A Randomized, Controlled, Open-label, 4-arm Parallel Group Study to Demonstrate Reductions in Exposure to Selected Harmful and Potentially Harmful Constituents (HPHC) in Healthy Smokers Switching to 2 Variants of P4M3 Gen 2.0, an Electronic Nicotine Delivery System (ENDS), Compared to Continuing Smoking Cigarettes, or Abstaining From Smoking, for 5 Days in a Confinement Setting
Phase: NA
Conditions: Nicotine, Vaping, Nicotine Vaping
Sponsor: Philip Morris Products S.A.

 
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Clinical Study Protocol 
 
 
Study Number: 
P4-REXC-06 
Study Title: 
A randomized, controlled, open-label, 4-arm parallel 
group study to demonstrate reductions in exposure to 
selected harmful and potentially harmful constituents 
(HPHC) in healthy smokers switching to 2 variants 
of P4M3 Gen 2.0, an Electronic Nicotine Delivery 
System (ENDS), compared to continuing smoking 
cigarettes, or abstaining from smoking, for 5 days in 
a confinement setting 
Short title: 
Reduced HPHC exposure in cigarette smokers 
switching to P4M3 Gen. 2.0 compared to continuing 
smoking, or smoking abstinence 
Product Name: 
P4M3 Gen 2.0 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 3 
2000 Neuchâtel, Switzerland 
Version: 
4.0, 
Approved 
Date: 
13 Apr 2022 
Authors: 
, PhD, Clinical Scientist 
, PhD, Study Statistician  
, MD, Medical Safety Officer 
 
 
 

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VERSION HISTORY 
 
 
Version 
Date 
Protocol Update/Amendment 
Original 
Document 
1.0 
07 Mar 2022 
Not applicable 
2.0 
07 Mar 2022 
Protocol Update 
3.0 
18 Mar 2022 
Protocol Update 
4.0 
12 Apr 2022 
Protocol Update 
 

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Synopsis 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 3 
2000 Neuchâtel 
Switzerland 
Name of Product: 
P4M3 Gen 2.0 
Study Title: 
A randomized, controlled, open-label, 4-arm parallel group study to demonstrate 
reductions in exposure to selected harmful and potentially harmful constituents (HPHC) 
in healthy smokers switching to 2 variants of P4M3 Gen 2.0, an Electronic Nicotine 
Delivery System (ENDS), compared to continuing smoking cigarettes, or abstaining 
from smoking, for 5 days in a confinement setting 
Study Number: 
P4-REXC-06-EU 
Short Title: 
Reduced HPHC exposure in cigarette smokers switching to P4M3 Gen. 2.0, compared 
to continuing smoking, or smoking abstinence 
Primary Objective and Endpoints: 
1. To demonstrate the reduction of biomarkers of exposure (BoExp) listed in Table 1 to 
selected harmful and potentially harmful constituents (HPHC) in smokers switching 
from cigarette (CIG) to P4M3 (combined CA35 and CM35 arms) compared to 
continuing cigarette smoking for 5 days. 
Table 1 
List of BoExp used in the primary objective 
BoExp 
HPHC 
Matrix 
3-hydroxypropyl mercapturic acid (3-
HPMA) 
Acrolein 
Urine1  
2-cyanoethyl mercapturic acid (2-CyEMA) 
Acrylonitrile 
Urine1 
Total 4-(methylnitrosamino)-1-(3-pyridyl)-
1-butanol (total NNAL) 
4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK) 
Urine1 

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Carboxyhemoglobin (COHb) 
Carbon monoxide (CO) 
Blood2 
1BoExp in urine will be expressed as concentration adjusted for creatinine in 24-hour urine; 
 2BoExp in blood expressed as % of saturation of hemoglobin. 
Secondary Objectives: 
Key secondary objectives  
1. To demonstrate the reduction of BoExp given in Table 2 to selected HPHC in 
smokers switching from CIG to P4M3 (combined CA35 and CM35 arms) compared 
to continuing CIG smoking for 5 days.  
Table 2 
List of BoExp used in the key secondary objective 
BoExp 
HPHC 
Matrix 
S-phenylmercapturic acid (S-PMA) 
Benzene 
Urine1  
3-hydroxy-1-methylpropylmercapturic acid 
(3-HMPMA) 
Crotonaldehyde 
Urine1 
Total N-nitrosonornicotine (total NNN) 
N-nitrosonornicotine 
Urine1 
Total 3-hydroxybenzo(a)pyrene (3-OH-B[a]P) 
Benzo(a)pyrene 
Urine1 
1BoExp in urine expressed as concentration adjusted for creatinine in 24-hour urine. 
2. To demonstrate the reduction of BoExp to selected HPHC given in Table 1 in 
smokers switching from CIG to P4M3 CA35 only compared to continuing CIG 
smoking for 5 days. 
3. To demonstrate the reduction of BoExp to selected HPHC given in Table 2 in 
smokers switching from CIG to P4M3 CA35 only compared to continuing CIG 
smoking for 5 days. 
4. To demonstrate the reduction of BoExp to selected HPHC given in Table 1 in 
smokers switching from CIG to P4M3 CM35 only compared to continuing CIG 
smoking for 5 days. 
5. To demonstrate the reduction of BoExp to selected HPHC given in Table 2 in 
smokers switching from CIG to P4M3 CM35 only compared to continuing CIG 
smoking for 5 days. 
Other secondary objectives 
1. To monitor safety and tolerability in all subjects during the study. 

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Endpoints: 
• 
Incidence of adverse events (AEs) and serious adverse events (SAEs) 
• 
Incidence of P4M3 product events including malfunction/misuse 
• 
Electrocardiogram (ECG) changes from baseline (heart rate, PR, QRS, QT, QTcF 
intervals) 
• 
Vital signs changes from baseline (systolic and diastolic blood pressure, heart rate 
and respiratory rate)  
• 
Spirometry changes from baseline (FEV1, FEV1 % predicted, FVC, FVC % 
predicted, FEV1/FVC) 
• 
Changes from baseline in clinical chemistry, hematology, and urine analysis 
safety panel (Appendix D) 
• 
Concomitant medications. 
Exploratory Objectives 
1. To determine the levels of BoExp given in Table 3 to selected HPHC in smokers 
switching from CIG to P4M3 (CA35 and CM35 arms combined and separately) 
compared to continuing CIG smoking for 5 days. 
Table 3 
List of BoExp used as exploratory objective 
BoExp 
HPHC 
Matrix 
2-hydroxypropylmercapturic acid (2-HPMA) 
Propylene oxide 
Urine1  
2,3-dihydroxypropylmercapturic acid (DHPMA) 
Glycidol 
Urine1 
Nicotine equivalents (NEQ2)  
Nicotine 
Urine1 
1BoExp in urine expressed as concentration adjusted for creatinine in 24-hour urine; 
 2NEQ = molar sum of free nicotine, nicotine-glucuronide, free cotinine, cotinine-glucuronide, free trans-3’-
hydroxycotinine, trans-3’hydroxy-cotinine-glucuronide. 
2. To determine the reductions of BoExp given in Table 1, Table 2, and Table 3 to 
selected HPHC in smokers quitting smoking compared to continuing CIG smoking 
or switching from CIG to P4M3 (CA35 and CM35 arms combined and separately) 
over 5 days. 
3. To describe nicotine/tobacco product use in smokers switching from CIG to P4M3 
(combined CA35 and CM35 arms; and CA35 and CM35 separately) compared to 
continuing CIG. 
Endpoints (Day -1 to Day 5): 
• 
Daily number of CIG (Day -1 all subjects, Day 1 to 5 subjects of CIG arm only) 
• 
Daily number of P4M3 Cartridges (Day 1 to 5 subjects of P4M3 arms only), 
• 
Daily e-liquid used determined by weight difference of the Cartridge(s) before 
and after daily use 

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4. To describe investigational product experience in smokers switching from CIG to 
P4M3 compared to continued CIG smoking. 
Endpoints (Day -1 to Day 5): 
• 
Subscale scores of Product Experience (ABOUT – Product Experience) 
questionnaire (assessed only in subjects randomized to P4M3 or CIG) 
5. To describe Human Puffing Topography (HPT) over the entire exposure period in 
smokers switching to P4M3 (CA35 or CM35). 
Endpoints (Day 1 to Day 5): 
• 
Per-product use experience and per-day parameters (Appendix C) 
6. To evaluate cytochrome P450 1A2 (CYP1A2) enzymatic activity in smokers 
switching to P4M3 (CA35 or CM35) and smoking abstinence compared to 
continued CIG smoking. 
Endpoints (Day -1 and Day 5): 
• 
Molar metabolic ratio of paraxanthine/caffeine in plasma 
The estimands requested as per ICH guidelines [1] for all objectives are described in 
protocol statistical section. 
Study Hypothesis: 
All the BoExp examined for the primary objective will demonstrate a reduction in 
subjects switching to P4M3 (subjects of CA35 and CM35 pooled together) compared to 
subjects continuing CIG.  
Study Design: 
This is a randomized, controlled, open-label, 4-arm parallel study with a stratified 
randomization by sex. Quotas will be applied to ensure that the randomized subjects 
contain at least 40% of both sexes (males and females) per arm. 
This is an ad libitum study with unrestricted product use (P4M3 or CIG, in the respective 
arms) for a 5-day exposure period in the confinement setting (Figure 1). 

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Figure 1 
Study Design 
• Screening period (from Day -30 until Day -3):  
The screening period covers up to four weeks prior to admission. A presentation of P4M3 
(without product use) will be done by the site staff during the Screening visit. All subjects 
will receive information on the risks of smoking and smoking cessation advice. Eligible 
subjects will return to the investigational site for verification of eligibility at Admission 
visit. 
• Admission (from admission on Day -2 until morning of Day -1):  
On Day -2 (Admission), after all selected inclusion/exclusion criteria have been verified, 
all eligible subjects will be enrolled and perform a product test using both P4M3 variants: 
tobacco flavor “Classic Auburn” 3.5% nicotine (CA35) and menthol flavor “Classic 
Menthol” 3.5% nicotine (CM35) for a duration of approximately 10 minutes ad libitum 
use per flavor. After the product test, subjects not willing to use P4M3 during the study 
will be discontinued and will be replaced. Subjects willing to continue participation will 
start their confinement period. CIG smoking will be allowed ad libitum from the time of 
admission of the subject until approximately 11:00 PM, except before/during 
assessments requiring smoking breaks. Use of any tobacco/nicotine containing product 

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(TNP) other than CIG (and P4M3 for the product test) will not be allowed after 
admission.  
• Baseline (from Day -1, 06:30 AM until Day 1, 06:29 AM):  
Subjects may continue smoking their CIG ad libitum, except before/during assessments 
requiring smoking breaks. The 24-hour urine collection for Day -1 will start in the 
morning of Day -1 (urine collection details provided in Appendix A). Baseline 
assessments will be performed as indicated in Appendix A.  
On Day -1, subjects will be randomized. Subjects will be informed about their 
randomization arm by the study site staff on Day 1 prior to start of product use.   
o 
P4M3 Classic Auburn 3.5% nicotine (CA35) arm:  
18 subjects, ad libitum use of P4M3 using CA Cartridges 
o 
P4M3 Classic Menthol 3.5% nicotine (CM35) arm:  
18 subjects, ad libitum use of P4M3 using CM Cartridges  
o 
CIG smoker arm:  
18 subjects, ad libitum smoking of their own preferred CIG brand  
o 
SA subject arm:  
18 subjects who will abstain from CIG smoking  
• Exposure period in confinement setting (from Day 1 until Day 5 11:00 PM, 
followed by Discharge on Day 6):  
The Exposure period in confinement consists of 5 days of ad libitum use of the assigned 
product in the P4M3 and CIG arms. Use of any TNP other than the assigned product will 
not be allowed and may, at the discretion of the investigator, result in the subject’s 
discontinuation from the study. Subjects allocated to the SA arm will be asked to abstain 
from CIG smoking.  
Daily 24-hour urine will be collected from Day 1 to Day 5. On Day 1, use of P4M3 or 
CIG smoking in the respective arms must not start before the end of 24-hour urine 
collection of Day -1. The 24-hour urine collection period for Day 5 will end in the 
morning of Day  6 prior to Discharge.   
The Exposure period to the assigned investigational product (IP) will end at 11:00 PM 
on Day 5, followed by Discharge on Day 6 after completion of all study procedures. 
Subjects may smoke CIG or use other TNP at their discretion after Discharge only.  
During the confinement period, site staff will distribute assigned products to the subjects 
and record all products distributed in the source documentation.  
Any subject who wants to attempt to quit using any TNP at any time during the study 
(i.e., P4M3, CIGs) will be encouraged to do so and will be referred to appropriate 

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medical services. This will not affect subject’s financial compensation, and the subject 
will remain in the study.  
• Safety follow-up period (from Discharge at Day 6 until the end of the safety follow-
up period):  
After Discharge at Day 6 or from the day of early termination, subjects will enter a 3-
day Safety follow-up period during which AEs/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.  
Biobanking: 
If the subject consents, from the 24-hour urine collection, additional samples will be 
taken for long-term biobanking (two years at most) in view of further measurements of 
BoExp and stored at the bioanalytical laboratory (Appendix B). 
Study Population and Main Criteria for Inclusion/Exclusion: 
A sufficient number of healthy female and male smokers who meet all the following 
inclusion criteria will be enrolled into the study to ensure randomization of 72 subjects: 

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Inclusion Criteria 
Screening 
Day -2 
1. Subject has signed the ICF and is able to understand the 
information provided in the ICF,  
X 
 
2. Subject is male or female and between 21 and 65 years old 
(inclusive).  
X 
 
3. Subject has been a smoker for ≥3 years prior to the 
screening visit (smoking cessation attempts during this 
period, if any, did not last >6 months).  
X 
 
4. Subject has continuously smoked on average ≥10 
commercially available mentholated or non-mentholated 
CIGs per day over the last 4 weeks prior to screening and 
admission. Smoking status will be verified based on a 
urinary cotinine test (cotinine ≥200 ng/mL).  
X 
X 
5. Subject is healthy as judged by the Investigator based on 
available assessments from the screening period (e.g., 
safety laboratory, spirometry, vital signs, physical 
examination, ECG, and medical history).  
X 
 
 
Subjects who meet any of the following exclusion criteria will not be enrolled into the 
study: 
Exclusion Criteria  
Screening   
Day -2 
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., in emergency 
situations, under guardianship, prisoners).  
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), which as per the judgment 
X  
  

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of the Investigator would jeopardize the safety of the 
subject.   
4. 
Subject 
experienced 
within 
30 days 
prior 
to 
screening/admission a body temperature >37.5°C or an 
acute illness (e.g., upper respiratory-tract infection, viral 
infection, etc.)  
X  
X  
5. As per the Investigator’s judgment, the subject has medical 
conditions which do or will require a medical intervention 
(e.g., start of treatment, surgery, hospitalization) during 
the study participation, which may interfere with the 
study participation and/or study results.   
X  
  
6. Subject has relevant history of, or current asthma condition 
or COPD condition, and/or clinically significant 
spirometry findings at Screening or Baseline  
X  
  
7. Subject has donated blood or received whole blood or 
blood products within 3 months prior to screening.   
X  
  
8. BMI <18.5 kg/m2 or ≥32.0 kg/m2.   
X  
  
9. Positive serology test for HIV 1/2, HBV, or HCV.   
X  
  
10. Subject has a positive alcohol breath test and/or has a 
history of alcohol abuse which as per judgement of the PI 
could interfere with their participation in the study.   
X  
X  
11. The subject has a positive urine drug test.   
X  
X  
12. Subject or one of their family membersa is a current or 
former employee of the tobacco or e-cigarette 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 
1 month or five half-lives of the previous investigational 
drug/product (whatever the longer) prior to screening.   
X  
  
15. Subject has been previously screened or enrolled in this 
study.   
X  
  
16. Subject is pregnant (does not have negative pregnancy 
tests at screening and at admission) or is breastfeeding.   
X  
X  

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17. For women of childbearing potential onlyb: subject does 
not agree to use an acceptable method of effective 
contraception.c   
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, bilateral oophorectomy, or bilateral tubal ligation,  
• 
Have primary ovarian insufficiency, or  
• 
Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 
consecutive months with no alternative pathological or physiological cause). 
c. 
Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) 
with spermicidal foam/gel/film/suppository, hormonal contraception, vasectomized partner(s), or 
true abstinence (periodic abstinence and withdrawal are not effective methods) from Screening until 
the end of the Safety Follow-Up Period. 
Sample Size: 
In this study, 72 healthy adult smokers will be randomized. This will provide more than 
90% power to demonstrate a reduction for all BoExp tested in the primary objective in 
the combined P4M3 arms compared to the CIG arm, using a one-sided two-sample t-test 
with 2.5% type I error probability. This assumes, based on a previous similar study 
conducted by PMP (see ClinicalTrials.gov Identifier: NCT01959932), that the geometric 
mean ratio (GM) and the related geometric coefficient of variation (GCV) of the ratio 
between the combined P4M3 arms and the CIG arm are the following:   
• 
GMR = 23.45% and GCV = 16.84% for COHb at Day 5, 
• 
GMR = 41.63% and GCV = 26.10% for 3-HPMA at Day 5, 
• 
GMR = 13.16% and GCV = 6.5% for 2-CyEMA at Day 5, 
• 
GMR = 43.54% and GCV = 5.2% for Total NNAL at Day 5. 
Investigational Products; Dose; and Mode of Administration: 
Investigational Product: 
P4M3 Battery Units and Cartridges will be provided by the Sponsor.  
The following P4M3 variants will be investigated:  
Name  
Nicotine 
concentration 
e-liquid 
flavor 
Name in 
study 
P4M3 Classic Auburn  
3.5 % 
Tobacco 
CA35 
P4M3 Classic Menthol  
3.5 % 
Menthol 
CM35 

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Comparator:   
CIG arm: Subject’s own preferred brand of commercially available, regular or 
mentholated CIG (not provided by the Sponsor).   
Reference:   
Not applicable.  
Duration of Study: 
The entire study duration per subject will be 11 to 38 days. This will include a Screening 
period of up to 28 days prior to Admission (Day -30 to Day -3), followed by a 7-day 
confinement period (Day -2 to Day 5, followed by Discharge on Day 6), and a 3-day 
Safety follow-up period.  
The End of the study (EOS) for a subject is defined as the completion of the 3-day Safety 
follow-up period either after the Discharge at Day 6, or after the early termination of the 
subject. The end of the whole study corresponds to the EOS of the last subject.   
Statistical Methods:  
Analysis Sets:  
The Full Analysis Set (FAS) consists of all randomized subjects who have at least one 
post-randomization product use experience (if randomized to CIG or one of the P4M3 
arms) and who have at least one valid non-safety assessment. The FAS will be analyzed 
by randomized study arm.  
The Per Protocol Set (PPS) is a subset of FAS and includes all randomized subjects who 
fulfil key compliance criteria of the protocol and have no major protocol deviation impacting 
the evaluability of the primary objective. The PPS will be analyzed by randomized study 
arm.  
Additional analysis sets may be defined in the SAP.   
Statistical Analysis:  
The primary objective will be analyzed using a linear mixed model for repeated 
measurements. A 1-sided pairwise comparison in the PPS between continuous smokers 
and smokers who switch to one of the P4M3 variants will be used to assess the primary 
study hypothesis. 
The main comparison will be between the P4M3 arms (combined CA35 and CM35 arms) 
versus the CIG arm. Additional comparisons will be performed to compare each P4M3 
arm against the CIG arm. Finally, comparisons between the other arms will be done as 
well (e.g., P4M3 arms combined and separately vs smoking abstinence; CIGs vs smoking 
abstinence).  

