1 for each subject and will 
be used for all further HPT assessments. A replacement device will be provided in case of 
malfunction of the device assigned. The Sponsor will provide training on the use of the 
MDEDR puffing topography device to the investigational site staff which will be responsible 
for the HPT assessment. All MDEDR puffing topography devices will be returned to the 
Sponsor after completion of the study. 
Prior to calculation of the per-product experience parameters, the Sponsor’s HPT group will 
process, validate and discard any invalid data, as per the Sponsor’s SOPs. The Sponsor will 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 61 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
provide copies of both the raw and validated HPT datasets to the Investigator. Only valid data 
for the per-puff and per-product use experience parameters will be part of the study database 
and will be analyzed. 
7.8.3 
Weighing of P4M3 Gen 2.0 Cartridge 
P4M3 Gen 2.0 Cartridges will be weighed before T0 and within 120 min after T0 as described 
in the Schedule of events to estimate the amount of nicotine delivered during product use.  
The weight will be determined with a scale with an accuracy of 1 mg. 
7.9 
Questionnaires 
The questionnaires will be asked to the subject as described in the Schedule of events 
(Appendix A) and will be completed by the subjects. All subject-reported outcome as well as 
instructions will be provided in the subject’s local language. 
7.9.1 
Fagerström Test for Nicotine Dependence (FTND, Revised Version) 
At the Screening visit, potential nicotine dependence will be assessed as per Schedule of Event 
using the FTND in its revised version [18] as updated in 2012 [26]. 
The questionnaire consists of six questions which have to be answered by the subject 
himself/herself. The scores obtained on the test permit the classification of nicotine dependence 
into three levels: Mild (0 to 3 points); Moderate (4 to 6 points); Severe (7-10 points) [26]. 
7.9.2 
Nicotine/Tobacco Product Use History 
At the Screening Visit, subjects will be asked questions about their tobacco-and/or nicotine-
containing products use history. The questions will capture frequency and quantity of tobacco 
and/or nicotine-containing product use over the past 4 weeks, and number of continuous years 
of cigarette smoking. This information will be used as characteristics of the study subjects and 
to assess their eligibility to participate in the study.  
7.9.3 
ABOUT-Product Experience Questionnaire 
Product experience will be assessed via a subject self-reported outcome measure, part of the 
ABOUT toolbox [27, 28].  
The questionnaire consists of 3 multi-item scales and 2 single-item scales, arising from an 
adaptation and rewording of the modified cigarette evaluation questionnaire (mCEQ) [19] to 
RRPs and the Product Evaluation Scale [29]. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 62 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
The questionnaire assesses the degree to which subjects experience the reinforcing effects of 
P4M3 Gen 2.0 with CA35 and CM 35 Cartridges 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 items of the questionnaire on a 7-point scale, ranging from 
“not at all” to “extremely”. 
7.9.4 
VAS Craving Assessment 
Cigarette craving will be assessed using a 1 item self-reported craving VAS [30], asking 
subjects to rate craving for cigarettes (How strong is your craving for cigarettes?), on a 100 
mm unipolar scale, ranging from 0 (no craving), to 100 (strong craving). 
7.9.5 
VAS Liking Assessment 
Cigarette and P4M3 Gen 2.0 liking will be assessed using a one item self-reported liking VAS, 
asking subjects to rate liking for product (At this moment, my liking for this product is:) on a 
100 mm bipolar scale, ranging from 0 (strong disliking), to 100 (strong liking), with a neutral 
middle point, as recommended in the FDA guidance for industry on abuse liability assessment 
[31]. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 63 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
8 
ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
An adverse event (AE) 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 are still 
ongoing at Screening (concomitant disease), and whose severity 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 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 64 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
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 Screening 
(concomitant disease) and whose severity 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 
AEs should be collected mainly via face-to-face interview with the subject by the use of 
consistent, open, non-directive questions from the investigator(s) or designee(s) (e.g., “How 
have you been feeling since you were last asked?”). 
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.  
Information recorded will include: verbatim description of the AE/SAE, start and stop dates 
and times, 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 individual 
EOS for each participant. 
Any AEs which occur during the screening period will be captured by the investigational site 
staff and assessed by the Investigator or designee(s) in order to establish relationship to study 
procedures. 
During a 3-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 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 65 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
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 or subject is lost to follow up. Any AEs or SAEs 
that are ongoing at the end of the Safety Follow-Up Period will be managed as described in 
section 8.2.6. 
8.2.3 
Intensity of Adverse Event 
The Investigator must assess the intensity of each reported AE according to the following 
grading scale: 
Table 4 
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 (P4M3 Gen 
2.0 and cigarettes) 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 (P4M3 Gen 2.0 or cigarettes) 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 in section 6.5 of the current Investigator’s Brochure [5].  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 66 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
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, 
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. If the subject is not responding 
at the first phone call additional two attempts will be made, then subject will be declared lost 
to follow-up.  
At the end of the 3-day Safety FU Period, all ongoing non-serious AEs will have the outcome 
documented as “unknown” and will not be followed-up by the Investigator. At the discretion 
of the Investigator, the subject will be referred to his General Practitioner to have his/her 
ongoing AEs addressed accordingly. 
All SAEs will be followed up by the Investigator or designee 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). In case the subject cannot 
be reached for additional information related to SAE(s), a total 3 attempts should be performed 
before the subject will be declared as lost to follow-up. 
8.3 
Reporting of Serious Adverse Events 
Any SAE observed during the period of collection in this study must be reported within 24 
hours of first awareness to Sponsor, via email, having the SAE form attached as detailed in the 
Safety Management Plan (SMP). 
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 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 IRB, according to local regulations and in accordance with the 
respective safety management plan (SMP).  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 67 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
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 Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 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 as 
described 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 either be 
recorded as AEs (and handled as described in section 8.2) or linked to a concomitant disease 
or to an already reported AE.  
The principles for assessing and reporting abnormal laboratory test results, emerging after the 
Screening Visit, using CTCAE 5.0 grading scales are set up in Table 5: 
Table 5  
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. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 68 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
 
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 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 as described in 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 the time before 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. 
In case of pregnancies detected between enrollment and prior to randomization, subject will 
be discontinued, and reported as “enrolled but not randomized” subject. Early termination 
procedures shall apply. No pregnancy form will be filled. 
Any pregnancy detected after randomization must be reported by the Investigator within 24 
hours. This also includes pregnancies spontaneously reported to the Investigator after the end 
of the study for a subject. A dedicated pregnancy form will be used to report reportable cases 
of pregnancy. 
 
Any pregnancy that was potentially associated with exposure to IP (P4M3 Gen 2.0 or cigarette) 
will be followed-up until an outcome is reached (e.g., normal delivery, spontaneous abortion, 
or voluntary termination) and also until 8 weeks after delivery. Any pregnancy complication, 
adverse pregnancy outcome or maternal complications will be recorded as an AE accordingly. 
 
The procedure outlined in section 8.3 should be followed to collect pregnancy reports and 
provide any additional/follow-up information to Sponsor. 
 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 69 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
 
8.5.2 
Reporting of Pregnancies 
The Investigator is responsible for informing the responsible IRB 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 9.7), as soon as practical after discontinuation and will enter 
the 3-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 P4M3 Gen 2.0 product events, affecting P4M3 Gen 2.0 Battery unit and /or 
P4M3 Gen 2.0 Cartridge, including malfunction or misuse (use not in accordance with its 
instruction) by a subject will be documented by the Investigator. Information regarding P4M3 
Gen 2.0 product events should be actively collected during the study and assessed for severity 
as Minor or Major: 
Minor – Can be resolved easily. 
Major – Cannot be resolved. 
P4M3 Gen 2.0 product events will be categorized into: Break, Fluid Leak, Intermittent Loss of 
Power, Power Problem, Premature Indicator Activation or Other. 
Investigational product misuse may result in use-related hazards (section 2.3.4). 
Furthermore, any malfunction or misuse of P4M3 Gen 2.0 that leads to an AE/SAE will follow 
the same processes as described above. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 70 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
9 
STUDY ACTIVITIES 
A detailed schedule of assessment can be found in Appendix A. Measurements not conducted 
at the exact time point but conducted within the given time window (if applicable) do not 
constitute a protocol deviation but an accepted variability for the given time point. 
In general, if no start time for the procedures is provided, then the procedure can be performed 
at any time during the day. 
The main objective for this study is the evaluation of the plasma concentration-time profile of 
nicotine and derived PK parameters. Therefore, the collection of blood samples for 
determination of plasma nicotine concentration should be as close to the schedule time as 
possible and should take precedence over any other assessments required at the same time. 
9.1 
Screening Visit (Day -29 to Day -2) 
The Screening Visit will be performed within 28 days prior to enrollment at Admission (Day 
-1). 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 6. 
Table 6 
Time Schedule – Screening Visit 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V1 
 
Prior to any 
other study 
procedure 
 
Informed consent process and 
signature of ICF 
 
During the visit 
 
Information on the risks of 
smoking/advice on smoking 
cessation and debriefing on 
P4M3 Gen 2.0 
 
 
 
Nicotine/Tobacco product use 
history  
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 71 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V1 
 
 
 
FTND questionnaire 
 
 
 
Demographics data 
 
 
 
Medical history/ concomitant 
diseases 
 
 
 
Prior (within 4 weeks prior to the 
Screening Visit) and 
concomitant medication 
 
 
 
Physical examination 
 
 
 
Body height, weight and 
calculated BMI 
 
 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 min in supine position 
prior to measurement. At least 15 
minutes abstinence from any 
nicotine/tobacco containing 
products prior to measurement. 
 
