A Single-center, Open-label, Randomized, Crossover Study to Investigate the Nicotine Pharmacokinetic Profile, Pharmacodynamics, Safety and Tolerability of Four P3P Variants in Smoking Healthy Adult Subjects
Phase: NA
Conditions: Pharmacokinetics
Sponsor: Philip Morris Products S.A.



Philip Morris Products S.A.
Clinical Study Protocol
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Study P3P-PK-01-CH
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SYNOPSIS 
Sponsor:
Philip Morris Products S.A.
Quai Jeanrenaud 5
2000 Neuchâtel
Switzerland
Product Name:
P3P
Study Title:
A single-center, open-label, randomized, crossover study to investigate the nicotine 
pharmacokinetic profile, pharmacodynamics, safety and tolerability of four P3P 
variants in smoking healthy adult subjects
Study Number:
P3P-PK-01-CH
Short Study Title:
Nicotine pharmacokinetics and pharmacodynamics, safety and tolerability of P3P
Objectives and Endpoints:
The goal of the proposed research study is to evaluate the pharmacokinetic profiles of four 
P3P variants (differing in nicotine powder particle size, nicotine concentration and in the 
absence or presence of a flavoring system), following a fixed puffing regimen and an ad
libitum use period. In addition, pharmacodynamic effects (subjective effects and related 
behavioral assessments), as well as human puffing topography will be evaluated, to provide 
further insights on product acceptance and product use. Safety will also be assessed throughout 
the study.
Primary Objective and Endpoints:
1. To evaluate the plasma concentration-time profile of nicotine and the derived PK
parameters (with and without adjustment for baseline nicotine concentrations) of four P3P
variants from the fixed puffing regimen.
Endpoints:
x
Plasma nicotine concentration-time profile
x
Maximum plasma concentration [Cmax]

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x
Time to the maximum concentration [tmax]
x
Area  under the concentration-time curve from start of product use (T0 fix) to 4 hours
[AUCfix (0-4h)]
Secondary Objectives and Endpoints:
1. To evaluate the plasma concentration-time profile of nicotine and the derived PK 
parameters (with and without adjustment for baseline nicotine concentrations) of four P3P
variants from the ad libitum use period.
Endpoints: 
x
Plasma nicotine concentration-time profile
x
Peak plasma nicotine concentration [Cpeak]
x
Time to peak plasma nicotine concentration [tpeak]
x
Trough plasma nicotine concentration [Ctrough]
x
Average of plasma nicotine concentration from T0 ad lib to 1 hour [Caverage]
x
Area under the concentration-time curve from start of product use (T0 ad lib) to 4 hours
[AUCad lib (0-4h)]
2. To evaluate the pharmacodynamic effects (subjective effects and related behavioral 
assessments) of four P3P variants.
Endpoints:
x
Visual Analogue Scale (VAS)-craving assessment from the fixed puffing regimen and 
ad libitum use period
x
Product evaluation by an adapted version of the modified Cigarette Evaluation 
Questionnaire (adapted mCEQ) following the ad libitum use period
x
Sensory Questionnaire (SQ) following the ad libitum use period
3. To evaluate human puffing topography (HPT) of four P3P variants during the fixed puffing 
regimen and the ad libitum use period.
Endpoints:
x
Per-puff parameters and per-product use experience parameters
4. To estimate the amount of powder aerosolized from P3P from the fixed puffing regimen 
and the ad libitum use period.
Endpoints:
x
Weight difference of P3P before and after use

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5. To monitor the safety and tolerability during the study.
Endpoints:
x
Incidence of adverse events (AEs), serious adverse events (SAEs) 
x
Frequency of AEs, SAEs 
x
Incidence of P3P product events including malfunction/misuse 
x
Frequency of P3P product events including malfunction/misuse 
x
Physical examination changes from baseline
x
Cough changes from baseline (Visual Analogue Scale and three Likert scales)
x
Electrocardiogram (ECG) changes from baseline (heart rate; PR, QRS, QT intervals,
and QT interval corrected according to Bazett’s [QTcB] and Fridericia’s [QTcF]
formula)
x
Vital signs changes from baseline (systolic and diastolic blood pressure, pulse rate and 
respiratory rate)
x
Spirometry changes from baseline (FEV1, FEV1 % predicted, FVC, FVC % predicted,
FEV1/FVC)
x
Changes from baseline in clinical chemistry, hematology, and urine analysis safety 
panel
x
Concomitant medications
Additional Study Assessments (for eligibility assessment and baseline characteristics):
x
Serology for human immunodeficiency virus (HIV) 1/2 and hepatitis B and C
x
Pregnancy test 
x
Urine cotinine test
x
Urine drug screen (amphetamine type substances, barbiturates, benzodiazepines, 
cannabinoids, cocaine and opiates)
x
Alcohol breath test
x
Nicotine dependence to be assessed with the Fagerström Test for Nicotine Dependence 
revised version (FTND)
x
Cytochrome P450 2A6 (CYP2A6) activity expressed as trans-3'-hydroxycotinine 
/cotinine molar metabolite ratio in plasma
Study Hypothesis:
There are no statistical hypotheses to be tested. 

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without the written consent of Philip Morris Products S.A. 
Study Design:
This is a single-center, open-label, randomized, crossover
study to evaluate the 
pharmacokinetic profiles of four P3P variants (differing in nicotine powder particle size, 
nicotine concentration and in the absence or presence of a flavoring system), following a fixed 
puffing regimen and an ad libitum use period. In addition, pharmacodynamic effects 
(subjective effects and related behavioral assessments), as well as human puffing topography,
will be evaluated, to provide further insights on product acceptance and product use. Safety 
will also be assessed throughout the study.
A Screening Visit will be conducted within 3 weeks prior to Admission to the investigational 
site (see Figure 1). A demonstration of P3P, without product use, will be done by the 
investigational site staff during the Screening Visit. 
Figure 1
Study Flow Chart
Subjects will return to the investigational site for Admission (Day -1). Subjects should have 
been fasting for at least 6 hours prior to Admission. After confirmation of eligibility, subjects 
will be enrolled. All subjects that are not enrolled will be considered as screen failures. At 
Admission, enrolled subjects will perform a product test using up to three P3P 3 products.
After the product test, subjects not willing and/or unable to use P3P will be discontinued from 
the study. Subjects willing to continue their participation in the study after product test will 
start their confinement phase. 
On Day 1, after at least 10 hour abstinence from any tobacco/nicotine containing products, 
subjects will use P3P 3 during a fixed puffing regimen comprising of 12 puffs in total at a rate 
of one inhalation every 30 seconds (± 5 seconds) in the morning and during an ad libitum use 
period for 60 minutes (± 5 minutes) in the afternoon. The start of product use for fixed puffing 

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and for the ad libitum use period will be defined as T0 fix and T0 ad lib, respectively. There will 
be a washout period of at least 10 hours between T0 fix and T0 ad lib.
A total of 10 blood samples will be taken for fixed puffing PK parameter estimation. One 
blood sample will be taken 15 minutes ± 5 minutes (T-1) prior to T0 fix. Thereafter in relation 
to T0 fix, blood will be drawn at the following time points: T1 after 2 minutes ± 1 minute, T2
after 4 minutes ± 1 minute, T3 after 7 minutes ± 1 minute, T4 after 10 minutes ± 1 minute, T5 
after 15 minutes ± 2 minutes, T6 after 30 minutes ± 2 minutes, T7 after 1 hour ± 5 minutes,
T8 after 2 hours ± 5 minutes, and T9 after 4 hours ± 5 minutes. 
A total of 8 blood samples will be taken for the ad libitum PK parameter estimation. One blood 
sample will be taken 15 minutes ± 5 minutes (T-1) prior to T0 ad lib. In relation to T0 ad lib, blood 
will be drawn at the following time points: T1 after 10 minutes ± 1 minute, T2 after 20 minutes 
± 2 minutes, T3 after 30 minutes ± 2 minutes, T4 after 40 minutes ± 5 minutes and T5 after 1 
hour ± 5 minutes, T6 after 2 hours ± 5 minutes, and T7 after 4 hours ± 5 minutes. 
Pharmacodynamic effects related to craving will be assessed using a VAS scale at different 
timepoints. For the fixed puffing regimen the first assessment will be done 15 minutes ± 5 
minutes prior to T0 fix, all other assessments will be done after T0 fix, at 4 minutes ± 2 minutes,
at 10 minutes ± 2 minutes, at 15 minutes ± 2 minutes, 30 minutes ± 5 minutes, 1 hour, 2 hours, 
4 hours ± 10 minutes each. For the ad libitum use period the first assessment will be done 15 
minutes ± 5 minutes prior to T0 ad lib, all other assessments will be done after T0 ad lib, at 10 
minutes ± 2 minutes, at 20 minutes ± 2 minutes, 30 minutes ± 5 minutes, 40 minutes ± 5 
minutes, 1 hour, 2 hours, 4 hours ± 10 minutes each. VAS will be assessed immediately after 
the collection of the time-matching PK samples.
Product evaluation and sensory questionnaires will be assessed after the end of the ad libitum
use period.
A puffing topography device will be attached to each P3P during both the fixed puffing 
regimen and the ad libitum use period. There will be one recording of HPT parameters per 
product use. Each P3P will be weighed before and after product use to estimate the amount of 
nicotine delivered in the aerosol. The number of P3P used during the ad libitum use period 
will be recorded.
In the morning of Day 2, after confirmation that there are no safety concerns for each subject 
to continue in the study based on the Investigator’s judgement, 18 subjects will be randomized 
to one of the following six sequences of the remaining P3P variants in order to cross-over the 
use of P3P 1, P3P 2 and P3P 4 following a 2 Latin squares design balanced for first order 
carryover effects among the 3 variants.
Sequence
Day 2
Day 3
Day 4
1
P3P 2
P3P 4
P3P 1
2
P3P 4
P3P 1
P3P 2
3
P3P 1
P3P 2
P3P 4

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4
P3P 1
P3P 4
P3P 2
5
P3P 2
P3P 1
P3P 4
6
P3P 4
P3P 2
P3P 1
Subjects discontinued before randomization will be replaced to reach 18 randomized subjects.
Subjects discontinued after randomization will not be replaced.
If a sufficient number of subjects are already randomized to the study sequences, any 
supernumerous subjects will be discontinued from the study prior to randomization only.
On Days 2, 3 and 4, subjects will be instructed to use the assigned P3P variant for the given 
study day for a fixed puffing regimen in the morning and an ad libitum use period in the 
afternoon as described for Day 1. At each study day including Day 1, start of product use 
should be at approximately the same time for fixed puffing in the morning and for ad libitum
use in the afternoon with at least 10 hour washout period between T0 fix and T0 ad lib. There will 
be a washout of at least 10 hours following T0 ad lib with respect to the T0 fix of the morning of 
the following study day to allow adequate background correction of the nicotine plasma 
concentrations. The assessments performed at Days 2, 3 and 4 will be the same as those 
described for Day 1.
On Day 5, there will be no product use but subjects will remain at the investigational site for 
additional PK blood sampling for the purposes of estimating the terminal elimination half-life.
A total of 5 blood samples will be taken in relation to T0 ad lib from the last product use at the 
following time points: T1 after 14 hours ± 30 minutes, T2 after 16 hours ± 30 minutes, T3 
after 18 hours ± 30 minutes, T4 after 20 hours ± 30 minutes and T5 after 24 hours ± 30 minutes.
During confinement, the use of any tobacco and nicotine containing products, apart from P3P 
use assigned on the assessment days, will not be allowed. Use of tobacco and nicotine 
containing products will not be restricted after Discharge on Day 5.
After Discharge on Day 5 or early termination date, the subjects will enter a 7-day Safety 
Follow-Up Period during which new AE/SAEs spontaneously reported by the subjects will be 
collected.
Any non-serious AE that is ongoing at the time of Discharge or early termination will be 
followed-up by the Investigator or designee 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) or lost to follow up. At the end of the Safety Follow-
Up Period, all ongoing non-serious AEs will be documented as “ongoing” and no follow-up 
information will be sought for them anymore by the Investigator or designee. At that point, 
the Investigator will assess whether the subject should be referred to his/her General 
Practitioner to have their ongoing AEs addressed accordingly. 

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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A. 
All SAEs will be followed up by the Investigator or designee, despite their continuation after 
the end of the Safety Follow-Up Period, until their resolution, stabilization (i.e., no worsening 
of the condition), or an acceptable explanation has been found (e.g., a chronic condition).
SAE reported after the end of the study and considered related to the investigational product 
by the Investigator must be captured and reported to UBC/PMI regardless of time after end of 
the study.
All subjects discontinued from the study at any time after enrollment, will enter the 7 day 
Safety Follow-Up Period.
Study Population and Eligibility Criteria:
Subjects must meet all of the following inclusion criteria to be enrolled into the study:
1. Subject has signed the ICF and is able to understand the information provided in the ICF.
2. Smoking male or female aged between 21 and 65 years old.
3. Subject is White.a
4. Subject has been a smoker for at least the last 3 years prior to the Screening Visit.
5. Has smoked ≥ 10 commercially available cigarettes per day for the last 4 weeks prior to 
Screening Visit. Smoking status will be verified based on a urinary cotinine test (cotinine 
≥ 200 ng/mL).
6. Subject does not plan to quit smoking within 2 months after Screening Visit.
7. Smoking, healthy subject as judged by the Investigator or designee based on available 
assessments from the Screening period (e.g., safety laboratory, spirometry, vital signs, 
physical examination, ECG and medical history).
8. Availability for the entire study period and willingness to comply with study procedures, 
including smoking interruptions.
9. Ready to accept using the P3P product.
Subjects who meet any of the following exclusion criteria must not be enrolled into the study:
1. As per the Investigator’s judgment, the subject cannot participate in the study for any 
reason other than medical (e.g., psychological and/or social reason).
2. Subject is legally incompetent, or physically or mentally incapable of giving consent (e.g., 
emergency situation, under guardianship, prisoners, or subjects who are involuntarily 
incarcerated).
3. Subject has a clinically relevant disease which requires medication (including but not 
limited to gastrointestinal, renal, hepatic, neurological, hematological, endocrine,
oncological, urological, immunological, pulmonary, and cardiovascular disease) or any 
other clinically significant medical condition (including safety laboratory), which as per 
the judgment of the Investigator would jeopardize the safety of the subject.

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4. As per the Investigator’s judgment, the subject has medical conditions which require or 
will require in the course of the study, a medical intervention (e.g., start of treatment, 
surgery, hospitalization) which may interfere with the study participation and/or study 
results.
5. Subject has donated or received whole blood or blood products within 3 months prior to 
Screening Visit.
6. Subject has a BMI < 18.5 kg/m2 or > 32.0 kg/m2..
7. Subject has received medication within 14 days or within 5 half-lives of the drug prior to 
Admission (whichever is longer) which has an impact on CYP2A6 activity.
8. Subject has a positive serology test for HIV 1/2, Hepatitis B, or Hepatitis C.
9. Subject has a positive alcohol breath test and/or a history of alcohol abuse that could 
interfere with the subject’s participation in study.
10. Subject has a positive urine drug test.
11. Subject or one of their family membersb is a current or former employee in the tobacco 
industry.
12. Subject or one of their family membersb is an employee of the investigational site or of 
any other parties involved in the study.
13. Subject has participated in another clinical study within 3 months prior to the Screening 
Visit. The 3-month interval is calculated as the time between the first calendar day of the 
month that follows the last visit of the previous study and the first day of the present study.
14. Subject has been previously screened or enrolled in this study.
15. For women only: subject is pregnant (does not have negative pregnancy tests at Screening 
Visit and at Admission Visit) or is breastfeeding.
16. For women of childbearing potential only c: subject does not agree to use an acceptable 
method of effective contraception.d
17. Use of estrogen-containing hormonal contraception or hormone replacement therapy.
a As defined by FDA guidance on Collection of Race and Ethnicity Data in Clinical Trials(1)
b 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”
c Women who are not of childbearing potential meet at least one of the following criteria: 
Have undergone hysterectomy or bilateral tubal ligation, 
Have medically confirmed ovarian failure, 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).
d Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with spermicidal 
foam/gel/film/suppository, hormonal contraception containing progesterone only, vasectomized partner(s), from Screening 
until the end of the Safety Follow-up Period. Hormonal contraception with estrogen containing products is NOT allowed in 
this study. 

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Investigational Products
P3P generates an inhalable aerosol from nicotine powder when air is drawn through it. P3P is 
a single use product that has a body in the form of a tube, similar to a cigarette, and contains 
a capsule. The capsule is pierced (activated) using a P3P piercing accessory before use. The 
P3P capsule contains the nicotine powder composed of either solely nicotine salt or nicotine 
salt blended with mentholated flavor powder in a 4:1 ratio. The nicotine powder is generated 
by spray-drying nicotine, 
 
 
 and 
 The nicotine powder has a median 
particle size of 1.8 ± 0.2 μm or 2.25 ± 0.2 μm allowing deep lung deposition whereas the 
flavor particles have a particle size > 50 μm and deposit in the oropharyngeal cavity. A single 
P3P product contains 1 or 2 mg of nicotine, depending on the P3P variant.
The following P3P variants will be tested in this study and they differ in nicotine powder
particle size, nicotine concentration, and in the absence or presence of a flavoring system:
P3P variant
Nicotine content 
Nicotine powder 
particle size
Total amount of 
nicotine/ product
Contains flavor 
particles
P3P 1
5%
2.25 ± 0.2 μm
2 mg
no
P3P 2
5%
2.25 ± 0.2 μm
2 mg
yes
P3P 3
2.5%
2.25 ± 0.2 μm
1 mg
yes
P3P 4
5%
1.8 ± 0.2 μm
2 mg
yes
Study Duration:
The entire study per subject will last 14 to 34 days. This will include a Screening period of up 
to 3 weeks prior to Admission (Day -22 to Day -2), 6 days of confinement (Day -1 to time of 
Discharge on Day 5), and a 7-day passive Safety Follow-Up Period (from time of Discharge 
at Day 5 until Day 12). The end of the study (EOS) for a subject is defined as either the 
Discharge on Day 5, or the date of early termination of the subject, plus the 7 days for the 
passive Safety Follow-Up Period. The end of the whole study corresponds to the individual 
EOS of the last subject.
Statistical Methods:
All endpoints will be summarized with descriptive statistics including number of subjects (n), 
number and percent of subjects with missing data, arithmetic means and standard deviations 
(mean and SD), median, first and third quartiles, minimum and maximum; for log normally 
distributed endpoints geometric mean, geometric coefficient of variation (CV) will be 
presented instead of arithmetic mean and SD. Categorical variables will be summarized by 
frequency statistics (number and percentage). For endpoints relating to sampling times (e.g.,
tmax) only median, first and third quartiles, and minimum and maximum will be presented.
The PK population is the primary analysis set for all PK, PD, and HPT endpoints. The PK 
population is composed of all subjects who gave informed consent, completed at least one of 

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the single use of P3P, for whom at least one primary PK parameter could be derived and with 
no major protocol deviation impacting evaluability. In particular, non-safety endpoints will be 
analyzed as follows:
PK: Nicotine PK parameters will be derived from plasma nicotine concentration versus time 
data using non-compartmental analysis (NCA). For both the fixed puffing regimen and the 
ad libitum use period, PK parameters will be derived and reported with and without baseline 
nicotine concentration adjustment.
PK parameters will be summarized by P3P variant and analyzed logarithmically transformed 
using a mixed model with fixed terms for sequence, study day, product variant, and using 
subject nested within sequence as random effect.
PD: PD will be summarized as follows:
x
VAS craving assessments will be summarized over time by P3P variant and by product 
use regimen. The scores will be assessed using a mixed model with sequence, study 
day, product variant, baseline value prior to product use, and the interaction of product
variant and time point as fixed effects and subjects nested within sequence as random 
effect including the assessment time points as repeated measurements. Additionally, 
the VAS craving score will be analyzed as AUCVAS for each puffing regimen: AUCVAS
fix (0-4h) and AUCVAS ad lib (0-4h) (similar to the calculation of nicotine plasma AUCVAS (0-
4h), averaged over the total time of VAS collection period) and analyzed using the same 
model as for the PK parameters , with PD parameters analyzed in the regular scale.
x
Adapted mCEQ subscale scores and SQ answers will be summarized with descriptive 
statistics and displayed graphically by P3P variant. The scores/answers will be 
analyzed using a mixed model with fixed terms for sequence, study day, product 
variant, and using subject nested within sequence as a random effect.
Least squares mean differences (ratios for log-normal data) will be presented for the analysis 
of PK and PD endpoints, together with 95% confidence interval for the following effects of 
interest:
x
P3P 2 vs P3P 3, to describe the effect of an increase of nicotine powder concentration
from 2.5% to 5% 
x
P3P 2 vs P3P 4, to describe the effect of a decrease from 2.25 to 1.8 μm of the median 
particle size of the nicotine powder
x
P3P 2 vs P3P 1, to describe the effect of flavor
HPT parameters will be summarized by P3P variant and by product use regimen.
Safety analysis: The safety population will comprise all enrolled subjects who are exposed to 
P3P during the study. AE records will serve for the primary assessment of safety data. All 
safety data will be listed and AEs will be summarized by product variant (fixed puffing

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regimen and ad libitum use periods will be combined at the product variant level). Safety 
measurements assessed both after fixed puffing regimen and ad libitum use (vital signs, ECG 
etc.) will be summarized per fixed puffing/ad libitum use regimen and product variant.
Sample Size:
The sample size is empirically based, as there is no prior information on which to base it, and 
as there are no considerations for statistical hypothesis. 
As per study design P3P 3 is the first product variant used by all subjects at Day 1 for safety 
reasons (i.e P3P 3 has the lowest nicotine concentration of all P3P variants). As a result, only 
the 3 remaining product variants will be randomized over Day 2-4, which leads to 6 possible 
sequences. Considering that this study is a pilot investigation, and that we are expecting a low 
drop-out rate, 3 subjects will be allocated to each sequence. Therefore, 18 subjects will be 
randomized.
A sufficient number of eligible subjects will be enrolled and exposed to P3P 3 at Admission 
(Day -1) and Day 1 to ensure randomization of 18 subjects to one of six possible sequences at 
Day 2. At least 8 subjects of each sex will be randomized to ensure each sex represents at least 
40% of the randomized population.