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Descriptive statistics will be presented at each timepoint, where applicable. Descriptive 
statistics will be presented for each arm separately as well as for the combined P4M3 
variants (P4M3 CA35 + P4M3 CM35).    
The other BoExp will be analyzed using a similar model to the primary analysis. Product 
use, HPT and questionnaires will be summarized using descriptive statistics.  
Human Subject Protection and Independent Ethics Committee (IEC):  
The study will follow the principles as defined in the International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) and in the Declaration of Helsinki 
and applicable regulation. Prior to the start of the study, the clinical study protocol, 
together with any other documents as required by the Independent Ethics Committee 
[IEC]), will be submitted for review and approval to the relevant IEC.  
Safety Reporting:  
AEs will be collected from the time the subjects have signed their ICF until the end of 
the study. The Investigator must notify sponsor of all SAEs within 24 hours of the first 
awareness.   
Any pregnancy detected after enrolment, must be reported by the Investigator to the 
sponsor within 24 hours of the first awareness and must be followed-up until the 
pregnancy outcome is reached.  
Expedited reporting of SAEs and, if applicable, pregnancies, to competent authorities 
will be done as locally required.   
Information regarding AEs related to P4M3 product events should be actively collected 
during the study visits. Furthermore, any events of the P4M3 device that do lead to an 
AE/SAE will follow the same processes as described above.   
 
 
 

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TABLE OF CONTENTS 
Version History .................................................................................................................... 2 
Synopsis ............................................................................................................................... 3 
Abbreviations and Definitions of Terms ............................................................................ 22 
1. 
Ethics and Regulations ............................................................................................... 26 
1.1 
Independent Ethics Committee (IEC) Approval .................................................. 26 
1.2 
Ethical Conduct of the Study ............................................................................... 27 
1.3 
Subject Information and Consent ........................................................................ 27 
1.3.1 
Informed Consent Form for Study Participation ......................................... 27 
1.3.2 
Amendment to the Informed Consent Form ................................................ 28 
1.4 
Good Clinical Practice and Regulatory Requirements ........................................ 28 
2 
Introduction ................................................................................................................ 29 
2.1 
Background .......................................................................................................... 29 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy .......................... 29 
2.1.2 
Description of the Product and Scientific Findings ..................................... 30 
2.2 
Purpose of the Study ............................................................................................ 31 
2.3 
Anticipated Benefits and Risks ............................................................................ 31 
2.3.1 
Anticipated Benefits..................................................................................... 31 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures ............................. 31 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product .................... 32 
2.3.4 
Unforeseeable Risks..................................................................................... 33 
3 
Study Objectives ........................................................................................................ 34 
3.1 
Primary Objective ................................................................................................ 34 
3.2 
Secondary Objectives .......................................................................................... 34 
3.2.1 
Key Secondary Objectives and Endpoints ................................................... 34 
3.2.2 
Secondary Objective and Endpoints ............................................................ 35 
3.3 
Exploratory Objectives ........................................................................................ 36 
3.3.1 
Exploratory Objective 1 and Endpoints ....................................................... 36 
3.3.2 
Exploratory Objective 2 and Endpoints ....................................................... 36 
3.3.3 
Exploratory Objective 3 and Endpoints ....................................................... 37 
3.3.4 
Exploratory Objective 4 and Endpoints ....................................................... 37 
3.3.5 
Exploratory Objective 5 and Endpoints ....................................................... 37 
3.3.6 
Exploratory Objective 6 and Endpoints ....................................................... 37 
4 
Investigational Plan .................................................................................................... 38 

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4.1 
Overall Study Design and Plan ............................................................................ 38 
4.2 
Rationale for Study Design .................................................................................. 40 
4.3 
Appropriateness of Measurements ...................................................................... 41 
4.4 
Study Duration ..................................................................................................... 41 
5 
Study Population ........................................................................................................ 43 
5.1 
Selection of Study Population ............................................................................. 43 
5.1.1 
Inclusion Criteria ......................................................................................... 43 
5.1.2 
Exclusion Criteria ........................................................................................ 44 
5.2 
Discontinuation of Subjects from the Study ........................................................ 45 
5.3 
Lost to Follow-up ................................................................................................ 47 
5.4 
Violation of Selection Criteria ............................................................................. 47 
6 
Investigational Products ............................................................................................. 48 
6.1 
Description of Investigational Products ............................................................... 48 
6.1.1 
Test Product ................................................................................................. 48 
6.1.2 
Reference Product / Baseline Product.......................................................... 49 
6.1.3 
Packaging and Labeling ............................................................................... 49 
6.2 
Use of Investigational Product(s) ........................................................................ 49 
6.2.1 
Admission Day (Day -2 to Day -1) .............................................................. 50 
6.2.2 
Baseline Period (Day -1 to Day 1) ............................................................... 50 
6.2.3 
Exposure Period (Day 1 to Day 5) ............................................................... 50 
6.2.4 
Day of Discharge (Day 6) ............................................................................ 51 
6.2.5 
Safety Follow-up Period .............................................................................. 51 
6.2.6 
Stopping Rules for Investigational Product ................................................. 51 
6.3 
Method for Assigning Subjects to Study Arms ................................................... 51 
6.4 
Blinding ............................................................................................................... 51 
6.5 
Investigational Product Accountability and Compliance .................................... 52 
6.5.1 
Dispensing Investigational Product ............................................................. 52 
6.5.2 
Storage and Accountability .......................................................................... 52 
6.5.3 
Investigational Product Retention ................................................................ 52 
6.5.4 
Compliance to Investigational and Reference Products .............................. 52 
6.6 
Restrictions .......................................................................................................... 53 
6.6.1 
Smoking Restrictions ................................................................................... 53 
6.6.2 
Dietary Restrictions ..................................................................................... 53 

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6.7 
Concomitant Medication ..................................................................................... 54 
7 
Study Procedures ....................................................................................................... 55 
7.1 
Informed Consent ................................................................................................ 55 
7.2 
Information on the Risk of Smoking and Smoking Cessation Advice and 
Briefing .......................................................................................................................... 55 
7.3 
Support during Abstinence from any Tobacco and Nicotine Containing Products
 
56 
7.4 
Clinical and Other Assessments .......................................................................... 56 
7.4.1 
Demographic Data ....................................................................................... 56 
7.4.2 
Medical History, Concomitant Disease, Previous and Concomitant 
Medications ................................................................................................................ 56 
7.4.3 
Physical Examination................................................................................... 57 
7.4.4 
Body Height and Weight ............................................................................. 57 
7.4.5 
Vital Signs .................................................................................................... 57 
7.4.6 
Spirometry.................................................................................................... 57 
7.4.7 
Electrocardiogram ........................................................................................ 58 
7.4.8 
Biomarker Assessment................................................................................. 58 
7.4.9 
Laboratory Assessments .............................................................................. 59 
7.4.10 Sample Handling, Storage, and Shipment ................................................... 60 
7.5 
Other Study Procedures ....................................................................................... 61 
7.5.1 
Demonstration P4M3 and Product Test ....................................................... 61 
7.5.2 
Human Puffing Topography Assessment .................................................... 62 
7.5.3 
Weighing of P4M3 Cartridge....................................................................... 63 
7.6 
Questionnaires ..................................................................................................... 63 
7.6.1 
Nicotine/Tobacco Product Use History ....................................................... 63 
7.6.2 
Fagerström Test for Nicotine Dependence (Revised Version) .................... 63 
7.6.3 
ABOUT – Product Experience Questionnaire ............................................. 63 
8 
Adverse Events .......................................................................................................... 65 
8.1 
Definitions ........................................................................................................... 65 
8.1.1 
Adverse Events ............................................................................................ 65 
8.1.2 
Serious Adverse Events ............................................................................... 65 
8.1.3 Conditions Existent Before the Start of the Period of Collection (ICF 
Signature) ................................................................................................................... 65 
8.2 
Collection and Reporting of Adverse Events ...................................................... 66 

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8.2.1 
Collection of Information ............................................................................ 66 
8.2.2 
Period of Collection ..................................................................................... 66 
8.2.3 
Intensity of Adverse Event........................................................................... 66 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures .................................................................................................................. 67 
8.2.5 
Expectedness ................................................................................................ 67 
8.2.6 
Follow-up of Non-serious and Serious Adverse Events .............................. 67 
8.3 
Reporting of Serious Adverse Events .................................................................. 68 
8.4 
Reporting of Other Abnormal Findigs ................................................................. 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 Period .................................................................................................. 70 
9.1.1 
Screening Visit (Day -30 to Day -3) ............................................................ 70 
9.2 
Baseline Period (Enrollment and Randomization) .............................................. 71 
9.2.1 
Admission Day -2 ........................................................................................ 71 
9.2.2 
Baseline Visit Day -1 ................................................................................... 73 
9.3 
Randomized Exposure Period .............................................................................. 74 
9.3.1 
Exposure in Confinement Period ................................................................. 74 
9.4 
Safety Follow-up Period ...................................................................................... 75 
9.5 
Early Termination Procedures ............................................................................. 76 
10 Quality Control and Quality Assurance ..................................................................... 77 
10.1 Monitoring ........................................................................................................... 77 
10.2 Training of Staff .................................................................................................. 78 
10.3 Audits and Inspections ......................................................................................... 78 
10.4 Risk Management ................................................................................................ 78 
11 Data Management Activities...................................................................................... 80 
11.1 Data Capture ........................................................................................................ 80 
11.1.1 Case Report Forms and Study Records ....................................................... 80 
11.1.2 Protocol Deviations ...................................................................................... 80 

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11.2 Data Handling ...................................................................................................... 81 
11.2.1 Data Verification .......................................................................................... 82 
11.2.2 Coding .......................................................................................................... 82 
11.2.3 Database Lock .............................................................................................. 82 
12 Planned Statistical Methods ....................................................................................... 83 
12.1 General Considerations ........................................................................................ 83 
12.1.1 Stratification Criteria ................................................................................... 83 
12.1.2 Definitions for Statistical Data Analysis...................................................... 83 
12.1.3 Descriptive Statistics .................................................................................... 83 
12.1.4 Handling of Missing Values and of Values outside the Detection Limits ... 84 
12.2 Product Use .......................................................................................................... 84 
12.3 Analysis Sets ........................................................................................................ 84 
12.3.1 Full Analysis Set (FAS) ............................................................................... 84 
12.3.2 Per Protocol Set (PP) ................................................................................... 84 
12.3.3 Safety Set (SAF) .......................................................................................... 85 
12.4 Demographics and Baseline Characteristics ........................................................ 85 
12.5 Primary Objective ................................................................................................ 85 
12.5.1 Primary Estimand Analysis.......................................................................... 85 
12.5.2 Secondary Estimand Analysis ...................................................................... 88 
12.6 Secondary Objectives .......................................................................................... 90 
12.6.1 Key Secondary Objectives ........................................................................... 90 
12.6.2 Secondary Objective .................................................................................... 92 
12.7 Exploratory Objectives ........................................................................................ 93 
12.8 Interim Analysis ................................................................................................... 93 
12.9 Measures to Control Bias ..................................................................................... 93 
12.9.1 Method for Assigning Subjects to Study Arms ........................................... 93 
12.9.2 Blinding........................................................................................................ 94 
12.9.3 Study Significance Level and Multiple Testing Procedures ........................ 94 
12.9.4 Determination of Sample Size and Power Consideration ............................ 95 
13 Administrative Considerations................................................................................... 99 
13.1 Study Administrative Structure ........................................................................... 99 
13.1.1 Sponsor ........................................................................................................ 99 
13.1.2 List of Principal Investigators and Sites ...................................................... 99 

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13.2 Subject Confidentiality ........................................................................................ 99 
13.3 Access to Source Documents ............................................................................... 99 
13.4 Record Retention ............................................................................................... 100 
13.5 Clinical Study Report ........................................................................................ 101 
13.6 Financial Disclosure .......................................................................................... 101 
13.7 Publication and Disclosure Policy ..................................................................... 102 
13.8 Insurance ............................................................................................................ 102 
14 Reference List .......................................................................................................... 103 
 
 
 

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LIST OF IN-TEXT TABLES 
Table 1 
List of BoExp used in the primary objective ................................... 3 
Table 2 
List of BoExp used in the key secondary objective ......................... 4 
Table 3 
List of BoExp used as exploratory objective ................................... 5 
Table 4 
List of BoExp used in the primary objective ................................. 34 
Table 5 
List of BoExp used in the key secondary objective ....................... 35 
Table 6 
List of BoExp used as exploratory objective ................................. 36 
Table 7 
P4M3 Gen 2.0 variants .................................................................. 48 
Table 8 
Intensity of Adverse Events ........................................................... 66 
Table 9 
Time Schedule – Screening Visit ................................................... 70 
Table 10 
Time Schedule – Admission Visit Day -2 ..................................... 72 
Table 11 
Time Schedule – Baseline Visit Day -1 ......................................... 73 
Table 12 
Time Schedule – Day 1, 2, 3, 4, and 5 ........................................... 74 
Table 13 
Time Schedule – Discharge Day 6 ................................................. 75 
Table 14 
Time Schedule – Early Termination Visit ..................................... 76 
Table 15 
Blinding Scheme ............................................................................ 94 
Table 16  
Power Computations for Primary Objective .................................. 96 
Table 17  
Power Computations for 1st Key Secondary Objective ................. 96 
Table 18  
Power Computations for Key Secondary Objectives 2 & 4 .......... 97 
Table 19  
Power Computations for Key Secondary Objectives 3 & 5 .......... 97 
 
List of In-Text Figures 
Figure 1 
Study Design .................................................................................... 7 
Figure 2 
Study Design .................................................................................. 38 
Figure 3 
Representation of the Procedure of Fixed Sequence Testing ........ 91 
 
List of Appendices 
Appendix A 
Schedule of Events ....................................................................... 106 
Appendix B 
Participating Laboratories ............................................................ 109 
Appendix C 
Human Puffing Topography Parameters ..................................... 110 
Appendix D 
Clinical Laboratory Parameters Safety Panel .............................. 111 
 

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Abbreviations and Definitions of Terms 
Abbreviations  
2-CyEMA 
2-Cyanoethyl mercapturic acid N-Acetyl-S-(2-cyanoethyl)-L-
cysteine 
2-HPMA 
2-hydroxypropylmercapturic acid 
3-HMPMA 
3-hydroxy-1-methylpropylmercapturic acid 
3-HPMA 
3-hydroxypropylmercapturic acid 
3-OH-B[a]P 
3-hydroxybenzo(a)pyrene 
ABOUT 
Assessment of behavioral outcomes related to tobacco and 
nicotine products 
AE 
Adverse event 
BMI 
Body mass index 
BoExp 
Biomarker of exposure 
CA35 
P4M3 Gen 2.0 variant Classic Auburn 3.5% nicotine 
CAF 
Caffeine 
CI 
Confidence interval 
CIG 
Conventional cigarette (smoking) 
CM35 
P4M3 Gen 2.0 variant Classic Menthol 3.5% nicotine 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTMS 
Clinical trial management system 
CV 
Coefficient of variation 
CYP1A2 
Cytochrome P450 1A2 
DHPMA 
2,3-dihydroxypropylmercapturic acid 
DMP 
Data management plan 
ECG 
Electrocardiogram 
EOS 
End of study 
FAS 
Full analysis set 
FDA 
Food and Drug Administration  
FEF 
Forced expiratory flow 

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FEV1  
Forced expiratory volume in 1 second 
FTND 
Fagerström test for nicotine dependence (revised version) 
FVC 
Forced vital capacity 
GCV 
Geometric coefficient of variation 
GCP 
Good Clinical Practice 
GMR 
Geometric mean ratio 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HPHC(s) 
Harmful and potentially harmful constituent(s) 
HPT 
Human puffing topography  
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IP 
Investigational product 
IEC 
Independent Ethics Committee 
IxRS 
Interactive web/voice response system 
LLN 
Lower limit of the normal range 
LLOQ 
Lower limit of quantification 
MCEQ 
Modified cigarette evaluation questionnaire 
MDEDR 
Miniaturized detachable external data recorder 
MedDRA 
Medical dictionary for regulatory activities 
MHBMA 
Monhydroxybutenyl mercapturic acid 
NEQ 
Nicotine equivalents 
NNAL 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
NNK 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 
NNN 
N-nitrosonornicotine 
NRT 
Nicotine replacement therapy 
PMP 
Philip Morris Products S.A. 
PP 
Per protocol set 
PI 
Principal investigator 
PX 
Paraxanthine 
QC 
Quality control 
SA 
Smoking abstinence 

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SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SHM 
Sample handling manual 
SOP 
Standard operating procedure 
S-PMA 
S-phenylmercapturic acid 
TNP 
Tobacco and/or nicotine containing product 
ULN 
Upper limit of the normal range 
ULOQ 
Upper limit of quantification 
vs 
Versus 
WHO 
World Health Organization 
 

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Explanation of Terms 
The following special terms are used in this protocol:  
Alternate subjects 
Subjects who have signed the ICF, have met the inclusion and 
exclusion criteria, and have been enrolled, but have not been 
randomized due to a sufficient number of subjects available for 
randomization at that time. In case the Admission Day-2 of the 
following group does not exceed the 28-day Screening period, 
to qualify for randomization, alternate subjects have to repeat 
the Admission visit to re-confirm their eligibility. 
Cigarette(s) (CIG) 
The term ‘CIG’ refers to commercially available regular or 
menthol cigarettes (manufactured) and excludes hand-rolled 
cigarettes, cigars, pipes, bidis, and other nicotine-containing 
products. 
Early termination 
Premature termination of exposure to the Investigational 
Product after the start of the Exposure period in the confinement 
setting. 
End of study (EOS) 
The EOS for a randomized subject is defined as the completion 
of the 3-day Safety follow-up period either after Discharge on 
Day 6, or after the date of early termination of the subject. The 
EOS of the entire study is the end of the Safety Follow-up Period 
for the last subject. 
Randomization  
Allocation of the respective product at any time on Day -1 
utilizing an interactive web and voice response system (IxRS). 
On Day 1, the subjects will be individually informed about the 
product they are randomized to prior to the first product use.  
Screening failure 
All subjects that are not enrolled are considered as screen 
failures. Re-screening of subjects who did not meet any entry 
criteria will not be permitted. 

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1. Ethics and Regulations 
1.1 
Independent Ethics Committee (IEC) Approval 
Prior to the start of the study, the clinical study protocol, together with its associated 
documents (informed consent form [ICF] 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 
Principal Investigator(s) (PI(s)) and designee(s) and/or other evidence of qualifications and 
any other documents requested by an Independent Ethics Committee [IEC]), will be 
submitted for review and approval to the relevant IEC. The IEC shall be appropriately 
constituted and perform its functions in accordance with the International Council for 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Guidance for Good Clinical Practice (GCP) [2] and local requirements, as applicable. 
In accordance with GCP, a written confirmation of the IEC approval should be provided to 
the Sponsor. This should identify the study (name of the PI(s) and designee(s), study 
number, and title) and the documents that have been approved by the IEC, with dates and 
version numbers, as well as the date of approval. The composition of the IEC, including 
the name and occupation of the chairperson, will be supplied to the Sponsor together with 
a GCP compliance statement. 
The written approval from the IEC will be filed in the Principal 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 IEC. 
Any substantial change or addition to this protocol will require a written protocol 
amendment that must be approved by the Sponsor and the Principal Investigator(s). All 
amendments will be submitted to the IEC, and substantial amendments will only be 
implemented after approval by the IEC. 
These requirements for approval should in no way prevent any action from being taken by 
the PI(s) or designee(s) or by the Sponsor to eliminate immediate hazards to the subjects. 
If such a change to the protocol is felt to be necessary by the PI(s) or designee(s), and is 
implemented for safety reasons, the Sponsor and the IEC should be informed immediately. 
The PI(s) is(are) responsible for local reporting (e.g., to the IEC) of serious adverse events 
(SAEs) that occur during the study, according to local regulations. 
Relevant safety information will be submitted to the IEC during the study in accordance 
with national regulations and requirements.  
Medically qualified study personnel will be available during the study. 

