A Single-center, Randomized, Controlled, Open-label Study to Investigate the Nicotine Pharmacokinetic Profiles and Subjective Effects of Four Variants of Nicotine Pouch 1.0 Compared to Velo® Ice Cool and Zyn® Cool Mint Mini Dry in Healthy Smokers
Phase: NA
Conditions: Smoking, Nicotine
Sponsor: Philip Morris Products S.A.

 
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Clinical Study Protocol 
 
 
Study Number: 
P5-PK-01-EXP 
Study Title: 
A single-center, randomized, controlled, open-label 
study to investigate the nicotine pharmacokinetic 
profiles and subjective effects of four variants of 
Nicotine pouch 1.0 compared to Velo® Ice Cool 
and Zyn® Cool Mint Mini Dry in healthy smokers 
Short title: 
Nicotine pharmacokinetics and subjective effects of 
Nicotine pouch 1.0 nicotine pouches compared to 
Velo® Ice Cool and Zyn® Cool Mint Mini Dry in 
healthy smokers 
Product Name: 
Nicotine pouch 1.0 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel, Switzerland 
Version: 
2.0, 
Approved 
Date: 
07 Mar 2022 
Authors: 
, PhD, Clinical Scientist 
, PhD, Biostatistician 
, MD, Medical Safety 
Officer 
 
 
 

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Clinical Study Protocol 
Confidential 
P5-PK-01-EXP 
2.0, Approved 
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Related to QMS-0017588 
 
Document ID: VV-TMF-00821 
 
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Philip Morris Products S.A 
VERSION HISTORY 
 
Version 
Date 
Protocol Update/Amendment 
2.0 
07 Mar 2022 
Amendment 1 
Original 
Document 
1.0 
04 Feb 2022 
Not applicable 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
• Appendix B: Safety laboratory amended  

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SYNOPSIS 
Sponsor: 
Philip Morris Products S.A. 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Name of Product: 
Nicotine pouch 1.0  
Study Title: 
A single-center, randomized, controlled, open-label study to investigate the nicotine 
pharmacokinetic profiles and subjective effects of four variants of Nicotine pouch 1.0 
compared to Velo® Ice Cool and Zyn® Cool Mint Mini Dry in healthy smokers 
Study Number: 
P5-PK-01-EXP 
Short Title: 
Nicotine pharmacokinetics and subjective effects of Nicotine pouch 1.0 nicotine pouches 
compared to Velo® Ice Cool and Zyn® Cool Mint Mini Dry in healthy smokers 
Exploratory Objective and Endpoints: 
 
1. To describe the plasma concentration-time profile of nicotine and derived 
pharmacokinetic (PK) parameters of 4 variants of Nicotine pouch 1.0 nicotine 
pouches compared to Velo-NP and Zyn-NP in healthy smokers from a 30 minutes 
product use period. 
Endpoints (Day 1 to Day 3): 
• Background-corrected maximum plasma concentration [Cmax] 
• Background-corrected time to the maximum concentration [Tmax] 
• Area under the background-corrected concentration-time curve (AUC) from start 
of product use (T0), to all subsequent timepoints and extrapolated to infinity 
[AUC0-5min, AUC0-10min, AUC0-15min AUC0-20min, AUC0-25min, AUC0-30min, AUC0-
35min, AUC0-40min, , AUC0-1h, AUC0-3h, AUC0-6h, AUC0-infinity] 

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2. To describe pharmacodynamic (PD) effects (subjective effects and related behavioral 
assessments) of 4 variants of Nicotine pouch 1.0 compared to Velo-NP and Zyn-NP 
in healthy smokers from a 30 minutes product use period. 
Endpoints (Day 1 to Day 3): 
• Score of cigarette craving by the visual analog sale (VAS)-craving assessment 
[VAS-C-15min, VAS-C5min, VAS-C10min, VAS-C15min, VAS-C20min, VAS-C25min, 
VAS-C30min, VAS-C35min, VAS-C40min, VAS-C1h, VAS-C3h, VAS-C6h] 
• Score of “in the moment” product liking by the VAS-liking assessment [VAS-
L5min, VAS-L10min, VAS-L15min, VAS-L20min, VAS-L25min, VAS-L30min, VAS-
L35min, VAS-L40min, VAS-L1h] 
• Score of overall product liking by the VAS-liking assessment  
• Score of product satisfaction by the VAS- satisfaction assessment [VAS-S5min, 
VAS-S10min, VAS-S15min, VAS-S20min, VAS-S25min, VAS-S30min, VAS-S35min, 
VAS-S40min, VAS-S1h, VAS-S3h, VAS-S6h] 
• Score of product intention to use again by the VAS-intention to use again 
assessment [VAS-ITU30min, VAS-ITU3h] 
• Subscale scores from the Product Evaluation Scale (PES) 
• Scores from items of the Sensory questionnaire  
3. To evaluate the safety and tolerability during the study 
Endpoints (from Enrollment to EOS): 
• Incidence of adverse events (AEs) and serious adverse events (SAEs)  
• Incidence of product events  
• Changes in electrocardiogram (ECG) from baseline (heart rate, PR, QRS, QT, 
QTcF interval) 
• Changes in vital signs from baseline (systolic and diastolic blood pressure, pulse 
rate and respiratory rate) 
• Concomitant medication 
• Changes from baseline in clinical chemistry, hematology, and urine analysis 
safety panel 

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4. To describe the associations between PK and PD parameters. 
Endpoints (Day 1 to Day 3): 
• Between the score of “in the moment” product liking by the VAS-liking 
assessment averaged over the product use period (from T1 to T6) and during the 
sequence period (T1 to T9) and Cmax, Tmax, and AUC0-infinity PK endpoints 
• Between the average score of “in the moment” product satisfaction by the VAS-
product satisfaction assessment during the sequence’s period (from T1 to T11) 
and Cmax, Tmax, and AUC0-infinity PK endpoints 
• Between the score of “in the moment” craving by the VAS-craving assessment 
averaged during the sequence’s period (from T1 to T11) and Cmax, Tmax, and 
AUC0-infinity PK endpoints 
• Between the subscale scores of Product Evaluation Scale and AUC0-infinity PK 
endpoint 
• Between the item scores of the Sensory questionnaire and AUC0-infinity PK 
endpoint 
5. To describe the extent of nicotine extracted during product use from 4 variants of 
Nicotine pouch 1, Velo-NP and Zyn-NP. Reporting of this objective will be separate 
from the main Clinical Study Report. 
Endpoint (Day 1 to Day 3) 
• Estimated amount of nicotine extracted derived from analysis of nicotine after use. 
Study Design: 
This is a single-center, randomized, controlled, open-label, cross-over study in healthy 
smoking subjects to investigate the nicotine PK profiles of 4 variants of Nicotine pouch 
1.0 compared to marketed Velo-NP and Zyn-NP. In addition, PD effects will be 
evaluated to provide further insights on Nicotine pouch 1.0 product acceptance and abuse 
liability. The study will be conducted with 3 periods and 6 sequences in a Williams 
design (cross-over). The assessments to be performed will be as described in the schedule 
of events (Appendix A). The overall design will be as follows: 
A Screening Visit will be conducted within 21 days (Day -22 to Day -2) prior to 
Admission (Day -1) to the investigational site (Figure 1). Subjects will be screened 
against eligibility criteria.  

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Figure 1 
Study Design 
Qualified subjects will return to the investigational site for Day -1. Subjects should have 
fasted for at least 10 hours prior to the safety laboratory assessments. After confirmation 
of eligibility, subjects will be enrolled. All subjects that are not enrolled will be 
considered as screen failures. 
At Day -1, enrolled subjects will perform a product test using NP-1 for 30 minutes (± 1 
minute). After the product test, subjects not willing and/or not ready to use Nicotine 
pouch 1.0 during the study will be discontinued from the study, will enter the 3-day 
Safety follow-up period and will be replaced. 
Subjects willing and ready to use Nicotine pouch 1.0, Velo-NP and Zyn-NP during the 
study after product test will start their exposure period of 3 days.  
Twenty-four subjects will be randomized to 1 of 6 possible sequences of product use on 
Day 1 to Day 3 with at least 25% of each sex. 

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On Day 1 to Day 3, after at least 8 hours of abstinence from any nicotine/tobacco 
containing products (nicotine wash-out), subjects will use one nicotine pouch (NP) for 
30 minutes (± 1 minute) according to randomized product use sequence in the morning 
and in the afternoon, by placing the NP between the upper lip and gum. Subjects will 
complete self-reported assessments of product evaluation, craving, liking, satisfaction, 
and intent to use again.  
The start of the 30 minutes use period will be defined as T0. T0 in the morning (T0M) and 
in the afternoon (T0A) on Day 1 to Day 3 should be approximately at the same time, 
within a window of ± 30 minutes. Venous blood samples will be obtained according to 
the standard operating procedures (SOPs) at the investigational site.  
On Day 1, 12 blood samples will be collected for determination of nicotine concentration 
at the following time points in relation to T0 with a time window as indicated in brackets: 
Morning prior to T0M and afternoon prior to T0A: 
• T-1: 5 minutes (± 1 minute)  
After T0M and T0A 
• T1 after 5 minutes (± 1 minute) 
• T2 after 10 minutes (± 1 minute) 
• T3 after 15 minutes (± 1 minute) 
• T4 after 20 minutes (± 1 minute) 
• T5 after 25 minutes (± 1 minute) 
• T6 after 30 minutes (± 1 minute) 
• T7 after 35 minutes (± 1 minute) 
• T8 after 40 minutes (± 1 minute) 
• T9 after 1 hour (± 5 minutes) 
• T10 after 3 hours (± 5 minutes) 
• T11 after 6 hours (± 5 minutes) 
For each product use, subjective effects of liking, craving, satisfaction, and intention to 
use will be assessed at the following time points in relation to T0 with a time window as 
indicated in brackets: 
Prior to T0M and T0A (for VAS craving only) 
• T-15: within 15 minutes prior to T0  