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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS .........................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................17 
Abbreviations ...................................................................................................................17 
Definitions of Terms ........................................................................................................19 
1 
ETHICS AND REGULATIONS .....................................................................................20 
1.1 
Ethics Committee Approval ...................................................................................20 
1.2 
Ethical Conduct of the Study .................................................................................20 
1.3 
Subject Information and Consent...........................................................................21 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................22 
2 
INTRODUCTION ...........................................................................................................23 
2.1 
Background ............................................................................................................23 
2.2 
Purpose of the Study ..............................................................................................24 
2.3 
Anticipated Benefits and Risks ..............................................................................24 
3 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................27 
3.1 
Primary Objective and Endpoints ..........................................................................27 
3.2 
Secondary Objectives and Endpoints.....................................................................27 
4 
INVESTIGATIONAL PLAN ..........................................................................................29 
4.1 
Overall Study Design and Plan ..............................................................................29 
4.2 
Rationale for Study Design ....................................................................................32 
4.3 
Appropriateness of Measurements .........................................................................33 
4.4 
Study Duration .......................................................................................................33 
5 
STUDY POPULATION ..................................................................................................34 
5.1 
Selection of Study Population ................................................................................34 
5.2 
Discontinuation of Subjects from the Study ..........................................................38 
5.3 
Lost to Follow-Up ..................................................................................................39 
5.4 
Violation of Selection Criteria ...............................................................................39 
6 
INVESTIGATIONAL PRODUCTS ...............................................................................40 
6.1 
Description of Investigational Products .................................................................40 
6.2 
Use of Investigational Products .............................................................................40 
6.3 
Method for Assigning Subjects to Sequence .........................................................42 
6.4 
Blinding..................................................................................................................43 
6.5 
Investigational Product Accountability and Compliance ......................................43 

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6.6 
Restrictions ............................................................................................................44 
7 
STUDY PROCEDURES .................................................................................................47 
7.1 
Informed Consent...................................................................................................47 
7.2 
Information on the Risk of Smoking, Smoking Cessation Advice and Product 
Debriefing ............................................................................................................47 
7.3 
Support during Smoking Abstinence/Periods of Reduced Smoking .....................47 
7.4 
Clinical Assessments .............................................................................................47 
7.5 
Biomarker Assessment...........................................................................................50 
7.6 
Laboratory Assessments ........................................................................................51 
7.7 
Sample Handling, Storage, and Shipment .............................................................53 
7.8 
Questionnaires........................................................................................................53 
7.9 
Other Study Procedures .........................................................................................56 
8 
ADVERSE EVENTS .......................................................................................................57 
8.1 
Definitions..............................................................................................................57 
8.2 
Collection and Reporting of Adverse Events.........................................................58 
8.3 
Reporting of Serious Adverse Events ....................................................................60 
8.4 
Reporting of Other Events Critical to Safety Evaluations .....................................61 
8.5 
Reporting and Follow–Up of Pregnancies .............................................................62 
8.6 
Adverse Events Leading to Discontinuation..........................................................63 
8.7 
Investigational Product Malfunction and Misuse ..................................................63 
9 
STUDY ACTIVITIES .....................................................................................................64 
9.1 
Screening Visit .......................................................................................................64 
9.2 
Admission Visit .....................................................................................................66 
9.3 
Investigational Period (Day 1 to Day 4) ................................................................67 
9.4 
Day of Discharge ...................................................................................................71 
9.5 
Safety Follow-Up Period .......................................................................................72 
9.6 
Early Termination Procedures ...............................................................................72 
10 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................74 
10.1 Monitoring .............................................................................................................74 
10.2 Training of Staff .....................................................................................................74 
10.3 Audits and Inspections ...........................................................................................75 
11 DATA MANAGEMENT ACTIVITIES..........................................................................76 
11.1 Data Capture ..........................................................................................................76 
11.2 Data Handling ........................................................................................................77 

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12 PLANNED STATISTICAL METHODS ........................................................................79 
12.1 General Considerations ..........................................................................................79 
12.2 Determination of Sample Size and Power Consideration ......................................80 
12.3 Analysis Populations ..............................................................................................80 
12.4 Demographics and Baseline Characteristics ..........................................................81 
12.5 Primary Objectives and Endpoints.........................................................................81 
12.6 Secondary Objectives and Endpoints.....................................................................83 
12.7 Interim Analysis .....................................................................................................85 
13 ADMINISTRATIVE CONSIDERATIONS ....................................................................86 
13.1 Investigators and Study Administrative Structure .................................................86 
13.2 Study subjects’ recruitment....................................................................................87 
13.3 Subject Confidentiality ..........................................................................................88 
13.4 Access to Source Documentation ..........................................................................88 
13.5 Record Retention ...................................................................................................88 
13.6 Clinical Study Report .............................................................................................90 
13.7 Financial Disclosure...............................................................................................90 
13.8 Publication and Disclosure Policy .........................................................................90 
13.9 Insurance ................................................................................................................91 
14 REFERENCE LIST .........................................................................................................92 
15 APPENDICES .................................................................................................................95 
Appendix A – Schedule of Events ...................................................................................95 
Appendix B - Participating Laboratories .........................................................................99 
Appendix C - Laboratory Values ...................................................................................100 
Appendix D – Human Puffing Topography Parameters ................................................103 

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LIST OF IN-TEXT TABLES 
Table 1  
P3P variants tested in this study.................................................................40 
Table 2  
Description of sequences to allocate subjects to........................................42 
Table 3 
CYP2A6: Substrates, Inhibitors, and Inducers (14)...................................46 
Table 4 
Clinical Laboratory Parameters for Safety Panel.......................................52 
Table 5 
Intensity of Adverse Events.......................................................................59 
Table 6  
Principles for assessing and reporting abnormal laboratory test results....61 
Table 7 
Time Schedule – Screening Visit...............................................................64 
Table 8 
Time Schedule – Admission Visit .............................................................66 
Table 9 
Time Schedule – Fixed puffing period (Day 1, 2, 3, 4 - Morning)............67 
Table 10 
Time Schedule – Ad libitum use period (Day 1, 2, 3, 4  - Afternoon).......69 
Table 11 
Time Schedule – Day of Discharge (Day 5)..............................................71 
Table 12 
Time Schedule – Early Termination..........................................................73 
Table C1 
Abnormal Laboratory Values Rating: Serum Chemistry Parameters......100 
Table C2 
Abnormal Laboratory Values Rating: Hematology Parameters ..............101 
Table C3 
Abnormal Laboratory Values Rating: Urine analysis Parameters...........102 
Table D1 
Per-puff parameters..................................................................................103 
Table D2 
Per-product use experience parameters ...................................................103 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Flow Chart .........................................................................................5 
Figure 2 
Study Flow Chart .......................................................................................29 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
Adapted mCEQ
Adapted version of the modified cigarette evaluation questionnaire
AE
Adverse event
AUCad lib (0-4h)
Area under the concentration-time curve from T0 ad lib to 4h after T0 ad 
lib
AUCfix (0-4h)
Area under the concentration-time curve from T0 fix to 4h after T0 fix
BMI
Body mass index
Caverage
Average plasma nicotine concentration during ad libitum use period
Cmax
Maximum concentration
Cpeak
Highest plasma nicotine concentration during ad libitum use period
Ctrough
Trough plasma nicotine concentration during ad libitum use period
CDISC
Clinical data interchange standards consortium
CI
Confidence interval
CRF
Case report form
CRO
Contract research organization
CSR
Clinical study report
CTCAE
Common terminology criteria for adverse events and common toxicity 
criteria
CTMS
Clinical trial management system
CV
Coefficient of variation
CYP2A6
Cytochrome P450 2A6
DCF
Data clarification form
DMP
Data management plan
DVP
Data validation plan
ECG
Electrocardiogram
EOS
End of study
FEV1
Forced expiratory volume in 1 second
FTND
Fagerström test for nicotine dependence (revised version)
FVC
Forced vital capacity
GCP
Good clinical practice
GMP
Good manufacturing practice
HIV
Human immunodeficiency virus

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HPHCs
Harmful and potentially harmful constituents 
HPT
Human puffing topography
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International council for harmonisation 
IEC
Independent ethics committee
IP
Investigational product
LLOQ
Lower limit of quantification
λz
Terminal elimination rate constant
MedDRA
Medical dictionary for regulatory activities
NCA
Non-compartmental analysis
PD
Pharmacodynamics
PK
Pharmacokinetic(s)
PMI
Philip Morris International
RRP
Reduced risk product
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SHM
Sample handling manual
SMF
Study master file
SMP
Safety management plan
SOP
Standard operating procedure
SQ
Sensory questionnaire
T0 ad lib
Time point of start of first product use at the ad libitum use period
T0 fix
Time point of start of product use at the fixed puffing regimen
t1/2z
Terminal elimination half-life
tmax
Time to maximum concentration
tpeak
Time to peak plasma nicotine concentration at the ad libitum use period
UBC
United BioSource Corporation
ULOQ
Upper limit of quantification
VAS
Visual analogue scale
WHO
World health organisation

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Definitions of Terms 
End of Study
The end of the study (EOS) for a subject is defined as either the 
Discharge at Day 5, or the date of early termination of the subject, 
plus the 7 days for the Safety Follow-up Period. 
The end of the whole study corresponds to the individual EOS of 
the last subject.
Enrollment
On Admission Visit for eligible subjects after all applicable 
inclusion and exclusion criteria have been satisfactorily assessed 
and met.
Randomization
Assignment to the respective sequence of product use at Day 2.
Screen failure
Subject who signs the ICF but is not enrolled at Admission. 

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

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The Investigator or designee agrees to conduct the clinical study in compliance with the 
protocol agreed with the Sponsor and approved by the IEC. The Investigator and the Sponsor 
must sign the protocol (and protocol amendments, if applicable) to confirm this agreement. A 
copy of the Declaration of Helsinki is located in the Investigator’s study file.
1.3
Subject Information and Consent
1.3.1 
Informed Consent Form for Study Participation 
Before or at Screening, the Investigator or designee will ensure that each subject is given full 
and adequate oral and written information about the nature, purpose, possible risks and benefits 
of the study, and the Investigator or the designee will answer all questions the subject might 
have to his/her full satisfaction. The subject will have sufficient time for consideration of 
his/her participation in the study and will be notified that he/she is free to discontinue his/her 
participation at any time.  
Once the subject has received all the necessary information, and if he/she agrees to participate, 
this will be documented in the ICF by the date and signature of both the subject and the 
Investigator who conducted the informed consent discussion during Screening Visit. Any 
procedures specifically described in and related to the study protocol and study conduct, will 
not be performed before the ICF has been signed. The exact date and time of ICF signature 
will be captured in the volunteers registration log.  
The personally signed and dated original ICF(s) must be kept by the Investigator and filed in 
the Investigator study file at the site or with the subject’s files and a copy must be given to the 
subject. The subject will be informed that if he/she withdraws from the study, the data collected 
until the point of withdrawal will be maintained as part of the study data and the samples 
collected prior to withdrawal will be analyzed, unless he/she refuses in writing. The subject 
will be informed that additional data analysis not mentioned in the protocol or in the statistical 
analysis plan (SAP) might be performed with the collected data at a later time. Any additional 
analysis performed will be covered by data confidentiality, as for the main analysis described 
in this protocol.
1.3.2 
Amendment to the Informed Consent Form  
If a protocol amendment is required, or if any new information regarding the risk profile of the 
investigational product (IP) becomes available, or for any other reason deemed necessary, an 
amendment to the ICF may be required. If a revision of the ICF is necessary, the Investigator 
or designee will, with the support of the Sponsor, ensure that the documents have been 
reviewed and approved by a relevant IEC before subjects are required to re-sign the ICF 
(including date and time). If new and important safety information is received, subjects who 
already completed or are discontinued from the study will be informed in writting. 

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1.4
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator and designee abide by the principles of the ICH GCP Guideline 
(2). These guidelines apply specifically to pharmaceutical development, but nevertheless 
provide a robust and ethical framework for conducting a clinical study with products such as 
P3P. The study will also be conducted in accordance with the general ethical principles 
outlined in the Declaration of Helsinki (3).  
In addition, the Investigator or designee will carry out the clinical study in accordance with 
applicable national and local laws of the pertinent regulatory authorities. 

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2 
INTRODUCTION 
2.1 
Background 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy 
Cigarette smoking causes pulmonary, cardiovascular and other serious diseases in smokers (4).
There is no safe cigarette, and the best way for smokers to reduce the adverse health 
consequences of smoking is to quit. Despite the risks which are attributable to smoking, some 
smokers decide to continue smoking. The development of novel tobacco and nicotine 
containing products with the potential to be less harmful than cigarettes represents an approach 
to reduce cigarette-related deaths and diseases among smokers who would have otherwise 
continued smoking (5). Philip Morris International (PMI) is developing such alternative 
products that have the potential to reduce individual risk and population harm in comparison 
to smoking cigarettes. These products aim to substantially reduce or eliminate the exposure to 
harmful and potentially harmful constituents (HPHCs), with the exception of nicotine, while 
providing an acceptable substitutes for cigarettes.
One of these products is P3P which is based on aerosolization of a nicotine containing powder 
that could satisfy smokers in terms of nicotine absorption similar to that of cigarettes. The aim 
of this study is to explore the nicotine absorption and subjective effects from four different 
variants of P3P and evaluate if these can provide an acceptable option to smokers as substitutes 
for cigarettes. 
2.1.2 
Description of the Product and Scientific Findings 
P3P generates an inhalable aerosol from nicotine powder when air is drawn through it. P3P is 
a single use product that has a body in the form of a tube, similar to a cigarette, and contains a 
capsule. The capsule is pierced (activated) using a P3P piercing accessory before use. The P3P 
capsule contains nicotine powder composed of either solely nicotine salt or nicotine salt 
blended with mentholated flavor powder in a 4:1 ratio. The nicotine powder is generated by 
spray-drying nicotine, 
 
 
 and 
 The nicotine powder has a median
particle size of 1.8 ± 0.2 μm or 2.25 ± 0.2 μm allowing deep lung deposition whereas the flavor 
particles have a particle size > 50 μm and deposit in the oropharyngeal cavity. A single P3P 
product contains 1 or 2 mg of nicotine, depending on the P3P variant. P3P is used in a similar 
way to cigarettes i.e. with a 2-step process with 1) puffing and 2) inhalation. The puffing step 
should be of sufficient intensity to trigger the spinning of the capsule.
An important factor to be optimized in order to achieve pulmonary delivery, while minimizing 
deposition of the aerosol in the oropharynx and upper airway, is the aerosol particle size. An 
aerosol comprising particles with diameters less than 5 μm is required for deep lung deposition 
and rapid absorption of nicotine. However, if the particles are very small (< 1 μm) they may 
be exhaled (6). Therefore, to achieve deep lung deposition while minimizing exhalation, 

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different variants of P3P with particle sizes in a respirable range (but higher than 1 μm) will 
be tested in this study.  
In humans, there is no scientific data available to date on nicotine absorption following P3P 
use. However, nicotine absorption following the use of P3L has been studied in a clinical study 
in healthy adult cigarette smokers (7). P3L is another product developed by PMI that contains 
both nicotine and lactic acid like P3P, with the difference that these two components are in a 
liquid form. P3L generates inhalable nicotine-lactate aerosol formed by mixing and 
condensation of two gas streams resulting from the heating of nicotine and lactic acid present 
in a liquid, with the lactic acid acting as the carrier or aerosol forming vehicle. In the study, 
P3L PK parameters were compared to nicotine replacement therapy (Nicorette®inhalator). P3L 
provided peak plasma nicotine concentrations higher and faster compared to the Nicorette®
inhalator with Cmax of 9.7 ng/mL for P3L compared to 6.1 ng/mL for Nicorette® inhalator and 
Tmax of 7 minutes for P3L versus 30 minutes for Nicorette® inhalator. The concentration-time 
profile supported a pulmonary route of nicotine absorption for P3L compared to the 
oromucosal absorption of Nicorette® inhalator (7). The PK profile of nicotine of P3L was 
comparable to the one for cigarettes (8).
Non-clinical information on P3P to support this clinical study is presented in the Investigator’s 
brochure (IB) (9). 
2.2
Purpose of the Study 
The purpose of the study is to evaluate the PK profiles of four P3P variants (differing in 
nicotine powder particle size, nicotine concentration, and in the absence or presence of a
flavoring system) following a fixed puffing regimen and an ad libitum use period. In addition, 
pharmacodynamic effects (subjective effects and related behavioral assessments) as well as 
human puffing topography will be evaluated, to provide further insights on product acceptance 
and product use. Safety will also be assessed throughout the study. 
2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
Information on health risks associated with smoking and smoking cessation advice will be 
provided. Subjects who are motivated to quit smoking during the study will be given the 
opportunity to continue their smoking cessation attempt and will be referred to appropriate 
stop smoking services for continuing support and counselling at a higher level. Subjects who 
participate in this study will also benefit from repeated and detailed health check-ups.  
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures 
The risk of scheduled procedures in the present study (e.g., blood samples) are deemed to be 
on par with procedures routinely performed during normal or extended health examinations by 

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the subject’s healthcare professional. The total volume of blood to be drawn is approximately 
464 mL and does not exceed the levels for a standard blood donation. The risks related to blood 
sampling include for example: excessive bleeding, fainting, haematoma, paresthesia or 
infection, and those related to the total amount of blood taken over a period of time such as 
weakness, dizziness or anemia. 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product  
Although by product design, P3P does not generate toxins and carcinogens as observed with 
cigarette smoking (10), given the current state of knowledge of the product, it has not been 
demonstrated that P3P reduces the risk of developing smoking-related diseases compared to 
cigarettes.  
Due to sensorial and technological differences between P3P and cigarettes, it is 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. A confinement setting may also have an 
influence on puffing behavior and may lead to an increase of P3P use when ad libitum use is 
allowed.
An adult smoker using P3P may experience:
•
Transient nicotine withdrawal symptoms (e.g., urge to smoke, irritability, anxiety feelings, 
restlessness, and difficulty to concentrate) similar to cravings observed during smoking 
cessation
•
Transient symptoms suggesting mild nicotine overdose such as stimulatory effects on 
sympathetic tone (increased blood pressure, increased heart rate), central nervous system 
(tremor, blunting of emotions, and decreased ability to concentrate), gastric acid secretion, 
and vomiting. Individuals who experience AEs (suggesting excessive stimulant effects) 
should be instructed to reduce their intensity of product use by decreasing the number of 
puffs and/or the intensity of puffing
•
Change in smoking habits due to study requirements and related concomitant symptoms, 
e.g., craving 
Support during periods of smoking abstinence will be provided. Further risk mitigation will 
include:  
•
Using commonly accepted research and scientific standards (e.g., blood samples not to 
exceed blood donation standards) 
•
Medical supervision of all study subjects with follow-up of those who have experienced an 
AE(s)/SAE(s)

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2.3.4 
Unforeseeable Risks 
The possibility of unforeseeable events/risks will be explained in detail to study subjects. 
Subjects will be informed that P3P has not currently been demonstrated to be less harmful than 
cigarettes. Unexpected malfunction of the P3P may lead to unforeseeable risk. Mitigation will 
include close monitoring and medical supervision to detect any unforeseeable risk or safety 
signals at the earliest time possible. 