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1.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki [3] and are consistent with ICH/GCP [2] applicable regulatory 
principles. 
The PI(s) or designee(s) agree(s) to conduct the clinical study in compliance with the 
protocol agreed with the Sponsor and approved by the IEC. The PI(s) and the Sponsor must 
sign the protocol (and protocol amendments, if applicable) to confirm this agreement. A 
copy of the Declaration of Helsinki will be filed 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 Visit, the PI(s) or designee(s) 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 PI(s) or the designee(s) 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 
withdraw his/her participation at any time. 
Once the subject has received all the necessary information, and if he/she agrees to 
participate in the study, the subject and the person who conducted the informed consent 
discussion during Screening Visit will both sign, date, and time the ICF. The ICF includes 
both the subject information sheet and informed consent. No study-specific procedures will 
be performed before the ICF has been signed (including date and time). 
In addition to consenting to study participation, the subject will be asked for their consent 
to the storage of urine samples for long-term biobanking (two years at most), i.e., the 
storage of samples from the 24-hour urine collection at the bioanalytical laboratory 
(Appendix B), in view of further measurements of BoExp. These analyses are not described 
in the protocol or statistical analysis plan (SAP) and will not be included in the clinical 
study report (CSR), but in a separate report. Any additional analysis performed will also be 
covered by data confidentiality, as it is for the main analysis described in this protocol. 
The subject’s consent to urine sample biobanking is not a requirement for the study 
participation and the subject’s participation in the study does not depend on their consenting 
to biobanking. 
The original dated and signed ICF(s) must be kept by the PI(s) and filed in the Principal 
Investigator’s file at the site or with the subject’s files and a copy must be given to the 
subject. 

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and confidential commercial information, and the legal protections provided to such trade 
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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 disagrees. 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 any 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 amendment to the ICF may be required. If a revision of the ICF is necessary, the PI(s) 
or designee will, with the support of the Sponsor, ensure that the documents have been 
reviewed and approved by a relevant IEC before subjects are required to re-sign the ICF 
(including date and time). If new and important safety information is received, subjects 
who already completed or are discontinued from the study will be informed by letter, email, 
or phone call. 
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, PI(s) or designee(s) abide by the principles of the ICH guidelines on GCP 
[2]. These guidelines apply specifically to pharmaceutical development, but nevertheless 
provide a robust and ethical framework for conducting clinical studies 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 [3]. 

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2 
Introduction 
2.1 
Background 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy 
Cigarette (CIG) smoking causes pulmonary, cardiovascular and other serious diseases in 
smokers [4] due to the exposure of toxicants in the CIG smoke, i.e., its harmful and 
potentially harmful constituents (HPHC). There is no safe CIG smoking, 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 (TNP) with the potential 
to be less harmful than CIG represent an approach to reduce CIG-related deaths and 
diseases among smokers switching to ENDS who would have otherwise continued smoking 
[5].  
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 CIG. 
These products aim to substantially reduce or eliminate the exposure to HPHC generated 
from CIG smoke except nicotine, while providing an acceptable substitute for CIG smoking 
and lowering the health risk. 
One of these products is P4M3 Gen 2.0 (P4M3), which is an electronic nicotine delivery 
system (ENDS) or electronic cigarette (e-cigarette). The liquid used in P4M3 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 CIG. However, in 
some specific conditions of e-cigarette 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.  

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Given that context, when developing new products such as P4M3, appropriate assessment 
including comprehensive understanding of product characterization, its safety, and related 
impact of product use in humans is critical. P4M3 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). 
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, 
vegetable glycerol, water, nicotine, lactic acid, benzoic acid, and flavors. P4M3 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 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 composed of a fine 
mesh of stainless-steel wires heated by an electric current. 
The aerosol generated by P4M3 is free from the majority of HPHC associated with heating 
or burning tobacco, except nicotine. P4M3 does not contain tobacco and there is no 
combustion during use. 
The non-clinical assessment of P4M3 is described in the Investigator’s Brochure [6] and 
supports the clinical assessment of P4M3. P4M3 will also be tested in a pharmacokinetic 
study in humans; this study has been submitted. 
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 [7]. Experienced e-cigarette users may extract more nicotine by puffing with a 
low flow rate and long duration puffs in comparison to CIG smokers. E-cigarette design 
features also affect nicotine exposure; increasing the battery voltage output and e-liquid 
nicotine concentration increases the nicotine delivery [8]. 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 [9]. Battery output, type of wicks, 
ventilation holes, and other mechanical characteristics of each individual e-cigarette 

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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 [10]. 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. 
2.2 
Purpose of the Study 
The overall goal of the study is to demonstrate reduction in the levels of Biomarkers of 
Exposure (BoExp) to selected HPHC and to obtain safety information in healthy subjects 
switching from CIG to P4M3 as compared to smoking abstinence (SA), or to smokers 
continuing smoking CIG in a confinement setting for 5 days.  
Product use patterns, puffing behavior and overall exposure to nicotine from two P4M3 
variants, CA35 and CM35, will also be assessed. 
Information on changes in investigational product experience upon switching to P4M3 will 
be provided by measuring self-reported behavioral outcomes, compared to CIG smoking. 
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 at the Screening Visit, Admission Visit, and at Discharge on Day 6, respectively. 
The advice will follow the recommendations of the World Health Organization (WHO) 
“Evidence based Recommendations on the Treatment of Tobacco Dependence” [11]. 
Subjects who are motivated to quit smoking during the study will be encouraged to do so 
and will be referred to appropriate medical services for necessary support and counselling. 
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 81 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 time span such as weakness, dizziness, or anemia. 

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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 
HPHC 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 
or other e-cigarettes reduce the risk of developing smoking-related diseases compared to 
CIG.  
Due to sensorial and technological differences between P4M3 and CIG, 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 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 (see section 7.3). 
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) 

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2.3.4 
Unforeseeable Risks 
The possibility of unforeseeable events/risks will be explained in detail to study 
participants. Unexpected malfunction of the P4M3 device may lead to unforeseeable risk. 
Risk mitigation will include close monitoring and medical supervision to detect any 
unforeseeable risk or safety signals at the earliest time possible. 

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3 
Study Objectives 
The estimands requested as per ICH guidelines [1] for all objectives are listed in section 
12.5 for the primary objective, section 12.6 for secondary objectives, and section 12.7 for 
exploratory objectives. 
3.1 
Primary Objective  
The primary objective of this study is: 
1. To demonstrate the reduction of BoExp to selected HPHC given in Table 4 in smokers 
switching from CIG to P4M3 (combined CA35 and CM35 arms) compared to 
continuing CIG smoking for 5 days. 
Table 4 
List of BoExp used in the primary objective 
BoExp 
HPHC 
Matrix 
3-hydroxypropyl mercapturic acid (3-
HPMA) 
Acrolein 
Urine1  
2-cyanoethyl mercapturic acid (2-CyEMA) 
Acrylonitrile 
Urine1 
Total 4-(methylnitrosamino)-1-(3-pyridyl)-
1-butanol (total NNAL) 
4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK) 
Urine1 
Carboxyhemoglobin (COHb) 
Carbon monoxide (CO) 
Blood2 
1BoExp in urine will be expressed as concentration adjusted for creatinine in 24-hour urine; 2BoExp in blood 
expressed as % of saturation of hemoglobin. 
The main assessment of the primary objective will be done in subjects who are adherent to 
their randomized arms (who belong to the Per Protocol Set, see section 12.3). 
3.2 
Secondary Objectives  
3.2.1 
Key Secondary Objectives and Endpoints 
The key secondary objectives of this study are: 
1. To demonstrate the reduction of BoExp to selected HPHC given in Table 5 in smokers 
switching from CIG to P4M3 (combined CA35 and CM35 arms) compared to 
continuing CIG smoking for 5 days. 

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Table 5 
List of BoExp used in the key secondary objective 
BoExp 
HPHC 
Matrix 
S-phenylmercapturic acid (S-PMA) 
Benzene 
Urine1  
3-hydroxy-1-methylpropylmercapturic acid (3-
HMPMA) 
Crotonaldehyde 
Urine1 
Total N-nitrosonornicotine (total NNN) 
N-nitrosonornicotine 
Urine1 
Total 3-hydroxybenzo(a)pyrene (3-OH-B[a]P) 
Benzo(a)pyrene 
Urine1 
1BoExp in urine expressed as concentration adjusted for creatinine in 24-hour urine. 
2. To demonstrate the reduction of BoExp to selected HPHC given in Table 4 in smokers 
switching from CIG to P4M3 CA35 only compared to continuing CIG smoking for 5 
days. 
3. To demonstrate the reduction of BoExp to selected HPHC given in Table 5 in smokers 
switching from CIG to P4M3 CA35 only compared to continuing CIG smoking for 5 
days. 
4. To demonstrate the reduction of BoExp to selected HPHC given in Table 4 in smokers 
switching from CIG to P4M3 CM35 only compared to continuing CIG smoking for 5 
days. 
5. To demonstrate the reduction of BoExp to selected HPHC given in Table 5 in smokers 
switching from CIG to P4M3 CM35 only compared to continuing CIG smoking for 5 
days. 
The main assessment of the key secondary objectives will be done in subjects who are 
adherent to their randomized arms (who belong to the Per Protocol Set, see section 12.3).  
These key secondary objectives will only be evaluated if the primary objective is 
successfully demonstrated. They will be assessed sequentially, and the fixed sequence of 
testing will stop if any of the primary or key secondary objectives are not demonstrated 
(see section 12.6.1). 
3.2.2 
Secondary Objective and Endpoints 
1. The secondary objective of this study is to monitor safety and tolerability in all subjects 
during the study. 
Endpoints 
• Incidence and frequency of adverse events (AEs) and serious adverse events (SAEs) 

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• Incidence and frequency of P4M3 product events including malfunction/misuse 
• Electrocardiogram (ECG) changes from baseline (heart rate, PR, QRS, QT, QTcF 
intervals) 
• Vital signs changes from baseline (systolic and diastolic blood pressure, heart rate 
and respiratory rate 
• Spirometry changes from baseline (FEV1, FEV1 % predicted, FVC, FVC % 
predicted, FEV1/FVC) 
• Changes from baseline in clinical chemistry, hematology, and urine analysis safety 
panel (Appendix D) 
• Concomitant medications. 
3.3 
Exploratory Objectives  
3.3.1 
Exploratory Objective 1 and Endpoints 
The exploratory objective 1 of this study is to determine the levels of BoExp to selected 
HPHC given in Table 6 in smokers switching from CIG to P4M3 (CA35 and CM35 arms 
combined and separately) compared to continuing CIG smoking for 5 days.  
Table 6 
List of BoExp used as exploratory objective 
BoExp 
HPHC 
Matrix 
2-hydroxypropylmercapturic acid (2-HPMA) 
Propylene oxide 
Urine1  
2,3-dihydroxypropylmercapturic acid (DHPMA) 
Glycidol 
Urine1 
Nicotine equivalents (NEQ2)  
Nicotine 
Urine1 
1BoExp in urine expressed as concentration adjusted for creatinine in 24-hour urine; 2NEQ = molar sum of free 
nicotine, nicotine-glucuronide, free cotinine, cotinine-glucuronide, free trans-3’-hydroxycotinine, trans-3’hydroxy-
cotinine-glucuronide. 
3.3.2 
Exploratory Objective 2 and Endpoints 
The exploratory objective 2 of this study is to determine the reductions of BoExp to selected 
HPHC given in Table 4, Table 5, and Table 6 in smokers quitting smoking compared to 
continuing CIG smoking or switching from CIG to P4M3 (CA35 and CM35 arms combined 
and separately) for 5 days.  

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3.3.3 
Exploratory Objective 3 and Endpoints 
The exploratory objective 3 of this study is to describe the nicotine/tobacco product use in 
smokers switching from CIG to P4M3 (CA35 and CM35 arms combined and separately) 
compared to continuing CIG smoking. 
Endpoints (Day -1 to Day 5) 
• Daily number of CIG (Day -1, all subjects; Day 1 to 5, subjects of CIG arm only),  
• Daily number of P4M3 Cartridges (Day 1 to 5, subjects of P4M3 arms only), 
• Daily e-liquid used determined by weight difference of the Cartridge(s) before and 
after use. 
3.3.4 
Exploratory Objective 4 and Endpoints 
The exploratory objective 4 of this study is to describe reinforcing effects related to 
tobacco/nicotine containing products use in smokers switching from CIG smoking to P4M3 
(CA35 and CM35 arms combined and separately) compared to continued CIG smoking. 
Endpoints (Day -1 to Day 5) 
• Subscale scores of Product Experience (ABOUT - Product Experience) (assessed 
only in subjects randomized to P4M3 or CIG) 
3.3.5 
Exploratory Objective 5 and Endpoints 
The exploratory objective 5 of this study is to describe the Human Puffing Topography 
(HPT) over the entire exposure period in subjects switching to P4M3 (CA35 or CM35 arms 
combined and separately). 
Endpoints (Day 1 to Day 5) 
• Puffing topography parameters as per-product use experience and per-day 
parameters (Appendix C). 
3.3.6 
Exploratory Objective 6 and Endpoints 
The exploratory objective 6 of this study is to evaluate the cytochrome P450 1A2 
(CYP1A2) enzymatic activity in smokers switching to P4M3 (CA35 and CM35 arms 
combined and separately) and smoking abstinence compared to continued CIG smoking. 
Endpoint (Day -1, Day 5) 
• Molar metabolic ratio of paraxanthine/caffeine in plasma. 

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4 
Investigational Plan 
4.1 
Overall Study Design and Plan 
This is a randomized, controlled, open-label, 4-arm parallel study with a stratified 
randomization by sex. Quotas will be applied to ensure that the randomized subjects contain 
at least 40% of both sexes (males and females) per arm. 
This is an ad libitum smoking/vaping study with unrestricted product use (P4M3 or CIG, 
in the respective arms) for 5 days exposure period in confinement followed by a 3-day 
Safety follow-up period (Figure 2).  
 
Figure 2 
Study Design 
• Screening period (from Day -30 until Day -3):  
The screening period covers up to four weeks prior to admission. A presentation of 
P4M3 (without product use) will be done by the site staff during the Screening visit. 
All subjects will receive information on the risks of smoking and smoking cessation 
advice. Eligible subjects will return to the investigational site for verification of 
eligibility.  

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• Admission (from Day -2 until morning of Day -1):  
On Day -2 (admission), after all inclusion/exclusion criteria are checked, all eligible 
subjects will be enrolled and perform a product test using both P4M3 variants: tobacco 
flavor “Classic Auburn” 3.5% nicotine (CA35) and menthol flavor “Classic Menthol” 
3.5% nicotine (CM35), with an ad libitum use regimen for a duration of approximately 
10 minutes ad libitum use per flavor. After the product test, subjects not willing to use 
P4M3 during the study will be discontinued and will be replaced. Subjects willing to 
continue participation will start their confinement period. CIG smoking will be allowed 
ad libitum from the time of admission of the subject until approximately 11:00 PM, 
except before/during assessments requiring smoking breaks. Use of any TNP other than 
CIG (and P4M3 for the product test) will not be allowed after admission.  
Provided that the 28-day Screening period is not exceeded, alternate subjects (not yet 
randomized) have to repeat the Admission visit of the following group to re-confirm 
their eligibility for randomization. 
• Baseline (from Day -1, 06:30 AM until Day 1, 06:29 AM):  
Subjects may continue smoking their CIG ad libitum, except before/during assessments 
requiring smoking breaks. The 24-hour urine collection for Day -1 will start in the 
morning of Day -1 (urine collection details provided in Appendix A). Baseline 
assessments will be performed as indicated in Appendix A.  
On Day -1, subjects will be randomized. Subjects will be informed about their 
randomized study arm by the study site staff on Day 1 prior to start of product use.  The 
four randomization arms are:  
o P4M3 CA35 arm: 18 subjects, ad libitum use of P4M3 using CA Cartridges 
o P4M3 CM35 arm: 18 subjects, ad libitum use of P4M3 using CM Cartridges  
o CIG arm: 18 subjects, ad libitum use of their own preferred CIG brand  
o SA arm: 18 subjects who will abstain from CIG smoking  
• Exposure period in confinement setting (from Day 1 until Day 5 11:00 PM, followed by 
Discharge at Day 6):  
The exposure period in confinement consists of 5 days of ad libitum use of the assigned 
product in the P4M3 and CIG arms. Use of any TNP other than the assigned product 
will not be allowed and may, at the discretion of the investigator, result in the subject’s 
discontinuation from the study. Subjects allocated to the SA arm will be asked to abstain 
from CIG smoking. 

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Daily 24-hour urine will be collected from Day 1 to Day 5. On Day 1, product use must 
not start before the end of 24-hour urine collection of Day -1. The 24-hour urine 
collection period for Day 5 will end in the morning of Day 6 prior to Discharge. 
During the confinement period, site staff will distribute assigned products to the 
subjects and record all products distributed in the source documentation. 
Any subject who wants to attempt to quit using tobacco or nicotine containing products 
at any time during the study (i.e., P4M3, CIG) will be encouraged to do so and will be 
referred to appropriate medical services. This will not affect subject’s financial 
compensation, and the subject will remain in the study.  
• Safety follow-up period (from Discharge at Day 6 until the end of the Safety follow-up 
period):  
After Discharge at Day 6 or from the day of early termination, 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 ongoing at Discharge will be conducted by 
the investigational site.  
4.2 
Rationale for Study Design  
This clinical study aims to demonstrate the reduction of BoExp to selected HPHC in 
smokers switching from CIG to P4M3, a candidate RRP1, as compared smokers continuing 
smoking CIG, or to smoking abstinence (SA). A reduction of exposure to HPHC derived 
from CIG smoke is expected to diminish the health risk of nicotine consumption if 
switching completely to ENDS. 
The exposure period in confinement will provide information on exposure reductions 
achievable in a well-controlled environment with full control on daily P4M3/CIG 
consumption and compared to SA.  
HPHC considered to be of health concern have been reported by different regulatory bodies 
and health organizations [12, 13]. Lists of HPHC to be reported in tobacco smoke have 
consequently been developed, as described, for example in the FDA draft guidance on 
“Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and 
Tobacco Smoke” [14]. More recently, a guidance was issued by the FDA on which HPHC 
to be considered for reporting in e-liquids or aerosols of ENDS [15]. 
                                                 
1 Reduced risk products (“RRPs”) is the term used by PMI to refer to products that present, are likely to present, or have 
the potential to present less risk of harm to smokers who switch to these products versus continued smoking. 

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It is not possible to measure each of those potentially toxic constituents in humans, due to 
constraints in availability of validated, reliable methods, or simply the absence of suitable 
BoExp. A selection of HPHC to be evaluated in this study was thus performed based on 
the following criteria: 
1. The HPHC selected are representative of a variety of chemical classes and organ 
toxicity classes as defined by the FDA (carcinogen, cardiovascular toxicant, 
respiratory toxicant, reproductive and development toxicant, and addiction 
potential) [13] 
2. The HPHC reflects a specific toxic exposure or is a reliable surrogate of exposure 
to HPHC 
3. The HPHC assessed cover a broad range of formation temperatures 
4. The HPHC is specific to smoking with other sources being minor or non-existent 
5. The BoExp to a HPHC is reliably detectable using validated, reproducible, precise 
analytical methods 
6. The BoExp to a HPHC has a half-life that is suitable with the schedule of 
assessments 
Other parameters such as product evaluation, and subjective effects related to smoking 
including smoking urges and withdrawal symptoms, and the intent to use, will be evaluated. 
Twenty-four hours urine collection conducted in this study is the standard method to 
measure the levels of excretion of BoExp. 
All subjects in the CIG arm will be asked to buy their own CIG according to their 
anticipated needs for the study to minimize any changes in their smoking behavior. 
4.3 
Appropriateness of Measurements 
All laboratory measures utilized for this study are validated and are appropriate for the 
study assessments.  
All the self-report measures to be used in this study have been developed following the best 
practices (including the FDA’s Guidance for Industry Patient-Reported Outcome (PRO) 
Measures [16]), which provide the scientific basis for the development, modification, and 
validation of PRO measures in support of clinical and regulatory research. They are 
validated and previously published or adapted versions of validated questionnaires.  
4.4 
Study Duration 
The entire study duration per subject will be 11 to 38 days. This will include a screening 
period of up to 28 days prior to Admission (Day -30 to Day -3), followed by a 7-day 

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confinement period (Day -2 to Day 5, and Discharge on Day 6), and a 3-day Safety follow-
up period.  
The EOS for a randomized subject is defined as the completion of the 3-day Safety follow-
up period either after Discharge on Day 6, or after the date of early termination of the 
subject. The EOS of the entire study is the end of the Safety Follow-up Period for the last 
subject. 