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After T0M and T0A: (for VAS craving, VAS liking “in the moment”, and VAS 
satisfaction “in the moment” assessments) 
• T1 after 5 minutes (± 1 minute) 
• T2 after 10 minutes (± 1 minute) 
• T3 after 15 minutes (± 1 minute) 
• T4 after 20 minutes (± 1 minute) 
• T5 after 25 minutes (± 1 minute) 
• T6 after 30 minutes (± 1 minute) 
• T7 after 35 minutes (± 1 minute) 
• T8 after 40 minutes (± 1 minute) 
• T9 after 1 hour (± 5 minutes) 
• T10 after 3 hours (± 5 minutes) (VAS craving and VAS satisfaction only) 
• T11 after 6 hours (± 5 minutes) (VAS craving and VAS satisfaction only) 
After T0M and T0A: (for VAS liking (overall) assessment) 
• T10 after 3 hours (± 5 minutes) 
After T0M and T0A: (for VAS intention-to-use again) 
• T6 after 30 minutes (± 1 minute) 
• T10 after 3 hours (± 5 minutes) 
Additional subjective effects will be assessed in the morning and in the afternoon on Day 
1 to Day 3 by the Product Evaluation Scale (PES) and the Sensory questionnaire 
administered  at T9, 1  hour (± 5 minutes) after T0M and T0A. 
Additional blood samples will be taken for determination of the nicotine concentration 
to evaluate terminal elimination half-life (t1/2z) in relation to T0A on Day 2 at the following 
time points with a time window as indicated in brackets:  
• T1z after 8 hours (± 5 minutes) after T0A  
• T2z after 12 hours (± 5 minutes) after T0A 
After discharge at Day 3, the subjects will enter a 3-day Safety follow-up period during 
which AE/SAEs reported by the subjects associated with IP use will be collected and the 
follow-up of the ongoing AEs/SAEs will be conducted by the study investigational site. 

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Study Population and Main Criteria for Inclusion/Exclusion: 
Subjects who meet all the following inclusion criteria will be enrolled into the study: 
1. Subject has signed the ICF and is able to understand the information provided in the 
ICF. 
2. Smoking male or female aged between 21 and 65 years inclusive. 
3. Subject has smoked continuously for at least the last 3 years prior to the Screening 
visit. 
4. Subject has smoked ≥ 10 commercially available cigarettes per day for 4 weeks prior 
to Screening Visit and Admission. Smoking status will be verified based on a urinary 
cotinine test (cotinine ≥ 500 ng/mL). 
5. Subject does not plan to quit using tobacco and/or nicotine products within the next 
3 months. 
6. Smoking, healthy subject as judged by the Investigator or designee based on available 
assessments from the Screening period (e.g., safety laboratory, spirometry, vital 
signs, physical examination, ECG and medical history). 
Subjects who meet any of the following exclusion criteria must not be enrolled into the 
study: 
1. As per the Investigator’s judgment, the subject cannot participate in the study for any 
reason other than medical (e.g., psychological, social reason).  
2. Subject is legally incompetent, or physically or mentally incapable of giving consent 
(e.g., emergency situation, under guardianship, prisoners). 
3. Subject has a clinically relevant disease which requires medication (including but not 
limited to gastrointestinal, renal, hepatic, neurological, hematological, endocrine, 
oncological, urological, immunological, pulmonary, and cardiovascular disease) or 
any other medical condition including safety laboratory, which as per the judgment 
of the Investigator would jeopardize the safety of the subject.  
4. As per the Investigator’s judgment, the subject has medical conditions which require 
or will require in the course of the study, a medical intervention (e.g., start of 
treatment, surgery, hospitalization), which may interfere with the study participation 
and/or study results.  
5. Subject has donated or received whole blood or blood products within 30 days prior 
to Screening Visit.  
6. BMI < 18.5 kg/m2 or > 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 history of alcohol abuse, which as per the judgment of the Investigator 
could interfere with the subject’s participation in study.  
10. Subject has a positive urine drug including alcohol test.  
11. Subject or one of their family members a is a current or former employee of the 
tobacco industry.  

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12. Subject or one of their family members a is employee of the investigational site or of 
any other contracted vendors involved in the study.  
13. Subject has participated in another clinical study within 30 days prior to the Screening 
Visit.  
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) or is breastfeeding.  
16. For women of childbearing potential only b: subject does not agree to use an 
acceptable method of effective contraception c. 
17. Use of estrogen-containing hormonal contraception or hormone replacement therapy. 
a. 
As defined by US Food and Drug Administration (FDA) guidance on Human Subject Protection (21 CFR 
50.3(l), (m), 50.24(a)(6), (a)(7)(v), b)):  
"Family member” means among other things “parent”, “spouse”, "brothers, sisters, and spouses of brothers and 
sisters" and “any individual related by affinity…whose close association with the subject is equivalent of a 
family relationship” 
b. 
Women who are not of childbearing potential meet at least one of the following criteria:  
• 
Have undergone hysterectomy or bilateral tubal ligation,  
• 
Have primary ovarian insufficiency, or  
• 
Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 
consecutive  months with no alternative pathological or physiological cause). 
c. 
Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with 
spermicidal foam/gel/film/suppository, hormonal contraception without estrogens, vasectomized partner(s), or 
true abstinence (periodic abstinence and withdrawal are not effective methods) from Screening until the end of 
the Safety follow-up period. 
 
 

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Investigational Products; Dose; and Mode of Administration: 
The 4 variants of Nicotine pouch 1.0, Velo-NP and Zyn-NP will be provided by the 
Sponsor. The distribution will be controlled by the Investigator or a qualified and 
appropriately trained designee. 
The following variants of NP 1.0, Velo-NP and Zyn-NP will be investigated: 
Test Product 
Name 
Name in this 
study 
Nicotine per 
pouch 
pH 
Moisture 
Flavor  
NP-1 
NP-1 
8.4 mg  
8.0 
30 
Cool mint 
NP-2 
NP-2 
8.4 mg  
9.0 
30 
Cool mint 
NP-3 
NP-3 
3.6 mg  
8.0 
15 
Cool mint 
NP-4 
NP-4 
3.6 mg  
8.0 
30 
Cool mint 
 
Comparator Product 
Name 
Name in this 
study 
Nicotine per 
pouch 
Flavor 
Velo® Ice 
Cool  
Velo-NP 
10 mg  
Cool mint 
Zyn® Cool 
Mint Mini 
Dry 
Zyn-NP 
3 mg  
Cool mint 
Duration of Study: 
The entire study per subject will between 8 and 27 days. This will include a screening 
period of up to 21 days prior to Admission (Day -22 to Day -2), 3 days of confinement 
(after enrollment on Day -1 to discharge on Day 3, (3 overnight stays), and a 3-day Safety 
follow-up period (from time of Discharge at Day 4 to Day 6). The end of the study (EOS) 
for a subject is defined as the end of the Safety follow-up period. The end of the whole 
study corresponds to the individual EOS of the last subject. 
 
 

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Statistical Methods:  
Demographics and baseline characteristics will be summarized for the safety  population 
and PK populations. 
PK, PD, and extent of use parameters will be summarized in the PK population, by 
product and for all the planned timepoints. 
Nicotine PK parameters will be derived from Background-Corrected Plasma Nicotine 
Concentrations using NCA. 
Safety data will be listed and tabulated in the Safety population. Safety variables 
collected during exposure period will also be reported by sequence. All data will be 
presented in listings, ordered by randomized sequence, subject, and time point unless 
otherwise specified. 
All endpoints will be summarized with descriptive statistics including number of subjects 
(n), number and percent of subjects with missing data, arithmetic means, and standard 
deviations (mean and SD), median, first and third quartiles, minimum and maximum, 
and change from baseline.  
For log normally distributed endpoints, geometric mean, geometric CV, confidence 
interval of the geometric mean, and percent change from baseline will be presented in 
addition.  
Categorical variables will be summarized by frequency statistics (number and 
percentage).  
For endpoints relating to sampling times (e.g., Tmax), only median, first and third 
quartiles, and minimum and maximum will be presented. 
A mixed model analysis of variance (ANOVA) will be conducted on Cmax, AUC0-5min, 
AUC0-10min, AUC0-15min, AUC0-20min, AUC0-25min, AUC0-30min, AUC0-35min, AUC0-40min,  
AUC0-1h, AUC0-3h, AUC0-6h, and AUC0-infinity endpoints in the natural logarithmic scale. 
The results of this analysis will be presented in terms of geometric least square mean 
ratios and 95% confidence intervals (95% CI).  
The analysis of Tmax will be conducted using non-parametric tests and Hodges-Lehmann 
estimates of median difference with its derived 95% CI. 
Sample Size and Evaluation: 
The sample size is empirically based as there are no considerations for statistical 
hypothesis. A total of 24 subjects is expected to be sufficient to obtain a precision smaller 
than 15% if the NP-1: Velo-NP Cmax ratio is 1 and the within correlation is 0.7. 
A total of 24 subjects is expected to be sufficient to obtain a precision smaller than 15% 
if the NP-1: Velo-NP Cmax ratio is 1 and the within correlation is 0.7. 
 