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3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective and Endpoints 
1.
To evaluate the plasma concentration-time profile of nicotine and the derived PK 
parameters (with and without adjustment for baseline nicotine concentrations) of four P3P 
variants from the fixed puffing regimen. 
Endpoints:  
x
Plasma nicotine concentration-time profile 
x
Maximum plasma concentration [Cmax] 
x
Time to the maximum concentration [tmax] 
x
Area under the concentration-time curve from start of product use (T0 fix) to 4 hours
[AUCfix (0-4h)]
3.2 
Secondary Objectives and Endpoints 
1.
To evaluate the plasma concentration-time profile of nicotine and derived PK parameters 
(with and without adjustment for baseline nicotine concentrations) of the four P3P variants
from the ad libitum use period.
Endpoints:  
x
Plasma nicotine concentration-time profile 
x
Peak plasma nicotine concentration [Cpeak] 
x
Time to peak plasma nicotine concentration [tpeak]  
x
Trough plasma nicotine concentration [Ctrough] 
x
Average of plasma nicotine concentration from T0 ad lib to 1 hour  [Caverage] 
x
Area under the concentration-time curve from start of product use (T0 ad lib) to 4 hours 
[AUCad lib (0-4h)] 
2. To evaluate the pharmacodynamic effects (subjective effects and related behavioral 
assessments) of four P3P variants.
Endpoints: 
x
Visual Analogue Scale (VAS)-craving assessment from the fixed puffing regimen and 
ad libitum use period 
x
Product evaluation by an adapted version of the modified Cigarette Evaluation 
Questionnaire (adapted mCEQ) following the ad libitum use period 
x
Sensory Questionnaire (SQ) following the ad libitum use period 

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3. To evaluate human puffing topography of four P3P variants during the fixed puffing 
regimen and the ad libitum use period. 
Endpoints: 
x
Per-puff parameters and per-product use experience parameters
4. To estimate the amount of powder aerosolized from P3P from the fixed puffing regimen 
and the ad libitum use periods. 
Endpoints: 
x
Weight difference of P3P before and after use  
5. To monitor the safety and tolerability during the study. 
Endpoints: 
x
Incidence of adverse events (AEs), serious adverse events (SAEs)  
x
Frequency of AEs, SAEs  
x
Incidence of P3P product events including malfunction/misuse  
x
Frequency of P3P product events including malfunction/misuse  
x
Physical examination changes from baseline 
x
Cough changes from baseline (VAS and three Likert scales) 
x
Electrocardiogram (ECG) changes from baseline (heart rate, PR, QRS, QT, QTcB, 
QTcF intervals) 
x
Vital signs changes from baseline (systolic and diastolic blood pressure, pulse rate and 
respiratory rate) 
x
Spirometry changes from baseline (FEV1, FEV1 % predicted, FVC, FVC % predicted
FEV1/FVC) 
x
Changes from baseline in clinical chemistry, hematology, and urine analysis safety 
panel 
x
Concomitant medications 

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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a single-center, open-label, randomized, crossover study to evaluate the PK profiles of 
four P3P variants (differing in nicotine powder particle size, nicotine concentration and in the 
absence or presence of a flavoring system), (section 6.1), following a fixed puffing regimen 
and an ad libitum use period. In addition, PD effects (subjective effects and related behavioral 
assessments) as well as human puffing topography will be evaluated, to provide further insights 
on product acceptance and product use. Safety will also be assessed throughout the study. 
Each subject will receive the four P3P variants starting with P3P 3, which has the lowest 
nicotine concentration, on Day 1 and continuing with P3P 1, P3P 2 and P3P 4 in a random 
order at the following assessment days (Figure 2). The subjects will be in confinement during 
the investigational period (Day -1 to Day 5).  
Figure 2 Study Flow Chart 
The Screening Visit (Day -22 to Day -2) 
A Screening Visit will be conducted within 3 weeks prior to Admission to the investigational 
site. Eligibility criteria will be verified at the Screening Visit (section 5.1). A demonstration of 
P3P (without product use) will be done by the investigational site staff. 
The Admission Visit (Day -1) 
Subjects will return to the investigational site for Admission (Day -1). Subjects should have 
been fasting for at least 6 hours prior to Admission. After confirmation of eligibility, subjects 
will be enrolled. All subjects that are not enrolled will be considered as screen failures. At 

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Admission, enrolled subjects will perform a product test using up to three P3P 3 products.
After the product test, subjects not willing and/or unable to use P3P will be discontinued from 
the study. Subjects willing to continue their participation in the study after the product test will 
start their confinement phase.
The Confinement Period (Day -1 to Day 5) 
On Day 1, after at least 10 hour abstinence from any tobacco/nicotine containing products, 
subjects will use P3P 3 during a fixed puffing regimen comprising of 12 puffs in total at a rate 
of one inhalation every 30 seconds (± 5 seconds) in the morning and during an ad libitum use 
period for 60 minutes (± 5 minutes) in the afternoon. The start of product use for fixed puffing 
and for the ad libitum use period will be defined as T0 fix and T0 ad lib, respectively. There will 
be a washout period of at least 10 hours between T0 fix and T0 ad lib.  
A total of 10 blood samples will be taken for fixed puffing PK parameter estimation. One blood 
sample will be taken prior to the product use (T0 fix) 15 minutes ± 5 minutes (T-1). Thereafter 
in relation to T0 fix, blood will be drawn at the following time points: T1 after 2 minutes ± 1
minute, T2 after 4 minutes ± 1 minute, T3 after 7 minutes ± 1 minute, T4 after 10 minutes ± 1 
minute, T5 after 15 minutes ± 2 minutes, T6 after 30 minutes ± 2 minutes, T7 after 1 hour ± 5 
minutes, T8 after 2 hours ± 5 minutes, and T9 after 4 hours ± 5 minutes. 
A total of 8 blood samples will be taken for the ad libitum PK parameter estimation. One blood 
sample will be taken prior to product use (T0 ad lib) at 15 minutes ± 5 minutes (T-1). In relation 
to T0 ad lib, blood will be drawn at the following time points: T1 after 10 minutes ± 1 minute, 
T2 after 20 minutes ± 2 minutes, T3 after 30 minutes ± 2 minutes, T4 after 40 minutes ± 5 
minutes and T5 after 1 hour ± 5 minutes, T6 after 2 hours ± 5 minutes, and T7 after 4 hours ± 
5 minutes.  
PD effects related to craving will be assessed using a VAS scale at different timepoints. For 
the fixed puffing regimen the first assessment will be done 15 minutes ± 5 minutes prior to T0
fix, all other assessments will be done after T0 fix, at 4 minutes ± 2 minutes, at 10 minutes ± 2 
minutes, at 15 minutes ± 2 minutes, 30 minutes ± 5 minutes, 1 hour, 2 hours, 4 hours ± 10 
minutes each. For the ad libitum use period the first assessment will be done 15 minutes ± 5 
minutes prior to T0 ad lib, all other assessments will be done after T0 ad lib, at 10 minutes ± 2 
minutes, at 20 minutes ± 2 minutes, 30 minutes ± 5 minutes, 40 minutes ± 5 minutes, 1 hour, 
2 hours, 4 hours ± 10 minutes each. VAS will be assessed immediately after the collection of 
the time-matching PK samples. 
Product evaluation and sensory questionnaires will be assessed after the end of the ad libitum
use period. 
A puffing topography device will be attached to each P3P during both the fixed puffing 
regimen and the ad libitum use period. There will be one recording of HPT parameters per 
product use (section 7.9.1). Each P3P will be weighed before and after product use to estimate 

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the amount of nicotine delivered in the aerosol. The number of P3P used during the ad libitum
use period will be recorded.
In the morning of Day 2, after confirmation that there are no safety concerns for each subject 
to continue in the study based on Investigator’s judgement, 18 subjects will be randomized in 
order to cross-over the use of P3P 1, P3P 2 and P3P 4 (section 6.3).
Subjects discontinued before randomization will be replaced to reach 18 randomized subjects.
Subjects discontinued after randomization will not be replaced.
If a sufficient number of subjects are already randomized to the study sequences, any 
supernumerous subjects will be discontinued from the study prior to randomization only
(section 5.2).
On Days 2, 3 and 4, subjects will be instructed to use the assigned P3P variant for the given 
study day for a fixed puffing regimen in the morning and an ad libitum use period in the 
afternoon as described for Day 1. On each study day including Day 1, start of product use 
should be at approximately the same time for fixed puffing in the morning and for ad libitum
use in the afternoon with at least a 10 hour washout period between T0 fix and T0 ad lib. There 
will be a washout of at least 10 hours following T0 ad lib with respect to the T0 fix of the morning 
of the following study day to allow adequate background correction of the nicotine plasma 
concentrations. The assessments performed on Days 2, 3 and 4 will be the same as those 
described for Day 1.
On Day 5, there will be no product use, but subjects will remain at the investigational site for 
additional PK blood sampling for the purposes of estimating the terminal elimination half-life.
A total of 5 blood samples will be taken in relation to T0 ad lib from the last product use at the 
following time points: T1 after 14 hours ± 30 minutes, T2 after 16 hours ± 30 minutes, T3 after 
18 hours ± 30 minutes, T4 after 20 hours ± 30 minutes and T5 after 24 hours ± 30 minutes.
Safety measurements including vital signs, ECG, safety laboratory parameters will be 
performed at several timepoints during the confinement period (Appendix A).
During confinement, the use of any tobacco and nicotine containing products, apart from 
product use assigned on the assessment days, will not be allowed. Use of tobacco and nicotine 
containing products will not be restricted once the subjects have left the investigational site.
The Safety Follow-Up Period (from Discharge or Early Termination plus 7 days) 
After Discharge on Day 5 or early termination date, the subjects will enter a 7-day Safety 
Follow-Up Period during which AE/SAEs spontaneously reported by the subjects will be 
collected.
Any non-serious AE that is ongoing at the time of Discharge or early discontinuation will be 
followed-up by the Investigator or designee during the Safety Follow-Up Period until it has 
been resolved, stabilized (i.e., no worsening of the condition), or an acceptable explanation has 

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been found (e.g., a chronic condition) or lost to follow up. At the end of the Safety Follow-Up 
Period, all ongoing non-serious AEs will be documented as “ongoing” and no further follow-
up information will be sought for them by the Investigator or designee. At that point, the 
Investigator will assess whether the subject should be referred to his/her General Practitioner 
to have their ongoing AEs addressed accordingly. All SAEs will be followed up by the 
Investigator or designee, despite their continuation, after the end of the Safety Follow-Up 
Period until their resolution, stabilization (i.e., no worsening of the condition), or an acceptable 
explanation has been found (e.g., a chronic condition). 
SAEs reported after the end of the study and considered related to the investigational product 
by the Investigator must be captured and reported to UBC/PMI regardless of the time after end 
of the study. 
All subjects discontinued from the study at any time after enrollment, will enter the 7 day 
Safety Follow-Up Period. 
4.2
Rationale for Study Design
The minimum age of 21 years old in the inclusion criteria was selected based on the legal age 
of smoking in Switzerland (Canton of Ticino) of 18 years; and to account for the 3 years of 
smoking history.
Variants with two different nicotine contents (1 mg/product and 2 mg/product) will be tested. 
These two nicotine contents are evaluated in this study to identify which one would yield 
plasma nicotine concentrations as close as possible to those achieved after smoking a single 
cigarette. All of the subjects will initially use the lowest nicotine content product (P3P 3). The 
subject will be randomized to continue the study using the three remaining products (P3P 1,
P3P 2 and P3P 4) containing 2 mg nicotine/product only on the Investigator’s judgment who 
will be responsible to assess safety information following the use of P3P 3.
Two product use regimens: fixed puffing and ad libitum use will be applied to provide insight 
into nicotine absorption. The fixed puffing regimen with consistent use conditions across 
subjects will be applied in order to minimize variability and thereby provide a better 
understanding of the respective impact of nicotine content, particle size and presence or not of 
a flavoring system in the different P3P variants with regards to nicotine PK profile. The ad 
libitum use period will provide information on nicotine PK and product acceptance when 
subjects use the P3P according to their own puffing behavior which is closer to a real-world 
setting.  
Sampling timepoints for determination of nicotine concentrations were selected to ensure 
reliable estimation of PK parameters. In particular, frequent sampling during the first 15 
minutes from T0 fix will be performed in order to reliably assess tmax which is expected to be 
around 7 minutes, similar to what was observed with P3L (7) and cigarettes (8), and compatible 
with absorption by the pulmonary route.  

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Plasma nicotine presents a biphasic profile, with a typical rapid initial disposition half-life 
(t1/2α) of 1.35 hours, followed by a slower terminal elimination half-life (t1/2z) of 17 hours (11). 
To ensure a full nicotine washout between each product use, a separation of 3 days would have 
been required (~ 5 x elimination t1/2z). Based on nicotine population PK modeling, it was 
estimated that subjects nicotine has entered in the terminal elimination phase with 
concentrations decreasing according to the terminal elimination rate constant (λz) after 8 to 10 
hours post administration. As a consequence, a minimum of 10 hours have been established in 
this study design between the start of each use regimen to ensure appropriate washout of 
nicotine. Background-concentration correction will be applied to adjust for carry-over effects 
with adjustment of baseline values to the estimated
t1/2z (or the terminal elimination rate 
constant λz) which will be derived from additional blood sampling on Day 5 for each subject.  
The use of estrogen contraceptive is known to accelerate nicotine clearance by 20% to 30% 
compared to women who do not take oestrogen contraceptive (12). Therefore, for the purpose 
of this study, use of hormonal contraception containing estrogens is prohibited. This also 
applies to hormone replacement therapy.  
The activity of CYP2A6 will be measured. CYP2A6 activity drives the metabolism of nicotine 
to cotinine and subsequent metabolites. Nicotine metabolism by CYP2A6 varies between 
individuals of the same ethnicity/race and across ethnicity/race due to genetic variations. These 
genetic differences could be associated with reduced/increased nicotine metabolism (8).
4.3 
Appropriateness of Measurements 
All laboratory measures utilized for this study are validated and are appropriate for the study 
assessments. Questionnaires used in this study, except craving VAS and cough questionnaires, 
are available as validated/previously published or adapted versions of validated questionnaires.  
4.4 
Study Duration 
The entire study per subject will last 14 to 34 days. This will include a Screening period of up 
to 3 weeks prior to Admission (Day -22 to Day -2), 6 days of confinement (Day -1 to time of 
Discharge on Day 5), and a 7-days passive Safety Follow-Up (from time of Discharge at Day 
5 until Day 12). The end of the study (EOS) for a subject is defined as either the Discharge at 
Day 5, or the date of early termination of the subject, plus the 7 days for the Safety Follow-Up
Period. The end of the whole study corresponds to the individual EOS of the last subject.

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5 
STUDY POPULATION 
5.1
Selection of Study Population
A sufficient number of eligible subjects will be enrolled and exposed to P3P 3 at Admission 
(Day -1) and Day 1 to ensure randomization of 18 subjects at Day 2. At least 8 subjects of each 
sex will be randomized to ensure each sex represents at least 40% of the randomized 
population.
5.1.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be enrolled into the study: 
Inclusion Criteria
Rationale
Screening
Visit
Admission
Visit
1. Subject has signed the ICF and is able to 
understand the information provided in the 
ICF.
Administrative
X
2. Smoking male or female aged between 21 
and 65 years old.
Safety
X
3. Subject is White.a
Effect
X
4. Subject has been a smoker for at least the 
last 3 years prior to the Screening Visit.
Effect
X
5. Has smoked ≥ 10 commercially available 
cigarettes per day for 4 weeks prior to 
Screening Visit. Smoking status will be 
verified based on a urinary cotinine test 
(cotinine ≥ 200 ng/mL).
Effect
X
6. Subject does not plan to quit smoking 
within 2 months after Screening Visit.
Safety
X
X
7. Smoking, healthy subject as judged by the 
Investigator or designee based on available 
assessments from the Screening period 
(e.g., safety laboratory, spirometry, vital 
signs, physical examination, ECG and 
medical history).
Safety
X
8. Availability for the entire study period and 
willingness 
to 
comply 
with 
study 
Effect
X
X

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without the written consent of Philip Morris Products S.A. 
Inclusion Criteria
Rationale
Screening
Visit
Admission
Visit
procedures, 
including 
smoking 
interruptions.
9. Ready to accept using the P3P product.
Effect
X
5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the study:
Exclusion Criteria
Rationale
Screening
Visit
Admission 
Visit
1. As per the Investigator’s judgment, the 
subject cannot participate in the study for 
any reason
other than
medical
(e.g., 
psychological and/or social reason). 
Safety 
X
2. Subject 
is 
legally 
incompetent, 
or 
physically or mentally incapable of giving 
consent (e.g., emergency situation, under 
guardianship, prisoners, or subjects who are 
involuntarily incarcerated).
Administrative 
X
3. Subject has a clinically relevant disease 
which requires medication (including but 
not limited to gastrointestinal, renal, 
hepatic, 
neurological, 
hematological, 
endocrine, 
oncological, 
urological, 
immunological, 
pulmonary, 
and 
cardiovascular disease) or any other 
clinically significant
medical condition 
(including safety laboratory), which as per 
the judgment of the Investigator would 
jeopardize the safety of the subject. 
Safety
X

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Exclusion Criteria
Rationale
Screening
Visit
Admission 
Visit
4. As per the Investigator’s judgment, the 
subject has medical conditions which 
require or will require in the course of the 
study, a medical intervention (e.g., start of 
treatment, surgery, hospitalization) which 
may interfere with the study participation 
and/or study results. 
Effect
X
5. Subject has donated or received whole 
blood or blood products within 3 months 
prior to Screening Visit. 
Safety
X
6. Subject has a BMI < 18.5 kg/m2 or > 32.0 
kg/m2.
Safety
X
7. Subject has received medication within 14 
days or within 5 half-lives of the drug prior 
to Admission (whichever is longer) which 
has an impact on CYP2A6 activity.
Effect
X
8. Subject has a positive serology test for HIV 
1/2, Hepatitis B, or Hepatitis C. 
Safety
X
9. Subject has a positive alcohol breath test 
and/or a history of alcohol abuse that could 
interfere with the subject’s participation in 
study. 
Administrative
X
X
10. Subject has a positive urine drug test. 
Administrative
X
X
11. Subject or one of their family membersb is
a current or former employee in the tobacco 
industry. 
Administrative
X
12. Subject or one of their family membersb is
an employee of the investigational site or of 
any other parties involved in the study. 
Administrative
X

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Exclusion Criteria
Rationale
Screening
Visit
Admission 
Visit
13. Subject has participated in another clinical 
study within 3 months prior to the 
Screening Visit. The 3-month interval is 
calculated as the time between the first 
calendar day of the month that follows the 
last visit of the previous study and the first 
day of the present study.
Safety
X
14. Subject has been previously screened or 
enrolled in this study.
Administrative
X
15. For women only: subject is pregnant (does 
not have negative pregnancy tests at
Screening Visit and at Admission Visit) or 
is breastfeeding. 
Safety 
X
X
16. For women of childbearing potential only c:
subject does not agree to use an acceptable 
method of effective contraception.d
Safety 
X
X
17. Use of estrogen-containing hormonal 
contraception or hormone replacement 
therapy
Effect
X
X
a As defined by FDA guidance on Collection of Race and Ethnicity Data in Clinical Trials(1)
b 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”
c Women who are not of childbearing potential meet at least one of the following criteria: 
Have undergone hysterectomy or bilateral tubal ligation,  
Have medically confirmed ovarian failure, 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).
d Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with spermicidal 
foam/gel/film/suppository, hormonal contraception containing progesterone only, vasectomized partner(s) from Screening 
until the end of the Safety Follow-up Period. Hormonal contraception with estrogen containing products is NOT allowed in 
this study.