 
ECG 
After resting for at least 10 min in 
supine position prior to recording 
 
 
Spirometry 
Has to be done at least 1 hour 
after stopping smoking. After 
resting in sitting position for at 
least 15 minutes prior to testing.  
 
 
Alcohol breath test 
 
 
✓ 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
 
 
 
Collection of spot urine for: 
- 
Urine analysis safety panel 
- 
Urine drug test including 
testing for alcohol 
- 
Urine cotinine test 
- 
Urine pregnancy test (all 
female subjects) 
 
 
✓ 
Serology 
HIV 1/2, Hepatitis B and C,  
 
 
Review of inclusion/exclusion 
criteria based on all relevant 
assessments 
Includes willingness to comply 
with study procedures, including 
periods of abstinence from any 
nicotine/tobacco containing 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 72 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V1 
 
products; intention to quit 
smoking or using other 
nicotine/tobacco-containing 
products in the next 3 months 
 
 
P4M3 Gen 2.0 demonstration 
Without product use 
During the visit 
 
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. 
If the inclusion and exclusion criteria are met, the investigational site staff will contact the 
subject to arrange Day -1 visit at site. 
 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 73 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
9.2 
Admission (Day -1) 
The assessments performed at Admission are listed in Table 7. 
Table 7 
Time Schedule – Admission (Day -1) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
 
Before enrollment 
 
Information on the risks of 
smoking/advice on smoking 
cessation and debriefing on 
P4M3 Gen 2.0 
 
 
 
Nicotine/Tobacco product use 
history 
 
 
 
Concomitant medication/ 
concomitant disease status 
check 
 
 
 
Physical examination 
 
 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 min in supine position 
prior to measurement. At least 15 
minutes abstinence from any 
nicotine/tobacco containing 
products prior to measurement. 
 
 
ECG 
After resting for at least 10 min in 
supine position prior to recording. 
 
 
Spirometry 
Has to be done at least 1 hour 
after stopping smoking. After 
resting in sitting position for at 
least 15 minutes prior to testing.  
 
 
Serology 
 
 
 
Alcohol breath test 
 
 
 
Collection of spot urine for: 
- 
Urine analysis safety 
panel 
- 
Urine drug test including 
testing for alcohol 
- 
Urine cotinine test 
- 
Urine pregnancy test (all 
female subjects) 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 74 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
 
 
 
 
Re-check of Inclusion criteria 
4, 5 and 7 and exclusion 
criteria 7, 10, 15, 16 and 17. 
 
 
 
Enrollment 
 
 
✓ 
Clinical laboratory 
parameters (hematology, 
clinical chemistry) 
After at least 10 hours of 
fasting.  
 
 
Urine analysis safety panel 
 
After enrollment 
✓ 
CYP2A6 activity 
Before product test 
After collection of 
sample for 
CYP2A6  
 
P4M3 Gen 2.0 product test 
with CA35 Cartridge by subject 
Up to 10 minutes ad libitum use. 
During the visit 
 
AE/SAE recording 
 
During the visit 
 
Product events 
malfunctions/misuse 
 
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; SAE = Serious adverse event. 
 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 75 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
9.3 
Day 1 
The study activities performed on Day 1 are listed in Table 8.  
Table 8 
Time Schedule – Day 1 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Prior to T0  
 
Weighing of P4M3 Gen 2.0 
CA35 and CM35 Cartridge 
and connection of P4M3 
Gen 2.0 to MDEDR HPT 
device  
 
Prior to T0 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 min in supine position 
prior to measurement. 
Within 15 minutes 
prior to T0 
 
VAS craving assessment 
 
5 minutes ± 1 minute 
prior to T0 
✓ 
Blood sampling for baseline 
nicotine level  
 
Just before T0 
 
Turning on P4M3 Gen 2.0 or 
lighting of cigarette 
Performed by investigational 
site staff 
Start of product use: 
T0  
 
P4M3 Gen 2.0 product use 
with MDEDR HPT recording 
Cigarette smoking without 
HPT recording 
After at least 12 hours of 
nicotine washout. 
During/after 6 min ad 
libitum product use 
✓ 
Blood sampling for nicotine 
PK  
Post T0, blood will be drawn at 
the following time points:  
T1 after 1 minute + 30 seconds 
T2 after 2 minutes + 1 minute 
T3 after 4 minutes + 1 minute 
T4 after 6 minutes + 1 minute 
T5 after 8 minutes + 1 minute 
T6 after 10 minutes + 1 minute 
T7 after 12 minutes + 1 minute 
T8 after 15 minutes ± 2 minutes 
T9 after 30 minutes ± 2 minutes 
T10 after 1 hour ± 5 minutes 
T11 after 2 hours ± 5 minutes 
T12 after 4 hours ± 5 minutes 
T13 after 10 hours ± 5 minutes.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 76 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
T14 after 24 hours ± 10 minutes 
(Day 2 baseline) 
 
 
VAS craving assessment, 
VAS liking assessment 
Post T0, assessments will be 
done at the following timepoints: 
T1 after 4 minutes ± 1 minute 
T2 after 10 minutes ± 1 minute 
T3 after 15 minutes ± 1 minute 
T4 after 30 minutes ± 2 minutes 
T5 after 1 hour ± 5 minutes 
T6 after 2 hours ± 5 minutes 
T7 after 4 hours ± 5 minutes 
T8 after 10 hours ± 5 minutes 
Within 120 minutes 
after T0 
 
Breakfast 
 
Between 60 minutes 
and 120 minutes 
after T0  
 
ABOUT-Product experience 
questionnaire 
 
Within 120 min after 
T0 
 
Collection and weighing of 
used P4M3 Gen 2.0 CA35 
and CM35 Cartridges, 
collection of cigarette buttes 
 
After at least 4 hours 
after T0  
 
Lunch 
 
During nicotine 
washout 
 
Nicotine washout 
Optional: snacks and water 
Ongoing 
 
Support during period of 
abstinence from any tobacco 
and nicotine containing 
products 
 
Ongoing 
 
AE/SAE, concomitant 
medication recording/ 
concomitant diseases status 
check 
 
Ongoing 
 
Product events 
malfunctions/misuse 
 
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; HPT = Human puffing topography; PK = Pharmacokinetic; 
SAE = Serious adverse event; VAS = Visual analogue scale 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 77 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
9.4 
Day 2 
The study activities performed on Day 2 are listed in Table 9. 
Table 9 
Time Schedule – Day 2  
Time 
Blood 
Sample 
Procedures 
Additional Information 
Prior to T0  
 
Weighing of P4M3 Gen 2.0 
CA35 and CM35 Cartridge 
and connection of P4M3 
Gen 2.0 to MDEDR HPT 
device  
 
Prior to T0 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 min in supine position 
prior to measurement. 
Within 15 minutes 
prior to T0 
 
VAS craving assessment 
 
5 minutes ± 1 minute 
prior to T0 
✓ 
Blood sampling for 
baseline nicotine level  
Sample T14 after 24 hours ± 10 
minutes from T0 on Day 1 
Just before T0 
 
Turning on P4M3 Gen 2.0 
or lighting of cigarette 
Performed by investigational 
site staff 
Start of product use: 
T0  
 
P4M3 Gen 2.0 product use 
with MDEDR HPT 
recording 
Cigarette smoking without 
HPT recording  
Cigarette smoking without 
HPT recording 
After approximately 24 hours of 
nicotine washout. Within ± 20 
minutes of T0 of prior study day. 
During/after 6 min ad 
libitum product use 
✓ 
Blood sampling for nicotine 
PK  
Post T0, blood will be drawn at 
the following time points:  
T1 after 1 minute + 30 seconds 
T2 after 2 minutes + 1 minute 
T3 after 4 minutes + 1 minute 
T4 after 6 minutes + 1 minute 
T5 after 8 minutes + 1 minute 
T6 after 10 minutes + 1 minute 
T7 after 12 minutes + 1 minute 
T8 after 15 minutes ± 2 minutes 
T9 after 30 minutes ± 2 minutes 
T10 after 1 hour ± 5 minutes 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 78 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
T11 after 2 hours ± 5 minutes 
T12 after 4 hours ± 5 minutes 
T13 after 10 hours ± 5 minutes 
 