 

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TABLE OF CONTENTS 
Version History .................................................................................................................... 2 
Synopsis ............................................................................................................................... 3 
Table of Contents ............................................................................................................... 13 
Abbreviations ..................................................................................................................... 19 
Explanation of Terms ......................................................................................................... 22 
1 
Ethics and Regulations ............................................................................................... 23 
1.1 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) 
Approval ........................................................................................................................ 23 
1.2 
Ethical Conduct of the Study ............................................................................... 24 
1.3 
Subject Information and Consent ........................................................................ 24 
1.3.1 
Informed Consent Form for Study Participation ......................................... 24 
1.3.2 
Amendment to the Informed Consent Form ................................................ 24 
1.4 
Good Clinical Practice and Regulatory Requirements ........................................ 25 
2 
Introduction ................................................................................................................ 26 
2.1 
Background .......................................................................................................... 26 
2.1.1 
Smoking-Related Diseases and Harm Reduction Strategy .......................... 26 
2.1.2 
Description of the Product and Scientific Findings ..................................... 27 
2.2 
Purpose of the Study ............................................................................................ 28 
2.3 
Anticipated Benefits and Risks ............................................................................ 28 
2.3.1 
Anticipated Benefits..................................................................................... 28 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures ............................. 28 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product .................... 28 
2.3.4 
Unforeseeable Risks..................................................................................... 29 
3 
Study Objectives ........................................................................................................ 30 
3.1 
Exploratory Objective and Endpoints .................................................................. 30 
4 
Investigational Plan .................................................................................................... 32 
4.1 
Overall Study Design and Plan ............................................................................ 32 
4.2 
Rationale for Study Design .................................................................................. 35 
4.3 
Appropriateness of Measurements ...................................................................... 36 
4.4 
Study Duration ..................................................................................................... 37 
5 
Study Population ........................................................................................................ 38 
5.1 
Selection of Study Population ............................................................................. 38 

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5.1.1 
Inclusion Criteria ......................................................................................... 38 
5.1.2 
Exclusion Criteria ........................................................................................ 38 
5.2 
Discontinuation of Subjects from the Study ........................................................ 41 
5.3 
Lost to Follow-up ................................................................................................ 42 
5.4 
Violation of Selection Criteria ............................................................................. 42 
6 
Investigational Products ............................................................................................. 43 
6.1 
Description of Investigational Products ............................................................... 43 
6.1.1 
Test Product ................................................................................................. 43 
6.1.2 
Comparator Product ..................................................................................... 43 
6.1.3 
Packaging and Labeling ............................................................................... 43 
6.2 
Use of Investigational Product(s) ........................................................................ 43 
6.2.1 
Admission Day (Day -1) .............................................................................. 44 
6.2.2 
Exposure Period (Day 1 to Day 3) ............................................................... 44 
6.2.3 
Day of Discharge (Day 3) and Safety Follow-up Period ............................. 44 
6.2.4 
Stopping Rules for Investigational Product ................................................. 44 
6.3 
Method for Assigning Subjects to Product Sequences ........................................ 44 
6.4 
Blinding ............................................................................................................... 44 
6.5 
Investigational Product Accountability and Adherence ...................................... 45 
6.5.1 
Dispensing Investigational Product ............................................................. 45 
6.5.2 
Storage and Accountability .......................................................................... 45 
6.5.3 
Investigational Product Retention ................................................................ 45 
6.5.4 
Adherence to Investigational and Comparator Products ............................. 45 
6.6 
Restrictions .......................................................................................................... 45 
6.6.1 
Smoking Restrictions ................................................................................... 45 
6.6.2 
Dietary Restrictions ..................................................................................... 46 
6.7 
Concomitant Medication ..................................................................................... 46 
7 
Study Procedures ....................................................................................................... 48 
7.1 
Informed Consent ................................................................................................ 48 
7.2 
Information on the Risk of Smoking and Smoking Cessation Advice and 
Debriefing on Nicotine pouch 1.0 .................................................................................. 48 
7.3 
Support during Abstinence from any Tobacco and Nicotine Containing Products
 
48 
7.4 
Clinical Assessments ........................................................................................... 48 

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7.4.1 
Demographic Data ....................................................................................... 48 
7.4.2 
Medical History, Concomitant Disease, Prior and Concomitant Medication
 
49 
7.4.3 
Physical Examination................................................................................... 49 
7.4.4 
Body Height and Weight and BMI .............................................................. 49 
7.4.5 
Vital Signs .................................................................................................... 50 
7.4.6 
Spirometry.................................................................................................... 50 
7.4.7 
Electrocardiogram ........................................................................................ 50 
7.5 
Biomarker Assessment ........................................................................................ 51 
7.5.1 
Biomarkers of Exposure to Nicotine............................................................ 51 
7.5.2 
CYP2A6 Activity ......................................................................................... 51 
7.6 
Laboratory Assessments ...................................................................................... 51 
7.6.1 
Clinical Chemistry, Hematology, and Urine Analysis for Safety Panel ...... 51 
7.6.2 
Serology ....................................................................................................... 52 
7.6.3 
Urine Drug Test ........................................................................................... 52 
7.6.4 
Urine Cotinine Test ...................................................................................... 53 
7.6.5 
Urine Pregnancy Test ................................................................................... 53 
7.7 
Sample Handling, Storage, and Shipment ........................................................... 53 
7.7.1 
Blood Samples ............................................................................................. 53 
7.8 
Questionnaires ..................................................................................................... 54 
7.8.1 
Fagerström Test for Nicotine Dependence (FTND, Revised Version)........ 54 
7.8.2 
Nicotine/Tobacco Product Use History ....................................................... 54 
7.8.3 
Product Evaluation Scale (PES)................................................................... 54 
7.8.4 
VAS Craving Assessment ............................................................................ 55 
7.8.5 
VAS Liking Assessment .............................................................................. 55 
7.8.6 
VAS Satisfaction .......................................................................................... 56 
7.8.7 
VAS Intention to Use Again ........................................................................ 56 
7.8.8 
Sensory questionnaire .................................................................................. 56 
8 
Adverse Events .......................................................................................................... 57 
8.1 
Definitions ........................................................................................................... 57 
8.1.1 
Adverse Events ............................................................................................ 57 
8.1.2 
Serious Adverse Events ............................................................................... 57 

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8.1.3 
Conditions Existent Before the Start of the Period of Collection (ICF 
Signature) ................................................................................................................... 57 
8.2 
Collection and Reporting of Adverse Events ...................................................... 58 
8.2.1 
Collection of Information ............................................................................ 58 
8.2.2 
Period of Collection ..................................................................................... 58 
8.2.3 
Intensity of Adverse Event........................................................................... 58 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures .................................................................................................................. 59 
8.2.5 
Expectedness ................................................................................................ 59 
8.2.6 
Follow-up of Non-serious and Serious Adverse Events .............................. 59 
8.3 
Reporting of Serious Adverse Events .................................................................. 60 
8.4 
Reporting of Other Events Critical to Safety Evaluations ................................... 60 
8.5 
Reporting and Follow–Up of Pregnancies ........................................................... 60 
8.5.1 
Period of Collection and Follow-up ............................................................. 60 
8.5.2 
Reporting of Pregnancies ............................................................................. 61 
8.6 
Adverse Events Leading to Discontinuation ....................................................... 61 
8.7 
Product Events ..................................................................................................... 61 
9 
Study Activities .......................................................................................................... 62 
9.1 
Screening Visit (Day -22 to Day -2) .................................................................... 62 
9.2 
Admission (Day -1) ............................................................................................. 64 
9.3 
Day 1 .................................................................................................................... 64 
9.4 
Day 2 .................................................................................................................... 66 
9.5 
Day 3 .................................................................................................................... 69 
9.6 
Safety Follow-Up Period ..................................................................................... 71 
9.7 
Early Termination Procedures ............................................................................. 71 
10 Quality Control and Quality Assurance ..................................................................... 73 
10.1 Monitoring ........................................................................................................... 73 
10.2 Training of Staff .................................................................................................. 73 
10.3 Audits and Inspections ......................................................................................... 74 
11 Data Management Activities...................................................................................... 75 
11.1 Data Capture ........................................................................................................ 75 
11.1.1 Case Report Forms and Study Records ....................................................... 75 

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11.1.2 Protocol Deviations ...................................................................................... 75 
11.2 Data Handling ...................................................................................................... 76 
11.2.1 Data Verification .......................................................................................... 76 
11.2.2 Coding .......................................................................................................... 77 
11.2.3 Database Lock .............................................................................................. 77 
12 Planned Statistical Methods ....................................................................................... 78 
12.1 General Considerations ........................................................................................ 78 
12.1.1 Stratification Criteria ................................................................................... 78 
12.1.2 Definitions for Statistical Data Analysis...................................................... 78 
12.1.3 Descriptive Statistics .................................................................................... 78 
12.1.4 Handling of Missing Values and of Values outside the Detection Limits ... 79 
12.2 Analysis Sets ........................................................................................................ 79 
12.2.1 Screened Population..................................................................................... 79 
12.2.2 Safety population (SAF) .............................................................................. 79 
12.2.3 PK Population .............................................................................................. 79 
12.3 Disposition of Subjects ........................................................................................ 80 
12.4 Protocol Deviations ............................................................................................. 80 
12.5 Demographics and Baseline Characteristics ........................................................ 80 
12.6 Exploratory Analysis ........................................................................................... 80 
12.6.1 Descriptive Statistics .................................................................................... 80 
12.6.2 Primary Estimand Analysis.......................................................................... 80 
12.7 Safety Analysis .................................................................................................... 83 
12.8 Interim Analysis ................................................................................................... 84 
12.9 Measures to Control Bias ..................................................................................... 84 
12.9.1 Method for Assigning Subjects to Study sequences .................................... 84 
12.9.2 Blinding........................................................................................................ 84 
12.9.3 Study Significance Level ............................................................................. 85 
12.9.4 Multiple Testing Procedures ........................................................................ 85 
12.9.5 Determination of Sample Size and Power Consideration ............................ 85 
13 Administrative Considerations................................................................................... 86 
13.1 Investigators and Study Administrative Structure ............................................... 86 
13.1.1 Investigator .................................................................................................. 86 

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13.1.2 Sponsor ........................................................................................................ 86 
13.1.3 Other Responsibilities .................................................................................. 86 
13.2 Subject Recruitment ............................................................................................. 87 
13.3 Subject Confidentiality ........................................................................................ 87 
13.4 Access to Source Documentation ........................................................................ 88 
13.5 Record Retention ................................................................................................. 88 
13.6 Clinical Study Report .......................................................................................... 89 
13.7 Financial Disclosure ............................................................................................ 89 
13.8 Publication and Disclosure Policy ....................................................................... 90 
13.9 Insurance .............................................................................................................. 90 
Reference List .................................................................................................................... 91 
Appendix A 
Schedule of Events ............................................................. 94 
Appendix B 
Participating Laboratories .................................................. 98 
 