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5.2
Discontinuation of Subjects from the Study 
Discontinued subjects will include both subjects who withdraw from the study (subject’s 
decision) or subjects who are discontinued from the study by the decision of the Investigator. 
A subject can only be discontinued from the study after enrollment.
Subjects will be informed that they are free to withdraw from the study at any time. Subjects 
will be questioned for the reason for withdrawal from the study, although they are not obliged 
to disclose it. If the subject withdraws from the study, he/she will be asked to confirm that 
he/she agrees to undertake the early termination procedures for safety assessments, and this 
information will be fully documented by Investigator.
The subject will be informed that if he/she withdraws from the study, the data collected until 
the point of withdrawal will be maintained as part of the study data and the samples collected 
prior to withdrawal will be analyzed, unless the subject disagrees in writing.  
When a subject is discontinued from the study, all early termination procedures (section 9.6)
will be performed unless the subject refuses to perform the assessments. Early termination 
procedures are to be performed only for subjects who have been exposed to P3P. After the date 
of termination, the subject will enter into the 7-day Safety Follow-Up Period. This applies to 
all subjects independent of the reason of discontinuation (for example, withdrawal of consent, 
or at the Investigator’s decision etc). 
Subjects must be discontinued from the study for any of the following reasons:  
•
Withdrawal of informed consent.
•
Any AE/SAE or condition (including clinically significant changes in a laboratory 
parameter), which at the discretion of the Investigator no longer justifies the subject’s 
participation in this study.
•
Positive pregnancy test (section 8.5).
•
The Sponsor or Investigator terminates the study or the study terminates at a particular 
investigational site. If the Sponsor or the Investigator decides to prematurely terminate the 
study, the subject will be promptly informed. The head of the investigational site should 
report the fact and the reason in writing to the IEC. 
•
Discontinuation is considered to be in the best interest of the subject or the other subjects 
as judged by the Investigator 
•
Subject is not willing to use P3P after the product test at Admission Visit. In such a
situation, the subject will be discontinued immediately after the product test.
•
Subject uses any tobacco or nicotine contaning product different from the assigned product 
during visits.
Subjects may be discontinued from the study for the following reason:  

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•
Non-compliance to the study procedures based on the judgment of the Investigator. 
•
Sufficient number of subjects are already randomized to the study sequences. In this case, 
supernumerous subjects will be discontinued prior to randomization based on their 
screening number. Further details about the randomization process will be provided in a
separate randomization plan. 
Until randomization, subjects can be replaced, however subjects that discontinue the study 
after randomization will not be replaced. 
5.3
Lost to Follow-Up
Reasonable number of attempts to contact the subject (including written correspondence and 
phone calls) should be done and documented in the source documents by the site. When the 
Investigator or designee(s) declare(s) a subject is lost to follow-up, the lost to follow-up date 
will be recorded. The date of lost to follow up corresponds to the date of the end of study of 
the subject.  
If the investigational site has lost track of the subject but the subject has reached the maximum 
number of study days (34 days), then the Investigator or designee(s) will declare the subject 
lost to follow-up at this date. 
5.4
Violation of Selection Criteria
Any subjects who do not meet the entry criteria after signing the ICF and prior to Enrollment 
at Admission Visit will be considered as screen failures and will be replaced by other subjects. 
Re-screening of subjects will not be permitted.

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6 
INVESTIGATIONAL PRODUCTS
6.1 
Description of Investigational Products 
6.1.1 
Investigational Products 
P3P will be provided by the Sponsor and its distribution will be controlled by a qualified and 
appropriately trained designee. 
P3P generates an inhalable aerosol from nicotine powder when air is drawn through it. P3P is 
a single use product that has a body in the form of a tube, similar to a cigarette, and contains a 
capsule. The capsule is pierced (activated) using a P3P piercing accessory before use. The P3P 
capsule contains nicotine powder composed of either solely nicotine salt or nicotine salt 
blended with mentholated flavor powder in a 4:1 ratio. The nicotine powder is generated by 
spray-drying nicotine, 
 
 
 and 
 The nicotine powder has a median
particle size of 1.8 ± 0.2 μm or 2.25 ± 0.2 μm allowing deep lung deposition whereas the flavor 
particles have a particle size > 50 μm and deposit in the oropharyngeal cavity. A single P3P 
product contains 1 or 2 mg of nicotine, depending on the P3P variant.
The following P3P variants will be tested in this study and differ in nicotine powder particle 
size, nicotine concentration, and in the absence or presence of a flavoring system:
Table 1  
P3P variants tested in this study 
P3P variant
Nicotine content 
Nicotine powder 
particle size
Total amount of 
nicotine/ product
Contains flavor 
particles
P3P 1
5%
2.25 ± 0.2 μm
2 mg
no
P3P 2
5%
2.25 ± 0.2 μm
2 mg
yes
P3P 3
2.5%
2.25 ± 0.2 μm
1 mg
yes
P3P 4
5%
1.8 ± 0.2 μm
2 mg
yes
6.1.2 
Packaging and Labeling 
The Sponsor will provide the P3P components separately. Assembly will be done at the 
investigational site (section 6.5.1). All parts will be packaged and labelled appropriately for 
on-site use. The capsules will be labelled with the necessary information for on-site use 
including, but not limited to, nicotine content, batch number, expiry date, indication that 
product is to be used for research purposes only, and storing conditions.  
6.2
Use of Investigational Products  
Subjects will never be forced to use P3P and will be free to stop using P3P at any time during 
the study.  

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6.2.1 
Admission (Day -1) 
After enrollment, subjects will be required to perform product test using up to three P3P 3 
products. Subjects will be instructed to use P3P in a similar way to their own cigarette i.e. with 
a 2-step process with 1) puffing and 2) inhalation. They will be asked to puff with sufficient 
intensity to trigger the spinning of the capsule. The subject should hear the sound of the capsule 
spin and/or feel the vibration of the product induced by the spinning. 
After the product test, subjects unable to use the product as specified (i.e. trigger the spinning 
of the capsule) as well as subjects not willing and/or unable to use P3P will be discontinued 
from the study and will enter a 7-day Safety Follow-Up Period. 
6.2.2 
Investigational Period (Day 1 to Day 5) 
Each subject will use P3P 3 on Day 1. In the morning of Day 2, subjects will be randomized 
to one of six sequences in order to cross-over to the use of P3P 1, P3P 2 and P3P 4 on Days 2, 
3 and 4 (section 6.3). 
On each assessment day (Day 1 to Day 4), following at least 10 hours of abstinence from any 
tobacco and nicotine containing products, subjects will use the assigned product for the given 
visit with two product use regimen as described in Figure 2:
x
using a fixed puffing regimen comprising of 12 puffs in total at a rate of one inhalation 
every 30 seconds (± 5 seconds) in the morning.  
x
using ad libitum use period for 60 minutes (± 5 minutes) in the afternoon.  
A puffing topography device will be attached to each P3P. There will be one recording of HPT 
parameters per product. Each P3P product will be weighed before and after product use to 
estimate the amount of nicotine delivered in the aerosol. During the ad libitum use period, the 
subjects can use the product according to their puffing behavior, without restrictions in the 
number of puffs, interpuff interval duration or number of products used. The number of P3P 
products used during the ad libitum use period will be recorded. The start and stop time of each 
product used during each puffing regimen will be recorded as well as the total number of puffs 
taken at the fixed puffing regimen.
The start of product use for fixed puffing and for the ad libitum use period will be defined as 
T0 fix and T0 ad lib, respectively. There will be a washout period of 10 hours between T0 fix and T0
ad lib.  
There will be no product use on the Discharge day (Day 5). 
Except for the assigned products, subjects will not be allowed to use any nicotine-containing 
products through Discharge or early termination. 
Subjects will be continuously supervised by the investigational site staff during P3P use. 

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6.2.3 
Safety Follow-Up Period 
Use of the investigational product will not be permitted during the Safety Follow-Up Period. 
Subjects will be allowed to use their own cigarettes. 
6.2.4 
Stopping Rules for Investigational Product  
For safety purposes, use of P3P should be temporarily reduced (decreasing number or/and 
intensity of puffs) or stopped in the event of any signs suggesting nicotine overexposure, e.g., 
gastrointestinal disturbance (nausea, vomiting, diarrhea, stomach or abdominal pain), cold 
sweats, headache, dizziness and breathing problems, or any reasons at the discretion of the 
Investigator.  
In the morning of Day 2 subjects will be randomized after confirmation that there are no safety 
concerns based on the Investigator’s judgement. 
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 9.6).
6.3 
Method for Assigning Subjects to Sequence 
On the morning of Day 2, after confirmation that there are no safety concerns for each subject 
to continue the study, 18 subjects will be randomized to one of the following six sequences of 
the remaining P3P variants in order to cross-over the use of P3P 1, P3P 2 and P3P 4 following 
a 2 Latin squares design balanced for first order carryover effects among the 3 variants.
Therefore, three subjects will be allocated to each sequence described in the table below: 
Table 2  
Description of sequences to allocate subjects to 
Sequence
Day 2
Day 3
Day 4
1
P3P 2
P3P 4
P3P 1
2
P3P 4
P3P 1
P3P 2
3
P3P 1
P3P 2
P3P 4
4
P3P 1
P3P 4
P3P 2
5
P3P 2
P3P 1
P3P 4
6
P3P 4
P3P 2
P3P 1
Randomization to product exposure sequence will be done through sealed envelopes.  
At least 8 subjects of each sex will be randomized to ensure each sex represents at least 40% 
of the randomized population.

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If a sufficient number of subjects are already randomized to the study sequences, any 
supernumerous subjects will be discontinued from the study prior to randomization only 
(section 5.2). 
Randomization details will be available in the randomization plan. The randomization scheme 
will be generated by an independent statistician and neither the Sponsor staff, nor Investigator 
or study subjects will have access to the randomization scheme prior to randomization. 
6.4
Blinding
This study will be conducted as an open label study with no blinding. However, in order to 
prevent selection bias, Sponsor staff, Investigator, the subjects and the investigational site will 
be blinded to the randomization sequences until they are assigned. Subjects will not be 
informed of the complete sequence to which they have been assigned. 
6.5 
Investigational Product Accountability and Compliance 
6.5.1 
Assembly of Investigational Product 
The Sponsor will provide the P3P piercing accessory, the P3P tube-shaped body and front plug 
and the P3P capsules according to local regulations.  
The P3P capsule should be inserted in the P3P body no earlier than 2 hours prior to product 
use and the assembled product should be activated by piercing the capsule immediately before
product use.
Responsibility for assembly and activation of the investigational product will be held by the 
investigational site pharmacist or other adequately trained investigational site collaborator.
6.5.2 
Dispensing Investigational Products  
From Day -1 until Day 4, the assembled and activated P3P products will be dispensed by the 
investigational site collaborator, as per the study design. Each dispensing of the investigational 
product to the subject will be recorded in a log. 
6.5.3 
Storage and Accountability 
The P3P components will be stored in a secured storage place at the investigational site with 
access limited to the authorized personnel only. Full accountability of the distributed products 
will be ensured by designated site staff. Subjects will return each P3P product immediately 
after use to the investigational site personnel for accountability and product weighing (section 
7.9.2).   

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6.5.4 
Investigational Products Retention  
Used and unused P3P products will be destroyed or returned to the Sponsor upon study 
completion. 
6.5.5 
Compliance to Investigational Products  
Compliance will be ensured by strict distribution of the products (product by product) and 
collection of any used and unused investigational product by the designated site staff.  
6.6
Restrictions
6.6.1 
Smoking Restrictions 
During the Screening period, subjects will be allowed to smoke according to their smoking 
habits except during the procedures of the Screening Visit (section 9.1). During confinement 
(from Admission to Discharge or early termination), smoking or use of any tobacco or nicotine-
containing products, except the allocated P3P on the assessment days, will not be permitted. A
washout period of at least 10 hours should be respected before product use at Day 1 and before 
the start of each product use regimen (ie. at least 10 hours washout between T0 fix and T0 ad lib
and vice versa). 
6.6.2 
Dietary and Activity Restrictions 
A standard diet will be designed for the whole confinement period. For each meal, the caloric 
and fat content should be controlled in order to avoid a “high-fat” diet. The FDA guidance on 
food-effect studies for bioequivalency testing identifies a “high-fat” diet as a diet which 
contains “approximately 50 percent of total caloric content of the meal [from fat] and is high 
in calories (approximately 800 to 1000 calories) (13).” 
Subjects are not allowed to bring their own food or beverages to the investigational site. Meals 
will be served according to the schedules provided in section 9. Additional light snacks, fruits, 
and raw vegetables can be distributed to the subjects without restrictions at any time during 
confinement (except during the product use periods) as long as they comply with the standard 
diet. Consumption of water is allowed as desired. Consumption of quinine-containing drinks 
(e.g., tonic water) is not allowed. Subjects should refrain from ingesting foods or beverages 
containing grapefruit or seville-type (sour) oranges and marmalade from 7 days prior to Day -
1 and throughout the study. The same menu and meal schedule will be administered uniformly 
for all subjects. Fasting state has to be observed for at least 6 hours prior to blood drawings for 
the safety laboratory at Admission, and on Days 2, 3, 4 and 5. 
Subjects should refrain from strenuous and/or unaccustomed exercise throughout the entire 
course of the study. 

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6.6.3 
Concomitant Medication 
All medication taken within 4 weeks prior to the ICF signature will be considered prior 
medication. All medication taken from Screening Visit to end of the Safety Follow-Up Period 
will be considered concomitant medication.  
Use of hormonal contraception containing estrogens and hormone replacement therapy are 
prohibited and are considered an exclusion criterion. Only hormonal contraception with 
products containing progesterone is allowed during this study. 
Any medication with an impact on the CYP2A6 metabolism (as prescription and over-the-
counter products), including, but not limited to medication listed in Table 3, must be avoided 
as CYP2A6 is involved in the nicotine metabolism. To be eligible for the study any medication 
with impact on CYP2A6 metabolism must have been discontinued at least 14 days prior to 
Admission or for at least 5 half-lives (whichever is longer). It is at the discretion of the
Investigator to assess if a termination of such medication is medically justified and safe for the 
subject. In addition, they must not be used during the entire study until the time of Discharge 
or early termination. Prior to database lock, concomitant medication will be reviewed 
according to their potential impact on CYP2A6 activity and assessed for their potential impact 
on the study results.

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Table 3
CYP2A6: Substrates, Inhibitors, and Inducers (14)
Inhibitor
Drug Class
Amiodarone
Antiarrhythmic agent, Class III
Desipramine
Antidepressant
Isoniazid
Anti-bacterial drug 
Ketoconazole
Anti-fungal medication 
Letrozole
Anti-estrogen drug
Methoxsalen
Systemic psoralens 
Miconazole
Anti-fungal medication 
Tranylcypromine
Antidepressant
Inducer
Drug Class
Amobarbital
Barbiturate
Pentobarbital
Barbiturates
Phenobarbital
Barbiturates/anticonvulsa
Rifampin
Antimycobacterials
Secobarbital
Barbiturates
Substrate
Drug Class
Dexmedetomidine
α2-Adrenoceptor, sedative
Ifosfamide
Anti-cancer, alkylating agents
Use of over the counter medication will be restricted during confinement, although exceptions 
may be made on a case by case basis at the discretion of the Investigator. 
Use of any other concomitant medication will be evaluated on a case by case basis by the 
Investigator. Any concomitant medications used will be fully documented (for details see 
section 7.4.4).  

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7 
STUDY PROCEDURES 
Site personnel performing or recording study assessments must have the appropriate and fully 
documented training. An overview of all study assessments is shown in the schedule of events 
(Appendix A). Appropriate medical advice will be provided to the subject in case of any 
medical findings requiring health care. Site personnel will adhere to the site’s standard 
operating procedures (SOPs) for study related procedures.  
7.1
Informed Consent
Prior to any study assessment being performed, subjects will be asked to provide their written 
consent to participate in the study (section 1.3). Study assessments must only start after the 
time of ICF signature by the subject. 
7.2
Information on the Risk of Smoking, Smoking Cessation Advice and 
Product Debriefing 
At Screening, Admission and Discharge all subjects will receive 1) information on the risks of 
smoking, 2) smoking cessation advice, and 3) debriefing on P3P.  
The information on the risk of smoking and advice on smoking cessation will take the form of 
a brief interview according to the WHO recommendations (15). The debriefing of subjects on 
P3P will address any intended or unintended beliefs that participants may have about P3P. The 
goal of the debriefing is to help ensure that subjects enter and exit the study with an accurate 
understanding of the product risks, including an understanding that P3P has not currently been 
demonstrated to be less harmful than cigarettes.  
Details of the sessions will be recorded in the source document file. This information will be 
given to the subjects on an individual basis during a face-to-face meeting between the subject 
and the Investigator or may be given in a group session. 
7.3
Support during Smoking Abstinence/Periods of Reduced Smoking 
Subjects will be offered support during periods of smoking abstinence while confined to the 
investigational site. Support will be given by the Investigator and investigational site staff. 
Support resources will include counselling and assistance, distraction, monitoring of the 
subject’s behavior, AEs, and the subject’s mood, clinical tests e.g., vital signs, physical 
examination.  
7.4
Clinical Assessments
7.4.1 
Demographic Data  
Sex, date of birth and race will be recorded for each subject at Screening Visit.

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7.4.2 
Smoking History 
At Screening Visit, subjects will be asked the following questions about their smoking history 
and habits: 
Have you smoked for at least the past 3 years? 
How many years have you smoked?
On average, how many cigarettes per day have you smoked since you started smoking? 
A. On average, how many cigarettes per day have you smoked over the last 4 weeks?
B. Of these, on average per day, how many were menthol cigarettes? 
What brand of cigarettes do you smoke?
This self-reported daily consumption of cigarettes at the Screening Visit will be used to assess 
eligibility for the study.  
At the Screening Visit the subject will also be asked if he/she is planning to quit smoking in 
the next 2 months i.e. before completion of the study.  
Furthermore, subjects will be asked if they are ready for 6 days of smoking interruption. Only 
subjects prepared and able to comply with this requirement will be considered for participation 
in the study. 
7.4.3 
Demonstration and P3P Test 
All subjects will have a demonstration of P3P (without product use) at the Screening Visit.
At Admission, after enrollment, subjects will be required to perform a product test using up to 
three P3P 3 products. Subjects will be instructed to use P3P in a similar way to their own 
cigarette i.e. with a 2-step process with 1) puffing and 2) inhalation. They will be asked to puff 
with sufficient intensity to trigger the spinning of the capsule. The subject should hear the 
sound of the capsule spin and/or feel the vibration of the product induced by the spinning.
After the product test, subjects unable to use the product as specified (i.e. trigger the spinning 
of the capsule) as well as subjects not willing and/or unable to use P3P will be discontinued 
from the study and will enter a 7-day Safety Follow-Up Period. 
7.4.4 
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. 
Medication taken within 4 weeks prior to Screening Visit and any concomitant medication will 
be documented. Any medication started prior to the Screening Visit and still being taken by 

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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 prescription and over-the-counter products.  
Records of medication taken should include the drug name (preferably both generic and trade 
name), route of administration (e.g., oral, intravenous), dose and frequency (expressed in 
metric units, for example, mg, mL, or IU), indication, and the start and, if applicable, the stop 
date (day, month, and year). Therapy changes (including changes of regimen) during the study 
have to be documented. If a concomitant medication is still being taken by the subject at the 
end of the study, this will be recorded in the CRF. 
7.4.5 
Physical Examination 
Physical examination will be conducted at Screening, Admission and at the day of Discharge 
or at early termination.
A full physical examination will include review of general appearance, hair and skin, head, 
eyes, ears, nose and throat, neck, chest, abdomen, dentition, cardiovascular, musculoskeletal 
and neurological systems. The physical examination is to be conducted by the Investigator or 
designated fully trained representative. 
7.4.6 
Body Height and Weight 
Body height and weight will be recorded at the Screening Visit and BMI will be calculated 
using the following formula:
BMI = weight in kilograms
height in meters2
ൌ݇݃
݉ଶ
The BMI will be used to assess eligibility for enrollment. 
7.4.7 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, respiratory rate and pulse rate) will be 
measured at Screening Visit, Admission and on every day of confinement (Day 1 to Day 5).
On Day 1 to Day 4, vital signs will be assessed within 60 minutes prior to product use and 60 
minutes ± 10 minutes after each product use period (fixed puffing regimen and ad libitum use).
All parameters will be recorded in supine position after the subject has rested for at least 5 
minutes. At Screening and Admission, the subject should have abstained from smoking for at 
least 15 minutes prior to measurement. 