 
✓ 
Blood sampling for 
determination of subject’s 
nicotine t1/2z 
Blood will be drawn at the 
following time points after T0 on 
Day 2:  
T1z after 8 hours ± 5 minutes 
T2z after 12 hours ± 5 minutes 
T3z after 16 hours ± 10 minutes,  
T4z after 20 hours ± 10 minutes,  
 
 
VAS craving assessment, 
VAS liking assessment 
Post T0, assessments will be 
done at the following timepoints: 
T1 after 4 minutes ± 1 minute 
T2 after 10 minutes ± 1 minute 
T3 after 15 minutes ± 1 minute 
T4 after 30 minutes ± 2 minutes 
T5 after 1 hour ± 5 minutes 
T6 after 2 hours ± 5 minutes 
T7 after 4 hours ± 5 minutes 
T8 after 10 hours ± 5 minutes 
Within 120 minutes 
after T0 
 
Breakfast 
 
Between 60 minutes 
and 120 minutes after 
T0  
 
ABOUT-Product 
experience questionnaire 
 
 
Within 120 min after 
T0 
 
Collection and weighing of 
used P4M3 Gen 2.0 CA35 
and CM35 Cartridges, 
collection of cigarette 
buttes 
 
After at least 4 hours 
after T0  
 
Lunch 
 
During nicotine 
washout 
 
Nicotine washout 
Optional: snacks and drinks 
Ongoing 
 
Support during period of 
abstinence from any 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 79 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
tobacco and nicotine 
containing products 
Ongoing 
 
AE/SAE, concomitant 
medication recording/ 
concomitant diseases 
status check 
 
Ongoing 
 
Product events 
malfunctions/misuse 
 
Abbreviations: ABOUT = Assessment of behavioral outcomes related to tobacco and nicotine products; AE = Adverse event; 
ECG = Electrocardiogram; HPT = Human puffing topography; PK = Pharmacokinetic; SAE = Serious adverse event; VAS = 
Visual analogue scale 
9.5 
Day 3 
The study activities performed on Day 3 prior to the time of discharge are listed in Table 10.  
Table 10 
Time Schedule – Discharge (Day 3) 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Prior to T0  
 
Weighing of P4M3 Gen 2.0 
CA35 and CM35 Cartridge 
and connection of P4M3 
Gen 2.0 to MDEDR HPT 
device  
 
Prior to T0 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 min in supine position 
prior to measurement. 
Within 15 minutes 
prior to T0 
 
VAS craving assessment 
 
5 minutes ± 1 minute 
prior to T0 
✓ 
Blood sampling for 
baseline nicotine level  
Sample T14 after 24 hours ± 10 
minutes from T0 on Day 2 
Just before T0 
 
Turning on P4M3 Gen 2.0 
or lighting of cigarette 
Performed by investigational 
site staff 
Start of product use: 
T0  
 
P4M3 Gen 2.0 product use 
with MDEDR HPT 
recording 
Cigarette smoking without 
HPT recording 
After approximately 24 hours of 
nicotine washout. Within ± 20 
minutes of T0 of prior study day. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 80 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
During/after 6 min ad 
libitum product use 
✓ 
Blood sampling for nicotine 
PK  
Post T0, blood will be drawn at 
the following time points:  
T1 after 1 minute + 30 seconds 
T2 after 2 minutes + 1 minute 
T3 after 4 minutes + 1 minute 
T4 after 6 minutes + 1 minute 
T5 after 8 minutes + 1 minute 
T6 after 10 minutes + 1 minute 
T7 after 12 minutes + 1 minute 
T8 after 15 minutes ± 2 minutes 
T9 after 30 minutes ± 2 minutes 
T10 after 1 hour ± 5 minutes 
T11 after 2 hours ± 5 minutes 
T12 after 4 hours ± 5 minutes 
T13 after 10 hours ± 5 minutes 
 
 
 
VAS craving assessment, 
VAS liking assessment 
Post T0, assessments will be 
done at the following timepoints: 
T1 after 4 minutes ± 1 minute 
T2 after 10 minutes ± 1 minute 
T3 after 15 minutes ± 1 minute 
T4 after 30 minutes ± 2 minutes 
T5 after 1 hour ± 5 minutes 
T6 after 2 hours ± 5 minutes 
T7 after 4 hours ± 5 minutes 
T8 after 10 hours ± 5 minutes 
Within 120 minutes 
after T0 
 
Breakfast 
 
Between 60 minutes 
and 120 minutes after 
T0  
 
ABOUT-Product 
experience questionnaire 
 
 
Within 120 min after 
T0 
 
Collection and weighing of 
used P4M3 Gen 2.0 CA35 
and CM35 Cartridges, 
collection of cigarette 
buttes 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 81 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Ongoing 
 
Support during periods of 
abstinence from any 
tobacco and nicotine 
containing products 
 
 
✓ 
Clinical laboratory 
parameters (hematology, 
clinical chemistry) 
Urine analysis safety panel 
After at least 10 hours of 
fasting. 
After at least 4 hours 
after T0 
 
Lunch 
 
 
 
Urine pregnancy test (all 
female subjects) 
 
 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
At least 5 min in supine position 
prior to measurement. 
 
 
AE/SAE, concomitant 
medication recording 
 
 
 
Discharge 
 
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; SAE = Serious adverse event 
9.6 
Safety Follow-Up Period 
After discharge at Day 3, the subjects will enter a 3-day Safety Follow-Up Period during which 
AE/SAEs reported by the subjects will be collected and the follow-up of AEs/SAEs will be 
conducted by the study investigational site as described in section 8.2.6. 
9.7 
Early Termination Procedures 
When a subject is discontinued from the study, all early termination procedures listed in Table 
11 are performed unless the subject refuses to perform the assessments or the procedures have 
already been performed during that study day.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 82 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Table 11 
Early Termination 
Blood 
Sample 
Procedures 
Additional Information 
 
 
 
✓ 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
 
 
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. 
 
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. 
 
Physical examination 
 
 
Information on the risks of 
smoking/advice on smoking cessation 
and debriefing on P4M3 Gen 2.0 
 