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5 
Study Population 
Approximately 72 smoking healthy female or male subjects who have smoked on average 
at least 10 regular or menthol CIG per day for the last 4 weeks prior to Admission will be 
randomized (stratified by sex) into this study. Quotas will be applied to ensure that the 
randomized subjects contain at least 40% of both sexes (males and females) per arm. 
The maximum number of CIG smoked daily is not limited. Subjects must have been 
smoking for at least 3 years of smoking prior to the Screening Visit. There will be no brand 
restrictions of CIG. Smoking status will be verified with a urinary cotinine test (cotinine 
≥200 ng/mL).  
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 
Day -2 
1. Subject has signed the ICF and is able to understand the 
information provided in the ICF.  
X 
 
2. Subject is male or female and between 21 and 65 years old 
(inclusive).  
X 
 
3. Subject has been a smoker for ≥3 years prior to the 
screening visit (smoking cessation attempts during this 
period, if any, did not last >6 months).  
X 
 
4. Subject has continuously smoked on average ≥10 
commercially available mentholated or non-mentholated 
CIGs per day over the last 4 weeks prior to screening and 
admission. Smoking status will be verified based on a 
urinary cotinine test (cotinine ≥200 ng/mL).  
X 
X 
5. Subject is healthy as judged by the Investigator based on 
available assessments from the screening period (e.g., 
safety laboratory, spirometry, vital signs, physical 
examination, ECG, and medical history).  
X 
 
 

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5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the 
study: 
Exclusion Criteria  
Screening   
Day -2 
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., in emergency 
situations, under guardianship, or prisoners).  
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), which as per the judgment 
of the Investigator would jeopardize the safety of the 
subject.   
X  
  
4. 
Subject 
experienced 
within 
30 days 
prior 
to 
screening/admission a body temperature >37.5°C or an 
acute illness (e.g., upper respiratory-tract infection, viral 
infection, etc.)  
X  
X  
5. As per the Investigator’s judgment, the subject has medical 
conditions which do or will require a medical intervention 
(e.g., start of treatment, surgery, hospitalization) during 
the study participation, which may interfere with the 
study participation and/or study results.   
X  
  
6. Subject has relevant history of, or current asthma condition 
or COPD condition, and/or clinically significant 
spirometry findings at Screening or Baseline  
X  
  
7. Subject has donated blood or received whole blood or 
blood products within 3 months prior to screening.   
X  
  
8. BMI <18.5 kg/m2 or ≥32.0 kg/m2.   
X  
  
9. Positive serology test for HIV 1/2, HBV, or HCV.   
X  
  

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10. Subject has a positive alcohol breath test and/or has a 
history of alcohol abuse which as per judgement of the PI 
could interfere with their participation in the study.   
X  
X  
11. The subject has a positive urine drug test.   
X  
X  
12. Subject or one of their family membersa is a current or 
former employee of the tobacco or e-cigarette 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 
1 month or five half-lives of the previous investigational 
drug/product (whatever the longer) prior to Screening.   
X  
  
15. Subject has been previously screened or enrolled in this 
study.   
X  
  
16. Subject is pregnant (does not have negative pregnancy 
tests at screening 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  
  
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, bilateral oophorectomy, or bilateral tubal ligation,  
• 
Have primary ovarian insufficiency, or  
• 
Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 
consecutive months with no alternative pathological or physiological cause). 
c. 
Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) 
with spermicidal foam/gel/film/suppository, hormonal contraception, vasectomized partner(s), or true 
abstinence (periodic abstinence and withdrawal are not effective methods) from Screening until the end 
of the Safety Follow-Up Period. 
5.2 
Discontinuation of Subjects from the Study 
Discontinued subjects (i.e., enrolled subjects that do not complete the study) will include 
both subjects who withdraw from the study (subject’s decision) or subjects who are 
discontinued from the study by the decision of the Investigator. 

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Subjects will be informed that they are free to withdraw from the study at any time. Subjects 
should be questioned for the reason of withdrawal from the study, although they are not 
obliged to disclose it. 
If the subject withdraws from the study, this information will be fully documented by the 
PI or designee including: 
• 
The early termination procedures for safety assessments will be performed as defined 
in section 9.5, unless the subject refuses to perform the assessments. 
• 
The samples collected up to the time of withdrawal that have been analyzed and data 
collected up to the time of withdrawal will be used in the analysis and report. If the 
subject refuses that non-analyzed samples and data will be used, he/she needs to 
document his disagreement in writing. 
Subjects must be discontinued from the study for any of the following reasons: 
• 
Withdrawal of informed consent 
• 
Non-adherence to allocated product or to smoking abstinence 
• 
Subject becomes an employee of the investigational site, or any other parties involved 
in the study, or their first-degree relatives (parent, sibling, and child) 
• 
Any AE or condition (including clinically significant changes in a laboratory 
parameter) which at the discretion of the Investigator no longer justifies the subject’s 
participation in this study 
• 
Positive pregnancy test 
• 
Discontinuation considered to be in the best interest of the subject or the other 
subjects, as judged by the Investigator 
• 
Subject unwilling to use the product during the entire study duration after having done 
the product test. 
• 
An alternate subject that has completed the Screening period and has not been 
randomized. 
• 
The Sponsor terminates the study, or the study terminates at a particular site. If the 
Sponsor decides to prematurely terminate the study, the subjects will be promptly 
informed. The Investigator or designee should report the fact and the reason in writing 
to the IEC 
• 
The Investigator terminates the study or suspends the trial (e.g., due to a loss of key 
staff members, change of circumstances). If the Investigator terminates or suspends a 
trial without prior agreement of the sponsor, the investigator must inform the 
institution as applicable, and must promptly inform in the sponsor and the IEC in 
writing, including a detailed explanation. 

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Subjects may be discontinued from the study for the following reason: 
• 
Non-compliance to the study procedures based on the judgment of the Investigator 
• 
Violation of eligibility criteria 
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 (except alternate subjects). In 
general, subjects that are discontinued after randomization will not be replaced. Should 
there be the need to discontinue all subjects from one cohort, e.g., all subjects suspected to 
have contracted a disease pathogen, subjects for a replacement cohort may be enrolled and 
randomized.  
5.3 
Lost to Follow-up 
A reasonable attempt will be made to contact all participants needing to complete or resolve 
post-study activities (e.g., safety laboratory, physical examination, on-going AEs). Two 
contacts will be made via contact information provided by the subject (e.g., telephone 
number, cell phone number, email address), allowing 1 day between attempts for response. 
The first contact attempt should take place within approximately 1-2 days of the 
participant’s last visit to the investigational site. If contact is not possible, a follow-up letter 
will be sent to the participant, allowing approximately 5 business days from the time of 
delivery for a response. A progress note will be added in the data collection system for 
documentation. After a letter is sent, there should be no additional phone calls unless the 
participant has attempted to contact the investigational site and a return call attempt is 
made.  
If post-study follow-up has not been resolved within approximately 5 business days 
following delivery confirmation or the letter is not deliverable, the participant is considered 
Lost to follow-up. This is documented in the progress note and outstanding AEs are 
updated. The date of Lost to follow-up corresponds to the date of the end of study of the 
subject. 
The Investigator or designee(s) will declare the subject Lost to follow-up if the 
investigational site lost contact to the subject and the subject has reached the maximum 
number of study days (31 days) without making any contact. 
5.4 
Violation of Selection 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. 
 

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6 
Investigational Products 
6.1 
Description of Investigational Products 
P4M3 Gen 2.0 will be provided by the Sponsor.  
The distribution, dispensation 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 Battery Unit provides electrical power when required, which is 
activated by puff detection. The Battery Unit enables two power settings for adjusting the 
volume of the aerosol cloud, i.e., regular (5.5 Watts) or low (4.5 Watts) power setting. 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 
(regular or low). 
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, vegetable 
glycerin, 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 7).  
Table 7 
P4M3 Gen 2.0 variants 
Name 
Name in the 
study 
Nicotine 
concentration 
e-liquid flavor  

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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.  
6.1.2 
Reference Product / Baseline Product 
Subjects’ preferred brand of commercially available, regular or mentholated CIGs will not 
be provided by the Sponsor.  
All eligible subjects will be asked to purchase their usual brand of CIG prior to Admission 
(Day -2). Every subject needs to bring a sufficient number of unopened, single-brand packs 
of CIGs for the entire confinement period which will be kept in secured storage room at 
site with access limited to authorized personnel only 
6.1.3 
Packaging and Labeling 
At Admission (Day -2), all study subjects will provide a sufficient number of sealed packs 
of CIGs to the investigational site staff. The CIG pack provided by the subject should not 
be opened and the cellophane should be intact.  
Each pack of CIGs provided by the subject will be labeled to identify to which subject the 
CIGs belong to. The investigational site staff will return all unused products to the subjects 
at Discharge or Early termination. 
For P4M3, packs of P4M3 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 CIGs or use P4M3 and will be free to stop 
smoking CIG/using P4M3 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). 

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6.2.1 
Admission Day (Day -2 to Day -1)  
After enrolment in the study, subjects will be provided with information on the risks of 
smoking, advice on smoking cessation, and will be briefed on P4M3 (see section 7.2). They 
will be informed on the use of P4M3, including how to switch the power setting, and will 
perform a product test with P4M3 with an ad libitum use regimen for a duration of 
approximately 10 minutes per flavor. After the product test, subjects not willing to use 
P4M3 during the study will be discontinued and will be replaced. Subjects willing to 
continue participation will start their confinement period. CIG smoking will be allowed ad 
libitum from the time of Admission of the subject until approximately 11:00 PM, except 
before and during assessments requiring smoking breaks. Use of any TNP other than CIG 
and P4M3 will not be allowed after admission.  
6.2.2 
Baseline Period (Day -1 to Day 1)  
All subjects may continue smoking their CIG ad libitum, except before and during 
assessments requiring smoking breaks.  
On Day -1, subjects will be randomized to one of the four study arms. Subjects will be 
informed about their randomized study arm by the study site staff on Day 1 prior to start 
of product use.   
• 
P4M3 Classic Auburn 3.5% nicotine (CA35) arm; ad libitum use of P4M3 using 
CA35 Cartridges 
• 
P4M3 Classic Menthol 3.5% nicotine (CM35) arm; ad libitum use of P4M3 using 
CM35 Cartridges  
• 
CIG smoker arm; ad libitum use of subject’s own preferred CIG brand  
• 
SA arm; subject will abstain from CIG smoking  
6.2.3 
Exposure Period (Day 1 to Day 5)  
The Exposure period in confinement consists of 5 days of ad libitum use of the assigned 
product in the P4M3 and CIG arms. Except during study procedures, subjects can use 
P4M3 or consume CIG, and select the power setting (P4M3 only). Site staff will distribute 
assigned products to the subject and record all products distributed in the source 
documentation. Use of any TNP other than the assigned product will not be allowed and 
may, at the discretion of the investigator, result in the subject’s discontinuation from the 
study. Subjects allocated to the SA arm will be asked to abstain from CIG smoking. The 
exposure period to the assigned investigational product (IP) will end at Day 5, 11:00 PM, 
after which subjects will be asked to remain abstinent of any use of TNP until the end of 
their 24-hour urine collection and completion of study procedures on Day 6. 

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6.2.4 
Day of Discharge (Day 6)  
Following the completion of study procedures (including receiving information on the risks 
of smoking and smoking cessation advice), subjects will be discharged from confinement. 
Subjects may smoke CIG or use other TNP at their discretion after Discharge. 
6.2.5 
Safety Follow-up Period  
During the 3-day safety follow-up period, subjects will be free to use any TNP according 
to their usual habits. 
6.2.6 
Stopping Rules for Investigational Product  
For safety purposes, using P4M3 or smoking CIG should be temporarily stopped in the 
event of any signs suggesting nicotine overexposure, e.g., gastrointestinal disturbance 
(nausea, vomiting, diarrhea, stomach pains, 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 9.5), unless they disagree, or certain procedures have already been 
performed. 
6.3 
Method for Assigning Subjects to Study Arms 
At the end of the Baseline period enrolled subjects will be randomized using an interactive 
web and voice response system (IxRS) on Day -1 at any time during the day. Subjects will 
be informed of their randomized study arm in the morning of Day 1, prior to 06:30 AM 
(the start of the exposure period). Subjects will be randomized (stratified by sex) to one of 
the four study arms (CA35, CM35, CIG, and SA) in a 1:1:1:1 ratio. 
Quotas will be applied to ensure that the randomized subjects contain at least 40% of both 
sexes (males and females) per arm. 
Any alternate subject that has not been randomized will enter the 3-day Safety follow-up 
period. 
6.4 Blinding 
This is an open-label study; hence the subjects and PI(s) or designees will be unblinded to 
the subject’s arm.  

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6.5 Investigational Product Accountability and Compliance 
6.5.1 
Dispensing Investigational Product 
CIGs for consumption during the confinement period, i.e., on Day -1 to end of Exposure 
period on Day 5 11:00 PM, will be dispensed by the investigational site staff as per the 
study design.  
P4M3 for use at the product test on Admission Day -2, and from Day 1 onwards to end of 
Exposure period on Day 5 11:00 PM, comprising of a fully charged Battery Unit with a full 
Cartridge, will be dispensed by the investigational site staff, as per the study design. 
On each day of the confinement period, the time of dispense and return for each product 
(CIG/ P4M3) use will be documented from Day -1 until end of Exposure period on Day 5 
11:00 PM. 
On the Discharge on Day 6, subjects who wish to smoke CIG or other TNPs will be allowed 
to do so only after the end of 24-hour urine collection, and after completion of all study 
procedures. 
P4M3 will not be promoted for commercial distribution or test market. 
6.5.2 
Storage and Accountability  
P4M3 and CIG will be stored in a secured storage location at site with access limited to 
authorized personnel only. The study collaborator designated by the PI will be responsible 
for the storage and accountability of the IPs in accordance with Sponsor’s requirements. 
P4M3 Battery Units and Cartridges must be stored under controlled conditions 
(temperature ≥5° C, ≤30° C; humidity <70%), whereas CIG can be stored in normal 
conditions (at ambient temperature with no temperature control). 
During the confinement period, subjects will return each used P4M3 Cartridge, or butt 
(immediately after smoking) of each used CIG to the site collaborators for accountability. 
The time of return of the products will be documented in an appropriate log. 
6.5.3 
Investigational Product Retention 
Used and unused P4M3 Battery Units and P4M3 Cartridges will be returned to the Sponsor 
or disposed as per Sponsor instruction upon study completion. Smoked CIG butts will be 
disposed upon study completion once accountability is completed adequately. 
6.5.4 
Compliance to Investigational and Reference Products 

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During the confinement period, compliance will be ensured by strict distribution and 
collection of any used and unused P4M3, comprising of the P4M3 Battery Unit and the 
P4M3 Cartridge, and CIG/CIG butts by designated investigational site staff. Distribution 
and return of these products will be documented in appropriate logs. 
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 9.1.1). Spirometry assessments at Screening and at Day -1 will be 
performed at least 1 hour after stopping smoking (section 9.1.1 and 9.2.2). 
From Admission (Day -1) to Discharge (Day 6) or Early termination, use of any 
nicotine/tobacco containing products, except use as per study design of the allocated 
product, will not be permitted.  
To avoid cross smoke contamination between the four study arms during confinement 
period, subjects must use their assigned product (P4M3 or CIG) in separate smoking rooms. 
Using P4M3 or smoking CIG will not be allowed during study procedures. 
6.6.2 
Dietary Restrictions 
A standard diet will be designed by a dietician for the whole confinement period. For each 
meal, the caloric and fat content should be controlled to avoid a “high-fat” diet. A “high-
fat” diet is defined 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)” 
[17]. 
To avoid any effect on assessment of biomarkers of exposure, grilled or pan-fried meat, 
pre-cooked meats (e.g., tuna, ham, corned beef, and smoked meats), bacon and sausage will 
not be permitted. In addition, alcohol, broccoli, brussels sprouts, cauliflower, grapefruit and 
xanthine-containing foods and beverages (coffee, tea, chocolate, cocoa, mate, guarana, etc.) 
will not be allowed except when the subject will be asked to take a caffeine tablet for one 
of the assessments of CYP1A2. 
Subjects will not be allowed to bring their own food (including sweets or chewing gum, 
etc.) or beverages to the investigational site. Meals will be served according to the agreed 
schedules. Additional light snacks, fruits (except grapefruits), and raw vegetables can be 
distributed to the subjects without restrictions at any time during confinement if they 
comply with the dietician’s standard diet. Consumption of non-carbonated water is 

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allowed. Consumption of quinine-containing drinks (e.g., tonic water) is not allowed during 
the study. The same menu and meal schedule will be administered uniformly for all subjects 
in all study arms. 
A fasting state will be observed for at least 6 hours prior to blood drawings for: 
• 
Safety laboratory on Day -1 and Day 6. 
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.  
Medications will be allowed and carefully monitored during the study by the Investigator 
or designee. The Investigator or designee is responsible for the medical care including 
medication of the subjects during their participation in the study. Any decisions regarding 
the prescription of medication will be taken in the best interest of the subject. The use of 
any concomitant medication must be fully documented in the source document and 
transcribed into the CRF.  
 

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7 
Study Procedures 
Personnel performing study assessments must have the appropriate and fully documented 
training. An overview of all study assessments is shown in the schedule of events (see 
Appendix A). In this section, only the expected/planned timepoints for the various 
assessments are described. Appropriate medical advice will be provided to the subject in 
case of any medical findings requiring health care. Site personnel will adhere to the site’s 
standard operating procedures (SOPs) for study related procedures. 
7.1 
Informed Consent 
Prior to any study assessment being performed, the subject will be asked to provide his/her 
written consent to participate to the study (ICF for study participation) (section 9.1.1). All 
the assessments must start after the time of ICF signature by the subject for study 
participation. 
In addition to the consent for study participation, the subject will be asked to provide her/his 
optional consent for biobanking (see section 1.3.1). The subject’s participation in the study 
does not depend on the optional consent.  
All consents will be captured in the eCRF. 
7.2 
Information on the Risk of Smoking and Smoking 
Cessation Advice and Briefing  
At the Screening visit, before enrollment at Day -2 and at Discharge on Day 6, each subject 
will be given during the same session i) information on the risks of smoking, ii) smoking 
cessation advice, and iii) briefing on P4M3. 
The information on the risk of smoking and the advice on smoking cessation will take the 
form of a brief interview according to the WHO recommendations and of the Public Health 
Service [18, 19]. The briefing of subjects on P4M3 will address any intended or unintended 
beliefs that participants may have about P4M3. The goal of the briefing is to help ensure 
that subjects enter and exit the study with an accurate understanding of the product risks, 
including an understanding that ENDS have not been demonstrated to be less harmful than 
CIG. 
Details of the sessions will be recorded in the source document file. These sessions will be 
given to the subjects on an individual basis during a face-to-face meeting between the 
subject and the PI(s) or designee(s) and may additionally be given in a group session. 