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7.4.8 
Other Clinical Assessments 
7.4.8.1 
Electrocardiogram 
A standard 12-lead ECG will be recorded after the subject has rested for at least 10 minutes in 
supine position at Screening, Admission and on every day of confinement (Day 1 to Day 5). 
During the investigational product-use days (Day 1 to Day 4) ECG will be recorded after the 
fixed puffing regimen and after the ad libitum use. 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 Bazett’s 
formula and Fridericia’s formula. Every ECG has to be assessed as normal, abnormal –
clinically not significant, or abnormal – clinically significant. A diagnosis has to be provided 
in the CRF for all ECGs assessed as abnormal – clinically significant. Any print-outs of ECGs 
on thermo-sensitive paper must be photocopied and stapled together for inclusion in the source 
documents. 
7.4.8.2 
Spirometry 
Spirometry without bronchodilator will be performed at Screening Visit and Discharge in
accordance with the 2005 guideline of the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) Joint Task Force on the standardization of spirometry (16).
Spirometry predicted values will be standardized to the National Health and Nutrition 
Examination Survey III predicted set (17).
Assessed parameters will include: FEV1, FEV1 % predicted, FVC, FVC % predicted,
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 having 
stopped using cigarettes (Screening Visit). 
7.5 
Biomarker Assessment 
7.5.1 
Biomarkers of Exposure to Nicotine 
For PK analysis of plasma nicotine levels, venous blood samples will be obtained according to 
the investigational site standard operating procedures (SOPs) at the following timepoints: 
a) Fixed puffing (Morning: Days 1 through 4): 
A total of 10 blood samples will be taken for fixed puffing PK parameter estimation. One blood 
sample will be taken prior to the product use (T0 fix) 15 minutes ± 5 minutes (T-1). Thereafter 
in relation to T0 fix, blood will be drawn at the following time points: T1 after 2 minutes ± 1 
minute, T2 after 4 minutes ± 1 minute, T3 after 7 minutes ± 1 minute, T4 after 10 minutes ± 1 

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minute, T5 after 15 minutes ± 2 minutes, T6 after 30 minutes ± 2 minutes, T7 after 1 hour ± 5 
minutes, T8 after 2 hours ± 5 minutes, and T9 after 4 hours ± 5 minutes.
b) Ad libitum use (Afternoon: Days 1 through 4): 
A total of 8 blood samples will be taken for the ad libitum PK parameter estimation. One blood 
sample will be taken prior to product use (T0 ad lib) at 15 minutes ± 5 minutes (T-1). In relation 
to T0 ad lib, blood will be drawn at the following time points: T1 after 10 minutes ± 1 minute, 
T2 after 20 minutes ± 2 minutes, T3 after 30 minutes ± 2 minutes, T4 after 40 minutes ± 5 
minutes and T5 after 1 hour ± 5 minutes, T6 after 2 hours ± 5 minutes, and T7 after 4 hours ± 
5 minutes.   
c) Day of Discharge (Day 5) 
A total of 5 blood samples  will be taken on Day 5. Blood samples will be taken in relation to 
T0 ad lib from Day 4 at the following time points: T1 after 14 hours ± 30 minutes, T2 after 16 
hours ± 30 minutes, T3 after 18 hours ± 30 minutes, T4 after 20 hours ± 30 minutes and T5 
after 24 hours ± 30 minutes. 
The actual collection time of each blood sample must be recorded on the CRF. 
Since the test for nicotine concentration is highly sensitive, precautions should be taken during 
blood sampling and processing to prevent the contamination of samples with environmental 
nicotine. 
7.5.2 
CYP2A6 Activity  
CYP2A6 activity will be assessed on Day 1 prior to P3P use. CYP2A6 activity drives the 
metabolism of nicotine to cotinine and subsequent metabolites. In this study the CYP2A6 
activity will be measured in plasma using the metabolic molar ratio of trans-3’-
hydroxycotinine/cotinine. 
7.6
Laboratory Assessments
7.6.1 
Clinical Chemistry, Hematology, and Urine Analysis Safety Panel  
A blood sample for hematology and clinical chemistry analysis will be taken from each subject 
at Screening, Admission and Day 2 to Day 5. Subjects should be fasting for at least 6 hours 
prior to sampling, except at Screening where non-fasting samples can be used. Tests will be 
conducted at a local laboratory (Appendix B). A urine sample will also be collected from each 
subject for urine analysis. Parameters to be tested are listed in Table 4. 

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Table 4 
Clinical Laboratory Parameters for Safety Panel 
Hematology
Clinical Chemistry
Urine Analysis
Hematocrit
Hemoglobin
Mean corpuscular 
hemoglobin
Mean corpuscular 
hemoglobin concentration
Mean corpuscular volume
Platelet count
Red blood cell count
White blood cell (WBC) 
count
Differential WBC count:
x
Neutrophils
x
Basophils
x
Eosinophils
x
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 will be assessed 
7.6.2 
Serology 
A test for hepatitis B surface antigen, hepatitis C virus and human immunodeficiency virus 
(anti-HIV1/2) will be performed at Screening. In case of positive results, the subject will be 
referred to appropriate medical care. 
7.6.3 
Urine Drug Screen 
A urine drug screen will be performed at the site at Screening and Admission. The urine will 
be screened for amphetamine type substances, barbiturates, benzodiazepines, cannabinoids, 
cocaine and opiates. 
7.6.4 
Urine Cotinine Screening  
A urine dip-stick cotinine test will be performed at Screening in order to confirm the subject’s 
smoking status. The test must detect cotinine with a threshold of ≥ 200 ng/mL, (e.g., One-Step 
Cotinine Test 008A086, Ultimed, Belgium). 
7.6.5 
Alcohol Breath Test 
An alcohol breath test will be conducted using an alcometer device at Screening and 
Admission. 

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7.6.6 
Urine Pregnancy Test 
A urine pregnancy test will be performed for all female subjects at Screening, Admission and 
at Discharge. Subjects with a positive urine pregnancy test at the Screening or Admission Visits 
will not be enrolled and will be considered as screen failures. In case of any positive pregnancy 
test, the Investigator or designee will inform the subject about the risks associated with 
smoking during pregnancy. 
All pregnancies detected during the study must be reported and handled as described in 
section 8.5.
7.7
Sample Handling, Storage, and Shipment 
Participating laboratories for blood samples testing and safety laboratory samples testing are 
listed in Appendix B. Urine drug screen, breath alcohol screen, urine pregnancy tests and urine 
cotinine tests will be done by the site personnel at the site.
Detailed procedures for handling of samples are described in the separate sample handling 
manual (SHM). Safety laboratory samples will be destroyed as per laboratory local regulations.
All other samples will be destroyed post database lock or post finalization of the bioanalytical 
reports, whichever occurs last. The facility/-ies at which the samples are stored will be 
informed in writing by the Sponsor when destruction of the samples shall be performed. 
7.7.1 
Blood Samples  
Blood samples will be drawn by qualified and trained site personnel. Since the test for nicotine 
concentration is highly sensitive, precautions should be taken during blood sampling and 
processing to prevent the contamination of samples with environmental nicotine. Subjects should 
be in a seated position during blood collection.  
In total, around 464 mL will be drawn for this study including samples for determination of 
nicotine concentrations, CYP2A6 activity and safety. This calculation is based on an individual 
volume of each sample of 5 mL for nicotine PK (of which 4 mL is needed for nicotine dosing 
and 1 mL for cannula rincing of saline solution as per site’s SOPs), 4 mL for CYP2A6 analysis 
and 12.5 mL for safety laboratory assessments. The total volume of blood drawn will not 
exceed the levels for a standard blood donation.  
More details on the procedures for collection, labeling, handling and shipment of samples are 
described in a separate SHM. 
7.8
Questionnaires
The subject questionnaires will be completed by the subjects directly following both fixed 
puffing and ad libitum use. The questionnaires will be reviewed for completeness by the study 
site collaborator and subjects will be requested to complete any missing information. 

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Symptoms or worsening of symptoms as documented on any of the questionnaires do not need 
to be documented as AEs because the questionnaires will be analyzed as part of the report. 
However, it is at the discretion of the Investigator to document such symptoms also as AEs. 
The main source for AE collection will be the face-to-face interview between the subject and 
investigational site staff using, open, non-directive questions (see section 8.2.1).
7.8.1 
Fagerström Test for Nicotine Dependence 
Potential nicotine dependence will be assessed via a subject self-reported questionnaire at 
Screening using the Fagerström test for nicotine dependence (FTND) in its revised version 
(18).  
The questionnaire consists of six questions that will be answered by the subject. The scores 
obtained allow the classification of nicotine dependence in three different levels: mild (0-3 
points), moderate (4-6 points), and severe (7-10 points). 
7.8.2 
Visual Analogue Scale for Craving 
A VAS-craving assessment will be used to assess the level of craving of the subject based on 
their response to the question, “How strong is your craving for cigarettes?” on a scale of 0 (no 
craving) to 10 (strong craving) (19). 
The VAS craving will be completed by the subject at Days 1 to 4. For the fixed puffing regimen 
the first assessment will be done 15 minutes ± 5 minutes prior to T0 fix, all other assessments 
will be done after T0 fix, at 4 minutes ± 2 minutes, at 10 minutes ± 2 minutes, at 15 minutes ± 
2 minutes, 30 minutes ± 5 minutes, 1 hour, 2 hours, 4 hours ± 10 minutes each. 
For the ad libitum use period the first assessment will be done 15 minutes ± 5 minutes prior to 
T0 ad lib, all other assessments will be done after T0 ad lib, at 10 minutes ± 2 minutes, at 20 minutes 
± 2 minutes, 30 minutes ± 5 minutes, 40 minutes ± 5 minutes, 1 hour, 2 hours, 4 hours ± 10 
minutes each.  
Questionnaires are to be completed after blood samples have been taken. 
7.8.3 
Adapted Version of the Modified Cigarette Evaluation Questionnaire 
An adapted mCEQ will be completed by each subject within 60 minutes after the ad libitum
use session on Days 1 through 4.  
The questionnaire to be used adapts the wording of mCEQ items (20) to RRPs, following a 
similar approach with the Product Evaluation Scale (21) which is an adaptation of the mCEQ 
for oral tobacco products. 
The questionnaire assesses the degree to which subjects experience the reinforcing effects of 
P3P use by measuring: 
x
Product satisfaction (satisfying, tastes good, enjoy the product).

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x
Psychological rewards (calms down, more awake, less irritable, helps concentrate, 
reduces hunger). 
x
Aversion (dizziness, nausea). 
x
Enjoyment of respiratory tract sensations (single-item assessment) 
x
Craving reduction (single-item assessment) 
7.8.4 
Sensory Questionnaire 
A sensory questionnaire (SQ) will be completed by each subject within 60 minutes after the 
ad libitum use session on Days 1 through 4 (adapted from (22)). The SQ assesses the subject’s 
opinion on the following sensory parameters: 
x
Puff information i.e., how they liked the puffs, harshness of puffs, and similarity to own 
brand; 
x
Strength of puffs on tongue, nose, mouth, windpipe, and chest. 
7.8.5 
Cough Assessment 
Subjects will be asked if they have experienced a regular need to cough, e.g., whether they 
have coughed several times in the previous 24 hours prior to assessment. If the answer is ‘yes’, 
they will be asked to complete a cough assessment questionnaire (which includes a VAS, three 
Likert scales, and an open question). 
The VAS will assess how bothersome cough is to the subject ranging from ‘not bothering me 
at all’ to ‘extremely bothersome’.
Furthermore, subjects will be asked to assess the intensity and frequency of cough and the 
amount of sputum production on Likert scales: 
x
The intensity of cough will be assessed on a 5-point Likert scale ranging from 1 to 5: 
1 = very mild; 2 = mild; 3 = moderate; 4 = severe; 5 = very severe. 
x
The frequency of cough will be assessed on a 5-point Likert scale ranging from 1 to 5: 
1 = rarely; 2 = sometimes; 3 = fairly often; 4 = often; 5 = almost always. 
x
The amount of sputum production will be assessed on a 4-point Likert scale ranging 
from 0 to 3: 
0 = no sputum; 1 = a moderate amount of sputum; 2 = a larger amount of sputum; 3 = a 
very large amount of sputum. 
Cough assessment will be conducted at Admission prior to product test and 24 hours (±1 hour)
after product use (T0 fix) for each variant (Day 2 through Day 5). Cough assessment should be 
done in the morning prior to any product use.  

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7.9
Other Study Procedures 
7.9.1 
Human Puffing Topography 
Human puffing topography involves the measurement of each subject’s unique way of using 
P3P using the HPT SODIM® device. The HPT SODIM® device, model SPA/M (SODIM®
Instrumentation, Fleury les Aubrais, France) is a device which is used to measure puffing 
topography. It consists of a special sample holder with mechanical adapter and a data logger. 
Both the sample holder and the mechanical adapter are associated prior the activation of the 
P3P, and its insertion into the mechanical adapter using a depth adjustment tool. The sample 
holder is connected by 2 narrow tubes to the portable data logger/recording system. Any 
malfunction of the HPT SODIM® portable device will be documented in the appropriate log.  
The HPT SODIM® device has to be used for every P3P used for all subjects from Day 1 to 
Day 4, both during the fixed puffing and the ad libitum use period. For each subject, one HPT 
Device will be assigned at Day 1 which will be used by that subject for all 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 HPT SODIM® device to the site 
collaborators which will be responsible for the HPT assessment. All HPT SODIM® devices 
will be returned to the Sponsor after completion of the study. 
The HPT SODIM® device measures and records the flow rate and other per-puff parameters 
listed in Appendix D. From the per-puff parameters, per-product use experience parameters,
representing average or total values per product, will be derived (Appendix D).
Prior to calculation of the per-product use experience 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 for the per-puff and per-product use experience parameters will be part of the study 
database and will be analyzed.  
7.9.2 
Weighing of P3P Products 
From Day 1 to Day 4, each P3P used should be weighed before product use (after assembly) 
and as early as possible (but within maximum 75 minutes) after the end of product use. The 
pre- and post- product use weight and time of weighing will be recorded in the CRF. 

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8 
ADVERSE EVENTS 
8.1
Definitions
8.1.1 
Adverse Events 
An adverse event (AE) is defined as any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a product or a study 
procedure, whether or not related to the product or the study procedure. Careful Investigator’s
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.
8.1.2 
Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose:  
•
results in death, 
•
is life-threatening,  
•
requires inpatient hospitalization or prolongation of existing hospitalization, 
•
results in persistent or significant disability/incapacity, or, 
•
is a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate Investigator’s medical 
judgment, they may jeopardize the subject or the subject may require medical or surgical 
intervention to prevent one of the outcomes listed in the above definitions. 
"Life-threatening" means that the subject was at immediate risk of death from the event. It 
might have caused death if it had occurred in a more serious form. 
8.1.3 
Conditions Existent Before the Start of the Period of Collection (ICF 
Signature)
Clinical conditions that existed before the start of the period of collection (concomitant 
disease), and whose severity or frequency remained unchanged after that point, should not be 
considered AEs and should not be captured as such. This includes medical therapies or surgical 
interventions that had been planned before the start of the period of collection regardless of 
involving admissions to hospital, if the medical condition to be addressed did not get worse 
after the start of the collection period. Otherwise, any medical condition that existed before the 
start of the period of collection and whose severity or frequency increased after that point is to 
be captured as an AE or SAE, depending on the seriousness criteria met.  

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8.2
Collection and Reporting of Adverse Events
8.2.1 
Collection of Information 
Any non-serious AE occurrence during the study must be documented in the subject’s medical 
records in accordance with the Investigator’s normal clinical practice and on the AE page of 
the CRF. SAEs that occur during the study must be documented in the subject’s medical record, 
on the AE CRF, and on the SAE form.
AEs should be collected mainly via face-to-face interview with the subject through 
spontaneous reporting or by the use of consistent, open, non-directive questions from the 
investigator(s) or designee(s) (e.g., “Have you had any health problems since you were last 
asked? or “How have you been feeling since you were last asked?”).
Information recorded will include: verbatim description of the AE/SAE, start and stop dates, 
seriousness, severity (intensity), action taken (e.g., whether or not the AE/SAE led to the 
subject’s discontinuation from the study), and outcome (e.g., resolved, stabilized).
Information to be recorded about an AE/SAE should include, whenever possible, onset and 
resolution dates and times, circumstances leading up to the event, clinical elements such as 
clinical course, specific vital signs and test results that may explain the pathophysiology of the 
event, as well as alternative explanations to its occurrence. 
Whenever a medically meaningful diagnosis is available to comprise a set of reported signs 
and/or symptoms, it should be preferentially provided as the AE or SAE term, rather than the 
individual signs and/or symptoms. Otherwise, each one of those signs and/or symptoms should 
be reported separately as event terms. 
8.2.2 
Period of Collection 
AEs (including SAEs) will be collected from the time of ICF signature until the EOS. 
During a 7-day Safety Follow-Up Period there will be recording of spontaneously reported 
new AEs/SAEs and follow-up of ongoing AEs/SAEs by the study site. In general, AEs will be 
followed-up until resolved, stabilized (i.e., no worsening of the event), or a plausible 
explanation for the event has been found and until the end of the study.  
Any AEs or SAEs that are ongoing at the end of the Safety Follow-Up Period will be managed 
as described in section 8.2.6.
SAEs spontaneously reported to the Investigator after the end of the Safety Follow-Up Period 
and considered related to the investigational product must also be reported to the sponsor.  
8.2.3 
Intensity of Adverse Event 
The Investigator must assess the intensity of each reported AE according to the following 
grading scale: 

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Table 5 
Intensity of Adverse Events 
Mild:
Easily tolerated, not interfering with normal everyday activities
Moderate:
Interferes with normal everyday activities, but the subject is still able to function
Severe:
Incapacitating and requires medical intervention
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures 
The Investigator must assess the causal relationship between the exposure to the IP and each 
of the reported AEs, using the classification system and the criteria described below. The same 
assessment must be made separately to assess the causal relationship between the study 
procedures and each of the reported AEs:
Not related: The temporal relationship of the adverse event to IP administration or study 
procedure(s) makes a causal relationship unlikely, or concomitant medication, 
therapeutic interventions, or underlying conditions provide a sufficient 
explanation for the observed event. 
Related: 
The temporal relationship of the adverse event to IP or study procedure(s) 
makes a causal relationship possible, and concomitant medication, therapeutic 
interventions, or underlying conditions do not provide a sufficient explanation 
for the observed event. 
8.2.5 
Expectedness 
Any AE assessed as related to the IP will be assessed for its expectedness. An AE will be 
regarded as “unexpected” if its nature or severity is not consistent with information already 
recorded about the IP P3P in section 6.5 of the current Investigator’s Brochure (9).  
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).
At the end of the Safety Follow-Up Period, all ongoing non-serious AEs will be documented 
as “ongoing” and no further follow-up information will be sought for on them by the 
Investigator. At that point, the Investigator will assess whether the subject should be referred 
to his/her General Practitioner to have their ongoing AEs addressed accordingly.
All SAE will be followed up by the Investigator or designee, despite their continuation after 
the end of the Safety Follow-Up Period, until their resolution, stabilization (i.e., no worsening 
of the condition), or an acceptable explanation has been found (e.g., a chronic condition). 

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8.3
Reporting of Serious Adverse Events
Any SAE observed during the period of collection by any of the parties involved in this study 
(including the Investigational site personnel) must be reported by that party within 24 hours of 
first awareness to UBC Pharmacovigilance, as described in the respective safety management 
plan (SMP). 
SAEs considered related to the IP and observed by, or reported to, any of the parties involved 
in this study (including the Investigational site personnel) after the period of collection must 
also be reported by that party within 24 hours of first awareness to UBC Pharmacovigilance 
for safety surveillance purposes. 
All the SAE report forms must be either faxed or sent as an attachment to an e-mail message 
to UBC Pharmacovigilance: 
UBC Pharmacovigilance:
Fax number:
E-mail:
Address:
United BioSource Corporation
As further information regarding an already reported SAE becomes available to any of the 
parties involved in this study, such follow-up information should be reported on a new SAE 
report form, marked as a follow-up report and submitted to UBC Pharmacovigilance according 
to the same timelines described above. The follow-up SAE report form must include the 
minimum information required for form completion and only changed/new information needs 
to be specified. Information provided in the follow-up SAE report form supersedes any 
information that was initially reported.
The SAE report form to be used in this study is provided as a separate document. All SAEs 
will also be recorded on the relevant CRF page, in addition to the SAE report form. 
The Investigator or designee is responsible for submitting the relevant reports of SAEs that 
occur during the study to the local IEC, according to local regulations and in accordance with 
the respective safety management plan (SMP).  