 
AE/SAE, concomitant medication 
recording 
 
 
Product events malfunctions/misuse 
If applicable 
 
Discharge  
 
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; SAE = Serious adverse event 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 83 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
A Clinical Research Associate (“Monitor”) from an independent contract research organization 
(CRO) not involved with the study site will be responsible for the monitoring of the study. 
Monitoring will be performed according to the CRO’s SOPs and as per the agreed monitoring 
plan with the Sponsor. 
Before the first subject is screened and included in the study, an Investigator meeting/site 
initiation visit will be conducted. During this meeting/visit, the general training of the study 
procedures and specific training on selected procedures will be performed and documented. 
All activities to be conducted will be 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 or designee, 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 
Prior to the screening of the first subject, an Investigator Meeting/Study Initiation Visit will be 
held. During this meeting/visit, 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/visit 
will be described in the monitoring plan.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 84 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Further to the Site Initiation Visit, 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.  
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 IRB may perform audits 
or inspections, including source data verification. The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data 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. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 85 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
11 DATA MANAGEMENT ACTIVITIES 
All data management activities will be described in detail in the data management plan (DMP) 
and documents specified therein. 
11.1 Data Capture 
11.1.1 
Case Report Forms and Study Records 
CRFs are produced by the CRO responsible for Data Management activities (DM-CRO), 
stored electronically, and are available to the designated study team members. Each CRF is 
reviewed and signed by the Investigator. The final signed CRFs are provided to the Sponsor in 
the format as decided upon between DM-CRO and the Sponsor (e.g., CD, flash drive, SFTP). 
This will be documented in the DMP). The subject questionnaires will be completed directly 
by the subject. 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 DM-
CRO will enter 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 correction 
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. A CRF will be generated for all subjects that sign the ICF. 
11.1.2 
Protocol Deviations 
Protocol deviations are defined as any departure from the procedures defined in this document, 
including, but not limited to, any violation of inclusion/exclusion criteria, mis-randomization, 
use of any nicotine or tobacco-containing product other than the assigned product during the 
exposure period, assessments not performed or performed outside the scheduled time windows, 
or use of medications 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 may be used to assess protocol deviations from 
the data programmatically. Protocol deviations will be reconciled and categorized prior to 
locking the clinical database as described in the DMP.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 86 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
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 database. The overall procedure for managing protocol 
deviations are defined in the SOPs and study specific procedures of the DM-CRO. All 
deviations will be reviewed, as defined 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 DM-CRO. The overall procedures for quality assurance 
of clinical study data are described in the SOPs of the DM-CRO. The DM-CRO will prepare 
the DMP that will be approved by the Sponsor, prior to the start of the study, i.e., First Subject 
Screened. This document will describe, in detail, the procedures and processes related to data 
management.  
All data of all subjects that are enrolled will be captured and stored in the study database. For 
screen failures, only the following information should be captured: date/time of ICF signature, 
date of birth, sex, race, 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 DM-CRO. 
The sponsor should ensure that the Investigator has control of and continuous access to the 
CRF data reported to the sponsor. The sponsor should not have exclusive control of those data. 
The Investigator should have control of all essential documents and records generated by the 
Investigator/investigational site before, during and after the study. 
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). Data 
clarification forms (DCFs) will be issued to the investigational site for discrepant or missing 
data.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 87 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
All changes to data will be captured in the database with a comprehensive audit trail. 
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 medication:  
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 all validation, quality 
review and cleaning activities are complete as defined in the DMP, the Sponsor organizes a 
data review and ensures that the resolution of all raised queries and quality control of the 
changed data are performed by the CRO before approving the database locked.  
Any changes to the database after that time can only be made by written agreement between 
the Sponsor and the data management and statistical teams at the CRO. Any changes must be 
documented in the database log file and if these impact the study analysis the PMP process for 
a database unlock may be requested.  
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 (SDTM) Data Structure Specifications. 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 88 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
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 clinical 
study report (CSR). The statistical evaluation will be performed using SAS®, version 9.2 or 
later. 
12.1.1 
Stratification Criteria 
The sample enrollment will enforce at least 40% of each sex, therefore analyses will be 
stratified by sex, as well as unstratified, as detailed in the SAP. 
12.1.2 
Definitions for Statistical Data Analysis 
For PK and PD analyses, baseline will be defined as the last assessment prior to T0 (5 minutes 
prior to T0) for each study day of exposure. 
Nicotine PK parameters (e.g., Tmax, Cmax, AUC0-Tmax) will be derived from background-
corrected nicotine concentrations. 
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by subject, study visit, product, and time point, 
unless otherwise specified.  
Continuous endpoints will be summarized with descriptive statistics including number of 
subjects (n), number and percent of subjects with missing data, arithmetic means and standard 
deviations (mean and SD), median, first and third quartiles, minimum and maximum.  
For log normally distributed endpoints, geometric mean, geometric CV, and confidence 
interval will be presented additionally.  
Nominal categorical variables will be summarized by frequency statistics (number and 
percentage), including the number of missing data as a category.  
Ordinal categorical data (e.g., Tmax) will be summarized by number of subjects (n), number 
and percent of subjects with missing data, median, first and third quartiles, and minimum and 
maximum. 
For PK and PD endpoints, all analyses and summaries will be performed by product. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 89 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
For safety endpoints, analyses and summaries will be performed by product and sequence, and 
overall. 
12.1.4 
Handling of Missing Values and of Values outside the Detection Limits 
In general, missing data will not be imputed in this study, due to the nature of the measurements 
and the short periods of exposure and use. However, for questionnaire data, total scores and 
domain or subscale scores may use a certain degree of imputation by averaging across 
individual item scores. Further details will be provided in the SAP. 
In general, bioanalytical 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), the ULOQ will be used for calculation and reporting in summary 
tables.  
For nicotine concentrations below the LLOQ (BLOQ): 
• BLOQ values before T0 will be imputed by LLOQ/2. 
• BLOQ values after the last quantifiable value are not included in the analysis (e.g., for 
the calculation of AUC). 
• Any BLOQ value (after T0 and before the last quantifiable value) would need to be 
queried and, if confirmed, it will be imputed by LLOQ/2.  
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 
In this study 36 subjects will be randomized to 6 product use sequences. This sample size is 
empirically based as there are no considerations for statistical hypothesis. 
In an analysis of confidence interval precision on the P4M3 Gen 2.0: cigarettes Cmax ratios, 
performed with SAS with 10,000 simulations, 
• The precision has been determined to be of 0.55, and 
• The geometric coefficient of variation (GCV) has been determined to be of 50%. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 90 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
12.2.1 
Assumptions 
The precision has been determined using the following geometric mean (GM), geometric 
coefficient of variation (GCV) and within subjects correlation assumptions for Cmax: 
• For all products the GCV is 80% (in previous study [5] GCV is in the range of 0.63 to 
0.83) 
• For usual brand of cigarettes, the GM is 12 ng/mL (in previous studies [32-34] this GM 
is in the range of 11 to 13)  
• For P4M3 Gen 2.0 variants with 3.5% nicotine, the GM is 11 ng/mL (in previous a 
previous study [5] GM is in the range of 9.4 to 12) 
• The correlation within subjects on log-transformed data is 0.8 (in previous studies [32-
34] this correlation is in the range of 0.82 to 0.88)  
12.2.2 
Method 
The analysis of confidence interval precision on the P4M3 Gen 2.0: cigarettes Cmax ratios has 
been implemented using SAS, simulating 10000 sets of log-transformed data for 36 subjects 
with the assumptions described in section 12.2.1, the 3 periods and the 6 sequences of this 
cross-over design. 
The statistical analysis has been performed with a linear model with repeated measurement 
including as fixed effect the sequence, the period, and the product exposure. 
The P4M3 Gen 2.0:cigarettes Cmax ratios and related confidence intervals have been 
determined by using the exponential of the difference between P4M3 Gen 2.0 variants and 
cigarettes on the log-transformed data. 
Then precision has been determined as the 90th percentile of the 95% confidence interval of 
the P4M3 Gen 2.0: cigarettes Cmax ratios. 
12.3 Analysis Populations 
Populations will be described on the screened population. 
Demographics, baseline characteristics, pharmacokinetics endpoints, pharmacodynamics 
endpoints, human puffing topography parameters, amount of nicotine delivered, will be 
analyzed using the randomized and PK population.  
Safety will be analyzed using the safety population.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 91 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
12.3.1 
Screened Population 
The screened population consists of all subjects who underwent screening. 
12.3.2 
Safety Population 
The safety population is a subset of the screened population and consists of all subjects who 
give informed consent, have at least one exposure to P4M3 Gen 2.0, including the product test 
at Admission (Day -1), and have at least one safety assessment. 
12.3.3 
Randomized Population 
The randomized population is a subset of the safety population and consists of all the subjects 
who were randomized at Admission (Day -1). 
12.3.4 
Pharmacokinetics Population 
The PK population Pharmacokinetic (PK) Population is a subset of the randomized population 
and consists of all randomized subjects for whom at least one 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 main objective will be included in the PK population. 
12.4 Demographics and Baseline Characteristics 
Demographic information and baseline characteristics will be summarized for the PK 
population. This summary will also be performed for the randomized population if there is at 
least a difference of 1 subject between the populations.  
Summaries will include sex, age, height, weight and BMI, nicotine/tobacco product use 
history, FTND, CYP2A6 activity and other endpoints that are only captured prior to product 
use.  
These data will be summarized using the appropriate summary statistics as described in 
section 12.1.3. 
12.5 Main Objective and Endpoints 
12.5.1 
Nicotine PK Parameter Analysis Variables  
Nicotine PK parameters (section 3.1) will be derived from plasma nicotine concentration 
versus time data using a non-compartmental analysis (NCA) technique.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 92 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
To minimize the carry-over effect in the nicotine plasma PK parameters (section 4.2), 
background-concentration correction will be applied to the concentration data. The baseline 
correction will be implemented by calculating the nicotine concentration parameters using 
adjusted concentration values as described below. 
The nicotine terminal elimination rate constant λz (and terminal elimination half-life t1/2z) 
will be estimated from the Day 2 PK samples (section 7.5.1) by using a linear regression on 
the log plasma nicotine concentration data. The regression analysis should contain data from 
at least 3 different time points in the terminal phase (including the last quantifiable 
concentration but Cmax), consistent with the assessment of a straight line on the log-transformed 
scale. The nicotine plasma background-corrected PK parameters will be derived by performing 
the NCA on the corrected concentrations.  
For the purposes of background-correction of the plasma concentrations post-baseline the 
following formula will be applied: Ct = uCt - uC0 * e-λz·t. Where, Ct is the corrected 
concentration at each time point, uCt is the uncorrected concentration at each time point, uC0 
is the pre-use baseline concentration, λz is the Day 2 terminal elimination rate constant and t is 
the actual time [35]. For the purposes of background-correction of the plasma concentrations 
post-baseline the following formula will be applied: Ct = uCt - uC0 * e-λz·t. Where, Ct is the 
corrected concentration at each time point, uCt is the uncorrected concentration at each time 
point, uC0 is the pre-use baseline concentration, λz is the Day 2 terminal elimination rate 
constant and t is the actual time [35].  
The procedure of the baseline adjustment will be detailed in the SAP.  
If plasma concentrations cannot be background-corrected in a sufficient number of subjects, 
alternative analysis methods will be used, as detailed in the SAP. 
In particular, the following PK parameters will be derived from nicotine levels adjusted for 
baseline: 
Cmax 
Maximum background-corrected plasma concentration. Cmax will be 
reported as long as there is at least one quantifiable concentration post T0. 
Tmax 
Time to maximum background-corrected plasma nicotine concentration 
Cmax. 
AUC0-2min  
Area under the background-corrected plasma concentration-time curve 
from start of product use (T0) to 2 minutes. 
AUC0-4min 
Area under the background-corrected concentration-time curve from T0 
to 4 minutes. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 93 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
AUC0-Tmax 
Area under the background-corrected plasma nicotine concentration-time 
curve from T0 to subject-specific time to maximum plasma concentration 
after T0. 
AUC0-10h 
 