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7.3 
Support during Abstinence from any Tobacco and Nicotine 
Containing Products 
Subjects will be offered support during periods of abstinence from any TNP during the 
study by the Investigator and/or investigational site staff. Support resources will include 
counselling and assistance, entertainment, monitoring of the subject’s behavior, and AEs. 
7.4 
Clinical and Other Assessments 
The results of the clinical assessments described in this section will be recorded in the CRF. 
Any clinically relevant medical condition detected during Screening visit assessments has 
to be documented as a concomitant disease. This also applies to clinically relevant findings 
in laboratory values, vital signs, spirometry, and ECGs detected during Screening visit 
assessments. Any untoward medical occurrence in a subject detected during the study 
which was not present at Screening visit must be documented as an AE. Worsening of a 
pre-existing condition from Screening visit onwards will also be documented as an AE.  
7.4.1 
Demographic Data 
Sex, date of birth, and race will be recorded.   
7.4.2 
Medical History, Concomitant Disease, Previous and Concomitant 
Medications 
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, e.g., 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 

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study will 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 
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, musculosceletal 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. 
7.4.4 
Body Height and Weight   
Body weight and height will be recorded at the Screening Visit, body weight will also be 
recorded at Admission Visit Day -2. 
The BMI will be calculated from the body weight and height using the following formula: 
BMI = weight in kilograms
height in meters2
= 𝑘𝑔
𝑚2 
The BMI will be used to assess eligibility for enrolment. 
7.4.5 
Vital Signs 
Vital signs will include systolic and diastolic blood pressure, respiratory rate and pulse rate. 
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 TNP for at least 15 minutes prior 
to Vital signs assessment. 
 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 will be performed at the Screening visit, at Baseline visit Day -1, and at 
Discharge (Day 6), or Early termination, in accordance with the 2019 guideline of the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) Joint Task Force 
on the standardization of spirometry [20, 21]. Spirometry predicted values will be 

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standardized to the National Health and Nutrition Examination Survey III predicted set 
[22].  
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 CIG (Screening visit). 
For those results outside of the normal range, the Investigator will determine appropriate 
follow-up including reporting of any AEs. 
Any printouts of Spirometry on thermo-sensitive paper must be photocopied and stapled 
together for inclusion in the source documents. 
7.4.7 
 Electrocardiogram 
 A standard 12-lead ECG will be recorded after the subject has rested for at least 10 minutes 
in supine position.  
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.  
 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. 
7.4.8 
Biomarker Assessment  
All bioanalytical assays and laboratory assessments will be carried out using validated 
methods (sections 7.5 and 7.6). The bioanalytical methods used will be documented in the 
respective bioanalytical plans/reports. A list of laboratories is provided in Appendix B. 
Blood samples and 24-hours urine samples will be collected according to the assessment 
schedule (Appendix A) to measure Biomarkers of Exposure to nicotine and some HPHC: 
• 
In blood: carboxyhemoglobin (% of saturation of hemoglobin) 
• 
In 24-hours urine: 3-HPMA, 2CyEMA, NNAL, S-PMA, 3-HMPMA, total NNN, 2-
HPMA, 3-OH-B[a]P, DHPMA, NEQ, Cd, Cr, Pb, and Ni (creatinine normalization) 

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7.4.9 
Laboratory Assessments 
Clinical Chemistry, Hematology, and Urine Analysis for Safety Panel 
Subjects should have fasted for at least 6 hours prior to hematology and clinical chemistry 
analyses, except at Screening visit and Early termination where non-fasting samples can be 
used. Tests will be conducted at a local laboratory (see 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 
also assessed.  
Parameters to be tested are listed in (Appendix D). 
Serology  
At the Screening visit, tests for hepatitis B virus, hepatitis C virus, and human 
immunodeficiency virus (anti-HIV1/2) will be performed. 
CYP1A2  
CYP1A2 activity will be assessed in plasma by measuring paraxanthine (PX) and caffeine 
(CAF) concentrations and calculating the PX/CAF molar metabolic ratio [23] on Baseline 
Day -1 and Day 5. Samples to measure PX and CAF will be drawn approximately 6 hours 
(±15 minutes) after the intake a caffeine tablet (approx. 200 mg caffeine). The exact time 
of intake of caffeine tablet in the morning and of the time of blood sampling must be 
recorded. 
Urine Drug Screening 
At Screening visit and on Admission Day -2, a urine drug screen will be performed. The 
urine will be screened for amphetamine type substances, barbiturates, benzodiazepines, 
cannabinoids, cocaine, and opiates. 
In case of a positive urine drug test, a re-test will not be allowed 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.  
Urine Cotinine Screening  
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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 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. 
Alcohol Test  
An alcohol breath test will be performed. 
Serum Pregnancy Test  
A serum pregnancy test will be performed for all female subjects. Subjects with a positive 
pregnancy test or unclear results (from one repetition) before product testing and enrolment 
will be considered as screen failures. In case of any positive pregnancy test, the Investigator 
or designee will inform the subject about the risks associated with smoking during 
pregnancy 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.  
7.4.10 
Sample Handling, Storage, and Shipment 
Urine drug tests and urine cotinine tests, as well as all safety panel tests and pregnancy 
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 will be described in the sample handling 
manual (SHM). Safety laboratory samples will be destroyed as per laboratory local 
regulations. All other samples (except biobanking samples) will be destroyed after the 
Clinical Study Report (CSR) has been finalized. The facilities at which the samples are 
stored will be informed in writing by the Sponsor when destruction of the samples shall be 
performed. 
Blood Samples  
Blood samples will be drawn by qualified and trained site personnel 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.  

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In total, approximately 81 mL of blood will be collected for this study including samples 
for determination of CYP1A2 activity (10 mL), COHb (30 mL) and safety laboratory 
(approximately 40.5 mL). This calculation is based on an individual volume of each sample 
of 5 mL for CYP1A2 analysis, 13.5 mL per safety laboratory assessments (including 
serology and pregnancy test), and 5 mL for COHb assessment. The total volume of blood 
drawn (approximately 81 mL) will not exceed the levels for a standard blood donation.  
Details on the procedures for collection, labelling, processing, and shipment of samples 
will be described in the SHM. 
Urine Samples  
Spot urine samples will be used for the urine drug screen, urine cotinine screen, and safety 
urine analysis at Screening visit and Baseline visit on Day -1, and after completion of 24-
hour urine sample collection on Day 6. 
24-hour urine collection Subjects will discard their first void in the morning of Day -1. 
The collection period will start immediately after. After 24-hours ±1h of urine collection, 
subjects will empty their bladder again in the morning of the visit and this urine will be 
used as the final portion of the 24-hour urine sample.  
During the collection period, all urine passed must be collected in the sampling container. 
No urine should be passed into the toilet. The start and the end time of urine collection will 
be recorded by the subject and checked by the site staff. The volume of 24-hour urine will 
be measured by the site staff upon collection of urine containers from the subjects. For 
assessment of urine BoExp, creatinine aliquots from the 24-hour urine collection will be 
taken. In the schedule of events for the 24-hour urine collection, the dot corresponds to the 
day on which the 24-hour urine collection period starts. 
Biobanking of urine If a subject gives additional consent for biobanking, additional 
samples of urine from the 24-hour collection will be collected, i.e., from the daily 
collections commencing Day -1, 1, 2, 3, 4, and 5. The samples intended for biobanking will 
be kept frozen and will be shipped to a central storage facility according to the SHM. After 
the final CSR is signed, samples of urine will be stored for a maximum duration of 2 years. 
7.5 
Other Study Procedures  
7.5.1 
Demonstration P4M3 and Product Test 
All subjects will have a demonstration of P4M3 by the investigational site staff at the 
Screening visit without product use.  

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At Admission (Day -2), after enrolment, investigational site staff will inform subjects on 
product use and subjects will have a product test with P4M3 ad libitum for a duration of 
approximately 10 minutes per flavor.  
7.5.2 
Human Puffing Topography Assessment 
Human puffing topography (HPT) involves the measurement of each subject’s unique way 
of using P4M3.  
The miniaturized detachable external data recorder (MDEDR) puffing topography device 
measures and records the flow rate, other per-puff parameters, and power setting of P4M3 
as listed in Appendix C. From the per-puff measurements, per-day parameters will be 
derived. 
The MDEDR puffing topography device will be used with the P4M3 on Day 1 to Day 5 
with data recording during ad libitum use. Data will not be collected during CIG smoking. 
The P4M3 is equipped with a pressure sensor, which measures the pressure at the Cartridge 
level. When a puff is drawn, the P4M3 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 P4M3. The MDEDR puffing topography device allows to collect these 
data when it is mechanically attached to the Battery Unit of P4M3 and electronically 
connected to its USB port. The MDEDR puffing topography device works as a data logger. 
Once connected to the P4M3, the MDEDR puffing topography device will 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 parameters, the Sponsor’s HPT group will process, validate, and 
discard any invalid data, as per the Sponsor’s SOPs. The Sponsor will provide copies of 
both the raw and validated HPT datasets to the Investigator. Only valid data will be part of 
the study database and will be analyzed. 

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7.5.3 
Weighing of P4M3 Cartridge 
P4M3 Cartridges will be weighed by the study personnel before and after daily product use 
by the subjects to estimate the amount of liquid used, to calculate delivered nicotine. 
The weight will be determined with a scale with an accuracy of 1 mg. 
7.6 
Questionnaires  
The questionnaires will be completed by the subjects (Appendix A). All subject-reported 
measures as well as instructions will be provided in the subject’s local language. 
7.6.1 
Nicotine/Tobacco Product Use History 
At the Screening visit and at Admission (Day -2), subjects will be asked questions about 
their TNP use history. The questions will capture frequency and quantity TNP use over the 
past 4 weeks, and number of continuous years of CIG smoking. This information will be 
used as characteristics of the study subjects, to assess their eligibility to participate in the 
study, and to serve as baseline values. 
7.6.2 
Fagerström Test for Nicotine Dependence (Revised Version) 
Self-reported level of nicotine dependence will be assessed via a questionnaire on Baseline 
Day -1 using the Fagerström Test for Nicotine Dependence (FTND) in its revised version 
[24]. 
The questionnaire consists of six questions which will be answered by the subjects 
themselves. The scores obtained on the test permit the classification of nicotine dependence 
into three levels: Mild (0-3 points), moderate (4-6 points), and severe (7-10 points) [24]. 
This information will be used as characteristics of the study subjects. 
7.6.3 
ABOUT – Product Experience Questionnaire 
Product experience will be assessed via a subject self-reported outcome measure, part of 
the ABOUT toolbox [25].  
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) [26] 
to RRPs and the Product Evaluation Scale [27]. 
The questionnaire assesses the degree to which subjects experience the reinforcing effects 
of P4M3 Gen 2.0 with CA35 and CM 35 Cartridges use in CIG smokers switching to P4M3 
compared to subjects continuing CIG smoking by measuring: 

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• 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”. A score for each subscale will be computed based on the 
scoring rule established by the questionnaire developer [26]. 
Symptoms or worsening of symptoms documented in the questionnaire do not need to be 
documented as additional AEs as  the main source for AE collection is be the face-to-face 
interview between the subject and study site staff, using open, non-directive questions, as 
described in section 8.2.  
 

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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) 
Concomitant diseases whose severity is increasing after the screening is to be captured as 
an AE or SAE, depending on if any seriousness criterion is met.  
Therapies or surgical interventions including admissions to hospital that had been planned 
before the ICF signature should not be considered AEs/SAEs.  

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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 for recording into safety database. 
Information recorded for AEs/SAEs will include verbatim description, start and stop dates 
and times, seriousness, severity (intensity), causal relationship with IP and study 
procedures, action taken with IP (e.g., reduced, not changed), other action taken (e.g., 
treatment administered, if led to the subject’s discontinuation from the study), and outcome 
(e.g., resolved, stabilized).  
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.  
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) 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, 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 8 
Intensity of Adverse Events 
Mild: 
Easily tolerated, not interfering with normal everyday activities 

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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 CIG) 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 or CIG) 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 6.7 of the current Investigator’s Brochure [6].  
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 additional 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. 

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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. 
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 Investigator or designee is responsible for submitting the relevant reports of SAEs that 
occur during the study to the IEC, according to local regulations. 
8.4 
Reporting of Other Abnormal Findigs 
The other abnormal findings discovered during different clinical assessments (e.g., ECG, 
spirometry, vital signs, body weight) should be evaluated for the clinical significance by 
the Investigator/designee based on his/her medical judgement. All abnormal clinically 
significant test results or clinical examination findings can, at the discretion of the 
Investigator, be reported as AEs and handled according to the directions from section 8.2. 
8.5 
Reporting and Follow-Up of Pregnancies 
8.5.1 Period of Collection and Follow-up 
Pregnancies detected between the time of signature of the ICF and the time before first 
exposure to the IP will be considered a reason for screen failure. No pregnancy form will 
be filled in for that case, however the diagnosed pregnancy must be captured in the screen 
failure page of the CRF. 
Any pregnancy detected after enrollment 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. 

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Any pregnancy that was potentially associated with exposure to IP (P4M3 and CIG) will 
be followed-up until an outcome is reached (e.g., normal delivery, spontaneous abortion, 
or voluntary termination), and 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. 
8.5.2 Reporting of Pregnancies 
The Investigator is responsible for informing the responsible IEC of any pregnancy case 
that was reported during the study, as determined by local regulations. 
8.6 
Adverse Events Leading to Discontinuation 
Subjects who are discontinued from the study because of an AE will undergo the early 
termination procedures (section 9.5), as soon as practical after discontinuation and will 
enter the 3-day Safety Follow-Up Period.  
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 product events, affecting P4M3 Battery Unit, P4M3 Cartridge, 
or MDEDR, including malfunction or misuse (use not in accordance with its label and 
instruction) by a subject will be documented by the Investigator. Information regarding 
P4M3 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 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 2.3.3). 
Furthermore, any malfunction or misuse of P4M3 that leads to an AE/SAE will follow the 
same processes as described above. 

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9 
Study Activities 
A detailed schedule of assessment can be found in Appendix A. Measurements not 
conducted at the exact timepoint but conducted within the given time window (if 
applicable) do not constitute a protocol deviation but an accepted variability for the given 
timepoint. 
In general, if no start time for the procedures is provided, then the procedure can be 
performed at any time during the day. 
9.1 
Screening Period 
9.1.1 
Screening Visit (Day -30 to Day -3) 
The Screening visit will be performed ≤28 days prior to enrollment at Admission (Day -2). 
First, the ICF along with study information will 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. Once the ICF is signed and dated and timed, the 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. 
Screening activities and examinations are listed in Table 9. 
Table 9 
Time Schedule – Screening Visit 
Time 
Procedures 
Additional Information 
Start of Procedure 
Screening Visit 
 
Prior to any other 
study procedure 
Informed consent process and 
signature of ICF 
 
During the Visit 
Information on risks of 
smoking, advice on smoking 
cessation  
 
 
Inclusion/exclusion criteria 
 
 
Smoking history 
Tobacco/Nicotine Product 
Use History questionnaire 
 
ECG 
 
 
Spirometry 
 
 
Demographics 
 
 
Medical History/  
Concomitant Diseases 
 

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Time 
Procedures 
Additional Information 
Start of Procedure 
Screening Visit 
 
 
Prior (≤4 weeks) and 
concomitant medication  
 
 
Physical examination 
 
 
Body height and weight/ BMI 
 
 
Vital signs  
 
 
Serology 
HBV, HCV, and HIV 
 
Collection of blood sample 
- 
Safety panel 
(hematology, clinical 
chemistry) 
- 
Pregnancy test (all 
female subjects) 
 
Collection of spot urine  
 
- 
Safety panel 
- 
Drug test  
- 
Cotinine test 
 
Alcohol breath test 
 
 
Review of eligibility criteria  
 
 
P4M3 demonstration 
Without product use 
 
Identification of current CIG 
brand 
Explain CIG provision for 
confinement period by 
subject 
 
AE/SAE recording 
 
Abbreviations:  
AE = Adverse event; BMI = Body mass index; CIG = Conventional cigarette(s); ECG = Electrocardiogram; HBV = 
Hepatitis B virus; HCV = Hepatitis C virus; HIV = Human immunodeficiency virus; ICF = Informed consent form; P4M3 
= e-cigarette; SAE = Serious adverse event. 
If the eligibility criteria are met, the investigational site staff will contact the subject to 
arrange Visit Day -2 at the site. 
9.2 
Baseline Period (Enrollment and Randomization) 
9.2.1 
Admission Day -2 
Day -2 should be scheduled within 27 days after Screening visit 2. The procedures of the 
Admission visit on Day -2 (Table 10) can be performed in order deemed most practical 
according to Table 10. 
                                                 
2 Alternate subjects will have to repeat the Admission Day -2 visit to qualify for randomization. The data of that 
repeated visit will be captured in the database as “Admission Day -2 visit – Second occurrence”.  
 

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Enrolment of a subject will take place at Day -2 only if all eligibility criteria are met, after 
confirmation of a negative pregnancy test (for female subjects only). The confinement 
period will start after the successful enrolment. All other procedures and data collection 
will be completed following the enrollment of the subject.  
Table 10 
Time Schedule – Admission Visit Day -2 
Time 
Procedures 
Additional Information 
Start of Procedure 
Admission Visit Day -2 
 
Start of the visit 
Check-in at site 
CIG use will be allowed on 
site on Day -2 
Prior enrolment 
Collection of blood sample  
- 
Pregnancy test 
 
Collection of spot urine  
 
- 
Drug test  
- 
Cotinine test 
 
Alcohol breath test 
 
 
Body weight 
BMI calculation 
 
Vital signs  
 
 
Smoking history 
Tobacco/Nicotine Product 
Use History questionnaire 
 
Inclusion/exclusion criteria 
 
 
Information on the risks of 
smoking, advice on smoking 
cessation, and briefing on 
P4M3 
 
Prior to breakfast 
Enrollment 
After confirmation of the 
eligibility of the subject 
During the visit 
Breakfast 
 
 
Lunch 
 
 
Detailed training on how to 
use P4M3 
Subject can use P4M3 ad 
libitum for approximately 
10 minutes per flavor 
 
Concomitant medication 
 
 
Concomitant disease status 
 
 
AE/SAE recording 
 
 
P4M3 product events 
 
End of the visit 
Subjects remain confined 
11:00 PM stop of smoking 
Abbreviations:  
AE = Adverse event; BMI = Body mass index; CIG = Conventional cigarette(s); P4M3 = e-cigarette; SAE = Serious 
adverse event. 

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9.2.2 
Baseline Visit Day -1 
Baseline exams will be performed, and subjects will be randomized at Baseline Visit. 
Randomization will take place only for subjects who are willing to comply with study 
procedures and to use P4M3 or keep abstinent from smoking (SA) for at least 5 days. Table 
11 shows the assessments that will be performed at Baseline Visit Day -1. 
Table 11 
Time Schedule – Baseline Visit Day -1 
Time 
Procedures 
Additional Information 
Start of Procedure 
Baseline Visit Day -1 
 
Prior to breakfast 
Spirometry 
 
 
Collection of blood sample 
After ≥6 hours of fasting 
- 
Safety panel 
(hematology, clinical 
chemistry) 
 
Collection of spot urine 
- 
Pregnancy test 
 
ECG 
 
 
Vital signs 
 
 
Concomitant medication 
 
 
Start 24-hour urine collection 
For Day -1 
 
COHb in blood 
 
 
CYP1A2 activity 
Intake of caffeine tablet 6 hrs 
(±15 min) ahead of blood 
sample collection 
Prior to randomization 
Breakfast 
 
During the visit 
Randomization 
Per IxRS 
 
FTND 
 Questionnaire 
 
Concomitant medication 
 
 
Concomitant disease status 
 
 
AE/SAE recording 
 
 
ABOUT–Product Experience 
Questionnaire 
 
Subjects are informed of their 
assigned study arm 
 
 
Collection of CIG butts for 
accountability 
 
End of visit (11:00 PM) 
CIG ad libitum consumption 
stop 
Subject remains confined 
Abbreviations: 
ABOUT = Assessment of behavioral outcomes related to tobacco and nicotine products; AE = Adverse event; CIG = 
Conventional cigarette(s); COHb = Carboxyhemoglobin; CYP1A2 = Cytochrome P450 1A2; ECG = Electrocardiogram; 
FTND = Fagerström test for nicotine dependence; IxRS = Interactive web and voice response system; SAE = Serious 
adverse event. 