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8.4
Reporting of Other Events Critical to Safety Evaluations
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator and assessed for clinical significance according to its severity. 
The severity of abnormal laboratory test result must be assessed using CTCAE version 4.03 
grading scales (Appendix C). Any clinical safety laboratory test result that is outside of the 
normal reference range will be reviewed by the Investigator and assessed for clinical 
significance according to its severity. Whenever that grading scheme is not available for the 
laboratory result of concern, the Investigator should assess the severity and the clinical 
significance of that result using his/her medical judgment. 
Subjects with clinically significant abnormal laboratory values at Screening will not be 
enrolled. Abnormal laboratory test results detected at the Screening Visit whose CTCAE 
grades are 2 or higher or still are CTCAE grade 1 and deemed clinically significant are usually 
concomitant disease or a manifestation of one and must be recorded accordingly.  However, in 
some instances, they may be assessed as AEs (and therefore must be handled according to the 
directions in section 8.2) or as manifestations of already reported AEs. This decision will 
require a careful assessment of the abnormal result within the clinical context on a case-by-
case basis and will depend on the Investigator's medical judgment. 
Abnormal laboratory test results detected after the Screening Visit whose CTCAE grades are 
2 or higher or still are CTCAE grade 1 and deemed clinically significant must be either 
recorded as AEs (and handled according to the directions in section 8.2) or linked to a 
concomitant disease or still to an already reported AE.  
The principles for assessing and reporting abnormal laboratory test results, emerging after the 
Screening Visit, using CTCAE 4.03 grading scales are set up in Table 6: 
Table 6  
Principles for assessing and reporting abnormal laboratory test 
results 
Grading
Clinically significant?
Is it a grade increase 
from previous results 
in study?§
Report?
Grade 1
No
Not applicable
No
Grade 1
Yes
No
No*
Grade 1
Yes
Yes
Yes, as AE or linked to 
an already reported AE
Grade 2 or higher
No/Yes
No
No*
Grade 2 or higher
No/Yes
Yes
Yes, as AE or linked to 
an already reported AE

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* in this situation, this abnormal lab test result is either a manifestation of a concomitant disease or of an already 
reported AE.
§ grade increase in this context means the value is higher than the one from the Screening Visit. 
In general, laboratory values will be recorded as “increased <lab parameter>” or “decreased 
<lab parameter>” to ensure consistency of recording/coding.  
8.4.2 
Reporting other abnormal findings 
The other abnormal findings discovered during different clinical assessments (e.g., ECG, 
spirometry, physical examination, vital signs, body weight) should be evaluated for the clinical 
significance by the Investigator/designee based on his/her medical judgement. All abnormal 
clinical 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 first exposure to the IP will 
be considered a reason for screen failure. No pregnancy form will be filled in that case, 
however the diagnosed pregnancy must be captured in the screen failure page of the CRF. 
Any pregnancy that was potentially associated with exposure to the IP, including pregnancies 
spontaneously reported to the Investigator after the EOS must be reported by the Investigator 
and followed-up until the pregnancy outcome is reached (e.g. normal delivery, spontaneous 
abortion, voluntary termination) and also until 8 weeks after delivery. Potential association 
with the exposure to the IP is defined as exposure to IP during or after the calculated conception 
date. 
Any pregnancy complication, adverse pregnancy outcome or maternal complications will be 
recorded as an AE accordingly. 
8.5.2 
Reporting of Pregnancies 
A dedicated pregnancy form will be used to report reportable cases of pregnancy. 
The procedure to report a pregnancy and provide any additional/follow-up information to UBC 
Pharmacovigilance is the same and performed within the same timelines as the one described 
for an SAE (section 8.3).
The Investigator is responsible for informing the corresponding IEC of the any pregnancy case 
that was reported during the study, as determined by local regulations. 

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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 9.6), as soon as practical after discontinuation and will enter 
the 7-day Safety Follow-Up Period. In general, AEs will be followed-up until resolved, 
stabilized (i.e., no worsening of the event), or a plausible explanation has been found and until 
the end of the study.  
Any AEs or SAEs that are ongoing at the end of the Safety Follow-Up Period will be managed 
as described in section 8.2.6.
8.7 
Investigational Product Malfunction and Misuse 
Any occurrence of P3P malfunction or misuse (use not in accordance with its instruction) by a 
subject will be documented by the Investigator using a Product Issue Log. Information 
regarding product malfunction or misuse should be actively collected during the study visits. 
Furthermore, any malfunction or misuse of P3P that leads to an AE/SAE will follow the same 
processes as described above. 

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9 
STUDY ACTIVITIES 
A detailed schedule of all study activities and assessments is provided in Appendix A. 
Measurements not conducted at the exact time point indicated, but conducted within the given 
time window (if applicable) do not constitute a protocol deviation but an accepted variability 
for the given time point.  
In general, if no start time for the procedure is provided, then the procedure can be performed 
at any time during the day. 
9.1 
Screening Visit 
The Screening Visit will be performed within 3 weeks prior to Admission. First, the ICF along 
with study information should be given to the subject. Prior to being asked to sign the consent 
form, subjects will be given time to review the study information and ask any questions. 
When/if the ICF is signed, dated and timed, the other screening procedures can be performed 
in the order deemed most practical. While it is recommended to complete as many screening 
procedures as possible in one day, it is permissible to complete those over more than one day. 
Smoking is allowed at the Screening Visit at the discretion of the investigational site. 
Screening activities are listed in Table 7. 
Table 7 
Time Schedule – Screening Visit 
Time
Blood 
Sample
Procedures
Additional Information
Start of 
Procedure
Prior to any 
other 
procedure
Collection of informed consent
Information on risks of smoking,
smoking cessation advice and 
product debrief
Smoking history/habits 
questionnaire
FTND questionnaire
Demographic data
Medical history/ concomitant 
disease
Prior (within 4 weeks prior to 
Screening) and concomitant 
medication

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Time
Blood 
Sample
Procedures
Additional Information
Start of 
Procedure
Physical examination
Body height, weight and 
calculated BMI
Vital signs (blood pressure, 
pulse rate, respiratory rate)
At least 5 min in supine position 
prior to measurement. At least 15 
minutes smoking abstinence 
prior to measurement.
ECG
After resting for at least 10 min in 
supine position prior to recording
Spirometry
Has to be done at least 1 hour 
after smoking. After resting in 
sitting position for at least 15 
minutes prior to testing.
9
Clinical laboratory parameters 
(hematology, clinical chemistry)
Collection of spot urine for:
-
Urine analysis safety panel
-
Urine drug screen
-
Urine cotinine screen
-
Urine pregnancy test (all 
female subjects)
9
Serology
HIV 1/2, Hepatitis B and C
Alcohol breath test
During the visit
Review of inclusion/exclusion 
criteria based on all relevant 
assessments
Includes readiness to comply to 
study procedures, including 
smoking interruptions; intention 
to quit smoking in the next 2 
months
P3P demonstration
Without product use
During the visit
AE/SAE recording
If the Screening Visit is 
performed on two separate days 
the AE/SAE questions will be 
asked again.
Abbreviations: AE = Adverse event; BMI = Body mass index; ECG = Electrocardiogram; FTND = Fagerström Test for 
Nicotine Dependence; HIV = Human immunodeficiency virus; SAE = Serious adverse event. 

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9.2 
Admission Visit  
The assessments performed at Admission are listed in Table 8.
Table 8 
Time Schedule – Admission Visit 
Time
Blood 
Sample
Procedures
Additional Information
Start of 
Procedure
Before enrollment
Information on risks of 
smoking, smoking cessation 
advice and product debrief
Concomitant medication
Physical examination
Vital signs (blood pressure, 
pulse rate, respiratory rate)
At least 5 min in supine position 
prior to measurement. At least 15 
minutes smoking abstinence 
prior to measurement.
ECG
After resting for at least 10 min in 
supine position prior to recording.
Urine drug screen
Urine pregnancy test (all 
female subjects)
Alcohol breath test
Review of Inclusion criteria 6
and 8 and exclusion criteria  7, 
9, 10, 15, 16 and 17
Enrollment
9
Clinical laboratory 
parameters (hematology, 
clinical chemistry)
After at least 6 hours of fasting. 
Urine analysis safety panel
Cough assessment
VAS, Likert and open question 
After enrollment
P3P product test by subject
Using up to three P3P 3 products
After product test
Collection of used products
During the visit
AE/SAE recording
During the visit
Product events 
malfunctions/misuse
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; SAE = Serious adverse event; VAS = Visual analogue scale 

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9.3 
Investigational Period (Day 1 to Day 4) 
At each assessment day subjects will use the assigned product for the given visit with two 
product use regimen: 
x
fixed puffing regimen comprising of 12 puffs in total at a rate of one inhalation every 
30 seconds (± 5 seconds) in the morning.  
x
ad libitum use period for 60 minutes (± 5 minutes) in the afternoon.  
The study activities performed in the morning (prior to and related to fixed puffing) for Days 
1, 2, 3 and 4 are listed in Table 9. The study activities performed in the afternoon (related to 
ad libitum product use and post product use activities) are listed in Table 10. The start of each 
product use regimen will be separated by at least 10 hours.
Table 9 
Time Schedule – Fixed puffing period (Day 1, 2, 3, 4 - Morning) 
Time
Blood 
Sample
Procedures
Additional Information
Start of Procedure
Prior to product use
9
Blood sampling for 
CYP2A6 assessment
Day 1 only
Prior to product use
9
Clinical laboratory 
parameters (hematology, 
clinical chemistry)
After at least 6 hours of fasting.
Day 2, 3 and 4
Prior to product use
Urine analysis safety panel
Day 2, 3 and 4
Prior to product use
Cough assessment
Day 2, 3 and 4.
24 ± 1 hour after T0 fix for the 
product used on the previous 
day
Prior to product use 
at Day 2
Randomization
Day 2 only. Discontinuation of 
supernumerous subjects, if 
applicable, should occur prior to 
randomization
Prior to product use 
(within 2 hours)
Assembly and weighing of 
product
Prior to product use
(within 1 hour)
Vital signs (blood pressure, 
pulse rate, respiratory rate)
At least 5 min in supine position 
prior to measurement.
15 ± 5 minutes prior 
to T0 fix
9
Blood sampling for 
baseline nicotine level for 
fixed puffing  

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Time
Blood 
Sample
Procedures
Additional Information
Start of Procedure
15 ± 5 minutes prior 
to T0 fix
VAS-craving: baseline for 
fixed puffing
Just before product 
use
Piercing of P3P capsule
Start of product use:
T0 fix 
Product use (fixed puffing) 
with HPT recording
After at least 10 hours of 
nicotine washout.
Day 1: P3P 3
Day 2, 3 and 4: P3P 1, 2 and 4.
One product variant used at a 
given visit. The order depends 
on the sequence a subject was 
randomized to.
1 puff every 30 seconds, 12 
puffs in total
During/after fixed 
puffing product use
9
Blood sampling for fixed 
puffing nicotine PK 
assessment
Post T0 fix, blood will be drawn at 
the following time points: 
T1 after 2 minutes ± 1 minute,
T2 after 4 minutes ± 1 minute,
T3 after 7 minutes ± 1 minute, 
T4 after 10 minutes ± 1 minute, 
T5 after 15 minutes ± 2 minutes, 
T6 after 30 minutes ± 2 minutes,
T7 after 1 hour ± 5 minutes, 
T8 after 2 hours ± 5 minutes, 
T9 after 4 hours ± 5 minutes.
During/after fixed 
puffing product use
VAS-craving
Post T0 
fix,
craving
will be 
assessed at the following time 
points
4 minutes (± 2 minutes)
10 minutes (± 2 minutes)
15 minutes (± 2 minutes)
30 minutes (± 5 minutes)
1 hour (± 10 minutes)
2 hours (± 10 minutes)
4 hours (± 10 minutes)
Between 30 minutes 
and 2 hours after T0 fix
Breakfast

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Time
Blood 
Sample
Procedures
Additional Information
Start of Procedure
60 ± 10 minutes post 
fixed puffing
Vital signs (blood pressure, 
pulse rate, respiratory rate)
At least 5 min in supine position 
prior to measurement.
Within 75 min after
product use
Collection and weighing of 
used product
After fixed puffing
product use
ECG 
After resting for at least 10 min 
in supine position prior to 
recording.
After the end of blood 
sampling for fixed 
puffing PK
Lunch
Nicotine washout
At least 10h between T0 fix and
T0 ad lib
During washout
Optional: snacks
Ongoing
Support during period of 
smoking abstinence
Ongoing
AE/SAE, concomitant 
medication recording
Ongoing
Product events 
malfunctions/misuse
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; HPT = Human puffing topography; PK = Pharmacokinetic; 
SAE = Serious adverse event; VAS = Visual analogue scale 
Table 10 
Time Schedule – Ad libitum use period (Day 1, 2, 3, 4  - Afternoon) 
Time
Blood 
Sample
Procedures
Additional Information
Start of Procedure
Prior to product use 
(within 2 hours)
Assembly and weighing of 
products for ad libitum use
15 ± 5 minutes prior 
to T0 ad lib
9
Blood sampling for 
baseline nicotine level for 
ad libitum use  
15 ± 5 minutes prior 
to T0 ad lib
VAS-craving: baseline for 
ad libitum use
Just before each 
product use
Piercing of P3P capsule

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Time
Blood 
Sample
Procedures
Additional Information
Start of Procedure
Start of product use: 
T0 ad lib
Product use (ad libitum for 
1 hour) with HPT recording
After at least 10 hours of 
nicotine washout.
At each day the same product 
which is used for fixed puffing in 
the morning will be used for the 1 
hour ad libitum session in the 
afternoon.  
During/after ad
libitum product use
9
Blood sampling for nicotine 
PK assessment from the 
ad libitum use
Post T0 ad lib, blood will be drawn 
at the following time points: 
T1 after 10 minutes ± 1 minute, 
T2 after 20 minutes ± 2 minutes, 
T3 after 30 minutes ± 2 minutes, 
T4 after 40 minutes ± 5 minutes, 
T5 after 1 hour ± 5 minutes,
T6 after 2 hours ± 5 minutes, 
T7 after 4 hours ± 5 minutes.
During/after ad
libitum product use
VAS-craving
Post T0
ad lib, craving will be 
assessed at the following time 
points
10 minutes (± 2 minutes)
20 minutes (± 2 minutes)
30 minutes (± 5 minutes)
40 minutes (± 5 minutes)
1 hour (± 10 minutes)
2 hours (± 10 minutes)
4 hours (± 10 minutes)
Within 75 min after 
start of product use
(T0 ad lib)
Collection and weighing of 
used products
Within 60 minutes 
after the end of ad 
libitum product use
Adapted mCEQ
Within 60 minutes 
after the end of ad 
libitum product use
Sensory Questionnaire
60 ± 10 minutes after 
the end of ad libitum
product use
Vital signs (blood pressure, 
pulse rate, respiratory rate)
At least 5 min in supine position 
prior to measurement.

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Time
Blood 
Sample
Procedures
Additional Information
Start of Procedure
ECG 
After resting for at least 10 
min in supine position prior 
to recording.
Between 30 minutes 
and 2 hours after T0 ad
lib
Evening meal
Ongoing
Support during period of 
smoking abstinence
Ongoing
AE/SAE, concomitant 
medication recording
Ongoing
Product events 
malfunctions/misuse
Abbreviations: Adapted mCEQ; Adapted version of the modified Cigarette Evaluation Questionnaire; AE = Adverse event; 
ECG = Electrocardiogram; HPT = Human puffing topography; PK = Pharmacokinetic; SAE = Serious adverse event; VAS = 
Visual analogue scale 
9.4 
Day of Discharge 
The assessments in Table 11 will be conducted prior to the time of Discharge on Day 5:  
Table 11 
Time Schedule – Day of Discharge (Day 5) 
Blood 
Sample
Procedures
Additional Information
Support during periods of smoking 
abstinence
Ongoing
9
Clinical laboratory parameters 
(hematology, clinical chemistry)
After at least 6 hours of fasting.
Urine analysis safety panel
Cough assessment
24 ± 1 hours after T0 fix for the product used 
on the previous day
Breakfast
9
Blood sampling for determination of 
subject’s nicotine t1/2z
Blood will be drawn at the following time 
points post T0 ad lib for the product used on 
Day 4:
T1 after 14 hours ± 30 minutes, 
T2 after 16 hours ± 30 minutes, 

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Blood 
Sample
Procedures
Additional Information
T3 after 18 hours ± 30 minutes, 
T4 after 20 hours ± 30 minutes, 
T5 after 24 hours ± 30 minutes.
Lunch
Urine pregnancy test (all female 
subjects)
Vital signs (blood pressure, pulse 
rate, respiratory rate)
At least 5 min in supine position prior to 
measurement.
ECG 
After resting for at least 10 min in supine 
position prior to recording.
Spirometry
After resting in sitting position for at least 
15 minutes.
Physical examination
Information on risks of smoking, 
smoking cessation advice and 
product debrief
AE/SAE, concomitant medication
recording
Discharge
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; SAE = Serious adverse event 
9.5 
Safety Follow-Up Period
After Discharge on Day 5 or at the time of early discontinuation all enrolled subject will enter 
a 7-day Safety Follow-Up Period during which new AE/SAEs spontaneously reported by the 
subject will be collected. The follow-up of ongoing AEs/SAEs will be conducted by the study 
investigational site as described in section 8.2.6.
9.6 
Early Termination Procedures 
When a subject is discontinued from the study, all early termination procedures listed below 
are performed unless the subject refuses to perform the assessments.

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Table 12 
Time Schedule – Early Termination 
Blood 
Sample
Procedures
Additional Information
9
Clinical laboratory parameters 
(hematology, clinical chemistry)
Urine analysis safety panel
Urine pregnancy test (all female 
subjects)
Vital signs (blood pressure, pulse rate, 
respiratory rate)
At least 5 min in supine position prior to 
measurement.
ECG 
After resting for at least 10 min in supine 
position prior to recording.
Spirometry
After resting in sitting position for at 
least 15 minutes.
Physical examination
Information on risks of smoking, 
smoking cessation advice and product 
debrief
AE/SAE, concomitant medication
recording
Discharge
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; SAE = Serious adverse event 

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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
A Clinical Research Associate (“Monitor”) from an independent contract research organization 
(CRO) not involved with the study site will be responsible for the monitoring of the study. 
Monitoring will be performed according to the CRO’s SOPs and as per the agreed monitoring 
plan with the Sponsor. 
Before the first subject is screened and included in the study, an Investigator meeting/site 
initiation visit will be conducted. During this meeting/visit, the general training of the study 
procedures and specific training on selected procedures will be performed and documented. All 
activities to be conducted will be described in the monitoring plan.  
During the study, the Monitor will have regular contact with the investigational site, including 
routine monitoring visits. The frequency and purpose of the monitoring visits will be defined 
in the monitoring plan agreed with the Sponsor.  
The Investigator or designee shall permit the Monitor to review study data as frequently as 
deemed necessary to ensure that data are being recorded in an adequate manner and that 
protocol adherence is satisfactory.  
The Investigator or designee shall access medical records for the Monitor so that entries in the 
CRFs may be verified. The Investigator or designee, as part of their responsibilities, is expected 
to ensure that the study adheres to GCP requirements. 
The Investigator, or a designated member of the Investigator’s staff, must be available during 
the monitoring visit to review the data and resolve any queries and to allow direct access to the 
subject’s records for source data verification.
The Monitor and the Sponsor’s personnel will be available between visits, should the 
Investigator or other staff at the investigational site need information and/or advice.  
Communication by telephone, mail and e-mail may be used as needed to supplement 
investigational site visits. The Investigator and study personnel will cooperate with the 
Monitor, provide all appropriate documentation and will be available to discuss the study.  
10.2
Training of Staff 
Prior to the screening of the first subject, an Investigator Meeting/Study Initiation Visit will be 
held. During this meeting/visit, the Sponsor or its authorized representative will discuss the 
requirements of the clinical study protocol and related documents and will also provide training 
to the relevant systems and other study-specific procedures. The activities of this meeting/visit 
will be described in the monitoring plan.  
Further to the Site Initiation Visit, the Investigator or designee will ensure that appropriate 
training relevant to the study is regularly provided to all staff involved in the study, and that 

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

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11 DATA MANAGEMENT ACTIVITIES 
All data management activities will be described in detail in the data management plan (DMP)
and referenced documents. 
11.1 Data Capture 
11.1.1 
Case Report Forms and Study Records 
With the exception of the subject-reported outcome data, all results from the clinical 
assessments will be recorded in the source documents by the Investigator or their authorized 
designee(s) and then transcribed into the CRFs at the investigational site. The subject 
questionnaires and the VAS will be entered by the subject directly in a paper copy. Trained 
study personnel will be responsible for capturing the data from the observations, tests and 
assessments specified in the protocol in the source documents and then transferring the data 
into the CRF, in accordance with the CRF Completion Guidelines.  
The Investigator has ultimate responsibility for the collection and reporting of all data related 
to the clinical study and ensuring that the data are accurate, authentic/original, legible, timely 
(contemporaneous), enduring and available when required. The CRF must be signed by the 
Investigator to attest that the data contained in the CRF are true and accurate. Any corrections 
made to source documents must be clearly recorded, without obscuring the original values and 
be accompanied by the date of change, reason for change and identification of the person 
making the change. The CRF for each subject will be checked against the source documents at 
the investigational site by the Monitor. Instances of missing or unclear data will be discussed 
with the Investigator for resolution. A CRF will be generated for all subjects that sign the ICF. 
11.1.2 
Protocol Deviations 
Protocol deviations are defined as any deviations from the procedures defined in this 
document, including but not limited to, any violation of inclusion/exclusion criteria, mis-
randomizations, 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 drugs that are known to affect study endpoints.  
Protocol deviations will be entered into the clinical trial management system (CTMS) or other 
approved format. The data collected in the CRF will be used to assess protocol deviations from 
the data programmatically. Protocol deviations will be reconciled prior to closing the study 
and locking the clinical database.  
Information from the source documents will represent the primary source of protocol 
deviations. Information following investigational site monitoring and other manual reviews 
will be documented in the investigational site visit reports, follow-up letters, audit 
documentation, or other manual review and will be recorded and tracked in the CTMS or other 

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approved format. Telecommunications and other verbal communications regarding deviations 
will be considered and handled as important communication, documented and tracked as 
protocol deviations, as necessary.  
Individual entries for protocol deviations that are recorded in the CTMS, or other approved 
format, following investigational site monitoring and other manual reviews, will be reviewed 
against the individual data points in the CRF database. The overall procedure for managing 
protocol deviations are defined in the SOPs and study specific procedures of the CRO data 
management team. All deviations will be reviewed, as determined at study start, to identify 
trends to improve monitoring and/or potential impact on the statistical analysis. 
11.2 Data Handling 
All study data will be managed by the data management CRO (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. This document will describe, in detail, the procedures and processes related 
to data management. 
All data of all subjects that sign the ICF will be captured and stored in the study database.  For 
Screen Failuers the following information should be captured: date/time of ICF signature, date 
of birth, sex, race, AEs, date and reason for screen failure. 
All data collected during the study is property of the Sponsor, irrespective of the location of 
the database and the DM-CRO.
The sponsor should ensure that the investigator has control of and continuous access to the 
CRF data reported to the sponsor. The sponsor should not have exclusive control of those data. 
The Investigator should have control of all essential documents and records generated by the 
Investigator/investigational site before, during and after the study. 
Additional details are covered in the DMP. 
11.2.1 
Data Verification 
The data will be verified as defined in the DMP and data validation plan (DVP). Discrepancy 
will be identified manually as well as systematically, and data clarification forms (DCFs) will 
be issued to the investigational site, as necessary.  
Data queries will be raised for discrepant or missing data. All changes to data will be captured 
in the database with a comprehensive audit trail. 