Area under the background-corrected plasma nicotine concentration-time 
curve from T0 to 10 hours. 
AUC0-last  
Area under the background-corrected plasma nicotine concentration-time 
curve from T0 to the time of last quantifiable concentration. 
AUC0-infinity 
Area under the background-corrected plasma nicotine concentration-time 
curve extrapolated from T0 to infinity. 
max(Ct/t)t∈]0,Tmax] 
Maximum ratio of background-corrected concentration over time, from 
T0 (excluded) to Tmax (included) 
Further details on nicotine PK parameter derivations will be provided in the SAP. 
12.5.2 
Baseline Comparability 
Not applicable. 
12.5.3 
Descriptive Summary 
Endpoints will be summarized as described in section 12.1.3 using the randomized and the PK 
population. 
12.5.4 
Inferential Analysis 
Additional details will be provided in the SAP. 
12.5.4.1 
Main Analysis 
A mixed model analysis of variance (ANOVA) will be conducted on AUC0-2min, AUC0-4min, 
AUC0-Tmax, AUC0-10h, AUC0-last, AUC0-infinity, Cmax, and max(Ct/t)t∈]0,Tmax] endpoints in the natural 
logarithmic scale.  
The model will include terms for sequence, period, product exposure as fixed effects and 
subject as a categorical random effect modeling the within subject correlations. 
The results of this analysis for each of are presented in terms of geometric least square ratios 
and 95% confidence intervals for the P4M3 Gen 2.0:cigarettes ratio.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 94 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
This approach is consistent with the guidelines in the European Medicines Agency’s guidelines 
for bioequivalence investigations [36] and FDA’s Center for Drug Evaluation and Research 
[37].  
The analysis of Tmax will be performed by conducting a Wilcoxon signed rank test and 
calculating the median Tmax for each product along with the Hodges-Lehmann [32] estimate of 
the median difference between products, and the related 95% CI. 
12.5.4.2 
Sensitivity Analysis 
In case of any uncorrected nicotine concentration at T0 [uC0] greater than 5% of their 
uncorrected maximum value, a sensitivity analysis of the endpoints will be performed similarly 
to the main analysis, whereby data of these subjects for this specific study day will be excluded 
from the analysis. 
12.6 Secondary Objectives and Endpoints 
12.6.1 
Pharmacodynamic (PD) Endpoints  
PD endpoints are listed in section 3.2. More details on PD endpoints derivations will be 
provided in the SAP. 
12.6.2 
Human Puffing Topography Parameters  
The following HPT Parameters will be measured per-puff on Day 1 to Day 3 using the 
MDEDR puffing topography device with P4M3 Gen 2.0: 
Table 12 Human Puffing Topography Parameters for MDEDR Puffing 
Topography Device Per-Puff 
Description 
Variable 
Unit 
Puff number 
Ni 
 
Puff volume 
Vi 
mL 
Puff duration 
Di 
s 
Average puff flow 
Qmi 
mL/s 
Peak flow 
Qci 
mL/s 
Inter puff interval 
Ii 
s 
Sum of Ii and Di 
DFi 
s 
Peak flow position 
PosQci 
% 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 95 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
 
The following HPT Parameters will be calculated per-product use experience from Day 1 to 
Day 3 using the MDEDR puffing topography device with P4M3 Gen 2.0 variants: 
 
Table 13 Human Puffing Topography Parameters for MDEDR Puffing 
Topography Device Per-Product Use 
Description 
Variable 
Formula 
Unit 
Total number of puffs 
NPC 
Σ Ni 
Total puff volume 
TVOL 
Σ Vi 
mL 
Average puff volume 
AvgVi 
Σ Vi / NPC, i=1 ... NPC 
mL 
Average puff duration 
AvgDi 
Σ Di / NPC, i=1 ... NPC 
s 
Total puff duration 
TDi 
Σ Di 
s 
Average flow 
AvgQmi 
Σ Qmi / NPC, i=1 … NPC 
mL/s 
Average peak flow 
AvgQci 
Σ Qci / NPC, i=1 … NPC 
mL/s 
Total inter puff interval 
TIi 
Σ Ii 
s 
Average inter puff interval 
AvgIi 
Σ Qci / NPC, i=1 … NPC 
s 
Total puffing duration 
TDFi 
Σ DFi 
s 
Puff Frequency 
PFeq 
NPC/(TDFi/60) 
 
12.6.3 
Extent of Product Use 
Endpoints related to amount of nicotine delivered from P4M3 Gen 2.0 and number of cigarettes 
are listed in section 3.2. 
12.6.4 
Descriptive Summary 
Endpoints will be summarized as described in section 12.1.3 using the randomized and the PK 
population.  
12.6.5 
Inferential Analysis 
Not applicable. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 96 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
12.6.6 
Safety Endpoints 
In general, all safety data will be listed and tabulated using the approach described in section 
12.1.3. Safety variables collected during exposure periods will also be reported by sequence. 
AE data will serve for the assessment of safety. Other safety variables monitored in this study 
include: incidence of P4M3 Gen 2.0 product events including malfunction/misuse; vital signs 
(systolic and diastolic blood pressure, pulse rate, respiratory rate); spirometry; ECG data; 
clinical chemistry, hematology, and urine analysis safety panel; physical examination; 
concomitant medication.  
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, AEs by 
severity, and laboratory AEs. Tabulations will be performed for both the number of subjects 
experiencing an event and the number of events. 
Safety laboratory assessments are performed on Day -1 and Day 3 in the morning prior to 
product use (Appendix A). Any lab related AEs on Day 3 will be assigned to the product used 
on the previous day. 
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 period for ECG and vital signs and by Day for laboratory parameters, 
ECG and vital signs.  
12.7 Exploratory Analyses 
Exploratory analyses endpoints are listed in section 3.3. 
12.7.1 
Descriptive Summary 
Endpoints will be summarized as described in section 12.1.3 using the randomized and the PK 
population.  
12.7.2 
Inferential Analysis 
An analysis of covariance (ANCOVA) will be conducted by product use. The PK parameters 
will be transformed in the natural logarithmic scale. The model will include terms for sequence, 
period and product liking by the VAS-liking assessment. The results of this analysis will be 
presented by product in terms of: 
• The percentage of variance explained by product liking by the VAS-liking assessment  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 97 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
• The standardized effect of product liking by the VAS-liking assessment on the 
endpoint, defined as the mean effect divided by the square root of its variance.  
Another analysis of covariance (ANCOVA) will be conducted similarly at the exception that 
it will be performed overall using mixed effects ANCOVA where the model will include 
additionally the subject as a categorical random effect to model the within subject correlations. 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 98 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Investigators and Study Administrative Structure 
13.1.1 
Investigator 
Investigator: 
Melanie Fein, MD 
 
 
  
13.1.2 
Sponsor 
The list of sponsor personnel will be provided as a separate document. 
13.1.3 
Other Responsibilities 
Project Management: 
 
 
 
 
Monitoring: 
 
 
 
Data Management: 
 
 
 
Pharmacokinetic Analyses: 
 
 
 
Statistical Analyses: 
 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 99 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
 
 
All duties and responsibilities transferred by the Sponsor to the above listed CROs will be 
defined in an 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 and bioanalyses 
are shown in Appendix C.  
13.2 Subject Recruitment 
Subjects will be recruited from the volunteers’ database maintained by the CRO. This database 
contains a pool of volunteers that are contacted whenever necessary to enroll subjects in a new 
study. Before the start of the new study, the Investigator and other relevant staff discuss with 
the volunteers’ recruiter the study recruitment needs and specific requirements. On the basis 
of this information, the volunteers’ recruiter queries the database, contacts potential volunteers 
to propose the study and evaluate their interest and availability. In addition to the volunteers 
database, new subjects often call or email the CRO asking to become a research volunteer, 
after hearing of the clinical site activities from other volunteers or friends or after checking the 
company web site. The CRO and its clinical site have detailed SOPs on the recruitment process. 
13.3 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 name 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 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 100 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
obscured before a copy of that document is supplied to the Sponsor or the Sponsor’s authorized 
representative. 
13.4 Access to Source Documentation 
Subjects will be informed that, during the study, the Sponsor, any authorized representatives 
of the Sponsor, IRB 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, IRB review and 
regulatory inspection(s). 
13.5 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 
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 [1] and any other applicable local or national regulations. 
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 [1]. 
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 IRB, composition of the 
IRB.  
• Record of all communications/contact between the Investigator, the Sponsor, and its 
authorized representatives.  