LIST OF IN-TEXT TABLES 
Table 1 
Concomitant Medication ................................................................ 47 
Table 2 
Clinical Laboratory Parameters for Safety Panel ........................... 52 
Table 3 
Intensity of Adverse Events ........................................................... 59 
Table 4 
Time Schedule – Screening Visit ................................................... 62 
Table 5 
Time Schedule – Admission (Day -1) ........................................... 64 
Table 6 
Time Schedule – Day 1 .................................................................. 64 
Table 7 
Time Schedule – Day 2 .................................................................. 67 
Table 8 
Time Schedule – Day 3 (Discharge) .............................................. 69 
Table 9 
Early Termination .......................................................................... 72 
Table 11 
Description of Blinded Study Personnel ........................................ 84 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design .................................................................................... 6 
Figure 2 
Study Design .................................................................................. 32 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Events ......................................................................... 94 
Appendix B 
Participating Laboratories .............................................................. 98 
 

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ABBREVIATIONS 
AE 
Adverse event 
ANOVA 
Analysis of variance 
ANCOVA 
Analysis of covariance 
AUC0-2min 
Area under the background-corrected plasma nicotine 
concentration-time curve from T0 to 2 minutes after T0 
AUC0-4min 
Area under the background-corrected plasma nicotine 
concentration-time curve from T0 to 4 minutes after T0 
AUC0-Tmax 
Area under the background-corrected plasma nicotine 
concentration-time curve from T0 to subject-specific time to 
maximum plasma concentration after T0 
AUC0-10hours 
Area under the background-corrected plasma nicotine 
concentration-time curve from T0 to 10 hours after T0 
AUC0-last 
Area under the background-corrected plasma nicotine 
concentration-time curve from T0 to time of last quantifiable 
concentration 
AUC0-infinity 
Area under the background-corrected plasma nicotine 
concentration-time curve from T0 extrapolated to infinity  
BMI 
Body mass index 
CDC 
Centers for disease control and prevention 
Cmax 
Background-corrected maximum concentration 
CI 
Confidence interval 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTMS 
Clinical trial management system 
CV (documentation) 
Curriculum vitae 
CV (statistics) 
Coefficient of variation 
CYP2A6 
Cytochrome P450 2A6 
DMP 
Data management plan 
ECG 
Electrocardiogram 
EOS 
End of study 

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FDA 
US Food and Drug Administration  
FEV1  
Forced expiratory volume in 1 second 
FTND 
Fagerström test for nicotine dependence (revised version) 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
HPHCs 
Harmful and potentially harmful constituents 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International 
Council 
for 
Harmonisation 
of 
Technical 
Requirements for Pharmaceuticals for Human Use 
IP 
Investigational product 
IRB 
Institutional Review Board 
IV 
Intravenous 
LLN 
Lower limit of the normal range 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities 
NCA 
Non-compartmental analysis 
PES 
Product evaluation scale 
PD  
Pharmacodynamics 
PK 
Pharmacokinetics 
PMP S.A. 
Philip Morris Products S.A. 
QC 
Quality control 
SAE 
Serious adverse event 
SAF 
Safety population 
SAP 
Statistical analysis plan 
SHM 
Sample handling manual 
SOP 
Standard operating procedure 
T 
Time point  
T0 
Time point of the start of product use 

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t½ 
Half-life 
t½z 
Terminal elimination half-life 
Tmax 
Time to background-corrected maximum plasma nicotine 
concentration  
uC 
uncorrected nicotine concentration (at T0: uC0) 
ULN 
Upper limit of the normal range 
ULOQ 
Upper limit of quantification 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
 

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EXPLANATION OF TERMS 
The following special terms are used in this protocol:  
 
Alternates 
Subjects who signed the ICF, met the inclusion and exclusion 
criteria, were enrolled but are not randomized due to a sufficient 
number of subjects are already randomized. Alternates will be 
discontinued from the study prior to randomization and will 
enter the 3-day Safety follow-up period. 
End of Study 
The end of the study (EOS) for a subject is defined as the end of 
the Safety follow-up period.  
The end of the whole study corresponds to the individual EOS 
of the last subject. 
Cigarette 
The term ‘cigarette’ refers to manufactured and commercially 
available regular or menthol cigarettes and excludes hand-rolled 
cigarettes, cigars, pipes, bidis, and other nicotine-containing 
products. 
Enrollment 
At Admission (Day -1) for eligible subjects after all applicable 
inclusion and exclusion criteria have been satisfactorily 
assessed and met. 
Randomization 
Assignment to the respective sequence of Nicotine pouch 1.0, 
Velo-NP and Zyn-NP use at Admission (Day -1).  
Screen failure 
Subject who signs the ICF but is not enrolled at Admission  
(Day -1). 
 

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1 ETHICS AND REGULATIONS 
1.1 
Independent Ethics Committee (IEC)/Independent Review Board 
(IRB) Approval 
Prior to the start of the study, the clinical study protocol, together with its associated 
documents (informed consent form [ICF] including the subject information sheet, subject 
recruitment procedures [e.g., advertisements], written information to be provided to the 
subjects, Investigator’s brochure [IB], available safety information, curriculum vitae of the 
Investigator(s) and designee(s) and/or other evidence of qualifications and any other 
documents requested by an Independent Ethics Committee (IEC)/Institutional Review 
Board [IRB]), will be submitted for review and approval to the relevant IEC/IRB according 
to the appropriate provisions. The IEC/IRB shall be appropriately constituted and perform 
its functions in accordance with the International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Guidance for Good Clinical 
Practice (GCP) [1] and local requirements, as applicable. 
In accordance with GCP, a written confirmation of the IEC/IRB approval should be 
provided to the Sponsor. This should identify the study (name of the Investigator(s) and 
designee(s), study number, and title) and the documents that have been approved by the 
IEC/IRB, with dates and version numbers, as well as the date of approval. The composition 
of the IRB, including the name and occupation of the chairperson, will be supplied to the 
Sponsor together with a GCP compliance statement. 
The written approval from the IEC/IRB will be filed in the Investigator file, and a copy will 
be filed in the study master file at the Sponsor or designated organization. The study must 
not start at a site before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IEC/IRB. 
Any change or addition to this protocol will require a written protocol amendment that must 
be signed by the Sponsor and the Investigator(s). All amendments will be submitted to the 
IRB, and substantial amendments will only be implemented after approval by the IEC/IRB. 
These requirements for approval should in no way prevent any action from being taken by 
the Investigator(s) or by the Sponsor in order to eliminate immediate hazards to the 
subjects. If such a change to the protocol is felt to be necessary by the Investigator(s), and 
is implemented for safety reasons, the Sponsor and the IEC/IRB should be informed 
immediately. The Investigator(s) is(are) responsible for local reporting (e.g., to the 
IEC/IRB) of serious adverse events (SAEs) that occur during the study, according to local 
regulations. 
Relevant safety information will be submitted to the IEC/IRB during the study in 
accordance with national regulations and requirements. Medically qualified study 
personnel will be available during the study. 

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1.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki [2] and are consistent with the principles of ICH/GCP [1]. 
The Investigator(s) or designee(s) agree(s) to conduct the clinical study in compliance with 
the protocol agreed with the Sponsor and approved by the IEC/IRB. The Investigator(s) 
and the Sponsor must sign the protocol (and protocol amendments, if applicable) to confirm 
this agreement. A copy of the Declaration of Helsinki is located in the Investigator’s study 
file. 
1.3 
Subject Information and Consent 
1.3.1 
Informed Consent Form for Study Participation 
Before or at Screening, the Investigator or designee will ensure that each subject is given 
full and adequate oral and written information about the nature, purpose, possible risks and 
benefits of the study, and the Investigator or the designee will answer all questions the 
subject might have to his/her full satisfaction. The subject will have sufficient time for 
consideration of his/her participation in the study and will be notified that he/she is free to 
discontinue his/her participation at any time.  
Once the subject has received all the necessary information, and if he/she agrees to 
participate, this will be documented in the ICF by the date and signature of both the subject 
and the Investigator or designee 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) may be performed with the collected data at a later 
time. Any additional analysis performed will be covered by data confidentiality, as for the 
main analysis described in this protocol. 
1.3.2 
Amendment to the Informed Consent Form 
If a protocol amendment is required, or if any new information regarding the risk profile of 
the investigational product (IP) becomes available for any other reason deemed necessary, 
an amendment to the ICF may be required. If a revision of the ICF is necessary, the 
Investigator(s) or designee will, with the support of the Sponsor, ensure that the documents 

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have been reviewed and approved by a responsible IEC/IRB before subjects are required 
to re-sign the ICF (including date and time). If new and important safety information is 
received, subjects who already completed or have been discontinued from the study will be 
informed by letters, emails or phone calls. 
1.4 
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation, 
and documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator and designee abide by the principles of the ICH GCP 
Guideline [1]. These guidelines apply specifically to pharmaceutical development, but 
nevertheless provide a robust and ethical framework for conducting a clinical study with 
products such as Nicotine pouch 1.0. The study will also be conducted in accordance with 
the general ethical principles outlined in the Declaration of Helsinki [2]. 
In addition, the Investigator or designee will carry out the clinical study in accordance with 
applicable national and local laws of the pertinent regulatory authorities. 

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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 
[3]. There is no safe cigarette, and the best way for smokers to reduce the adverse health 
consequences of smoking is to quit. Despite the risks which are attributable to smoking, 
some smokers decide to continue smoking. The development of novel tobacco and nicotine 
containing products with the potential to be less harmful than cigarettes represents an 
approach to reduce cigarette-related deaths and diseases among smokers who would have 
otherwise continued smoking [4]. Philip Morris Products S.A. (PMP S.A.) is developing 
such alternative products that have the potential to reduce individual risk and population 
harm in comparison to smoking cigarettes. These products aim to substantially reduce or 
eliminate the exposure to harmful and potentially harmful constituents (HPHCs) generated 
from cigarette smoke, with the exception of nicotine, while providing an acceptable 
substitute for cigarettes.  
The Tobacco Advisory Group of the Royal College of Physicians (RCP) suggested in 2007 
that “if nicotine could be provided in a form that is acceptable and effective as a cigarette 
substitute, millions of lives could be saved” [5]. In a report published in 2016 [5], the 
Tobacco Advisory Group of the RCP propounded further that “if nicotine could be 
delivered effectively and acceptably to smokers without smoke, most if not all of the harm 
of smoking could probably be avoided”. Tobacco health advocates and regulators are 
increasingly embracing this concept [6-10].  
PMP S.A. is developing a portfolio of smoke-free, nicotine-containing, products that 
replicate the sensorial and taste attributes of cigarettes as much as possible, while delivering 
nicotine in a manner that is significantly less harmful than cigarette smoke. As part of this 
portfolio, PMP S.A. has developed nicotine pouches.  
Nicotine Pouch 1.0 (NP 1.0) is a nicotine-containing, tobacco-free, oral product. NP 1.0 is 
pre-portioned and intended for uptake of the nicotine via the oral mucosa. In addition to 
nicotine, NP 1.0 contains among other ingredients flavorings, sweeteners, and pH buffering 
agents. The ingredients are 
 enclosed in a pouch. The 
nicotine is of pharmaceutical grade, all other powder ingredients are of food grade and the 
pouch material (fleece) is of food contact grade. NP 1.0 is placed between the lip and the 
gums. Nicotine transfers through the gum epithelium. The nicotine and flavors are released 
during a product use period of 20-40 mins. Product use ends by removing the pouch from 
the mouth. The used nicotine pouch can be discarded. 