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

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12 PLANNED STATISTICAL METHODS 
12.1 General Considerations 
Full details of the statistical analysis will be given in a detailed SAP. The following statistical 
analyses will not be performed prior to the finalization of the SAP. Any changes to the planned 
statistical methods from the SAP will be documented in the CSR. The statistical evaluation 
will be performed using SAS®, version 9.2 or later. 
12.1.1 
Stratification Criteria 
The sample enrollment will enforce at least 40% of each sex, therefore analyses will be 
stratified by sex, as detailed in the SAP.
12.1.2 
Definitions for Statistical Data Analysis 
For PK/PD analysis, baseline will be defined as the last assessment prior to T0 fix (15 minutes 
prior to T0 fix) during fixed puffing regimen, and as the last assessment prior to T0 ad lib (15 
minutes prior to T0 ad lib) during ad libitum use, for each study day of exposure. 
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by product variant, unless otherwise specified.  
All endpoints will be summarized with descriptive statistics including number of subjects (n), 
number and percent of subjects with missing data, arithmetic means and standard deviations 
(mean and SD), median, first and third quartiles, minimum and maximum.  
For log normally distributed endpoints geometric mean, geometric CV will be presented 
instead of arithmetic mean and SD.  
Categorical variables will be summarized by frequency statistics (number and percentage).  
For endpoints relating to sampling times (e.g., tmax) only median, first and third quartiles, and 
minimum and maximum will be presented.
All analyses and summaries will be performed by product and overall, and separately for fixed 
and ad libitum use regimen when applicable. 
12.1.4 
Handling of Missing Values and of Values outside the Detection Limits  
In general, missing data will not be imputed in this study, due to the nature of the measurements 
and the short periods of exposure and use. However, for questionnaire data total scores and 
domain or subscale scores may use a certain degree of imputation by averaging across 
individual item scores. Further details will be provided in the SAP. 
In general, values below the lower limit of quantification (LLOQ) will be imputed using 0.5 x 
lower limit of quantification. For values above the upper limit of quantification (ULOQ), i.e., 

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without the written consent of Philip Morris Products S.A. 
preceded by a “>”, for example “>xx,” the numerical xx will be used for calculation and 
reporting in summary tables.  
The number and percent of values below LLOQ or above ULOQ will be presented in each 
summary table. 
12.1.5 
Significance Level for Inferential Analysis 
Not applicable. 
12.2 Determination of Sample Size and Power Consideration 
The sample size is empirically based, as there is no prior information on which to base it, and 
as there are no considerations for statistical hypothesis.  
As per study design P3P 3 is the first product variant used by all subjects at Day 1 for safety 
reasons (i.e P3P 3 has the lowest nicotine concentration of all P3P variants).  As a result, only 
the 3 remaining product variants will be randomized over Day 2-4, which leads to 6 possible 
sequences. Considering that this study is a pilot investigation, and that we are expecting a low 
drop-out rate, 3 subjects will be allocated to each sequence. Therefore, 18 subjects will be 
randomized.
A sufficient number of eligible subjects will be enrolled and exposed to P3P 3 at Admission 
(Day -1) and Day 1 to ensure randomization of 18 subjects to one of six possible sequences at 
Day 2.
12.3 Analysis Populations 
All analyses will be based on actual product exposure. All endpoints (other than safety) will 
be analyzed using the PK analysis set. Safety will be analyzed using the safety population. 
12.3.1 
Pharmacokinetic Population 
The nicotine exposure analysis sets consist of all the enrolled subjects who gave informed 
consent, completed at least one of the single use of P3P, and for whom at least one primary 
nicotine PK parameter can be derived. Only subjects without major protocol deviations will be 
included in the nicotine exposure analysis sets. 
12.3.2 
Safety Population 
The safety set population, consists of all the subjects who give informed consent, have at least 
one exposure to P3P (including the product test at Admission [Day -1]) and have at least one 
safety assessment.

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without the written consent of Philip Morris Products S.A. 
12.4 Demographics and Baseline Characteristics 
Demographic information and baseline characteristics will be summarized for the PK
population. This summary will also be performed for the safety populations, if there is at least 
a difference of 3 subjects between the populations. 
Summaries will include sex, age, height, weight and BMI, smoking history, FTND, CYP2A6 
activity and other endpoints that are only captured prior to product use.  
These data will be summarized using the appropriate summary statistics as described in 
section 12.1.3.
12.5 Primary Objectives and Endpoints 
12.5.1 
Primary Endpoint Analysis Variables 
PK endpoints are listed in section 3.1.
Nicotine PK parameters for fixed puffing regimen will be derived from plasma nicotine 
concentration versus time data using a non-compartmental analysis (NCA) technique using 
Phoenix WinNonlin, Version 7.0 or higher.
To minimize the carry-over effect in the nicotine plasma PK parameters due to limited washout 
periods (see Section 4.2), background-concentration correction will be applied to the 
concentration data for the fixed puffing regimen and ad libitum use. The baseline correction 
will be implemented by calculating the nicotine exposure parameters using adjusted 
concentration values as described below. 
The nicotine terminal elimination rate constant λz (and t1/2z) will be estimated from the Day 
5 PK samples by using a linear regression on the log plasma nicotine concentration data. The 
regression analysis should contain data from at least 3 different time points in the terminal 
phase (including the last quantifiable concentration but excluding the concentration at tmax),
consistent with the assessment of a straight line on the log- transformed scale. The nicotine 
plasma background-corrected PK parameters will be derived by performing the NCA on the 
corrected concentrations.  
For the purposes of background-correction of the plasma concentrations post-baseline the 
following formula will be applied:  cCt = Ct - C0 ·* e-λz·t. Where, cCt is the corrected 
concentration at each time point, Ct is the concentration at each time point, C0 is the pre-use 
baseline concentration, λz is the Day 5 terminal elimination rate constant and t is the actual 
time. 
The procedure of the baseline adjustment will be detailed in the SAP.
If plasma concentrations cannot be background-corrected in a sufficient number of subjects, 
alternative analysis methods will be used, as detailed in the SAP. 

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In particular, the following PK parameters will be derived from nicotine levels adjusted for 
baseline:
cCmax
Background-corrected maximum observed plasma concentration. cCmax
will be reported as long as there is at least one quantifiable concentration 
post-exposure
tmax
Time to maximum concentration Cmax during fixed puffing regimen
cAUCfix(0-4h)
Background-corrected area under the plasma concentration-time curve 
from start of product use (T0 fix) to 4 hours [cAUCfix (0-4h)]
Unadjusted PK parameters will also be presented.  
More details on nicotine PK parameter derivations will be provided in the SAP. 
12.5.2 
Baseline Comparability 
Not applicable. 
12.5.3 
Statistical Analysis 
Endpoints for fixed puffing regimen will be summarized as described in section 12.1.3.
PK parameters for fixed puffing regimen will be summarized by P3P variant and analyzed 
using a mixed model conducted on logarithmically transformed PK parameters with fixed 
terms for sequence, study day, product variant, and using subject nested within sequence as 
random effect. Nicotine PK profiles will be summarized and plotted over time by P3P variant.
Details of model term categories for product variant and study day, accounting for 
multicollinearity between Day 1 and P3P 3 use, will be provided in the SAP. 
Adjusted geometric least square means and ratios will be presented for the analysis of PK 
endpoints together with 95% confidence interval for the following effects of interest: 
x
P3P 2 vs P3P 3, to describe the effect of an increase of nicotine powder concentration 
from 2.5% to 5%  
x
P3P 2 vs P3P 4, to describe the effect of a decrease from 2.25 μm to 1.8 μm of the 
median particle size in the nicotine powder 
x
P3P 2 vs P3P 1, to describe the effect of flavor 

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12.6 Secondary Objectives and Endpoints 
12.6.1 
Secondary Endpoint Analysis Variables 
12.6.1.1 
Nicotine Exposure Parameters for ad libitum use
PK endpoints related to the ad libitum use period are listed in section 3.2. 
Nicotine PK parameters for ad libitum use will be derived from plasma nicotine concentration 
versus time data using a NCA technique. The procedure of the baseline adjustment presented 
in section 12.5.1 will be used on secondary PK endpoints. In particular, the following PK 
parameters will be derived from nicotine levels adjusted for baseline:
cCpeak
Background-corrected peak plasma nicotine concentration
tpeak
Time to peak plasma nicotine concentration during ad libitum use, tpeak will 
be reported as long as there is at least one quantifiable concentration post-
exposure
cCtrough
Background-corrected trough plasma nicotine concentration
cCaverage
Background-corrected average of plasma nicotine concentration between 
T0 ad lib to 1 hour
cAUC ad lib (0-4h) Background-corrected area under the concentration-time curve from the 
start of ad libitum use (T0 ad lib ) to 4 hours.
Unadjusted Background-corrected PK parameters will also be presented.  
12.6.1.2 
PD endpoints for the fixed puffing regimen and ad libitum use
PD endpoints are listed in section 3.2.
For the VAS craving score AUCVAS will be derived for each puffing regimen:  AUCVAS fix (0-
4h) and AUCVAS ad lib (0-4h)  
12.6.2 
Statistical Analysis 
The same approach described in section 12.5.3 will be used for the analysis of PK parameters 
ad libitum and PD endpoints. PD endpoints will be analyzed in their original scale. 
12.6.2.1 
PK parameters for ad libitum use
PK parameters for ad libitum use will be summarized by P3P variant and analyzed using a 
mixed model with fixed terms for sequence, study day, product variant, and using subject 
nested within sequence as random effect. Nicotine PK profiles will be summarized and plotted 
over time by P3P variant.

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Details of model term categories for product variant and study day, accounting for 
multicollinearity between Day 1 and P3P 3 use, will provided in the SAP. 
12.6.2.2 
VAS Craving Assessments 
VAS craving assessments and AUCVAS scores will be summarized over time by P3P variant 
and by regimen. The VAS scores will be assessed using a mixed model with sequence, study 
day, product variant, baseline value prior to product use, and the interaction of product and 
time point as fixed effects and subjects as random effect including the assessment time points 
as repeated measurements. AUCVAS scores will be analyzed using the same model as for the 
PK parameters, including adjustment of baseline VAS value. 
Details of model term categories for product variant and study day, accounting for 
multicollinearity between Day 1 and P3P 3 use, will be provided in the SAP. 
12.6.2.3 
Questionnaires (Adapted mCEQ and SQ)  
Adapted mCEQ subscale scores and SQ answers will be summarized with descriptive statistics 
and displayed graphically by P3P variant. The scores/answers will be analyzed using a mixed 
model with fixed terms for sequence, study day, product variant, and using subject nested 
within sequence as a random effect. 
Details of model term categories for product variant and study day, accounting for 
multicollinearity between Day 1 and P3P 3 use, will be provided in the SAP. 
12.6.2.4 
Puffing Topography
HPT parameters will be summarized by P3P variant and by product use regimen with 
arithmetic means, arithmetic CV, and 95% CIs.
12.6.3 
Safety Endpoints 
In general, all safety data will be listed and tabulated using the approach described in 
section 12.1.3. Safety variables collected during exposure periods will also be reported by 
product exposure. 
AE data will serve for the primary assessment of safety. Other safety variables monitored in 
this study include: incidence
and frequency
of P3P product
events including 
malfunction/misuse; respiratory symptoms (cough assessment VAS and Likert scales); vital 
signs (systolic and diastolic blood pressure, pulse rate, respiratory rate); spirometry; ECG data; 
clinical chemistry, hematology, and urine analysis safety panel; physical examination;
concomitant medications.
All safety data will be listed and AEs will be summarized by product variant (fixed puffing 
regimen and ad libitum use periods will be combined at the product variant level). Safety 
measurements assessed both after fixed puffing regimen and ad libitum use (vital signs, ECG 
etc.) will be summarized per fixed puffing/ad libitum use regimen and product variant.

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The number and percentage of subjects with AEs, SAEs, and product events will be tabulated 
by system organ class and preferred term. Summaries will also be presented for AEs leading 
to discontinuation, AEs leading to death, AEs by relatedness to product exposure (with and 
without laboratory related AEs), AEs by severity, and laboratory AEs. Tabulations will be 
performed for both the number of subjects experiencing an event and the number of events. 
Safety laboratory assessments are performed on Day 2 to Day 5 in the morning prior to product 
use (Appendix A). Any lab related AEs will be assigned to the product used on the previous 
day. 
Summary tables showing actual values and change from baseline of clinical findings will be 
provided for spirometry, ECGs, vital signs, and laboratory parameter. Descriptive statistics 
will be summarized by fixed puffing/ad libitum use and product variant and change from 
baseline will be presented for laboratory parameters, ECG, respiratory symptoms, and vital
signs. Shift tables will be provided for laboratory and safety ECG data. 
12.6.4 
Exploratory Analyses 
There are no planned exploratory analyses. 
12.7
Interim Analysis
Quality assured and quality controlled data of plasma nicotine concentrations will be analyzed 
prior to database lock and the outcome of the analysis will be received and reviewed by the 
Sponsor. If plasma nicotine concentrations cannot be background corrected in a sufficient 
number of subjects e.g., in the event that the λz (or t1/2z) cannot be reliably estimated, 
modelling approaches alternative to NCA may be applied including conventional 
compartmental analyses.. 

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13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Investigators and Study Administrative Structure 
13.1.1 
Investigator 
Investigator:
, MD
CROSS Research
Phone: 
Fax:
E-mail: 
13.1.2 
Sponsor 
Sponsor:
Philip Morris Products S.A.
Quai Jeanrenaud 5,
2000 Neuchâtel,
Switzerland.
Phone: +41 (58) 242 2111
Fax: +41 (58) 242 2811
, PhD
Clinical Scientist
Phone: 
E-mail: 
.pmi.com
, MSc
Study Statistician
Phone :
E-mail :
.pmi.com
, MD
Medical Safety Officer
Phone :
Email1 :
E-mail2 :
.pmi.com
, MSc
Clinical Study Manager
Phone :
E-mail :
pmi.com
13.1.3 
Other Responsibilities 
Project Management:
Cross Research SA
,

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Switzerland
Monitoring:
Data Management:
Cross Research SA
Pharmacokinetic Analyses:
Statistical Analyses:
Cross Research SA
All duties and responsibilities transferred by the Sponsor to the above listed CROs will be 
defined in the agreement signed between the relevant two parties. 
Any SAEs or pregnancies will be handled by the Investigator, study monitor (or Sponsor), as 
per the instructions listed in section 8.3.
Details of the laboratories conducting the clinical safety laboratory services and bioanalyses 
are shown in Appendix B.
13.2
Study subjects’ recruitment
Study participants will be recruited from the volunteers’ database maintained by the CRO. This 
database contains a pool of volunteers that are contacted whenever necessary to enrol subjects 
in a new study. Before the start of the new study, the principal investigator and other relevant 
staff discuss with the volunteers’ recruiter the study recruitment needs and specific 
requirements. On the basis of this information, the volunteers’ recruiter queries the database, 
contacts potential participants to propose the study and evaluate their interest and availability. 
In addition to the volunteers’ database, new subjects often call or email the CRO asking to 
become a research volunteer, after hearing of the clinical site activities from other volunteers 

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or friends or after checking the company web site. The CRO and its clinical site have detailed 
SOPs on the recruitment process. 
13.3
Subject Confidentiality
All information obtained during the conduct of the study with respect to the subjects' state of 
health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subject in writing and signed by the subject, in compliance with all local and 
national data protection and privacy legislation. 
The name of the subjects participating in this study will be kept confidential. Subjects will be 
identifiable by the Sponsor (or Sponsor’s authorized representative) on CRFs and other 
documents by their subject (or randomization) number/code, sex and age, but not by name, 
initial, or any other details relating to identifiable person (e.g., address, social security number, 
medical chart number, etc.). The assignment of a subject number/code for subject identification 
will be based on the appropriate data protection rules. 
Any documents that allow full identification of the subject (e.g., the subject’s signed ICF) must 
be maintained in confidence by the Investigator. If any document relating to this study shows 
a subject’s name or any other details relating to an identifiable person (e.g., address, social 
security number, medical chart number, etc.), the name or other identifiable details must be 
obscured before a copy of that document is supplied to the Sponsor or the Sponsor’s authorized 
representative. 
13.4 Access to Source Documentation 
Subjects will be informed that, during the course of the study, the Sponsor, any authorized 
representatives of the Sponsor, IEC or regulatory authorities may inspect their medical records 
and source documentation to verify the information collected and ensure that all personal 
information made available for inspection is handled in the strictest confidence and in 
accordance with national and local data protection and privacy legislation. 
The Investigator and all investigational site staff involved with the study must permit direct 
access to source data/documents for study related monitoring, audits, IEC review and 
regulatory inspection(s). 
13.5 Record Retention 
All records of data, source data and source documents (original records or certified copies), in 
any form (including, but not limited to, written, electronic, magnetic, optical records and scans 
and ECGs) that describe or record the methods, conduct, and/or results of the study, the factors 
affecting the study and the actions taken will be maintained by the investigational site for the 
study, as required by ICH GCP (2) and any other applicable local or national regulations. 

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without the written consent of Philip Morris Products S.A. 
Essential study documents/records, which individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced, are described in section 8 of the 
ICH GCP Guideline (2). 
Essential documents must be retained by the Investigator for a minimum of:  
•
At least 15 years after completion or discontinuation of the study.  
However, these documents should be retained for a longer period if required by the applicable 
regulatory requirements or by agreement with the Sponsor.  
Examples of essential records/documents include, but are not limited to:  
•
Signed informed consent documents for all subjects and master ICF.  
•
Subject identification code list, Screening log and Enrollment log (if applicable).  
•
Record of all communications between the Investigator and the IEC, composition of the 
IEC.  
•
Record of all communications/contact between the Investigator, the Sponsor, and its 
authorized representatives.  
•
List of sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in the 
study, CVs, and their signatures. 
•
CRFs, study specific questionnaires (and associated data/scoring). 
•
AE reports and details of follow-up investigations, details of concomitant medication. 
•
All other source documents (e.g., ECGs, consultation reports, physical examination and 
laboratory records) or any electronically captured study source data. 
•
Clinical laboratory reports, laboratory normal ranges. 
•
Original medical/hospital records, if applicable (the medical files of study subjects must be 
retained in accordance with local legislation and in accordance with the maximum period 
of time permitted by the hospital or study site). 
•
Record of any body fluids or tissue samples collected and retained. 
•
IP Accountability Logs, dispensing records. 
•
Information regarding subjects’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the Investigator/study site as to when these 
documents no longer need to be retained. 
The Investigator/study site must take measures to prevent accidental or premature destruction 
of these documents. 