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 101 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
• 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). 
• AE reports and details of follow-up investigations, details of concomitant medication. 
• All other source documents (e.g., ECGs, consultation reports, physical examination and 
laboratory records) or any electronically captured study source data. 
• Clinical laboratory reports, laboratory normal ranges. 
• Original medical/hospital records, if applicable (the medical files of study subjects must be 
retained in accordance with local legislation and in accordance with the maximum period 
of time permitted by the hospital or study site). 
• Record of any body fluids or tissue samples collected and retained. 
• 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 or Sponsor’s authorized representative will maintain documentation relating to 
the study as long as the IP is on the market, and/or for 15 years after the CSR has been finalized. 
13.6 Clinical Study Report 
The Sponsor must ensure that a CSR for this study is prepared regardless of whether the study 
is completed or prematurely terminated.  
The CSR will be written based on standards of the ICH Guideline for the “Structure and 
Content of Clinical Study Reports” [39]. In certain circumstances, an abbreviated CSR may be 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 102 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
acceptable. Submission of the CSR to the IRB will be complied with as requested by local 
requirements. 
13.7 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 study 
and for one year following the completion of the study. 
13.8 Publication and Disclosure Policy 
This document contains information that is confidential and proprietary to the Sponsor. This 
information is being provided solely for the purpose of evaluation and/or conducting this study 
for the Sponsor. Disclosure of the content of this document is allowed only to study personnel, 
IRB, or duly authorized representatives of regulatory agencies for this purpose under the 
condition that confidentiality is maintained. The contents of this document may not be used in 
any other 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 study will be registered and published in a WHO primary register or at 
www.clinicaltrials.gov. 
13.9 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. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 103 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
14 REFERENCE LIST 
1. ICH E6 (R2), Integrated addendum to ICH E6 (R1): guideline for good clinical practice 
- Current Step 4 version dated 9 November 2016. 2016. Available from: 
https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf (Accessed on 17 
January 2020). 
2. World Medical Association (WMA), Declaration of Helsinki - Ethical principles for 
medical 
research 
involving 
human 
subjects. 
2013. 
Available 
from: 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-
for-medical-research-involving-human-subjects/ (Accessed on 12 July 2018). 
3. U.S. Department of Health and Human Services, The health consequences of smoking - 
50 years of progress: a report of the Surgeon General. 2014. 
4. WHO Study Group, 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. 
5. Philip Morris Products S.A., Unpublished on file data: Investigator's Brochure for Mesh 
2.0. Edition 3. 2020. 
6. Robinson, R.J., et al., Electronic cigarette topography in the natural environment. PLoS 
One, 2015. 10(6): p. e0129296. 
7. Talih, S., et al., Effects of user puff topography, device voltage, and liquid nicotine 
concentration on electronic cigarette nicotine yield: measurements and model predictions. 
Nicotine Tob Res, 2015. 
8. Farsalinos, K.E., et al., Nicotine absorption from electronic cigarette use: comparison 
between experienced consumers (vapers) and naive users (smokers). Sci Rep, 2015. 5: p. 
1-8. 
9. Caldwell, B., W. Sumner, and J. Crane, A systematic review of nicotine by inhalation: is 
there a role for the inhaled route? Nicotine Tob Res, 2012. 14(10): p. 1127-39. 
10. Ebajemito, J.K., et al., A randomised controlled single-centre open-label pharmacokinetic 
study to examine various approaches of nicotine delivery using electronic cigarettes. 
Scientific reports, 2020. 10(1): p. 1-10. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 104 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
11. Helen, G.S., et al., Impact of e-liquid flavors on nicotine intake and pharmacology of e-
cigarettes. Drug and alcohol dependence, 2017. 178: p. 391-398. 
12. Voos, N., et al., Effect of e-cigarette flavors on nicotine delivery and puffing topography: 
results from a randomized clinical trial of daily smokers. Psychopharmacology, 2020. 
237(2): p. 491-502. 
13. Helen, G.S., et al., Nicotine delivery, retention and pharmacokinetics from various 
electronic cigarettes. Addiction, 2015: p. 535-544. 
14. Hukkanen, J., P. Jacob, 3rd, and N.L. Benowitz, Metabolism and disposition kinetics of 
nicotine. Pharmacol Rev, 2005. 57(1): p. 79-115. 
15. Marchand, M., et al., Nicotine population pharmacokinetics in healthy adult smokers: a 
retrospective analysis. Eur J Drug Metab Pharmacokinet, 2017. 
16. Benowitz, N.L., et al., Female sex and oral contraceptive use accelerate nicotine 
metabolism. Clin Pharmacol Ther, 2006. 79(5): p. 480-8. 
17. Fagerström, K.O., Measuring degree of physical dependence to tobacco smoking with 
reference to individualization of treatment. Addict Behav, 1978. 3(3-4): p. 235-41. 
18. Heatherton, T.F., et al., The Fagerström test for Nicotine Dependence: a revision of the 
Fagerström Tolerance Questionnaire. Br J Addict, 1991. 86(9): p. 1119-27. 
19. Cappelleri, J.C., et al., Confirmatory factor analyses and reliability of the modified 
cigarette evaluation questionnaire. Addictive Behaviors, 2007. 32: p. 912–923. 
20. FDA (Food and Drug Administration), Food-effect bioavailability and fed bioequivalence 
studies. 2002. 
21. American Pharmacists Association, Cytochrome P450 enzymes: substrates, inhibitors, 
and inducers, in Drug information handbook. 2014. p. 2316-2324. 
22. Raw, M., et al., WHO Europe evidence based recommendations on the treatment of 
tobacco dependence. Tob Control, 2002. 11(1): p. 44-6. 
23. Miller, M.R., et al., Standardisation of spirometry. Eur Respir J, 2005. 26(2): p. 319-38. 
24. Graham, B.L., et al., Standardization of spirometry 2019 update. An official American 
Thoracic Society and European Respiratory Society technical statement. Am J Respir Crit 
Care Med, 2019. 200(8): p. e70-e88. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 105 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
25. Hu, G. and P.A. Cassano, Antioxidant nutrients and pulmonary function: the Third 
National Health and Nutrition Examination Survey (NHANES III). Am J Epidemiol, 2000. 
151(10): p. 975-81. 
26. Fagerstrom, K., et al., The Fagerstrom Test for Nicotine Dependence as a predictor of 
smoking abstinence: a pooled analysis of varenicline clinical trial data. Nicotine and 
Tobacco Research, 2012. 14(12): p. 1467-73. 
27. Salzberger, T., 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). 
28. Chrea, C., 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). 
29. Hatsukami, D.K., et al., Subjective responses to oral tobacco products: scale validation. 
Nicotine Tob Res, 2013. 15(7): p. 1259-64. 
30. Moyses, C., A. Hearn, and A. Redfern, Evaluation of a novel nicotine inhaler device: part 
2-effect on craving and smoking urges. Nicotine Tob Res, 2015. 17(1): p. 26-33. 
31. FDA (Food and Drug Administration), Guidance for industry - Assessment of abuse 
potential of drugs. 2017. 
32. Philip Morris Products S.A., Nicotine pharmacokinetic profile and safety of the Tobacco 
Heating System 2.2 (THS 2.2)[ZRHR-PK-01-EU]. In: ClinicalTrials.gov [Internet]. 
Bethesda (MD): National Library of Medicine (US). 2013-2014 [cited 2015 Jun 16]. 
Available from: http://clinicaltrials.gov/show/NCT01967732 NLM Identifier: 
NCT01967732. 
33. Brossard, P., et al., Nicotine pharmacokinetic profiles of the Tobacco Heating System 2.2, 
cigarettes and nicotine gum in Japanese smokers. Regul Toxicol Pharmacol, 2017. 89: p. 
193-199. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 106 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
34. Philip Morris Products S.A., A single-center, randomized, controlled, crossover study to 
investigate the nicotine pharmacokinetic profile and safety of THS 2.2 Menthol following 
single use in smokers compared to menthol conventional cigarettes and nicotine nasal 
spray [ZRHM-PK-06-US]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National 
Library of Medicine (US). 2013-2014 [cited 2015 Jun 16]. Available from: 
http://clinicaltrials.gov/show/NCT01967719 NLM Identifier: NCT01967719. 
35. Kraiczi, H., A. Hansson, and R. Perfekt, Single-dose pharmacokinetics of nicotine when 
given with a novel mouth spray for nicotine replacement therapy. Nicotine Tob Res, 2011. 
13(12): p. 1176-82. 
36. Committee for Medicinal Products for Human Use (CHMP) and European Medicines 
Agency 
(EMA), 
Guideline 
on 
the 
investigation 
of 
bioequivalence 
(CPMP/EWP/QWP/1401/98 Rev.1/Corr). 2010. 
37. FDA (Food and Drug Administration), Guidance for industry - Statistical approaches to 
establishing 
bioequivalence. 
2001. 
Available 
from: 
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070244.pdf (Accessed on 24 
April 2014). 
38. Hodges, J.L. and E.L. Lehmann, Estimation of location based on ranks tests. Annals of 
Mathematical Statistics, 1963. 34(2): p. 598-611. 
39. 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_Guideline.pdf (Accessed on 17 July 2014). 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 107 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
APPENDIX A 
SCHEDULE OF EVENTS 
Study Day 
Day -29 to -2 
Screening 
Day -1 
Admission 
Day 1  
 