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2.1.2 
Description of the Product and Scientific Findings 
Tobacco-free nicotine pouches (NP) are similar in appearance to an established form of 
smokeless tobacco product commonly used in Scandinavia called ‘snus’. Swedish-style 
snus is a type of pouched smokeless tobacco that does not produce excessive salivation. 
Like Swedish snus, NP are placed between the upper lip and gum but differ in that there is 
no leaf tobacco in them [11]. The user inserts the pouch NP between the upper lip and gum, 
leaves it there while the nicotine and flavor are released typically during a period of 20-40 
mins. NP 1.0 is similar in appearance and use to Swedish-style snus, another oral smokeless 
tobacco product traditionally used in Sweden since the 1800s. NP 1.0 is manufactured 
without tobacco and therefore TSNAs may further reduce the risk to consumers compared 
to the use of Swedish snus. 
NP were introduced for marketing in 2016 in the United States (US), 2017 in Scandinavia 
and 2018 in the United Kingdom (UK) [12]. 
The NP 1.0 is designed to deliver nicotine orally, through oro-mucosal absorption at the 
gums of the user. It has the following main components:  
• 
A wet nicotine containing powder 
• 
A pouch containing 560mg of powder 
• 
A plastic can containing 20 to 24 bags. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For details on composition of NP 1.0 see Investigator’s Brochure. 
Weight of the 
 powder in each NP 1.0 pouch is approximately 560 mg 
per NP. All 
 powder ingredients are food grade. 
NP 1.0 has not been tested in humans or marketed yet. Various other products with similar 
compositions are currently marketed, e.g.  Velo® Ice Cool, Zyn® Cool Mint Mini Dry. 
Nicotine pouches were first described in clinical studies as a new formulation for nicotine 
replacement treatment [13]. 
Various factors affect the absorption of nicotine from NP, including pH levels, nicotine 
content, and duration of product use. Other factors such as pouch surface area, saliva 
penetration, and product use characteristics are also relevant while flavor has been 
described not to influence the nicotine uptake [14]. While a direct correlation is suggested 
between the duration of product use and nicotine absorption, a correlation between the 
amount of nicotine per pouch did not correlate directly with the amount of nicotine 
absorbed [15].  

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Nicotine extraction from various NP has been described to range between approximately 
45% to 60% [16, 17]. NP usually have a longer time to reach maximum nicotine 
concentration (Tmax) and a lower maximum nicotine concentration (Cmax) and lower 
positive subjective effects compared to subjects’ own cigarettes [14]. Thus,   it is likely that 
NP results in lower reinforcing effects and abuse potential than cigarettes. Lower abuse 
potential than cigarettes with comparable extent of nicotine delivery. 
2.2 
Purpose of the Study 
The purpose of the study is to evaluate the nicotine pharmacokinetics (PK) profiles of 4 
variants of NP 1.0 versus Velo-NP and Zyn-NP following a 30-minute use period. In 
addition, pharmacodynamic effects (PD), including subjective effects and related 
behavioral assessments will be evaluated, to provide further insights on NP 1.0 product 
acceptance and abuse liability. Safety will be assessed throughout the study. 
The aim is to evaluate if NP 1.0 can provide an acceptable alternative to smoking cigarettes 
in terms of both, nicotine delivery and sensorial satisfaction for smokers who would 
otherwise continue smoking cigarettes. 
2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
Information on health risks associated with smoking and smoking cessation advice will be 
provided. Subjects who are motivated to quit smoking or using other nicotine/tobacco-
containing products during the study will be given the opportunity to continue their 
smoking cessation attempt and will be referred to appropriate stop smoking services for 
continuing support and counselling at a higher level. Subjects who participate in this study 
will also benefit from repeated and detailed health check-ups. 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures 
The risk of scheduled procedures in the present study (e.g., blood samples) are deemed to 
be on par with procedures routinely performed during normal or extended health 
examinations by the subject’s healthcare professional. The total volume of blood to be 
drawn is approximately 340 mL and does not exceed the levels for a standard blood 
donation. The risks related to blood sampling include for example: excessive bleeding, 
fainting, hematoma, paresthesia or infection, and those related to the total amount of blood 
taken over a period of time such as weakness, dizziness or anemia. 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product  
By product design, NP 1.0 variants are free from the majority of HPHCs associated with 
heating or burning tobacco, except nicotine. 

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Due to sensorial and technological differences between NP 1.0 versus cigarettes and the 
confinement setting, subjects may modify their nicotine uptake.  
An adult smoker using NP 1.0 may experience: 
• Transient nicotine withdrawal symptoms (e.g., urge to smoke, irritability, anxiety 
feelings, restlessness, and difficulty to concentrate) similar to cravings observed 
during smoking cessation 
• Transient symptoms suggesting mild nicotine overdose such as stimulatory effects 
on sympathetic tone (increased blood pressure, increased heart rate), central 
nervous system (tremor, blunting of emotions, and decreased ability to concentrate), 
gastric acid secretion, and vomiting.  
Support during periods of abstinence from any tobacco and nicotine containing products 
will be provided. 
Further risk mitigation will include:  
• Using commonly accepted research and scientific standards (e.g., blood samples 
not to exceed blood donation standards) 
• Medical supervision of all study subjects with follow-up of those who have 
experienced AEs/serious adverse events (SAEs)  
2.3.4 
Unforeseeable Risks 
The possibility of unforeseeable events/risks will be explained in detail to study subjects. 
Unexpected product events may lead to unforeseeable risk. Risk mitigation strategies will 
include close monitoring and medical supervision to detect any unforeseeable risk or safety 
signals at the earliest time possible. 

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3 
STUDY OBJECTIVES 
3.1 
Exploratory Objective and Endpoints 
1. To describe the plasma concentration-time profile of nicotine and derived 
pharmacokinetic (PK) parameters of 4 variants of Nicotine pouch 1.0 nicotine pouches 
compared to Velo-NP and Zyn-NP in healthy smokers from a 30 minutes product use 
period. 
Endpoints (Day 1 to Day 3) 
• Background-corrected maximum plasma concentration [Cmax] 
• Background-corrected time to the maximum concentration [Tmax] 
• Area under the background-corrected concentration-time curve (AUC) from start of 
product use (T0), to all subsequent timepoints and extrapolated to infinity [AUC0-
5min, AUC0-10min, AUC0-15min, AUC0-20min, AUC0-25min, AUC0-30min, 
AUC0-35min, AUC0-40min, AUC0-1h, AUC0-3h, AUC0-6h, AUC0-infinity] 
2. To describe pharmacodynamic (PD) effects (subjective effects and related behavioral 
assessments) of 4 variants of Nicotine pouch 1.0 compared to Velo-NP and Zyn-NP in 
healthy smokers from a 30 minutes product use period. 
Endpoints (Day 1 to Day 3) 
• Score of cigarette craving by the visual analog sale (VAS)-craving assessment 
[VAS-C-15min, VAS-C5min, VAS-C10min, VAS-C15min, VAS-C20min, VAS-C25min, 
VAS-C30min, VAS-C35min, VAS-C40min, VAS-C1h, VAS-C3h, VAS-C6h] 
• Score of in the moment product liking by the VAS-liking (in the moment) 
assessment [VAS-L5min, VAS-L10min, VAS-L15min, VAS-L20min, VAS-L25min, VAS-
L30min, VAS-L35min, VAS-L40min, VAS-L1h, VAS-L3h] 
• Score of overall product liking by the VAS-liking (overall) assessment  
• Score of product satisfaction by the VAS- satisfaction assessment [VAS-S5min, 
VAS-S10min, VAS-S15min, VAS-S20min, VAS-S25min, VAS-S30min, VAS-S35min, VAS-
S40min, VAS-S1h, VAS-S3h, VAS-S6h] 
• Score of product intention to use again by the VAS-intention to use again 
assessment [VAS-ITU30min, VAS-ITU3h] 
• Subscale scores from the Product Evaluation Scale (PES) 
• Scores from items of the Sensory questionnaire  

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3. To evaluate the safety and tolerability during the study 
Endpoints (from Enrollment to EOS): 
• Incidence of adverse events (AEs) and serious adverse events (SAEs)  
• Incidence of product events  
• Changes in electrocardiogram (ECG) from baseline (heart rate, PR, QRS, QT, 
QTcF interval) 
• Changes in vital signs from baseline (systolic and diastolic blood pressure, pulse 
rate and respiratory rate) 
• Concomitant medication 
• Changes from baseline in clinical chemistry, hematology, and urine analysis safety 
panel 
4. To describe the associations between PK and PD parameters. 
Endpoints (Day 1 to Day 3): 
• Between the score of “in the moment” product liking by the VAS-liking assessment 
averaged over the product use period (from T1 to T6) and during the sequence 
period (T1 to T9) and Cmax, Tmax, and AUC0-infinity PK endpoints 
• Between the average score of “in the moment” product satisfaction by the VAS-
product satisfaction assessment during the sequence’s period (from T1 to T11) and 
Cmax, Tmax, and AUC0-infinity PK endpoints 
• Between the score of “in the moment” craving by the VAS-craving assessment 
averaged during the sequence’s period (from T1 to T11) and Cmax, Tmax, and AUC0-
infinity PK endpoints 
• Between the subscale scores of Product Evaluation Scale and AUC0-infinity PK 
endpoint 
• Between the item scores of the Sensory questionnaire and AUC0-infinity PK 
endpoint 
5. To describe the extent of nicotine extracted during product use from 4 variants of 
Nicotine pouch 1, Velo-NP and Zyn-NP. Reporting of this objective will be separate 
from the main Clinical Study Report. 
Endpoint (Day 1 to Day 3) 
Estimated amount of nicotine extracted derived from analysis of nicotine after use. 
 