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without the written consent of Philip Morris Products S.A. 
If an Investigator wishes to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. The Investigator must obtain written 
approval from the Sponsor before destruction of any records. Normally, these records will be 
held in the Investigator’s archives. If an Investigator is unable to meet this obligation, they 
must ask the Sponsor for permission to make alternative arrangements. Details of these 
arrangements must be documented. 
The Sponsor or Sponsor’s authorized representative will maintain documentation relating to 
the study as long as the IP is on the market, and/or for 15 years after the CSR has been finalized. 
13.6
Clinical Study Report
The Sponsor must ensure that a CSR for this study is prepared regardless of whether the study 
is completed or prematurely terminated.  
The CSR will be written based on standards of the ICH Guideline for the “Structure and 
Content of Clinical Study Reports”(23). In certain circumstances, an abbreviated CSR may be 
acceptable. Submission of the CSR to the IEC will be complied with as requested by local 
requirements. 
13.7 Financial Disclosure 
Investigators and any designees are required to provide financial disclosure information to the 
Sponsor. In addition, the Investigators and designees must provide the Sponsor with a 
commitment to promptly update this information if any relevant changes occur during the 
course of the investigation and for one year following the completion of the study. 
13.8
Publication and Disclosure Policy
This document contains information that is confidential and proprietary to the Sponsor. This 
information is being provided solely for the purpose of evaluation and/or conducting this study 
for the Sponsor. Disclosure of the content of this document is allowed only to study personnel, 
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.  
According to The Federal Act on Research involving Human Beings and the Ordinance on 
Clinical Trials in Human Research, the study will be registered and published in a WHO 
primary register or clinicaltrials.gov as well as in the supplementary federal database. 

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13.9 Insurance 
The Sponsor is responsible for AEs and health damage of the subjects that are associated with 
the investigational products which are used during the study, except for AEs and health damage 
of the subjects caused by a negligent or an intentional misconduct and/or significant deviation 
to the protocol of the Investigator or the clinical investigational site or the subjects. The 
Sponsor has taken out insurance to cover any bodily injury and property damage caused by the 
operations carried out by the insured. 

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14 REFERENCE LIST 
1. FDA (Food and Drug Administration). Guidance for industry - Collection of race and 
ethnicity data in clinical trials. 2005. 
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: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R
2__Step_4.pdf (Accessed on 30 Jan 2017). 
3. World Medical Association (WMA). Declaration of Helsinki - Ethical principles for 
medical 
research 
involving 
human 
subjects. 
2013; 
Available 
from: 
http://www.wma.net/en/30publications/10policies/b3/ (Accessed on 16 March 2017). 
4. U.S. Department of Health and Human Services. The health consequences of smoking - 50 
years of progress: a report of the Surgeon General. 2014. 
5. WHO Study Group, Ashley DL, Ayo-Yusuf OA, Boobis AR, da Costa e Silva VL, 
Djordjevic MV, et al. WHO study group on tobacco product regulation - Report on the 
scientific basis of tobacco product regulations: fifth report of a WHO study group. 2015. 
6. Cipolla DC, Gonda I. Inhaled nicotine replacement therapy. Asian J Pharm Sci. 
2015;10(6):472-80. doi: 10.1016/j.ajps.2015.07.004. 
7. Teichert A, Brossard P, Felber Medlin L, Sandalic L, Franzon M, Wynn C, et al. Evaluation 
of nicotine pharmacokinetics and subjective effects following use of a novel nicotine delivery 
system. Nicotine Tob Res. Accepted article 2017. 
8. Hukkanen J, Jacob P, 3rd, Benowitz NL. Metabolism and disposition kinetics of nicotine. 
Pharmacol Rev. 2005;57(1):79-115. Epub 2005/03/01. doi: 57/1/79 [pii] 
10.1124/pr.57.1.3. PubMed PMID: 15734728. 
9. Philip Morris Products S.A. Unpublished on file data: Investigator's Brochure for P3P. 
Edition 1. 2017. 
10. National Institute for Health and Care Excellence (NICE). Tobacco: harm-reduction 
approaches to smoking (NICE public health guidance 45). 2013; Available from: 
http://www.nice.org.uk/guidance/ph45/resources/guidance-tobacco-harmreduction-
approaches-to-smoking-pdf (Accessed on 11 August 2014). 
11. Marchand M, Brossard P, Merdjan H, Lama N, Weitkunat R, Ludicke F. Nicotine 
population pharmacokinetics in healthy adult smokers: a retrospective analysis. Eur J Drug 

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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. 
Metab Pharmacokinet. 2017. Epub 2017/03/12. doi: 10.1007/s13318-017-0405-2. PubMed 
PMID: 28283988. 
12. Benowitz NL, Lessov-Schlaggar CN, Swan GE, Jacob P, 3rd. Female sex and oral 
contraceptive use accelerate nicotine metabolism. Clin Pharmacol Ther. 2006;79(5):480-8. 
Epub 2006/05/09. doi: 10.1016/j.clpt.2006.01.008. PubMed PMID: 16678549. 
13. FDA (Food and Drug Administration). Food-effect bioavailability and fed bioequivalence 
studies. 2002. 
14. American Pharmacists Association. Cytochrome P450 enzymes: substrates, inhibitors, and 
inducers.  Drug information handbook. 23rd ed2014. p. 2316-24.
15. Raw M, Anderson P, Batra A, Dubois G, Harrington P, Hirsch A, et al. WHO Europe 
evidence based recommendations on the treatment of tobacco dependence. Tob Control. 
2002;11(1):44-6. PubMed PMID: 11891367. 
16. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. Epub 2005/08/02. doi: 
10.1183/09031936.05.00034805. PubMed PMID: 16055882. 
17. Hu G, Cassano PA. Antioxidant nutrients and pulmonary function: the Third National 
Health and Nutrition Examination Survey (NHANES III). Am J Epidemiol. 2000;151(10):975-
81. Epub 2000/06/15. PubMed PMID: 10853636. 
18. Sajatovic M, Ramirez LF. Fagerstrom Test for Nicotine Dependence (FTND).  Rating 
scales in mental health. 3rd ed. USA: Baltimore : Johns Hopkins University Press; 2012. p. 
344-5. 
19. Moyses C, Hearn A, Redfern A. Evaluation of a novel nicotine inhaler device: part 2-effect 
on craving and smoking urges. Nicotine Tob Res. 2015;17(1):26-33. Epub 2014/08/02. doi: 
10.1093/ntr/ntu122. PubMed PMID: 25082830; PubMed Central PMCID: PMCPmc4282120. 
20. Cappelleri JC, Bushmakin AG, Baker CL, Merikle E, Olufade AO, Gilbert DG. 
Confirmatory factor analyses and reliability of the modified cigarette evaluation questionnaire. 
Addict Behav. 2007;32:912–23. doi: 10.1016/j.addbeh.2006.06.028. 
21. Hatsukami DK, Zhang Y, O'Connor RJ, Severson HH. Subjective responses to oral tobacco 
products: scale validation. Nicotine Tob Res. 2013;15(7):1259-64. Epub 2012/12/15. doi: 
10.1093/ntr/nts265. PubMed PMID: 23239843; PubMed Central PMCID: PMCPmc3682844. 

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without the written consent of Philip Morris Products S.A. 
22. Rose JE, Turner JE, Murugesan T, Behm FM, Laugesen M. Pulmonary delivery of nicotine 
pyruvate: sensory and pharmacokinetic characteristics. Exp Clin Psychopharmacol. 
2010;18(5):385-94. doi: 10.1037/a0020834. PubMed PMID: 20939642. 
23. ICH E3. Structure and content of clinical study reports - Guideline. 1995; Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_G
uideline.pdf (Accessed on 17 July 2014). 

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consent of Philip Morris Products S.A. 
15 APPENDICES 
Appendix A – Schedule of Events 
Study Day
Day -22 to -2
Screening
Day -1
Admission
Day 1
Day 2
Day 3
Day 4
Day 5
Discharge q
Day 5 to 12
Safety Follow-Up o
Informed consent
●
Information on the risks of 
smoking/advice on smoking cessation 
and debriefing on P3P
●
●
●
Inclusion/exclusion criteria a
●
●
P3P product demonstration
●
Smoking history
●
Readiness to comply to study 
procedures, including period of 
abstinence from any tobacco and 
nicotine containing products
●
●
Intention to quit smoking in the next 2 
months
●
●
Demographics b, medical history, 
concomitant diseases
●
Prior medication c
●
Concomitant medication
●
●
●
●
●
●
●
●
Physical examination
●
●
●

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Study Day
Day -22 to -2
Screening
Day -1
Admission
Day 1
Day 2
Day 3
Day 4
Day 5
Discharge q
Day 5 to 12
Safety Follow-Up o
Body height, weight and related BMI
●
Vital signs d
●
●
●
●
●
●
●
ECG e
●
●
●
●
●
●
●
Spirometry
●
●
Blood and urine sample collection for 
hematology, clinical chemistry, urine 
analysis safety panel f
●
●
●
●
●
●
Blood sample collection for serology 
●
Urine drug screen
●
●
Urine cotinine screen (dip stick)
●
Alcohol breath test
●
●
Urine Pregnancy test (females)
●
●
●
trans-3’-hydroxycotinine and cotinine 
(CYP2A6 activity) in plasma g
●
FTND questionnaire
●
Enrollment
●
P3P product test h
●
Randomization i
●
P3P product use. 
Fixed puffing in the morning with HPT 
followed by ad libitum use in the 
afternoon with HPT j
●
●
●
●

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Study Day
Day -22 to -2
Screening
Day -1
Admission
Day 1
Day 2
Day 3
Day 4
Day 5
Discharge q
Day 5 to 12
Safety Follow-Up o
Blood sample collection for plasma 
nicotine k
●
●
●
●
●
VAS-craving l
●
●
●
●
Adapted mCEQ m
●
●
●
●
Sensory Questionnaire m
●
●
●
●
Cough assessment n
●
●
●
●
●
AE/SAE recording o
●
●
●
●
●
●
●
●
Product events
Malfunctions/Misuse
●
●
●
●
●
Support during periods of smoking 
abstinence (as required)
●
●
●
●
●
Weighing of P3P products p
●
●
●
●
Abbreviations: Adapted mCEQ = adapted version of the modified Cigarette Evaluation Questionnaire; AE = Adverse event; BMI = Body mass index; ECG = Electrocardiogram; FTND = 
Fagerström Test for Nicotine Dependence (revised version); HPT = Human puffing topography; SAE = Serious adverse event; SQ = Sensory questionnaire; VAS= Visual Analog Scale.  
a.
Prior to enrollment at Admission the following inclusion and exclusion criteria will be re-checked: Inclusion Criteria: Subject is not planning to quit smoking within 2 months, Subject is 
available during the study period and ready to comply with study procedures. Exclusion criteria: Subject has a positive alcohol test and/or the subject has a history of alcohol abuse that could 
interfere with the subject’s participation in study, subject has a positive urine drug screen, subject uses estrogen containing medication, female subject who is pregnant or breast-feeding,
female subject of childbearing potential who does not agree to use effective contraception. The following eligibility criteria will only be checked at Admission: subjects will not be included 
if they have received medication within 14 days or within 5 half-lives of the drug prior to Admission (whichever is longer) which has an impact on CYP2A6 activity.
b.
Sex, date of birth, race. 
c.
All medication taken within 4 weeks prior to the Screening Visit will be documented. Prior medication which has an impact on CYP2A6 activity taken within 14 days or within 5 half-lives 
of the drug (whichever is longer) prior to Day -1 is an exclusion criteria. 
d.
Systolic and diastolic blood pressure, pulse rate and respiratory rate. Assessed in the morning within 60 minutes prior to fixed puffing regimen and 60 minutes ± 10 minutes after each product 
use period (fixed puffing regimen and ad libitum use). 
e.
On Days 1 to 4 ECG, will be performed after fixed puffing regimen and after the ad libitum use period. 

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f.
Blood samples should be taken after at least 6 hours of fasting, except at Screening where non-fasting samples can be used.  
g.
Sample taken in the morning prior to product use. 
h.
During the Admission Visit after enrollment, subjects will be asked to perform a product test with the use of up to 3 products of P3P 3. 
i.
A subject can be randomized only after confirmation that there are no safety concerns for the subject to continue the study as judged by the Investigator. If a sufficient number of subjects are 
already randomized to the study sequences, any supernumerous subjects will be discontinued from the study prior to randomization.  
j.
Subjects will use one variant of P3P on a given study day. They will use P3P with HPT recording in the morning at a fixed puffing regimen comprising of 12 puffs in total at a rate of one 
inhalation every 30 seconds (± 5 seconds). In the afternoon, subjects will use P3P with HPT recording ad libitum for 60 minutes. Subjects will use P3P 3 at Day 1 and P3P 1, P3P 2 and P3P
4 in a randomized sequence at Days 2, 3 and 4. 
k.
A total of 10 blood samples will be taken for fixed puffing PK parameter estimation at Days 1 to 4. One blood samples will be taken prior to the product use (T0 fix) 15 minutes ± 5 minutes 
(T-1). Thereafter in relation to T0 fix, blood will be drawn at the following time points: T1 after 2 minutes ± 1 minute, T2 after 4 minutes ± 1 minute, T3 after 7 minutes ± 1 minute, T4 after 
10 minutes ± 1 minute, T5 after 15 minutes ± 2 minutes, T6 after 30 minutes ± 2 minutes, T7 after 1 hour ± 5 minutes, T8 after 2 hours ± 5 minutes, and T9 after 4 hours ± 5 minutes.  
A total of 8 blood samples will be taken for the ad libitum PK parameter estimation at Days 1 to 4. One blood sample will be taken prior to product use (T0 ad lib) at 15 minutes ± 5 minutes 
(T-1). In relation to T0 ad lib, blood will be drawn at the following time points: T1 after 10 minutes ± 1 minute, T2 after 20 minutes ± 2 minutes, T3 after 30 minutes ± 2 minutes, T4 after 40 
minutes ± 5 minutes and T5 after 1 hour ± 5 minutes, T6 after 2 hours ± 5 minutes, and T7 after 4 hours ± 5 minutes.   
A total of 5 blood samples will be taken at Day 5. Blood samples will be taken in relation to T0 ad lib from the last product use at the following time points: T1 after 14 hours ± 30 minutes, 
T2 after 16 hours ± 30 minutes, T3 after 18 hours ± 30 minutes, T4 after 20 hours ± 30 minutes and T5 after 24 hours ± 30 minutes.
l.
The VAS craving will be completed by the subject at Days 1 to 4. For the fixed puffing regimen the first assessment will be done 15 minutes ± 5 minutes prior to T0 fix, all other assessments 
will be done after T0 fix, at 4 minutes ± 2 minutes, at 10 minutes ± 2 minutes, at 15 minutes ± 2 minutes, 30 minutes ± 5 minutes, 1 hour, 2 hours, 4 hours ± 10 minutes each. For the ad libitum
use period the first assessment will be done 15 minutes ± 5 minutes prior to T0 ad lib, all other assessments will be done after T0 ad lib, at 10 minutes ± 2 minutes, at 20 minutes ± 2 minutes, 30 
minutes ± 5 minutes, 40 minutes ± 5 minutes, 1 hour, 2 hours, 4 hours ± 10 minutes each. 
m.
The adapted mCEQ and SQ questionnaires will be answered within 60 minutes after the end of the ad libitum use period. 
n.
VAS, three Likert scales and one open question. The cough questionnaire will be completed at Admission prior to product test and 24 hours (± 1 hour) after T0 fix for each variant (but prior 
to next variant use). 
o.
Spontaneous reporting of new AEs/SAEs by the subject and follow-up of ongoing AEs/SAEs by the site. 
p.
All P3P products will be weighed before and after use. 
q.
All examinations listed at Discharge, with the exception of blood sampling for nicotine measurement and cough assessment, should also be conducted in subjects prematurely terminating the 
study (early termination procedures). 

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without the written consent of Philip Morris Products S.A. 
Appendix B - Participating Laboratories 
Bioanalytical laboratory (Plasma Nicotine and CYP2A6 analysis): 
Celerion, Inc. 
Clinical Safety Laboratory (Hematology, Clinical Chemistry and Urine Analysis): 

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

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Serum Chemistry
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Life-
Threatening
(Grade 4)
(mg/dL)
(mmol/L)
>ULN - 300;
>ULN - 7.75
>300-400;
>7.75-10.34
>400-500;
>10.34-12.92
>500;
>12.92
Triglycerides - Hypertriglyceridemia a
(mg/dL)
(mmol/L)
150 – 300;
1.71 – 3.42
>300 – 500;
>3.42 – 5.70
>500 – 1000;
>5.70 – 11.40
>1000;
>11.4 
Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; BUN = Blood urea nitrogen; 
GGT = Gamma-glutamyl transferase; LLN = Lower limit of the normal range; ULN = Upper limit of the normal range. 
Data Sources: 
a
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, 
FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
Table C2 
Abnormal Laboratory Values Rating: Hematology Parameters 
Hematology
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Life-
Threatening
(Grade 4)
Anemia (Hemoglobin) a
(g/dL)
(mmol)
(g/L)
<LLN-10.0
<LLN-6.2
< LLN-100
<10-8.0
<6.2-4.9
< 100-80
<8.0
<4.9
<80
Transfusion 
indicated
Life 
threateming 
consequences; 
urgent 
intervention 
indicated
Hemoglobin increase a –
(g/dL)
Increase in >0 –
2 above ULN or 
above Baseline 
if Baseline is 
above ULN
Increase in >2 – 4
above ULN or 
above Baseline if 
Baseline is above 
ULN
Increase in >4 
above ULN or 
above Baseline if 
Baseline is above 
ULN
-
WBC Decrease a -
(cell/mm3)
(10-9/L)
<LLN – 3000;
<LLN – 3.0
<3000 - 2000;
<3.0 – 2.0 
<2000 - 1000;
<2.0 – 1.0 
<1000;
<1.0 
Lymphocytes increase a
(cell/mm3)
-
>4,000 – 20,000
>20,000
-
Lymphocytes decrease a
(cell/mm3)
(10-9/L)
<LLN – 800;
<LLN – 0.8
<800 - 500;
<0.8 – 0.5
<500 - 200;
<0.5 – 0.2
<200;
<0.2

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Hematology
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Life-
Threatening
(Grade 4)
Neutrophils Decrease a
(cell/mm3)
(10-9/L)
<LLN – 1500;
<LLN – 1.5
<1500 - 1000;
<1.5 – 1.0
<1000 - 500;
<1.0 – 0.5
<500;
<0.5
Platelets decrease a
(cell/mm3) 
(10-9/l)
<LLN – 75,000;
<LLN – 75.0
<75,000 – 50,000;
<75.0 – 50.0
<50,000 – 25,000;
<50.0 – 25.0
<25,000;
<25.0
Abbreviations: LLN = Lower limit of the normal range; ULN = Upper limit of the normal range; WBC = White blood cell. 
Data Source: 
a
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human 
Services, FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
Table C3 
Abnormal Laboratory Values Rating: Urine analysis Parameters 
Urine
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Life-Threatening
(Grade 4)
Protein a
1+ proteinuria; 
urinary protein <1.0 
g/24 hours
2+ proteinuria; 
urinary protein 1.0-
3.4 g/24 hours
Urinary protein ≥3.5 
g/24 hours
-
Data Source: 
a
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human 
Services, FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 

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Appendix D – Human Puffing Topography Parameters 
Table D1 
Per-puff parameters 
Description
Variable
Unit
Puff number 
Ni
Puff volume
Vi
mL
Puff duration
Di
s
Average flow [Vi/Di]
Qmi
mL/s
Peak flow
Qci
mL/s
Inter puff interval
Ii
s
Sum of Ii and Di
DFi
s
Peak flow position
PosQci
%
Number of peaks
Pn
Table D2 
Per-product use experience parameters 
Description
Variable
Formula
Unit
Total number of puffs
NPC
в Ni
Total puff volume
TVOL
в Vi
mL
Average puff volume 
AvgVi
в Vi / NPC, i=1 ... NPC
mL
Average puff duration
AvgDi
в Di / NPC, i=1 ... NPC
s
Total puff duration
TDi
в Di
s
Average flow
AvgQmi
в Qmi / NPC, i=1 … NPC
mL/s
Peak flow 
AvgQci
в Qci / NPC, i=1 … NPC
mL/s
Total inter puff interval 
TIi
в Ii
s
Average inter puff interval
AvgIi
в Qci / NPC, i=1 … NPC
s
Total puffing duration
TDFi
в DFi 
s
Puffing Intensity
SMINT
TVOL/TDFi
mL/s
Puffing Time Index
PTI
(100*TDi)/TDFi
%
Puff Frequency
PFeq
NPC/(TDFi/60)