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9.3 
Randomized Exposure Period  
9.3.1 
Exposure in Confinement Period 
On Day 1, subjects will be informed about their allocation to a study arm, i.e., either 
P4M3 CA35, P4M3 CM35, CIG, or SA. Table 12 shows the assessments that will be 
performed at Day 1, 2, 3, 4, and 5; Table 13 shows the assessments that will be performed 
at Day 6 ahead of the Discharge from confinement: 
Table 12 
Time Schedule – Day 1, 2, 3, 4, and 5 
Time  
Procedures 
Additional Information 
Start of Procedure 
Day 1, 2, 3, 4, and 5 
 
Prior to breakfast 
Vital signs 
 
COHb in blood 
 
 
Completion of Day -1 urine 
collection 
 
 
Start of next 24-hour urine 
collection 
Each day of the confinement 
period.  
Day 5 collection will be 
completed in the morning of 
Day 6, ahead of Discharge 
 
Day 1 only:  
Inform subjects on allocated 
study arm 
 
During the visit 
Breakfast 
 
 
Distribution of the P4M3 
Battery Units and Cartridges 
to subjects in P4M3 arms 
 
 
HPT 
P4M3 arms only 
 
Day 5 only:  
CYP1A2 activity 
Intake of caffeine tablet 6 hrs 
(± 15 minutes) ahead of the 
blood sample collection 
 
Concomitant Medication 
 
 
Concomitant Diseases 
 
 
AE/SAE recording 
 
ABOUT–Product Experience Questionnaire 
 
P4M3 product events, 
malfunctions/ misuse 
P4M3 arms only 
End of visit (11:00 PM) Collection of CIG butts  
Subjects remain confined 
 
Cartridge/e-liquid use 
Subjects remain confined 
Abbreviations: 

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ABOUT = Assessment of behavioral outcomes related to tobacco and nicotine products; AE = Adverse event; COHb = 
Carboxyhemoglobin; CIG = Conventional cigarette(s); CYP1A2 = Cytochrome P450 1A2; HPT = Human puffing 
topography; P4M3 = e-cigarette; SAE = Serious adverse event. 
At Day 6, following completion of the procedures and examinations (Table 13), the 
subjects will be discharged for the Safety follow-up period.  
Table 13 
Time Schedule – Discharge Day 6 
Time 
Procedures 
Additional Information 
Start of Procedure 
Day 6 
 
Prior to breakfast 
Collection of blood sample 
After ≥6 hours of fasting 
- 
Safety panel 
(hematology, clinical 
chemistry) 
- 
Pregnancy test (all 
female subjects) 
 
Completion of Day 5 urine 
collection 
 
 
Collection of spot urine  
- 
Safety panel 
 
Vital signs 
 
 
Spirometry 
 
 
ECG  
 
During the visit 
Breakfast 
 
 
Concomitant medication 
 
 
Concomitant diseases 
 
 
AE/SAE recording 
 
Information on the risk of 
smoking/smoking 
cessation 
advice and debriefing on P4M3 
 
End of the visit 
Check-out from site 
 
Abbreviations:  
AE = Adverse event; ECG = Electrocardiogram; P4M3 = e-cigarette; SAE = Serious adverse event. 
9.4 
Safety Follow-up Period 
After Discharge at Day 6, 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 8.1.2. 

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9.5 
Early Termination Procedures 
When a subject is discontinued from the study, all early termination procedures listed in 
Table 14 are performed unless the subject refuses to perform the assessments or the 
procedures have already been performed during that study day. 
Table 14 
Time Schedule – Early Termination Visit 
Procedures 
Additional Information 
 
 
Clinical laboratory parameters (hematology, 
clinical chemistry) blood collection 
After ≥6 hours of fasting, if 
possible 
- 
Safety panel 
- 
Pregnancy test (female only) 
Urine analysis  
- 
Safety panel 
Vital signs  
 
ECG  
 
Spirometry 
 
Information on the risks of smoking, advice on 
smoking cessation and briefing on P4M3  
 
Concomitant medication 
 
Concomitant diseases 
 
AE/SAE recording 
 
P4M3 product events malfunctions/misuse 
P4M3 arms only 
Discharge  
 
Abbreviations:  
AE = Adverse event; ECG = Electrocardiogram; P4M3 = e-cigarette; SAE = Serious adverse event 
 

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10 Quality Control and Quality Assurance 
10.1 Monitoring 
The Clinical Research Associate (“Monitor”) of the contract research organization (CRO) 
will be responsible for the monitoring of the study. Monitoring will be performed according 
to CRO’s SOPs and as per the agreed monitoring plan with the Sponsor. 
The PI(s) or designee(s) shall permit the Monitor to review study data as frequently as 
considered necessary to ensure that data are being recorded in an adequate manner and that 
protocol adherence is satisfactory met. 
The PI(s) or designee(s) shall access medical records for the Monitor in order that entries 
in the CRFs may be verified. As part of his/her(their) responsibilities, the PI(s) or 
designee(s) is(are) expected to ensure that the study adheres to GCP requirements [2] . 
An Investigator’s meeting will be held prior to the site initiation visit. During this meeting, 
the general training of the study procedures and specific training on selected procedures 
will be completed and documented. 
Subsequently to the Investigator’s meeting, and before the first subject is screened into the 
study, the site initiation visit will be conducted by the Monitor and, if necessary, together 
with the Sponsor or its authorized representative. The purpose of the site initiation visit is 
described in the monitoring plan. 
During the study, the Monitor will have regular contact with the study site, including 
interim monitoring visits. The purpose of these visits is described in the monitoring plan. 
Communication by telephone, mail, and e-mail may be used as needed to supplement site 
visits. The Principal Investigator and study personnel will cooperate with the Monitor, 
provide all appropriate documentation, and will be available to discuss the study. 
The Monitor and the Sponsor’s personnel will be available between visits should the 
Principal Investigator or other staff at the sites need information and advice. 
Site visits will be made at regular intervals during the study. The frequency of the 
monitoring visits will be defined in the monitoring plan agreed with the Sponsor. 
The PI(s) or designee(s), must be available during the monitoring visit to review the data, 
resolve any queries and to allow direct access to the subject’s records for source data 
verification. 

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10.2 Training of Staff 
A formal meeting (Investigator’s meeting) will be conducted prior to site initiation. During 
this meeting, the Sponsor or its authorized representative will discuss the requirements of 
the clinical study protocol and related documents and will also provide training to the 
relevant systems and other study-specific procedures. The activities of this meeting will be 
described in the monitoring plan. 
Further to the Investigator meeting, the PI(s) or designee(s) will ensure that appropriate 
training relevant to the study is provided to all staff involved in the study, and that any new 
information relevant to the performance of this study is forwarded in a timely manner to 
the staff involved. The PI(s) or designee(s) will maintain a record of all individuals involved 
in the study. 
10.3 Audits and Inspections 
Good Clinical Practice regulations require that there are independent inspections of clinical 
program activities. Such inspections may be performed at any time before, during and/or 
after the study. 
Authorized representatives of the Sponsor, regulatory agencies and/or an IEC may perform 
audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted and data were recorded, 
analyzed, and accurately reported according to the protocol, ICH/GCP guidelines [2] , and 
any applicable regulatory requirements. The PI(s) or designee(s) will contact the Sponsor 
or the authorized representative immediately if contacted by a regulatory agency about an 
inspection at their site. 
The PI(s) or designee(s) is(are) responsible for maintaining a comprehensive and accurate 
filing system of all study-related documentation that will be suitable for inspection at any 
time by the Sponsor, its authorized representative, and/or regulatory agencies. In signing 
this protocol, the PI(s) or designee(s) understand(s) and agree(s) to provide access to the 
necessary documentation and files. 
10.4 Risk Management 
According to ICH-GCP E6(R2) Section 5, the sponsor will implement a system to manage 
quality throughout all stages of the study process. Pursuant to this, a risk management 
process will be implemented including identification and scoring of risks, identification of 
critical data and processes as well as the definition of Key Risk Indicators (KRI) and 
Quality Tolerance Levels (QTL).  

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This risk management approach will be described in an Integrated Risk and Quality 
Management Plan with risks described in a Risk Assessment and Categorization Tool 
(RACT) which will be developed during the set-up phase of the study and reviewed through 
all stages of the study.  
In addition, at the end of study, the sponsor will describe the quality management approach 
implemented in the study and summarize important deviations from the predefined quality 
tolerance limits and remedial actions taken in the CSR. 

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11 Data Management Activities 
All data management activities will be described in detail in the data management plan 
(DMP) and documents specified therein. The electronic systems used to collect subject data 
and CRF will be FDA 21 CFR Part 11 compliant. 
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 
any 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.  

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Information from the source documents will represent the primary source of protocol 
deviations. Information following investigational site monitoring and other manual reviews 
will be documented in the investigational site visit reports, follow-up letters, audit 
documentation, or other manual review and will be recorded and tracked in the CTMS or 
any 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 is 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. 

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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.  
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: 
Medical history:  
Medical Dictionary for Regulatory Activities 
(MedDRA®)  
Adverse events / Procedures:  
MedDRA®  
Medications:  
WHO Drug Global  
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 changes may 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. 

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12 Planned Statistical Methods 
12.1 General Considerations 
Full details of the statistical analyses will be described in the Statistical Analysis Plan 
(SAP). Any changes to the planned statistical methods will be documented in the SAP and 
clinical study report. The statistical evaluation will be performed using SAS®, version 9.2 
or later. 
12.1.1 
Stratification Criteria 
The following stratification factor at baseline will be used in some of the analyses: 
• Sex (male and female). 
12.1.2 
Definitions for Statistical Data Analysis 
The following definition will be used for the statistical analysis of safety data: 
Term 
Definition 
Actual exposure arm 
Categorical variable representing the actual study arm of enrolled 
subjects. Non-randomized subjects will be assigned to the 
category ‘Enrolled but not randomized’. Randomized subjects 
will be assigned to the category corresponding to their 
randomization study arm.  
In case of mis-randomization (use of a different product from the 
allocated one, use of a TNP while being assigned to the smoking 
cessation arm, or be smoking abstinent while being assigned to 
the CIG or one of the P4M3 arms), subjects will be assigned to 
the arm corresponding to their actual exposure.  
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by randomization study arm, subject, and 
study day unless otherwise specified. 
For continuous data, summary statistics will include the number of subjects (n), the number 
and percent of subjects with missing data, the arithmetic mean, arithmetic standard 
deviation (SD), 95% confidence interval (CI) of the arithmetic mean, median, first and third 
quartiles, minimum, maximum; for log-normal data, the geometric mean, geometric 
coefficient of variation (CV), and 95% CI of the geometric mean will be presented instead 
of arithmetic mean, SD, and 95% CI of the arithmetic mean, respectively. Post-baseline 

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summaries will include change from baseline apart from log-normal variables which will 
present % change from baseline.  
When applicable, the number and % of subjects with values below the lower limit of 
quantification (LLOQ) or above the upper limit of quantification (ULOQ) will also be 
presented.  
For categorical data, the number and % of subjects with missing data, frequency counts, 
and percentages will be presented. 
12.1.4 
Handling of Missing Values and of Values outside the Detection Limits 
Values outside detection limits will be substituted using the following rules (e.g., for BoExp 
parameters): 
• Values below LLOQ will be imputed using LLOQ/2. 
• Values above ULOQ will be imputed using ULOQ. 
Except otherwise stated, other missing values will not be imputed. 
Handling of missing answers to questionnaires will be described in the SAP. 
12.2 Product Use 
Considering the design of the study, it is expected that, during the exposure period, subjects 
will only use products corresponding to their randomization arm. 
Mis-randomized subjects will be classified according to their actual exposure arm for safety 
analysis (see section 12.1.2) and excluded from all analyses using the Per Protocol Set. 
12.3 Analysis Sets 
The following analysis sets will be used for the data analyses. 
12.3.1 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) will consist of all the randomized subjects who have at least 
one post-randomization product use experience (if randomized to CIG or one of the P4M3 
arms) and who have at least one valid non-safety assessment after randomization. The FAS 
will be analyzed by randomized study arm. 
12.3.2 
Per Protocol Set (PP) 
The Per Protocol Set (PP) will be a subset of FAS and include all randomized subjects who 
fulfill key compliance criteria of the protocol and have no major protocol deviation impacting 

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the evaluability of the primary objective (to be further described in the SAP). The PP will be 
analyzed by randomized study arm. 
12.3.3 
Safety Set (SAF) 
The safety population will consist of all the subjects enrolled in the study with at least one 
exposure to P4M3 (product test at Admission Day -2), and who have at least 1 valid value 
for a safety assessment. The SAF will be analyzed according to actual exposure arm (see 
definition in section 12.1.2). 
12.4 Demographics and Baseline Characteristics 
Demographics include sex, age, race, body weight, height, body mass index (BMI). 
Baseline characteristics include TNP use history, spirometry measurements (FEV1, FEV1 
% predicted, FVC, FVC % predicted, and FEV1/FVC), and FTND questionnaire score. 
Demographics and baseline characteristics will be summarized as follows: 
• By randomization study arm for the FAS, 
• By randomization study arm for the PP, 
• By actual exposure arm for the SAF. 
12.5 Primary Objective 
The primary objective of the study is to demonstrate the reduction of BoExp to selected 
HPHC in smokers switching from CIG to P4M3 (combined CA35 and CM35 arms) 
compared to continuing CIG smoking for 5 days. 
12.5.1 
Primary Estimand Analysis 
The primary estimand of the primary objective is defined by the following components: 
• Product Use Under Evaluation: This corresponds to the study arms (CIG, 
P4M3 CA35, P4M3 CM35, or SA) randomly allocated to subjects and for which 
they have fulfilled key compliance criteria of the protocol without major protocol 
deviation impacting the evaluability of the primary objective (as defined by the PP). 
• Target Population: This is the population of adult smokers who satisfy all eligibility 
criteria (see section 5.1). 
• Variables of Interest: 3-HPMA, 2CyEMA, total NNAL (all expressed as 
concentration adjusted for creatinine in 24-hour urine), and COHb (expressed as % 
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• Intercurrent Events (ICEs): 
o Non-adherences to the randomization study arm: these ICEs are out of scope 
of this primary estimand, and related subjects will be excluded from this 
analysis. 
o Study discontinuation and death: data related to subjects who discontinued 
or died during the exposure period will be included only if they were 
adherent until the time of discontinuation/death. Missing data after 
discontinuation/death will be dealt with as described in section 12.5.1.3. 
o Subjects being tested COVID positive during the study: subjects being 
tested COVID positive during the study will be included only until the time 
of the diagnosis or vaccination. Data collected after or at the date of the 
COVID positive test will be set to missing and dealt with as described in 
section 12.5.1.3. 
o Changes in comorbidities: subjects with comorbidities or worsening of an 
existing comorbidity will be included as this change may be linked to the 
reduction or modification of their CIG consumption. 
• Population-Level Summary Statistic: geometric mean ratios between P4M3 (CA35 
and CM35 combined) and CIG of the BoExp under consideration at Day 5. 
12.5.1.1 
Baseline Comparability 
Demographics and baseline characteristics (as described in section 12.4) will be reported 
by randomization study arm for the PP.  
Given that the study is randomized, demographics and baseline characteristics are expected 
to be balanced between study arms. Nevertheless, sex and baseline value of the BoExp will 
be used as covariates in the statistical model (see section 12.5.1.4).  
12.5.1.2 
Descriptive Analysis 
Descriptive statistics as mentioned in section 12.1.3 for the variables of interest and 
associated changes from baseline will be reported by randomization study arm for the PP 
and by study day. Descriptive statistics stratified by the factor described in section 12.1.1 
will also be computed. 
12.5.1.3 
Missing Data Strategy 
In this analysis, some missing data might occur because of ICEs or because of missing 
samples, laboratory measurements errors, etc. The main analysis model (see 
section 12.5.1.4) assumes that subjects with missing data would have outcome data like 

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those in similar subjects in the same group. This type of assumption is referred to as Missing 
at Random (MAR). This assumption is aligned with the definition of the primary estimand. 
12.5.1.4 
Main Analysis 
The primary analysis will be conducted in the PP and based on a mixed model for repeated 
measurements (MMRM). An unstructured matrix will be used to model the variance-
covariance structure within subjects. If this model fails to converge, then the following 
variance-covariance matrix will be used (in order) until one converges: Heterogeneous 
Toeplitz, Heterogeneous First Order Autoregressive, Heterogeneous Compound 
Symmetry, Variance Components, Compound Symmetry, and finally no repeated 
statement. 
The model for the endpoint expressed on the log-scale will adjust for the endpoint value at 
baseline (log-scale), the Day, the randomization study arm and its interaction with Day, 
and sex.  
The model described above will be implemented in the SAS® language as: 
PROC MIXED data=dataset method=reml nobound; 
    class Arm Day Subject Sex; 
    model Log(Endpoint) = Log(Baseline) Day Arm Arm*Day  
          Sex / ddfm=kenwardroger2 solution; 
    repeated Day / subject=Subject(Arm) type=un rcorr; 
    lsmeans Arm*Day / pdiff cl; 
    lsmestimate ‘Contrast P4M3 (CA35 and CM35 combined) vs. CIG’ exact syntax to be adjusted     
depending on the coding of class variables / cl upper alpha=0.025; 
    lsmestimate ‘Contrast P4M3 CA35 alone vs. CIG’ exact syntax to be adjusted     depending 
on the coding of class variables / cl upper alpha=0.025; 
    lsmestimate ‘Contrast P4M3 CM35 alone vs. CIG’ exact syntax to be adjusted     depending 
on the coding of class variables / cl upper alpha=0.025; 
RUN; 
LS-means per randomization study arm and day will be obtained (on the log-scale), as well 
as pairwise differences between arms per day, together with their 95%-confidence intervals 
and (unadjusted) p-values. Exponentiation of these quantities will lead to the geometric LS-
means per randomization study arm and (geometric) ratios between arms with their 
associated 95%-confidence intervals.  
The exponentiation of the ‘lsmestimate’ statement above entitled ‘Contrast P4M3 (CA35 
and CM35 combined) vs. CIG’ will allow contrasting the 2 P4M3 Gen 2.0 CA35 and CM35 
study arms combined against the CIG arm and will be used to assess the primary study 
hypothesis (see section 12.5.1.4.1). Similarly, the exponentiation of the 2 subsequent 
‘lsmestimate’ statements will be used to assess the key secondary objectives 2 and 4 if the 
procedure of fixed sequence testing allows it (see section 12.6.1). 