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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a single-center, randomized, controlled, open-label, cross-over study in healthy 
subjects to investigate the nicotine pharmacokinetic profiles of four variants of Nicotine 
pouch 1.0, compared to Velo-NP and Zyn-NP. In addition, PD effects (subjective effects 
and related behavioral assessments) will be evaluated to provide further insights on 
Nicotine pouch 1.0 product acceptance and abuse liability. The study will be conducted 
with 3 periods and in a 6 sequence-cross-over design.  
A Screening Visit will be conducted within 21 days (Day -22 to Day -2) prior to Admission 
(Day -1) to the investigational site (Figure 2). 
A sufficient number of subjects will be screened to ensure that 24 subjects will be 
randomized into the study with at least 25% of each sex. 
 
Figure 2 
Study Design 

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Qualified subjects will return to the investigational site for Day -1. Subjects should have 
fasted for at least 10 hours prior to the safety laboratory assessments. After confirmation of 
eligibility, subjects will be enrolled. All subjects that are not enrolled will be considered as 
screen failures. 
On Day -1, enrolled subjects will perform a product test using NP-1 for 30 minutes (± 1 
minute). After the product test, subjects not willing and/or not ready to use Nicotine pouch 
1.0 during the study will be discontinued from the study, will enter the 3-day Safety follow-
up period and will be replaced.  
Subjects willing and ready to use 4 variants of Nicotine pouch 1.0, Velo-NP and Zyn-NP 
during the study after product test will start their confinement period of 3 days.  
24 subjects will be randomized to 1 of 6 possible sequences of product use on Day 1 to Day 
3 with at least 25% of each sex. 
On Day 1 to Day 3, after at least 8 hours of abstinence from any nicotine/tobacco containing 
products (nicotine wash-out), subjects will use one variant of Nicotine pouch 1.0, Velo-NP 
or Zyn-NP according to randomized product use sequence for 30 minutes (± 1 minute). The 
used nicotine pouches will be collected for long-term storage to determine the residual 
nicotine after product use to estimate the amount of nicotine delivered during the 30 
minutes use period.  
Subjects will complete questionnaires about product evaluation, craving and liking 
assessments.  
The start of product use of the 30-minute use period will be defined as T0. T0 in the morning 
(T0M) and in the afternoon (T0A) on Day 1 to Day 3 should be at approximately at the same 
time, within a window of ± 30 minutes. Venous blood samples will be obtained according 
to the standard operating procedures (SOPs) at the investigational site.  
In the morning on Day 1, 12 blood samples will be collected for determination of nicotine 
concentration at the following time points in relation to T0 with a time window as indicated 
in brackets: 
Morning prior to T0M, and afternoon prior to T0A : 
• T-1: 5 minutes (± 1 minute)  
After T0M or after T0A : 
• T1 after 5 minutes (± 1 minute) 
• T2 after 10 minutes (± 1 minute) 
• T3 after 15 minutes (± 1 minute) 
• T4 after 20 minutes (± 1 minute) 

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• T5 after 25 minutes (± 1 minute) 
• T6 after 30 minutes (± 1 minute) 
• T7 after 35 minutes (± 1 minute) 
• T8 after 40 minutes (± 1 minute) 
• T9 after 1 hour (± 5 minutes) 
• T10 after 3 hours (± 5 minutes) 
• T11 after 6 hours (± 5 minutes) 
For each product use, subjective effects of liking, craving, satisfaction, and intention to use 
again will be assessed using a VAS (100 mm going from “strong disliking” to “strong 
liking” for VAS  liking (in the moment), and VAS liking (overall), from “no craving” to 
“strong craving” for VAS craving, from “not at all” to “extremely” for VAS satisfaction, 
and from “very unlikely” to “very likely” for VAS intention to use again) at the following 
time points in relation to T0 with a time window as indicated in brackets: 
Prior to T0M and T0A (for VAS craving only) 
• T-15: within 15 minutes prior to T0  
After T0M and T0A: (for VAS craving, VAS liking “in the moment”, and VAS 
satisfaction “in the moment” assessments) 
• T1 after 5 minutes (± 1 minute) 
• T2 after 10 minutes (± 1 minute) 
• T3 after 15 minutes (± 1 minute) 
• T4 after 20 minutes (± 1 minute) 
• T5 after 25 minutes (± 1 minute) 
• T6 after 30 minutes (± 1 minute) 
• T7 after 35 minutes (± 1 minute) 
• T8 after 40 minutes (± 1 minute) 
• T9 after 1 hour (± 5 minutes) 
• T10 after 3 hours (± 5 minutes) (VAS craving and VAS satisfaction only) 
• T11 after 6 hours (± 5 minutes) (VAS craving and VAS satisfaction only) 
After T0M and T0A: (for VAS liking (overall) assessment) 
• T10 after 3 hours (± 5 minutes) 

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After T0M and T0A: (for VAS intention-to-use-again) 
• T6 after 30 minutes (± 1 minute) 
• T10 after 3 hours (± 5 minutes) 
Additional subjective effects will be assessed in the morning and in the afternoon on Day 
1 to Day 3 by the Product Evaluation Scale (PES) and the Sensory questionnaire 
administered at T9 1 hour (± 5 minutes) after T0M and T0A. 
Additional blood samples will be taken for determination of the nicotine concentration to 
evaluate terminal elimination half-life (t1/2z) in relation to T0A on Day 2 at the following 
time points with a time window as indicated in brackets:  
• T1z after 8 hours (± 5 minutes) after T0A  
• T2z after 12 hours (± 5 minutes) after T0A 
After discharge at Day 3, the subjects will enter a 3-day Safety follow-up period during 
which AE/SAEs associated with IP use reported by the subjects will be collected and the 
follow-up of the ongoing AEs/SAEs will be conducted by the study investigational site 
(section 8.2.6). 
Subjects who will be discontinued from the study before enrolment will be replaced. After 
enrollment but before randomization, subjects who will be discontinued from the study will 
enter the 3-day Safety follow-up period and will be replaced. However, subjects that are 
discontinued after randomization will not be replaced. 
4.2 
Rationale for Study Design  
The minimum age of 21 years old in the inclusion criteria was selected based on the legal 
age of smoking in the United Kingdom of 18 years; and to account for the 3 years of 
smoking history. 
The goal of this study is to evaluate the nicotine absorption profiles and related PK 
parameters from four variants of NP 1.0 compared to Velo-NP and Zyn-NP. 
The 30 minutes use allow appropriate comparisons between different NP products [14]. 
The collection of PD data will also allow to explore effects of product liking on PK 
parameters.  
Sampling time points for determination of nicotine concentrations were selected to ensure 
reliable estimation of PK parameters. In particular, frequent sampling between 20 to 50 
minutes after T0 will be performed in order to reliably assess Tmax, which is expected to be 
comparable to what has been described previously e.g., for Zyn NP [14, 18].  
The PK of plasma nicotine presents a biphasic profile, with a typical rapid initial disposition 
half-life (t1/2α) of 1.35 hours, followed by a slower terminal elimination half-life (t1/2z) of 
17 hours [19]. To ensure a complete nicotine washout between each product use, 3 days 
without product use would have been required (~ 5 x terminal elimination t1/2z). Based on 

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nicotine population PK modeling, it was estimated that nicotine enters in the terminal 
elimination phase with concentrations decreasing with a terminal elimination rate constant 
(λz) 8 to 10 hours post administration. As a consequence, a minimum of 8 hours of nicotine 
abstinence has been established in this study prior to T0 on Day 1 to Day 3. In order to 
estimate the λz three valid data points are needed to fit a regression line including estimation 
of error. The last data point is potentially not estimable (below LOD). Then four data points 
are likely required to estimate λz. Background-concentration correction will be applied to 
adjust for carry-over effects with adjustment of baseline values to the estimated t1/2z (or λz) 
which will be derived from additional blood sampling on Day 2 and Day 3 for each subject.  
The use of estrogen contraceptive is known to accelerate nicotine clearance by 20% to 30% 
compared to women who do not take estrogen contraceptive [20]. Therefore, for the 
purpose of this study, use of hormonal contraception containing estrogens is prohibited. 
This also applies to hormone replacement therapy.  
The activity of CYP2A6 will be measured as this enzyme drives the metabolism of nicotine 
into cotinine and subsequent metabolites. CYP2A6 activity 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 [21]. 
4.3 
Appropriateness of Measurements 
All laboratory measures utilized for this study are validated and are appropriate for the 
study assessments. FTND [22, 23] and Product evaluation scale (PES) [24, 25] used in this 
study are validated and previously published or adapted versions of validated 
questionnaires.  
Cigarette craving will be assessed using a one-item self-reported craving VAS [26], asking 
subjects to rate craving for cigarettes (How strong is your craving for cigarettes?), on a 100 
mm unipolar scale, ranging from 0 (no craving) to 100 (strong craving). Liking will be 
assessed using a one-item self-reported liking VAS, asking subjects to rate liking for 
product (At this moment, my liking for this product is:) on a 100 mm bipolar scale, ranging 
from 0 (strong disliking) to 100 (strong liking), with a neutral middle point, as 
recommended in the FDA guidance for industry on abuse liability assessment [27]. 
Similarly, overall liking will be assessed using a one-item self-reported liking VAS 
(Overall, my liking for this product is:) on a 100 mm bipolar scale, ranging from 0 (strong 
disliking) to 100 (strong liking), with a neutral middle point. Satisfaction will be assessed 
using a one item self-reported satisfaction VAS, asking subjects to rate product satisfaction 
(Is the product ‘satisfying’ right now?) on a 100 mm unipolar scale, ranging from 0 (not at 
all) to 100 (extremely), as recommended by Vansickel [28] to meet current regulatory 
recommendations in human abuse liability of tobacco and nicotine products. 