Day 2 
Day 3 
Discharge 
Day 4 to 6 
Safety 
Follow-Up 
Informed consent 
● 
 
 
 
 
 
Information on the risks of 
smoking/advice on smoking 
cessation and debriefing on P4M3 
Gen 2.0 
● 
● 
 
 
● q 
 
Inclusion/exclusion criteria a 
● 
● 
 
 
 
 
P4M3 Gen 2.0 product 
demonstration 
● 
 
 
 
 
 
Nicotine/Tobacco product use 
history 
● 
● 
 
 
 
 
Demographics b, medical history, 
concomitant diseases  
● 
●c 
●c 
●c 
●c 
  
Prior medication/ Concomitant 
medication d 
● 
● 
● 
● 
● q 
 
Physical examination 
● 
● 
 
 
● q 
 
Body height, weight and related BMI 
● 
 
 
 
 
 
Vital signs e 
● 
● 
● 
● 
● q 
 
ECG f 
● 
● 
 
 
● q 
 
Spirometry 
● 
● 
 
 
● q 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 108 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Study Day 
Day -29 to -2 
Screening 
Day -1 
Admission 
Day 1  
 
Day 2 
Day 3 
Discharge 
Day 4 to 6 
Safety 
Follow-Up 
Blood and urine sample for 
hematology, clinical chemistry, urine 
analysis safety panel g 
● 
● 
 
 
● q 
 
Blood sample for serology h  
● 
 
 
 
 
 
Urine sample for drug test  
● 
● 
 
 
 
 
Urine sample for cotinine test  
● 
● 
 
 
 
 
Urine pregnancy test (females) 
● 
● 
 
 
● q 
 
Alcohol breath test 
● 
● 
 
 
 
 
Blood sample for trans-3’-
hydroxycotinine and cotinine 
(CYP2A6 activity) in plasma i 
 
● 
 
 
 
 
Fagerström Test for Nicotine 
Dependence 
● 
 
 
 
 
 
P4M3 Gen 2.0 product test j 
 
● 
 
 
 
 
Enrollment 
 
● 
 
 
 
 
Randomization 
 
● 
 
 
 
 
6 min ad libitum use 
 
 
● 
● 
● 
 
Human puffing topography k 
 
 
● 
● 
● 
 
Blood sample collection for plasma 
nicotine l 
 
 
● 
● 
● 
 
ABOUT-Product experience 
questionnaire m 
 
 
● 
● 
● 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 109 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Study Day 
Day -29 to -2 
Screening 
Day -1 
Admission 
Day 1  
 
Day 2 
Day 3 
Discharge 
Day 4 to 6 
Safety 
Follow-Up 
VAS craving assessment n 
 
 
● 
● 
● 
 
VAS liking assessment n 
 
 
● 
● 
● 
 
AE/SAE recording o 
● 
● 
● 
● 
● q 
● 
Product events, Malfunctions and 
Misuse 
 
● 
● 
● 
● q 
 
Support during periods of abstinence 
from any tobacco and nicotine 
containing products (as required) 
 
● 
● 
● 
● 
 
Collection of used products  
 
 
● 
● 
● 
 
Weight of P4M3 Gen 2.0 Cartridge p 
 
 
● 
● 
● 
 
Abbreviations: ABOUT = Assessment of Behavioral OUtcomes related to Tobacco and nicotine products; AE = Adverse event; BMI = Body mass index; ECG = Electrocardiogram; 
SAE = Serious adverse event;  
a. 
Prior to enrollment at Admission on Day -1, the following inclusion and exclusion criteria will be re-checked: Inclusion Criteria: (4) Subject has smoked ≥ 10 commercially 
available cigarettes per day for 4 weeks prior to Screening Visit and Admission. Smoking status will be verified based on a urinary cotinine test (cotinine ≥ 200 ng/mL), (5) 
Subject does not plan to quit smoking or using other nicotine/tobacco-containing products in the next 3 months (7) Subject is available during the study period and willing to 
comply with study procedures, including periods of abstinence from any nicotine/tobacco containing products. Exclusion criteria: (10) Subject has a positive urine drug test, 
(15) For women only: subject is pregnant (does not have negative pregnancy tests at Screening Visit and at Admission) or is breastfeeding, (16) For women of childbearing 
potential only: subject does not agree to use an acceptable method of effective contraception, (17) Use of estrogen-containing hormonal contraception or hormone replacement 
therapy. 
The following eligibility criteria will only be checked at Admission: (7) 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.  
b. 
Sex, date of birth/age, race and ethnicity. 
c. 
Concomitant disease status. 
d. 
All medication taken within 4 weeks prior to the Screening Visit will be documented. Prior medication which has an impact on CYP2A6 activity taken within 14 days or within 
5 half-lives of the drug (whichever is longer) prior to Day -1 is an exclusion criterion. 
e. 
Systolic and diastolic blood pressure, pulse rate and respiratory rate. On Day 1 to Day 3, vital signs will be assessed prior to T0. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 110 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
f. 
At Screening an ECG will be performed after signed ICF and at least 1 hour after smoking cigarettes, on Day -1 an ECG will be performed prior to enrollment, on Day 3 an 
ECG will be performed 60 minutes ± 10 minutes after T0. 
g. 
Blood samples should be taken in the morning of the Screening visit, Admission (Day -1) and Discharge (Day 3) or at Early termination. Subjects should have fasted for at least 
10 hours prior to safety laboratory assessments except at the Screening visit and Early termination where non-fasting samples will be used.  
h. 
Tests for hepatitis B (HbsAg), hepatitis C (HCV antibody) virus and human immunodeficiency virus (anti-HIV1/2) will be performed at the Screening Visit.  
i. 
Sample taken prior to P4M3 Gen 2.0 product test. 
j. 
On Day -1, after enrollment, subjects will perform a product test using P4M3 Gen 2.0 Classic Auburn 3.5% variant (CA35) ad libitum for up to 10 minutes.  
k. 
On Day 1 to Day 3, subjects will smoke a single cigarette or will use one P4M3 Gen 2.0 with CA35 and CM35 variant ad libitum for 6 minutes (±30 seconds) according to the 
randomized product use sequence. P4M3 Gen 2.0 use with the MDEDR puffing topography device connected with data recording for 6 minutes (±30 seconds). 
l. 
On Day 1, 15 blood samples will be taken for determination of nicotine concentration: one blood sample will be taken prior to the start of product use (T0) 5 minutes ± 1 
minute (T-1). Thereafter in relation to T0, blood will be drawn at the following time points: T1 after 1 minute + 30 seconds, T2 after 2 minutes + 1 minute, T3 after 4 minutes 
+ 1 minute, T4 after 6 minutes + 1 minute, T5 after 8 minutes + 1 minute, T6 after 10 minutes + 1 minutes, T7 after 12 minutes + 1 minute, T8 after 15 minutes ± 2 minutes, 
T9 after 30 minutes ± 2 minutes, T10 after 1 hour ± 5 minute, T11 after 2 hours ± 5 minutes, T12 after 4 hours ± 5 minutes, T13 after 10 hours ± 5 minutes and T14 after 24 
hours ± 10 minutes (Day 1 and Day 2 only). The sample T14 on Day 1 will also be used to determine the nicotine baseline concentration prior to T0 on Day 2. 
On Day 2, 14 blood samples will be collected for determination of nicotine PK after allocated product use at the same time points, except timepoint T-1. The sample T14 after 
T0 on Day 1 will also be used to determine the nicotine baseline concentration prior to T0 on Day 2 and similarly, T14 after T0 on Day 2 for nicotine baseline concentration 
prior to T0 on Day 3.  
On Day 3, 13 blood samples will be collected for determination of nicotine PK after allocated product use. The sample T14 after T0 on Day 3 will not be. 
On Day 2 and 3, 4 blood samples will be taken for determination of the terminal elimination half-life (t1/2z). Blood samples will be taken in relation to T0 from Day 2 at the 
following time points: T1z after 8 hours ± 5 minutes, T2z after 12 hours ± 5 minutes, T3z after 16 hours ± 10 minutes and T4z after 20 hours ± 10 minutes. 
m. On Day 1 to Day 3, the ABOUT-Product experience questionnaire will be answered within 60 to 120 minutes after T0. 
n. 
On Day 1 to Day 3, VAS craving and VAS liking assessment at: Within 15 minutes prior to T0 (VAS craving only), after T0 for VAS craving and VAS liking assessments at 4 
minutes ± 1 minute, 10 minutes ± 1 minute, 15 minutes ± 1 minute, 30 minutes ± 2 minutes, 1 hour ± 5 minutes, 2 hours ± 5 minutes, 4 hours ± 5 minutes, 10 hours ± 5 
minutes. 
o. 
Spontaneous reporting of new AEs/SAEs by the subject and active follow-up of ongoing AEs/SAEs by the site. 
p. 
On Day 1 to Day 3, P4M3 Gen 2.0 Cartridges will be weighed before T0. P4M3 Gen 2.0 Cartridges will be weighed within 120 min after T0. 
q. 
Early termination assessments to be conducted in subjects who withdraw consent / are discontinued from the study. 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 111 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
APPENDIX B 
PARTICIPATING LABORATORIES  
Bioanalytical laboratory (Plasma Nicotine and CYP2A6 analyses): 
 