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12.5.1.4.1 Success Criteria 
The primary study hypothesis is about demonstrating the reduction of the four BoExp to 
selected HPHC given in Table 4 in smokers switching from CIG to P4M3 (CA35 and CM35 
combined) for 5 days as compared to those who continue smoking CIG. For each individual 
BoExp, this will be evaluated using the 1-sided statistical test with a type I error level of 
2.5% given by the ‘lsmestimate’ statement ‘Contrast P4M3 (CA35 and CM35 combined) 
vs. CIG’ of the model described in section 12.5.1.4.  
The study will be declared successful if the ratio of the geometric means between P4M3 
(CA35 and CM35 combined) over CIG is statistically lower than 1 at Day 5 for all four 
BoExp tested in the primary objective given in Table 4. 
12.5.1.5 
Supplementary Analysis 
The model described in section 12.5.1.4 allows contrasting all randomization study arms at 
Days 1, 2, 3, 4, and 5. While only the contrast between the two P4M3 arms combined and 
CIG at Day 5 will be used for the primary objective assessment, the following pairwise 
comparisons at Days 1, 2, 3, 4, and 5 will also be reported, together with their unadjusted 
p-values and 95%-confidence interval: 
• P4M3 (CA35 and CM35 combined) vs. CIG 
• SA vs. CIG 
• P4M3 (CA35 and CM35 combined) vs. SA 
• P4M3 CA35 vs. CIG 
• P4M3 CM35 vs. CIG 
• P4M3 CA35 vs. SA 
• P4M3 CM35 vs. SA 
• P4M3 CA35 vs. P4M3 CM35 
Note that the contrasts P4M3 CA35 vs. CIG and P4M3 CM35 vs. CIG will also be 
estimated one-sided with a type I error level of 2.5% through the additional ‘lsmestimate’ 
statements provided in section 12.5.1.4. These contrasts will be used to assess the key 
secondary objectives 2 and 4 if the procedure of fixed sequence testing allows it (see 
section 12.6.1). 
12.5.2 
Secondary Estimand Analysis 
This analysis refers to the secondary estimand of the primary objective defined in 
section 3.1. This estimand is implementing the “treatment policy strategy” and reflects the 
intention‑to‑treat (ITT) principle. It will evaluate the effect of switching to P4M3 as 
compared to continuing to smoke CIG in the FAS rather than in the PP. It is defined by the 
following components: 

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• Product Use Under Evaluation: This corresponds to the study arm (CIG, 
P4M3 CA35, P4M3 CM35, or SA) randomly allocated to subjects and is 
independent of whether subjects were adherent or not (FAS). 
• Target Population: This is the population of adult smokers who satisfy all eligibility 
criteria (see section 5.1). 
• Variables of Interest: 3-HPMA, 2CyEMA, total NNAL (all expressed as 
concentration adjusted for creatinine in 24-hour urine), and COHb (expressed as % 
of saturation of hemoglobin). 
• Intercurrent Events (ICEs): All ICEs will be treated as ‘treatment policy strategy’. 
This means that the values of the variable of interest is used regardless of whether 
the ICEs occur. 
• Population-Level Summary Statistic: Geometric mean ratios between P4M3 (CA35 
and CM35 combined) and CIG of the BoExp under consideration at Day 5. 
12.5.2.1 
Baseline Comparability 
Demographics and baseline characteristics (as described in section 12.4) will be reported 
by randomization study arm for the FAS.  
Given that the study is randomized, demographics and baseline characteristics are expected 
to be balanced between study arms. Nevertheless, sex and baseline value of the BoExp will 
be used as covariates in the statistical model (see section 12.5.2.4). 
12.5.2.2 
Descriptive Analysis 
Descriptive statistics as mentioned in section 12.1.3 for the variables of interest and 
associated changes from baseline will be reported by randomization study arm for the FAS 
and by study day. Descriptive statistics stratified by the factor described in section 12.1.1 
will also be computed. 
12.5.2.3 
Missing Data Strategy 
In this analysis, some missing data might occur because of missing samples, laboratory 
measurements errors, etc. The main analysis model (see section 12.5.2.4) assumes that 
subjects with missing data would have outcome data like those in similar subjects in the 
same group (MAR assumption). This assumption is aligned with the definition of the 
secondary estimand. 

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12.5.2.4 
Main Analysis 
This analysis will be conducted using the same model as the one described in 
section 12.5.1.4, except that it will use the FAS instead of the PP and all available data will 
be included in the model. 
In section 12.5.1.4.1, the criterion to declare the study successful was provided. Here, the 
same difference will be computed and interpreted exploratorily using the same type I error 
level as for the primary confirmatory hypothesis.  
12.5.2.5 
Supplementary Analysis 
The model described in section 12.5.2.4 allows contrasting all randomization study arms at 
Days 1, 2, 3, 4, and 5. All the following pairwise comparisons at Days 1, 2, 3, 4, and 5 will 
be reported, together with their unadjusted p-values and 95%-confidence interval: 
• P4M3 (CA35 and CM35 combined) vs. CIG 
• SA vs. CIG 
• P4M3 (CA35 and CM35 combined) vs. SA 
• P4M3 CA35 vs. CIG 
• P4M3 CM35 vs. CIG 
• P4M3 CA35 vs. SA 
• P4M3 CM35 vs. SA 
• P4M3 CA35 vs. P4M3 CM35 
Like what will be done for the primary estimand analysis, the contrasts P4M3 CA35 vs. 
CIG and P4M3 CM35 vs. CIG will also be estimated one-sided with a type I error level of 
2.5% through the additional ‘lsmestimate’ statements provided in section 12.5.1.4. These 
contrasts will be used exploratorily to assess the key secondary objectives 2 and 4 if the 
procedure of fixed sequence testing allows it for the FAS (see section 12.6.1). 
12.6 Secondary Objectives 
12.6.1 
Key Secondary Objectives 
The 1st key secondary objective of the study is to demonstrate the reduction of additional 
BoExps to selected HPHC given in Table 5 in smokers who switch from CIGs to P4M3 
use compared to those who continue to smoke CIG. The statistical analysis for each of these 
additional BoExp will done similarly to those belonging to the primary objective (except 
the Success Criteria described in section 12.5.1.4.1). More specifically, the analyses 
described as primary estimand (see section 12.5.1) and secondary estimand (see 
section 12.5.2) can be repeated, replacing the endpoints listed in Table 4 by those of Table 
5. 

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The analysis of the subsequent key secondary objectives (from 2 to 5) will use the statistical 
models developed to assess the primary and 1st key secondary objectives, except that they 
will contrast either CA35 vs. CIG or CM35 vs. CIG (instead of CA35 and CM35 combined 
vs. CIG).  
The evaluation of the key secondary objectives will be done using a procedure of fixed 
sequence testing (see Figure 3). This first key secondary objective will only be tested if the 
primary objective is demonstrated. This fixed sequence of study hypotheses ensures that 
the overall study-wise risk of type I error is preserved at the 2.5% (see section 12.9.3). An 
additional benefit will be declared if the ratio of the geometric means between P4M3 (CA35 
and CM35 combined) over CIG is statistically lower than 1 at day 5 for all four additional 
key secondary BoExp listed in Table 5. 
If both the primary and first key secondary objectives are declared successful, then the 2nd 
key secondary objective will be tested with type I error level of 2.5%, this time using the 
contrast CA35 vs. CIG (also obtained from the model described in section 12.5.1.4) and 
the BoExp listed in Table 4. If this 2nd key secondary objective is also declared successful, 
then the 3rd key secondary objective can be tested similarly, this time with the BoExp listed 
in Table 5. The analysis will proceed similarly for the 4th and 5th key secondary objectives 
(except that the contrast will be CM35 vs. CIG), provided that all preceding objectives are 
declared successful (fixed sequence testing). If, along the procedure from the primary 
objective up to the last key secondary objective, any of the objectives are not declared 
successful, the sequence testing will stop, and further testing will not be permitted. 
 
Figure 3 
Representation of the Procedure of Fixed Sequence Testing 
Note that, at each level of testing, all BoExp need to lead to a statistically significant test. 
If the statistical test for one of the BoExp does not reach statistical significance (at the 2.5% 

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level), then the corresponding level of testing cannot be declared successful, and the fixed 
sequence testing will stop. 
The formal testing procedure of this study will use the primary estimand based on the PP 
(see section 12.5.1). The procedure will be repeated exploratorily using the secondary 
estimand based on the FAS (see section 12.5.2). 
12.6.2 
Secondary Objective 
This analysis refers to the secondary objective defined in section 3.2.2 about safety. All 
safety analyses will be conducted on the SAF (inferential analyses will not be performed 
on safety endpoints). 
All safety data will be provided in listings by actual exposure arm, subject, and safety 
period. The safety periods are defined as: 
• Screening: from Screening visit to baseline  
• Exposure: from Day 1 to Day 5 11:00 PM  
• Follow-up: from Day 6 (Discharge) to end of Safety follow-up 
Unless otherwise specified, summaries will be produced by actual exposure arm and safety 
periods. 
Adverse event data will serve as the primary assessment of safety. Other safety variables 
monitored in this study will include vital signs (systolic and diastolic blood pressure, pulse 
rate, respiratory rate), ECG data, spirometry data, clinical chemistry, hematology, urine 
analysis safety panel, concomitant medications, body weight, and BMI. 
The number and percentage of subjects with AEs and SAEs will be tabulated by the 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and 
preferred term (PT) for the safety population overall and by safety period. Summaries will 
also be presented for AEs leading to product discontinuation, AEs leading to study 
discontinuation, AEs by relatedness to product exposure (including expectedness) and 
relatedness to study procedures, AEs by severity, and AE by action taken related to the 
product. Tabulations will be performed for both the number of subjects experiencing an 
event and the number of events for the SAF. 
With respect to device malfunctions, the number and % of subjects with device events will 
be tabulated. The number and % of subjects with device events overall, leading to an AE, 
a SAE, discontinuation, or to non-adherence will also be tabulated. 

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Descriptive statistics as defined in section 12.1.3 for actual values and changes from 
baseline will be produced for the following parameters: vital signs, ECGs, spirometry, 
clinical chemistry, hematology, urinalysis safety panel, body weight, and BMI. 
12.7 Exploratory Objectives 
The exploratory objectives defined in sections 3.3.1, 3.3.2, and 3.3.6 will be analyzed 
similarly to the primary objective (except that there will be no success criteria). More 
specifically, for all endpoints expressed on the continuous scale, the analyses described as 
primary estimand (see section 12.5.1) and secondary estimand (see section 12.5.2) will be 
repeated.  
Except for CYP1A2 enzymatic activity, endpoints are assumed to be log-normally 
distributed, and the natural logarithm of the values will be used (the statistical model will 
then use the natural logarithm of the baseline as covariate). The results will then be 
transformed back to the original scale. 
For the exploratory objective (section 3.3.6), the CYP1A2 enzymatic activity will only be 
measured at baseline and at Day 5. Thus, the REPEATED statement described in 
sections 12.5.1.4 and 12.5.2.4 becomes irrelevant and will not be included. Similarly, the 
terms Day and Arm*Day in the MODEL statement will be removed and the LSMEANS 
statement will use Arm instead of Arm*Day.  
For the exploratory objectives defined in section 3.3.3, 3.3.4, and 3.3.5, only descriptive 
statistics will be computed for both the PP and FAS. 
12.8 Interim Analysis 
In this study, no interim analysis is planned. 
12.9 Measures to Control Bias 
12.9.1 
Method for Assigning Subjects to Study Arms 
Randomization will be used to assign subjects to study arms. Given that the study is 
randomized, demographics and baseline characteristics are expected to be balanced 
between study arms. Nevertheless, sex and baseline value of the BoExp will be used as 
covariates in the statistical models (see sections 12.5.1.4 and 12.5.2.4). 

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12.9.2 
Blinding 
This is an open-label study. Therefore, the subjects and Investigators or designees or staff 
will be unblinded to the subject’s study arm. However, there will be a limited degree of 
blinding in the data review and data analysis process. PMI and contract research 
organization (CRO) personnel will be blinded to the self-selected groups as summarized in 
Table 15. 
Table 15 
Blinding Scheme 
Blinded Study Personnel 
Blinded Data1  
End of Blinding Period  
PMI and CRO study statisticians  
Blinded to all BoExp data 
After the SAP finalization. 
PMI clinical scientist  
Blinded to all BoExp data 
After the SAP finalization 
1Blinded data will be made accessible to the blinded personnel by means of a dummy group or masking. As part of the PMI quality 
control (QC) activity, data listings will be reviewed by the CRO and PMI before database lock, with no access to the arm information. 
Full details will be available in the data review plan. 
Any PMI and CRO personnel who are not listed in the above table will not be blinded to 
the study data. 
Unblinded information will not be shared with the blinded study team, until the end of the 
blinding period. PMI will receive blinded and unblinded data for the pre-analysis data 
review as planned in the data review plan. Blinded data will be accessible by the blinded 
study personnel in a masked format or presented independently of the subject identifier to 
ensure that data cannot be associated to a subject. Unblinded data will only be reviewed by 
the unblinded study team. 
12.9.3 
Study Significance Level and Multiple Testing Procedures 
In this study, the overall familywise type I error will be preserved at the α-level of 2.5% (1-
sided tests will be conducted for the primary and key secondary study hypotheses). This 
will be done by using a fixed sequence of testing: primary objective → 1st key secondary 
objective → 2nd key secondary objective → 3rd key secondary objective → 4th key 
secondary objective → 5th key secondary objective. All objectives will be tested at the 
2.5% type I error level until one of the objectives is rejected and no further testing will be 
performed (in this case, only subsequent exploratory testing will be conducted).  
The primary study hypothesis (as assessed using the primary estimand defined in 
section 12.5.1) will be tested one-sided with a type I error α-level of 2.5%. The associated 
1-sided 97.5% confidence interval will be provided. This will be applied to all BoExps of 
Table 4 that are part of the primary study hypothesis (all need to pass for the objective to 
be considered as demonstrated). 

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If the primary study hypothesis is demonstrated, the same α-level of 2.5% will be used for 
the 1st key secondary hypothesis and the associated 1-sided 97.5% confidence interval will 
be provided. This will be applied to all BoExps of Table 5 that are part of the 1st key 
secondary study hypothesis (all need to pass for the 1st key secondary objective to be 
successful). 
If the primary study hypothesis is not demonstrated, the 1st key secondary hypothesis (and 
all subsequent key secondary objectives) will be considered exploratory and conducted 2-
sided at the α-level of 5% and the associated 2-sided 95% confidence interval will be 
provided.  
The analysis will proceed in a similar way for the following key secondary objectives.   
For all the exploratory objectives, the statistical tests will be considered exploratory, 2-
sided, and conducted at the α-level of 5%. Associated 2-sided 95% confidence intervals 
will be provided. 
12.9.4 
Determination of Sample Size and Power Consideration 
In this study, 72 subjects will be randomized as follows: 
• 36 in combined P4M3 arms (18 in CA35 and 18 in CM35), 
• 18 in CIG arm, 
• 18 in SA arm. 
Based on four previous similar studies conducted by PMI on the tobacco heating system 
(another alternative product to cigarette developed  by PMI which is likely to be less risky 
than cigarette; ClinicalTrials.gov identifiers are NCT01970995, NCT01989156, 
NCT01959932, and NCT01970982, respectively), Table 16 contains estimates of 
geometric mean ratios (GMR) and associated coefficients of variations (GCV) for the 
(adjusted) contrast of a tobacco heating system against CIG. The effect of P4M3 is expected 
to be similar (or better) on the BoExp selected in this study than this tobacco heating 
system. In addition, based on these studies, up to 15% of missing values may be expected 
for various reasons (e.g., withdrawals, mis-randomization, etc.). 
Using the statistics displayed in Table 16, the sample size planned for this study accounting 
for 15% of missing values (resulting in 30 and 15 subjects in P4M3 combined and CIG 
arms, respectively), and a one-sided two-sample t-test (on the log-scale) with 2.5% type I 
error probability, the estimated power for each BoExp is displayed in Table 16. By 
multiplying the power for each individual BoExp over the four to be tested in the primary 
hypothesis (per study), a global estimate of power is also obtained. 

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Note that 10’000 simulations of one-sided two-sample t-test were also conducted to 
determine the 90 percentiles of the (upper) half-width of the 97.5%-confidence interval 
(CI) of the ratio between P4M3 and CIG, as well as the 90 percentiles of the upper bounds 
of these CIs. These are also displayed in Table 16. These provide indications on the 
expected precision on the estimates of the ratios. 
Table 16  
Power Computations for Primary Objective 
NCT 
(Region) 
Endpoint 
GMR (%) 
GCV (%) 
Power 
Overall 
Power 
90%iles of the 
upper half-
width of CI (%) 
90%iles of the 
upper bound 
of CI (%) 
1970995 
(JP) 
2CyEMA 
18.23 
32.43 
>99% 
>99% 
4.9 
25.4 
3-HPMA 
50.67 
32.72 
>99% 
 
13.8 
71.0 
COHb 
44.94 
17.24 
>99% 
 
6.0 
53.8 
Total NNAL 
43.69 
26.09 
>99% 
 
9.2 
57.1 
1989156 
(US) 
2CyEMA 
17.23 
42.01 
>99% 
>99% 
6.2 
26.3 
3-HPMA 
45.77 
36.45 
>99% 
 
14.1 
66.3 
COHb 
38.14 
26.5 
>99% 
 
8.2 
50.3 
Total NNAL 
43.81 
40.7 
>99% 
 
15.3 
65.9 
1959932 
(EU) 
2CyEMA 
13.16 
34.41 
>99% 
>99% 
3.8 
18.7 
3-HPMA 
41.63 
26.1 
>99% 
 
8.7 
54.4 
COHb 
23.45 
16.84 
>99% 
 
3.1 
28.0 
Total NNAL 
43.54 
27.13 
>99% 
 
9.6 
57.5 
1970982 
(JP) 
2CyEMA 
21.21 
43.16 
>99% 
>99% 
7.9 
32.7 
3-HPMA 
52.86 
39.57 
>99% 
 
17.8 
78.9 
COHb 
47.1 
16.08 
>99% 
 
5.8 
55.6 
Total NNAL 
49.03 
42.51 
>99% 
 
18.0 
75.3 
 Table 16 shows that the power of this study for the primary objective is expected to be at 
least 99%. 
A similar reasoning and assumptions for the 1st key secondary objective can be made. Table 
17 displays the power estimates for the 1st key secondary hypothesiswith a power of at least 
99%. 
Table 17  
Power Computations for 1st Key Secondary Objective 
NCT 
(Region) 
Endpoint 
GMR (%) 
GCV (%) 
Power 
Overall 
Power 
90%iles of the 
upper half-
width of CI (%) 
90%iles of the 
upper bound 
of CI (%) 
1970995 
(JP) 
3-HMPMA 
43.06 
35.59 
>99% 
>98% 
12.9 
62.0 
3-OH-B[a]P 
27.19 
43.93 
>99% 
 
10.4 
42.0 
S-PMA 
10.97 
46.63 
>99% 
 
4.5 
17.4 
Total NNN 
27.02 
61.84 
>99% 
 
15.5 
49.1 
1989156 
(US) 
3-HMPMA 
38.26 
53.56 
>99% 
>98% 
18.4 
64.6 
3-OH-B[a]P 
28.94 
54.77 
>99% 
 
14.3 
49.4 
S-PMA 
12.58 
69.68 
>99% 
 
8.4 
24.4 
Total NNN 
14.06 
78.93 
>99% 
 
10.8 
29.1 
1959932 
(EU) 
3-HMPMA 
22.54 
30.76 
>99% 
>98% 
5.7 
30.9 
3-OH-B[a]P 
27.5 
46.17 
>99% 
 
11.1 
43.5 
S-PMA 
5.99 
37.3 
>99% 
 
1.9 
8.8 

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NCT 
(Region) 
Endpoint 
GMR (%) 
GCV (%) 
Power 
Overall 
Power 
90%iles of the 
upper half-
width of CI (%) 
90%iles of the 
upper bound 
of CI (%) 
Total NNN 
24.12 
95.15 
>99% 
 
22.9 
55.7 
1970982 
(JP) 
3-HMPMA 
37.71 
49.07 
>99% 
>98% 
16.4 
61.6 
3-OH-B[a]P 
29.99 
52.2 
>99% 
 
14.0 
50.2 
S-PMA 
15.68 
49.76 
>99% 
 
6.9 
25.6 
Total NNN 
30.06 
67.69 
>99% 
 
19.2 
57.4 
For the key secondary objectives 2 to 5, a similar reasoning is applied, but this time, a 
sample of size of 15 for the P4M3 (CA35 or CM35) arms needs to be used and 15 subjects 
in the CIG arm (with 15 subjects) (Table 18 and Table 19). As per Table 18 and Table 19 
the power was of at least of 99% for each BoExp in the previous studies.  
By multiplying the power for each objective (≈ 99%) across all 6 objectives (1 primary + 
5 key secondary), the power for all objectives altogether is then estimated to be at least 
94% (= 0.94 ≈ 0.996, assuming independence of the 6 objectives, each with a 99% power). 
Table 18  
Power Computations for Key Secondary Objectives 2 & 4 
NCT 
(Region) 
Endpoint 
GMR (%) 
GCV (%) 
Power 
Overall 
Power 
90%iles of the 
upper half-
width of CI (%) 
90%iles of the 
upper bound 
of CI (%) 
1970995 
(JP) 
2CyEMA 
18.23 
32.43 
>99% 
>95% 
6.1 
26.9 
3-HPMA 
50.67 
32.72 
>99% 
 