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4.4 
Study Duration 
The entire study per subject will between 8 and 27 days. This will include a screening 
period of up to 21 days prior to Admission (Day -22 to Day -2), 3 days of confinement after 
enrollment on Day -1 to discharge on Day 3, (3 overnight stays), and a 3-day Safety follow-
up period (from time of Discharge at Day 4 to Day 6). The end of the study (EOS) for a 
subject is defined as the end of the Safety follow-up period. The end of the whole study 
corresponds to the individual EOS of the last subject. 

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5 
STUDY POPULATION 
Twenty four healthy  smoking subjects will be randomized to 1 of 6 possible sequences of 
product use on Day 1 to Day 3 with at least 25% of each sex.  
5.1 
Selection of Study Population 
5.1.1 
Inclusion Criteria 
Subjects who meet all the following inclusion criteria can be enrolled into the study: 
Inclusion Criteria 
Screening  
Admission 
(Day -1) 
1. Subject has signed the ICF and is able to 
understand the information provided in the ICF. 
X 
 
2. Smoking male or female aged between 21 and 65 
years inclusive. 
X 
 
3. Subject has smoked continuously for at least the 
last 3 years prior to the Screening visit. 
X 
 
4. Subject has smoked ≥ 10 commercially available 
cigarettes per day for 4 weeks prior to Screening 
Visit and Admission. Smoking status will be 
verified based on a urinary cotinine test (cotinine 
≥ 500 ng/mL). 
X 
X 
5. Subject does not plan to quit using tobacco and/or 
nicotine products within the next 3 months. 
X 
X 
6. Smoking, healthy subject as judged by the 
Investigator or designee based on available 
assessments from the Screening period (e.g., 
safety laboratory, spirometry, vital signs, physical 
examination, ECG, and medical history). 
X 
 
5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the 
study: 

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Exclusion Criteria 
Screening  
Admission 
(Day -3) 
1. As per the Investigator’s judgment, the subject 
cannot participate in the study for any reason other 
than medical (e.g., psychological, social reason). 
X 
 
2. Subject is legally incompetent, or physically or 
mentally incapable of giving consent (e.g., 
emergency 
situation, 
under 
guardianship, 
prisoners). 
X 
 
3. Subject has a clinically relevant disease which 
requires medication (including but not limited to 
gastrointestinal, renal, hepatic, neurological, 
hematological, endocrine, oncological, urological, 
immunological, pulmonary, and cardiovascular 
disease) or any other medical condition (including 
safety laboratory), which as per the judgment of 
the Investigator would jeopardize the safety of the 
subject. 
X 
 
4. 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. 
X 
 
5. Subject has donated or received whole blood or 
blood products within 30 days prior to Screening 
Visit. 
X 
 
6. BMI < 18.5 kg/m2 or > 32.0 kg/m2. 
X 
 
7. Subject has received medication within 14 days or 
within 5 half-lives of the drug prior to Admission 
(whichever is longer), which has an impact on 
CYP2A6 activity  
 
X 
8. Subject has a positive serology test for HIV 1/2, 
Hepatitis B or Hepatitis C. 
X 
 
9. Subject has a history of alcohol abuse, which as 
per the judgment of the Investigator could 
interfere with the subject’s participation in study. 
X 
 

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Exclusion Criteria 
Screening  
Admission 
(Day -3) 
10. Subject has a positive urine drug including alcohol 
test. 
X 
X 
11. Subject or one of their family membersa is a 
current or former employee of the tobacco 
industry. 
X 
 
12. Subject or one of their family membersa is 
employee of the investigational site or of any other 
contracted vendors involved in the study. 
X 
 
13. Subject has participated in another clinical study 
within 30 days prior to the Screening Visit. 
X 
 
14. Subject has been previously screened or enrolled 
in this study. 
X 
 
15. For women only: subject is pregnant (does not 
have negative pregnancy test at Screening Visit 
and at Admission) or is breastfeeding. 
X 
X 
16. For women of childbearing potential onlyb: 
subject does not agree to use an acceptable method 
of effective contraception c. 
X 
X 
17. Use 
of 
estrogen-containing 
hormonal 
contraception or hormone replacement therapy. 
X 
X 
a. 
As defined by FDA guidance on Human Subject Protection (21 CFR 50.3(l), (m), 50.24(a)(6), 
(a)(7)(v), b)): "Family member” means among other things “parent”, “spouse”, "brothers, sisters, and 
spouses of brothers and sisters" and “any individual related by affinity…whose close association with 
the subject is equivalent of a family relationship” 
b. 
Women who are not of childbearing potential meet at least one of the following criteria:  
• 
Have undergone hysterectomy or bilateral tubal ligation,  
• 
Have primary ovarian insufficiency, or  
• 
Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 
consecutive months with no alternative pathological or physiological cause). 
c. 
Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) 
with spermicidal foam/gel/film/suppository, hormonal contraception without estrogens, vasectomized 
partner(s), or true abstinence (periodic abstinence and withdrawal are not effective methods) from 
Screening until the end of the Safety follow-up period. 

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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) and subjects who are discontinued from the study by the decision of the 
Investigator. A subject can only be discontinued from the study after enrollment.  Reason 
for discontinuation or withdrawal should be documented.  
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.  
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 or withdraw from the study, all early termination procedures 
(section 9.7) will be performed unless the subject refuses to perform the assessments or the 
procedures have already been performed during the study day. This information will be 
fully documented by the Investigator.  
Subjects must be discontinued from the study for any of the following reasons:  
• Withdrawal of informed consent. 
• Any AE/SAE or condition (including clinically significant changes in a laboratory 
parameter), which at the discretion of the Investigator is not compatible with the 
subject’s continued participation in this study. 
• Positive pregnancy test (section 8.5). 
• If the Sponsor decides to prematurely terminate the study, the subject will be 
promptly informed by the Investigator. The Investigator should report the fact and 
the reason in writing to the IEC. 
• Discontinuation is considered to be in the best interest of the subject, or the other 
subjects as judged by the Investigator, e.g. SARS-CoV-2 positive. 
• Subject is not willing and/or ready to use NP 1.0 after the product test at Admission 
(Day -1).  
• Subject uses any tobacco or nicotine containing product different from the assigned 
product during confinement. 
Subjects may be discontinued from the study for the following reasons:  
• Non-compliance to the study procedures based on the judgment of the Investigator. 
• A sufficient number of subjects are already randomized to the study sequences. In 
this case, additional subjects (alternates) will be discontinued prior to 
randomization.  

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• Violations of eligibility criteria have been determined (section 5.4). 
Subjects who will be discontinued from the study before enrolment will be replaced. After 
enrollment but before randomization, subjects who will be discontinued from the study will 
enter the 3-day Safety follow-up period and will be replaced. In general, subjects that are 
discontinued after randomization will not be replaced. Should there be the need to 
discontinue all subjects from one cohort, e.g. all subjects contracted a disease pathogen, 
subjects for a replacement cohort may be enrolled and randomized. 
5.3 
Lost to Follow-up 
A reasonable attempt will be made to contact all participants needing to complete or resolve 
post-study activities (e.g., safety laboratory, physical examination, on-going AEs). 
Two contacts will be made via contact information provided by the subject (e.g., telephone 
number, cell phone number, email address), allowing 1 day between attempts for response. 
The first contact attempt should take place within approximately 1-2 days of the 
participant’s last visit to the investigational site. If contact is not possible, a follow-up letter 
will be sent to the participant, allowing approximately 5 business days from the time of 
delivery for a response. A progress note will be added in the data collection system for 
documentation. After a letter is sent, there should be no additional phone calls unless the 
participant has attempted to contact the investigational site and a return call attempt is 
made. If post-study follow-up has not been resolved within approximately 5 business days 
following delivery confirmation or the letter is not deliverable, the participant is considered 
lost to follow-up. This is documented in the progress note and outstanding AEs are updated. 
The date of lost to follow-up corresponds to the date of the end of study of the subject.  
The Investigator or designee(s) will declare the subject lost to follow-up if the 
investigational site lost contact to the subject and the subject has reached the maximum 
number of study days (27 days). 
5.4 
Violation of Selection Criteria 
Detected violations of eligibility criteria post enrollment may require subjects to be 
discontinued from the study based on a case-by-case decision of the Investigator. 

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6 
INVESTIGATIONAL PRODUCTS 
6.1 
Description of Investigational Products 
NP 1.0, Velo-NP and Zyn-NP will be provided by the Sponsor.  
The distribution and return of investigational products will be controlled by qualified and 
appropriately trained investigational site staff. 
6.1.1 
Test Product 
Name 
Nicotine per 
pouch 
pH 
Moisture 
Flavor  
NP-1 
8.4 mg  
8.0 
30 
Cool mint 
NP-2 
8.4 mg  
9.0 
30 
Cool mint 
NP-3 
3.6 mg  
8.0 
15 
Cool mint 
NP-4 
3.6 mg  
8.0 
30 
Cool mint 
6.1.2 
Comparator Product 
Name 
Nicotine per 
pouch 
Flavor 
Velo-NP 
10 mg  
Cool mint 
Zyn-NP 
3 mg  
Cool mint 
6.1.3 
Packaging and Labeling 
NP 1.0 will be provided in sealed cans labelled with the required information including, 
but not limited to, product code and expiry date. 
Velo-NP and Zyn-NP are marketed products, packaged and labelled according to 
manufacturer specifications. 
6.2 
Use of Investigational Product(s) 
Subjects will not be forced to smoke cigarettes or use NP 1.0, Velo-NP and Zyn-NP and 
will be free to stop NP use at any time of the study.  