 
 
 
Safety Laboratory: 
 
 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 112 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
APPENDIX C 
ABNORMAL LABORATORY VALUES GRADING 
Abnormal Laboratory Values Rating: Clinical Chemistry Parameters 
Serum Chemistry 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
 (Grade 4) 
Sodium – Hyponatremia (mmol/L)  
<LLN - 130 
125-129 
mmol/L and 
asymptomatic 
125-129 
symptomatic;  
120-124 
regardless of 
symptoms 
<120 
Sodium – Hypernatremia (mmol/L)  
>ULN - 150 
>150 - 155 
intervention 
initiated 
>155 - 160; 
hospitalization 
indicated 
>160 
Potassium – Hyperkalemia (mmol/L)  
>ULN - 5.5 
>5.5 - 6.0 
intervention 
initiated 
>6.0 -7.0; 
hospitalization 
indicated 
>7.0 
Potassium – Hypokalemia (mmol/L)  
<LLN - 3.0 
<LLN - 3.0; 
symptomatic; 
intervention 
indicated 
<3.0 - 2.5; 
hospitalization 
indicated 
<2.5 
Glucose – Hypoglycemia 
(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:  
 
Abnormal 
glucose 
above 
baseline with 
no medical 
intervention 
Change in 
daily 
management 
from baseline 
for a diabetic; 
oral 
antiglycemic 
agent 
initiated; 
workup for 
diabetes 
Insulin therapy 
initiated; 
hospitalization 
indicated 
Life-
threatening 
consequences
; urgent 
intervention 
indicated 
Creatinine increased 
>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 
(g/dL) 
(g/L) 
<LLN – 3; 
<LLN - 30 
<3 – 2; 
<30 - 20 
<2; 
<20 
Life-
threatening 
consequences 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 113 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Serum Chemistry 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
 (Grade 4) 
Alkaline phosphatase increased 
>ULN - 2.5 x 
ULN if > 
>2.5 – 5.0 x 
ULN 
>5.0 – 20.0 x 
ULN 
>20.0 x ULN 
ALT / AST increased 
>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 
>ULN – 2.5 x 
ULN 
>2.5 – 5.0 x 
ULN 
>5.0 – 20.0 x 
ULN 
>20.0 x ULN 
Lactate dehydrogenase (LDH) 
increased 
>ULN 
- 
- 
- 
Blood bilirubin increased  
(total and direct)  
>ULN – 1.5 x 
ULN 
>1.5 – 3.0 x 
ULN 
>3.0 – 10.0 x 
ULN 
>10.0 x ULN 
Cholesterol high 
(mg/dL) 
(mmol/L) 
>ULN - 300; 
>ULN - 7.75 
>300-400; 
>7.75-10.34 
>400-500; 
>10.34-12.92 
>500; 
>12.92 
Triglycerides - Hypertriglyceridemia 
(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 5.0.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. 
 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 114 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Abnormal Laboratory Values Rating: Hematology Parameters 
Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
 (Grade 4) 
Anemia (Hemoglobin)  
(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 threatening 
consequences; 
urgent 
intervention 
indicated 
Hemoglobin increase – 
(g/dL) 
Increase in >0 - 
2 g/dL 
Increase in >2 - 4 
g/dL 
Increase in >4 
g/dL 
- 
WBC Decrease –  
(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 
(cell/mm3)  
 
- 
 
>4,000 – 20,000 
 
>20,000 
 
- 
Lymphocytes decrease 
(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 
(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 
(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 5.0. 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. 
 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 115 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
Abnormal Laboratory Values Rating: Urine analysis Parameters 
Urine 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-Threatening 
(Grade 4) 
Glucose 
Present 
- 
- 
- 
Red blood cell 
traces 
(Hematuria) 
Asymptomatic; 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; 
urinary catheter or 
bladder irrigation 
indicated; limiting 
instrumental 
Activities of Daily 
Living 
Gross hematuria; 
transfusion, IV 
medications, or 
hospitalization 
indicated; elective 
invasive 
intervention 
indicated; limiting 
self care Activities 
of Daily Living  
 
Life-threatening 
consequences; 
urgent invasive 
intervention 
indicated 
Protein 
1+ proteinuria; 
urinary protein 
≥ULN - <1.0 g/24 
hrs 
2+ and 3+ 
proteinuria; urinary 
protein 1.0 - <3.5 
g/24 hrs; 
 4+ proteinuria; 
≥3.5 g/24 hrs;  
 
Data Source: 
b 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 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. 
 

Philip Morris Products SA 
Clinical Study Protocol 
Confidential 
P4-PK-04-US 
Final 
Page 116 of 116 
Related to PMI-RRP-WKI-112465 
 
RD_SMF02_115104_CSP_P4-PK-04-US 
 
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. 
APPENDIX D 
HUMAN PUFFING TOPOGRAPHY PARAMETERS 
Per-Puff Parameters 
Description 
Variable 
Unit 
Puff number 
Ni 
 
Puff volume 
Vi 
mL 
Puff duration 
Di 
s 
Average puff flow 
Qmi 
mL/s 
Peak flow 
Qci 
mL/s 
Inter puff interval 
Ii 
s 
Sum of Ii and Di 
DFi 
s 
Peak flow position 
PosQci 
% 
 
 
Per-Product use experience Parameters 
Description 
Variable 
Formula 
Unit 
Total number of puffs 
NPC 
Σ Ni 
Total puff volume 
TVOL 
Σ Vi 
mL 
Average puff volume 
AvgVi 
Σ Vi / NPC, i=1 ... NPC 
mL 
Average puff duration 
AvgDi 
Σ Di / NPC, i=1 ... NPC 
s 
Total puff duration 
TDi 
Σ Di 
s 
Average flow 
AvgQmi 
Σ Qmi / NPC, i=1 … NPC 
mL/s 
Average peak flow 
AvgQci 
Σ Qci / NPC, i=1 … NPC 
mL/s 
Total inter puff interval 
TIi 
Σ Ii 
s 
Average inter puff interval 
AvgIi 
Σ Qci / NPC, i=1 … NPC 
s 
Total puffing duration 
TDFi 
Σ DFi 
s 
Puff Frequency 
PFeq 
NPC/(TDFi/60) 
 
 
 

Signature Page for VV-TMF-00031 v2.0
Signature Page for VV-TMF-00031 v2.0
Reason for signing: Approved
Name: 
Role: A
Date of signature: 19-Oct-2021 09:25:03 GMT+0000
Reason for signing: Approved
Name: 
Role: A
Date of signature: 19-Oct-2021 13:44:34 GMT+0000
Reason for signing: Approved
Name: 
Role: A
Date of signature: 19-Oct-2021 13:46:30 GMT+0000
Reason for signing: Approved
Name: 
Role: A
Date of signature: 20-Oct-2021 11:22:17 GMT+0000