17.2 
75.2 
COHb 
44.94 
17.24 
>99% 
 
7.3 
55.4 
Total NNAL 
43.69 
26.09 
>99% 
 
11.3 
59.7 
1989156 
(US) 
2CyEMA 
17.23 
42.01 
>99% 
>95% 
7.8 
28.3 
3-HPMA 
45.77 
36.45 
>99% 
 
17.5 
70.7 
COHb 
38.14 
26.5 
>99% 
 
10.1 
52.7 
Total NNAL 
43.81 
40.7 
>99% 
 
19.3 
71.0 
1959932 
(EU) 
2CyEMA 
13.16 
34.41 
>99% 
>95% 
4.7 
19.8 
3-HPMA 
41.63 
26.1 
>99% 
 
10.8 
56.9 
COHb 
23.45 
16.84 
>99% 
 
3.7 
28.8 
Total NNAL 
43.54 
27.13 
>99% 
 
11.9 
60.4 
1970982 
(JP) 
2CyEMA 
21.21 
43.16 
>99% 
>95% 
9.9 
35.0 
3-HPMA 
52.86 
39.57 
>99% 
 
22.4 
84.4 
COHb 
47.1 
16.08 
>99% 
 
7.1 
57.2 
Total NNAL 
49.03 
42.51 
>99% 
 
22.5 
80.9 
Table 19  
Power Computations for Key Secondary Objectives 3 & 5 
NCT 
(Region) 
Endpoint 
GMR (%) 
GCV (%) 
Power 
Overall 
Power 
90%iles of the 
upper half-
width of CI (%) 
90%iles of the 
upper bound 
of CI (%) 
1970995 
(JP) 
3-HMPMA 
43.06 
35.59 
>99% 
>94% 
16.0 
65.9 
3-OH-B[a]P 
27.19 
43.93 
>99% 
 
13.0 
45.2 
S-PMA 
10.97 
46.63 
>99% 
 
5.6 
18.9 
Total NNN 
27.02 
61.84 
>99% 
 
19.8 
54.2 
1989156 
(US) 
3-HMPMA 
38.26 
53.56 
>99% 
>94% 
23.2 
70.4 
3-OH-B[a]P 
28.94 
54.77 
>99% 
 
18.2 
54.2 
S-PMA 
12.58 
69.68 
>99% 
 
10.7 
27.3 

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NCT 
(Region) 
Endpoint 
GMR (%) 
GCV (%) 
Power 
Overall 
Power 
90%iles of the 
upper half-
width of CI (%) 
90%iles of the 
upper bound 
of CI (%) 
Total NNN 
14.06 
78.93 
>99% 
 
14.0 
33.1 
1959932 
(EU) 
3-HMPMA 
22.54 
30.76 
>99% 
>94% 
7.1 
32.6 
3-OH-B[a]P 
27.5 
46.17 
>99% 
 
14.0 
47.2 
S-PMA 
5.99 
37.3 
>99% 
 
2.4 
9.3 
Total NNN 
24.12 
95.15 
>99% 
 
30.0 
64.6 
1970982 
(JP) 
3-HMPMA 
37.71 
49.07 
>99% 
>94% 
20.6 
66.5 
3-OH-B[a]P 
29.99 
52.2 
>99% 
 
17.8 
55.1 
S-PMA 
15.68 
49.76 
>99% 
 
8.8 
27.9 
Total NNN 
30.06 
67.69 
>99% 
 
24.6 
63.8 
 

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13 Administrative Considerations 
13.1 Study Administrative Structure 
13.1.1 
Sponsor 
The list of sponsor personnel will be provided as a separate document. 
13.1.2 
List of Principal Investigators and Sites 
The list of principal investigators and sites will be provided as a separate document. 
13.2 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects' state 
of health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subject in writing and signed by the subject, in compliance with all local 
and national data protection and privacy legislation. 
The anonymity of subjects participating in this study will be maintained. 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 date of birth, 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 Principal Investigator or designee. If any 
document relating to this study shows a subject’s name or any other details relating to an 
identifiable person (e.g., address, social security number, medical chart number, etc.), the 
name or other identifiable details must be obscured before a copy of that document is 
supplied to the Sponsor or the Sponsor’s authorized representative. 
13.3 Access to Source Documents 
Subjects will be informed that, during as well as after the course of the clinical study, the 
Sponsor, any authorized representatives of the Sponsor, IEC, or regulatory authorities may 
inspect their medical records to verify the information collected and ensure that all personal 
information made available for inspection is handled in the strictest confidence and in 
accordance with national and local data protection and privacy legislation. 

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The PI(s) and all study site staff involved with the study must permit direct access to source 
data/documents for study related monitoring, audits, IEC review, and regulatory 
inspection(s). 
13.4 Record Retention 
All records of data, source data and source documents (original records or certified copies), 
in any form (including, but not limited to, written, electronic, 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 
Investigator/study site for the study, as required by ICH GCP [2]  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 Tripartite Guideline for Good Clinical Practice [2] . 
Essential documents must be retained by the Investigator for a minimum of: 
• At least 15 years after completion or discontinuation of the study. 
These documents should be retained for a longer period, however, if required by applicable 
regulatory requirements or by an agreement with the Sponsor. 
Examples of essential records/documents include, but are not limited to: 
• Signed informed consent documents for all subjects and master ICF. 
• Subject identification code list, screening log, and enrollment log (if applicable). 
• Record of all communications between the Investigator and the IEC, composition of 
the IEC. 
• Record of all communications/contact between the PI(s) or designee(s), Sponsor, and 
its authorized representatives. 
• List of sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curricula vitae, and their signatures. 
• Investigator logs. 
• CRFs, study specific questionnaires (and associated data/scoring), subject diaries. 
• AE reports and details of follow-up investigations, details of concomitant medication. 
• All other source documents (e.g., ECGs, consultation reports, physical examination, 
laboratory records) or any electronically captured study source data. 
• Clinical laboratory reports, laboratory normal ranges. 
• Original medical/hospital records, if applicable (the medical files of study subjects must 
be retained in accordance with local legislation and in accordance with the maximum 
period of time permitted by the hospital or study site). 

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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 
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• Device issue log, IP accountability logs, dispensing records. 
• Information regarding subjects’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the PI(s)/study site(s) as to when these 
documents no longer need to be retained. 
The PI(s)/study site(s) must take measures to prevent accidental or premature destruction 
of these documents. 
If the PI(s) wish(es) to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
The PI(s) or designee(s) must obtain written approval from the Sponsor before destruction 
of any records. Normally, these records will be held in the archives of the PI(s). If a 
Principal Investigator is unable to meet this obligation, he/she 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 for as long as the IP is on the market, and/or for 15 years after the CSR has 
been finalized. 
13.5 Clinical Study Report 
The Sponsor must ensure that a CSR for this study is prepared regardless of whether the 
study is completed or prematurely terminated. 
The CSR will be written based on standards of the ICH Guideline for the structure and 
content of clinical study reports. In certain circumstances, an abbreviated CSR may be 
acceptable. Submission of the CSR to the IEC will be complied with as requested by local 
requirements. 
The results of the additional variables for analysis will be presented in reports separate from 
the study CSR. 
13.6 Financial Disclosure 
Principal Investigator(s) 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. 

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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 
13.7 Publication and Disclosure Policy 
This document contains information that is confidential and proprietary to the Sponsor. 
This information is being provided solely for the purpose of evaluation and/or conducting 
this study for the Sponsor. Disclosure of the content of this document is allowed only to 
study personnel, IEC, or duly authorized representatives of regulatory agencies for this 
purpose under the 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. 
13.8 Insurance 
The Sponsor is responsible for AEs and health damage to patients associated with the 
investigational products that are used during the study, except for AEs and health damage 
to patients caused by a negligent or an intentional misconduct and/or significant deviation 
to the protocol of the Investigator or the clinical study site or the patients. The Sponsor has 
taken out insurance to cover any bodily injury and property damage caused by the 
operations carried out by the insured. 

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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 E9 (R1), Addendum on estimands and sensitivity analysis in clinical trials to 
the guideline on statistical principles for clinical trials - Step 5. 2020. 
2. 
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). 
3. 
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). 
4. 
U.S. Department of Health and Human Services, The health consequences of 
smoking - 50 years of progress: a report of the Surgeon General. 2014. 
5. 
WHO Study Group, et al., WHO study group on tobacco product regulation - 
Report on the scientific basis of tobacco product regulations: fifth report of a WHO 
study group. 2015. 
6. 
Philip Morris Products S.A., Unpublished on file data: Investigator's Brochure for 
Mesh 2.0. Edition 3. 2020. 
7. 
Robinson, R.J., et al., Electronic cigarette topography in the natural environment. 
PLoS One, 2015. 10(6): p. e0129296. 
8. 
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. 
9. 
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. 
10. 
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. 
11. 
Raw, M., et al., WHO Europe evidence based recommendations on the treatment of 
tobacco dependence. Tob Control, 2002. 11(1): p. 44-6. 
12. 
WHO Study Group, et al., The scientific basis of tobacco product regulation: 
second report of a WHO study group. World Health Organ Tech Rep Ser, 
2008(951): p. 1-277. 
13. 
U.S. Department of Health and Human Services and FDA (Food and Drug 
Administration), [Docket No. FDA-2012-N-0143]: harmful and potentially harmful 
constituents in tobacco products and tobacco smoke; established list. Federal 
Register, 2012. 77(64): p. 20034-37. 
14. 
FDA (Food and Drug Administration), Guidance for industry - Reporting harmful 
and potentially harmful constituents in tobacco products and tobacco smoke under 

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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 
Section 904(a)(3) of the Federal Food, Drug, and Cosmetic Act - Draft guidance. 
2012. 
15. 
FDA (Food and Drug Administration), Guidance for industry - Premarket tobacco 
product applications for electronic nicotine delivery systems. 2019. Available 
from: 
https://www.fda.gov/media/127853/download 
(Accessed 
on 
27 
September 2019). 
16. 
FDA (Food and Drug Administration), Guidance for industry - Patient-reported 
outcome measures: use in medical product development to support labeling claims. 
2009. 
17. 
FDA (Food and Drug Administration), Food-effect bioavailability and fed 
bioequivalence studies. 2002. 
18. 
U.S. Department of Health and Human Services, Treating tobacco use and 
dependence: 2008 update. Clinical practice guideline. 2008. Available from: 
http://bphc.hrsa.gov/buckets/treatingtobacco.pdf (Accessed on 18 July 2014). 
19. 
U.S. Department of Health and Human Services, Helping smokers quit. A guide for 
clinicians. 2008. 
20. 
Miller, M.R., et al., Standardisation of spirometry. Eur Respir J, 2005. 26(2): p. 
319-38. 
21. 
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. 
22. 
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. 
23. 
Faber, M.S. and U. Fuhr, Time response of cytochrome P450 1A2 activity on 
cessation of heavy smoking. Clin Pharmacol Ther, 2004. 76(2): p. 178-84. 
24. 
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. 
25. 
Chrea, C., et al., Developing fit-for-purpose self-report instruments for assessing 
consumer responses to tobacco and nicotine products: the ABOUT Toolbox 
initiative. F1000Res, 2018. 7: p. 1878. 
26. 
Cappelleri, J.C., et al., Confirmatory factor analyses and reliability of the modified 
cigarette evaluation questionnaire. Addictive Behaviors, 2007. 32: p. 912–923. 
27. 
Hatsukami, D.K., et al., Subjective responses to oral tobacco products: scale 
validation. Nicotine Tob Res, 2013. 15(7): p. 1259-64. 
  

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secrets and confidential information are hereby claimed under the provisions of applicable 
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Philip Morris Products S.A 
Appendices 
 

 
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 
 
Screening 
Confinement Period 
Early 
termination g 
Safety  
follow-up h 
Visit (Time Window) 
 
Admission f Baseline 
Exposure period 
Discharge 
 
3 days post 
Discharge 
Study Day 
-30 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6 
 
7 to 9 
Informed consent  
● 
Information on the risk of smoking; 
smoking cessation advice; debriefing  
● 
● 
 
 
 
 
 
 
● 
● 
 
Identification of current CIG brand  
● 
Inclusion/exclusion criteria  
● 
● 
Nicotine/tobacco product use history 
questionnaire  
● 
● 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
● 
 
● 
 
 
 
 
 
● 
● 
 
Spirometry   
● 
 
● 
 
 
 
 
 
● 
● 
 
Demographics   
● 
Medical history, concomitant diseases  
● 
Concomitant disease status  
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Prior/concomitant medication  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
●i
Physical examination  
● 
 
 
 
 
 
 
 
 
 
 
Body height and weight a 
● 
● 
 
 
 
 
 
 
 
 
 
Vital signs b 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
B: HIV, HBV and HCV  
● 
 
 
 
 
 
 
 
 
 
 
B/U: Hematology, clinical chemistry, 
urine analysis (safety panel)  
● 
 
● 
 
 
 
 
 
● 
● 
 

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Screening 
Confinement Period 
Early 
termination g 
Safety  
follow-up h 
Visit (Time Window) 
 
Admission f Baseline 
Exposure period 
Discharge 
 
3 days post 
Discharge 
Study Day 
-30 to -3 
-2 
-1 
1 
2 
3 
4 
5 
6 
 
7 to 9 
B: Pregnancy test  
● 
● 
 
 
 
 
 
 
● 
● 
 
U: Cotinine test  
● 
● 
 
 
 
 
 
 
 
 
 
U: Drug screen c 
● 
● 
 
 
 
 
 
 
 
 
 
Alcohol breath test  
● 
● 
 
 
 
 
 
 
 
 
 
P4M3 demonstration  
● 
 
 
 
 
 
 
 
 
 
 
AE/SAE recording  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Enrollment  
 
● 
 
 
 
 
 
 
 
 
 
P4M3 product test d 
 
● 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
● 
 
 
 
 
 
 
 
 
Informing subjects about study arm 
 
 
 
● 
 
 
 
 
 
 
 
Collection of CIG butts for 
accountability  
 
 
● 
● 
● 
● 
● 
● 
 
 
 
E-liquid use (weight difference of 
Cartridges)  
 
 
 
● 
● 
● 
● 
● 
 
 
 
B: BoExp in blood: COHb  
 
 
● 
● 
● 
● 
● 
● 
 
 
 
U: 24-h urine collection for BoExp (see 
table below)  
 
 
● 
● 
● 
● 
● 
● 
 
 
 
Intake of a caffeine tablet  
 
 
● 
 
 
 
 
● 
 
 
 
B: CYP1A2 activity  
 
 
● 
 
 
 
 
● 
 
 
 
FTND  
 
 
● 
 
 
 
 
 
 
 
 
ABOUT–Product Experience 
 
 
● 
● 
● 
● 
● 
● 
 
 
 
HPT recording e 
 
 
 
● 
● 
● 
● 
● 
 
 
 
P4M3 product events  
 
● 
 
● 
● 
● 
● 
● 
 
● 
 

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Abbreviations:  
ABOUT = Assessment of behavioral outcomes related to tobacco and nicotine products; AE = Adverse event; B = Blood sample required; BMI = Body mass index; BoExp = 
Biomarker(s) of exposure; BoPH = Biomarker(s) of potential harm; CO = Carbon monoxide; COHb = Carboxyhemoglobin; CYP1A2 = Cytochrome P450 1A2; FTND = 
Fagerström Tobacco and Nicotine Dependence; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = Human immunodeficiency virus; HPT = Human puffing topography; 
SA = smoking abstinence; SAE = Serious adverse event; U = Urine sample required.  
a) 
Height will be recorded only at screening.  
b) 
Systolic and diastolic blood pressure, pulse rate, and respiratory rate.  
c) 
Urine will be screened for the following drugs: amphetamine type substances, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates and methadone.  
d) 
On Day -2 (admission), after inclusion/exclusion criteria are re-checked, eligible subjects will be enrolled and perform a product test using the 2 P4M3 flavor variants (CA35 
and CM35). The site staff will provide them a training before on how to use the product. After the product test, subjects not willing to use P4M3 will be discontinued.  
e) 
HPT recording on an ongoing basis for subjects in P4M3 arms.  
f) 
Provided the 28-day Screening period has not exceeded, alternate subjects have to repeat the Admission visit Day -2of the following group to re-confirm their eligibility for 
randomization. 
g) 
If a subject is discontinued from the study after enrollment, listed early termination procedures are performed unless the subject refuses to perform the assessments or is lost to 
follow-up.  
h) 
Reporting of new AEs/SAEs by the subject and follow-up of ongoing AEs/SAEs by the site.  
i) 
During the safety follow-up period, only medication taken for the treatment of AEs will be recorded.  
 
Schedule of 24-hours Urine Collection Start 
 
Baseline   
Confinement Exposure Period   
Study Day  
Day -1  
Day 1  
Day 2  
Day 3  
Day 4  
Day 5  
BoExp and creatinine in 24-h urine  
●  
●  
●  
●  
●  
●  
Bio-banking samples   
● 
● 
● 
● 
● 
● 
Abbreviations:  
BoExp = Biomarker(s) of exposure  

 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
Appendix B 
Participating Laboratories 
 
Safety Laboratory 
 
 
 
 
 
Bioanalytical Laboratory 
 
 
 
 
 
 

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without the written consent of Philip Morris Products S.A 
Appendix C 
Human Puffing Topography Parameters  
Per-Puff Parameters 
Description 
Variable 
Unit 
Puff ID 
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 
% 
Power setting 
Powi 
W 
 
Per-Day Parameters 
Parameter  
Variable  
Formula  
Unit  
Total number of puffs/day  
NPC  
Count Ni  
  
Total puff volume  
TVOL  
∑ Vi  
mL  
Total puff duration/day  
TDi  
∑ Di  
s  
Average puff volume   
AvgVi  
∑ Vi / NPC, i=1 ... NPC  
mL  
Average puff duration  
AvgDi  
∑ Di / NPC, i=1 ... NPC  
s  
Average flow  
AvgQmi  
∑ Qmi / NPC, i=1 … NPC  
mL/s  
Average Peak flow   
AvgQci  
∑ Qci / NPC, i=1 … NPC  
mL/s  
Average inter puff interval  
AvgIi  
∑ Qci / NPC, i=1 … NPC  
s  
Total puffing duration (total product 
use duration, session length)  
TDFi  
∑ DFi   
s  
Puff Frequency  
PFeq  
NPC/(TDFi/60)  
 
% of puffs with higher power setting PctPuffsHighPow 100*Count Ni at high 
power/NPC 
% 
 
 

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Appendix D Clinical Laboratory Parameters Safety Panel  
 
Hematology  
Clinical Chemistry  
Urine Analysis  
- 
Hematocrit  
- 
Hemoglobin   
- 
Mean corpuscular 
hemoglobin  
- 
Mean corpuscular 
hemoglobin concentration  
- 
Mean corpuscular volume 
- 
Platelet count 
- 
Red blood cell count  
- 
White blood cell (WBC) count 
- 
Differential WBC count:  
• 
Neutrophils  
• 
Basophils  
• 
Eosinophils  
• 
Lymphocytes  
• 
Monocytes  
- 
Albumin  
- 
Total protein  
- 
Alkaline phosphatase  
- 
Alanine aminotransferase  
- 
Aspartate aminotransferase  
- 
Blood urea nitrogen  
- 
Creatinine  
- 
Gamma-glutamyl transferase  
- 
Fasting glucose*  
- 
Lactate dehydrogenase  
- 
Potassium  
- 
Sodium  
- 
Total bilirubin  
- 
Direct bilirubin  
- 
Total cholesterol  
- 
Triglycerides  
 
- 
pH  
- 
Bilirubin  
- 
Glucose  
- 
Nitrite  
- 
Red blood cell traces  
- 
Protein  
- 
Specific gravity 
 
* Except at Screening where non-fasting glucose can be assessed   
 

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