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During the screening period, subjects will be allowed to smoke and use tobacco/nicotine-
containing products according to their product use habits except during the procedures of 
the Screening Visit (section 9.1). 
6.2.1 
Admission Day (Day -1)  
After enrollment, subjects will perform a product test with NP-1 for 30 minutes (± 1 
minute). One NP-1 nicotine pouch will be placed between the upper lip and the gum for 30 
minutes and subjects will be instructed not to manipulate the pouch with the tongue or lips. 
After the product test, subjects will be required to abstain from any nicotine/tobacco 
containing product use until the first product use on Day 1. 
6.2.2 
Exposure Period (Day 1 to Day 3)  
After at least 8 hours of abstinence from any nicotine/tobacco containing products (nicotine 
wash-out), subjects will use one NP according to randomized product use sequence for 30 
minutes (± 1 minute) in the morning and in the afternoon. One nicotine pouch will be placed 
between the upper lip and the gum for 30 minutes and subjects will be instructed not to 
manipulate the pouch with the tongue or lips. The same application site should be used for 
all products. 
6.2.3 
Day of Discharge (Day 3) and Safety Follow-up Period  
Post discharge and during the safety follow-up period, subjects will be free to use any 
nicotine/tobacco products according to their usual habits. 
6.2.4 
Stopping Rules for Investigational Product  
For safety purposes, using NP 1.0, Velo-NP or Zyn-NP should be temporarily stopped in 
the event of any signs suggesting nicotine overexposure, e.g., gastrointestinal disturbance 
(nausea, vomiting, diarrhea, stomach or abdominal pain), cold sweats, headache, dizziness 
and breathing problems, or any reasons at the discretion of the Investigator.  
6.3 
Method for Assigning Subjects to Product Sequences 
The method for assigning subjects to product sequence is described in section 12.9.1. 
6.4 
Blinding 
The blinding procedure are described in section 12.9.2. 

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6.5 
Investigational Product Accountability and Adherence 
6.5.1 
Dispensing Investigational Product 
From Day -1 until Day 3, one single NP 1.0, Velo-NP or Zyn-NP will be dispensed by the 
investigational site staff, as per the study design.  
Each dispensing of investigational products (IP) to the subject will be recorded in a log.  
6.5.2 
Storage and Accountability  
NP 1.0, Velo-NP and Zyn-NP will be stored in a secured storage place at the investigational 
site with access limited to the authorized personnel only. The distribution and return of IP 
will be controlled by qualified and appropriately trained investigational site staff. 
6.5.3 
Investigational Product Retention 
Used NP 1.0, Velo-NP and Zyn-NP will be collected for long-term storage to determine 
the residual nicotine after product use to estimate the amount of nicotine delivered during 
the 30 minutes use period. 
Unused NP 1.0, Velo-NP and Zyn-NP will be destroyed or returned to the Sponsor upon 
study completion. 
6.5.4 
Adherence to Investigational and Comparator Products 
Adherence will be ensured by strict distribution and collection of any used and unused NP 
1.0, Velo-NP and Zyn-NP by designated investigational site staff. 
6.6 
Restrictions 
6.6.1 
 Smoking Restrictions 
During the Screening period, subjects will be allowed to use any nicotine/tobacco-
containing products according to their usual habits except during the procedures of the 
Screening Visit (section 9.1). Spirometry assessment at Screening will be performed 1 hour 
after stopping smoking (section 9.1). 
From Admission (Day -1) to Discharge (Day 3) or early termination, use of any 
nicotine/tobacco containing products, except use as per study design of the allocated 
product will not be permitted.  
A nicotine washout period of at least 8 hours should be respected before T0M and T0A of 
NP use at Day 1 to Day 3. 

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6.6.2 
Dietary Restrictions 
A standard diet will be designed for the whole confinement period. For each meal, the 
caloric and fat content should be controlled to avoid a “high-fat” diet. The FDA guidance 
on food-effect studies for bioequivalence testing identifies a “high-fat” diet as a diet which 
contains “approximately 50 percent of total caloric content of the meal [from fat] and is 
high in calories (approximately 800 to 1000 calories)” [29]. 
Subjects are not allowed to bring their own food or beverages to the investigational site. 
Meals will be served as described in section 8.1. Additional light snacks, fruits, and raw 
vegetables can be distributed to the subjects without restrictions at any time during 
confinement (except during product use periods) if they comply with the standard diet. 
Consumption of water is allowed as desired. Consumption of quinine-containing drinks 
(e.g., tonic water) is not allowed. Subjects should refrain from ingesting foods or beverages 
containing grapefruit or Seville-type (sour) oranges and marmalade from 7 days prior to 
Day -1 and throughout the study. The same menu and meal schedule will be administered 
uniformly for all subjects. Subjects should have fasted (black coffee or tea without sugar is 
possible) for at least 10 hours prior to safety laboratory assessments at Day -1 and on Day 
3. 
Subjects should refrain from strenuous and/or unaccustomed exercise throughout the entire 
course of the study. 
6.7 
Concomitant Medication 
All medication taken within 4 weeks prior to the ICF signature will be considered prior 
medication. All medication taken from Screening Visit to end of the Safety follow-up 
period will be considered concomitant medication.  
Only progesterone-containing hormonal contraception will be allowed. Hormonal 
contraception containing estrogens or hormone replacement therapy will be prohibited and 
subjects will be excluded based on eligibility criteria. 
Any medication with an impact on the CYP2A6 metabolism [30] (used as prescription and 
over-the-counter products), including, but not limited to medications listed in Table 1, 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) and should not 
be used during the entire study until the time of Discharge or early termination. Prior to 
database lock, concomitant medication will be reviewed for their potential impact on 
CYP2A6 activity and the study results. 

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Table 1 
Concomitant Medication 
Inhibitors  
Drug Class 
Amiodarone 
Antiarrhythmic agent, Class III 
Desipramine 
Antidepressant 
Isoniazid 
Anti-bacterial drug  
Ketoconazole 
Anti-fungal medication  
Letrozole 
Anti-estrogen drug 
Methoxsalen 
Systemic psoralens  
Miconazole 
Anti-fungal medication  
Tranylcypromine 
Antidepressant 
Inducers  
Drug Class 
Amobarbital 
Barbiturate 
Pentobarbital 
Barbiturates 
Phenobarbital 
Barbiturates/anticonvulsants 
Rifampin 
Antimycobacterials 
Secobarbital 
Barbiturates 
Substrates  
Drug Class 
Dexmedetomidine 
α2-Adrenoceptor, sedative 
Ifosfamide 
Anti-cancer, alkylating agents 
Use of over-the-counter medication will be restricted from Admission (Day -1) to 
Discharge or early termination, although exceptions may be made on a case-by-case basis 
at the discretion of the Investigator. 
Use of any other concomitant medication will be evaluated on a case-by-case basis by the 
Investigator. Any concomitant medication used will be fully documented (section 7.4.2). 

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7 
STUDY PROCEDURES 
Investigational site staff performing or recording study assessments must have the 
appropriate and fully documented training. An overview of study assessments and time 
points is shown in the schedule of events (Appendix A). Appropriate medical advice will 
be provided to the subject in case of any medical findings requiring health care. Site 
personnel will adhere to the site’s standard operating procedures (SOPs) for study related 
procedures. Timing of the different assessments are described in the schedule of events 
(Appendix A). 
7.1 
Informed Consent 
Subjects will be asked to provide their written consent to participate in the study (section 
1.3). Study assessments must only start after the time of ICF signature by the subject. 
7.2 
Information on the Risk of Smoking and Smoking Cessation 
Advice and Debriefing on Nicotine pouch 1.0  
Subjects will receive 1) information on the risks of smoking, 2) smoking cessation advice, 
and 3) debriefing on NP 1.0.  
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 [31]. The goal of the 
debriefing is to help ensure that subjects have an accurate understanding of NP 1.0 use 
risks.  
Details of the sessions will be recorded in the source document file. This information will 
be given to the subjects on an individual basis during a face-to-face meeting between the 
subject and the Investigator or designee or may be given in a group session. 
7.3 
Support during Abstinence from any Tobacco and Nicotine 
Containing Products  
Subjects will be offered support during periods of abstinence from any nicotine/tobacco 
containing products during the study by the Investigator and/or investigational site staff. 
Support resources will include counselling and assistance, entertainment, monitoring of the 
subject’s behavior, AEs. 
7.4 
Clinical Assessments 
7.4.1 
Demographic Data 
Sex, date of birth, race and ethnicity will be recorded for each subject. 

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7.4.2 
Medical History, Concomitant Disease, Prior and Concomitant 
Medication 
Relevant medical history or any concomitant disease will be documented at the Screening 
Visit. Medical history is defined as any condition that started and ended prior to the ICF 
signature at the Screening Visit. A concomitant disease is defined as any condition that is 
either detected or is still ongoing at the time of ICF signature. The final status of any 
concomitant disease (i.e., stop date or ongoing) should be verified at each visit. 
Prior medication taken within 4 weeks prior to the Screening Visit and any concomitant 
medication will be documented. Any medication started prior to the Screening Visit and 
still being taken by the subject will be considered concomitant medication. Medication 
initiated after the Screening Visit will also be referred to as concomitant medication. The 
definition of concomitant medication applies to both prescribed and over-the-counter 
products.  
Records of medication taken should include the drug name (preferably both generic and 
trade name), route of administration (e.g., oral, intravenous), dose and frequency (expressed 
in metric units, for example, mg, mL, or IU), indication, and the start and, if applicable, the 
stop date (day, month, and year). Therapy changes (including changes of regimen) during 
the study have to be documented. If a concomitant medication is still being taken by the 
subject at the end of the study, this will be recorded in the CRF. 
7.4.3 
Physical Examination 
Physical examinations will include review of general appearance, hair and skin, head, eyes, 
ears, nose and throat, neck, thyroid gland, chest, lungs, back, abdomen, dentition, 
gastrointestinal, cardiovascular, musculoskeletal, and neurological systems. The physical 
examination is to be conducted by the Investigator or designated fully trained representative 
and assessed as normal, abnormal – not clinically significant or abnormal – clinically 
significant and recorded into the clinical database. 
For those results outside of the normal range, the Investigator will determine appropriate 
follow-up including reporting of any AEs. 
7.4.4 
Body Height and Weight and BMI 
Body height and weight will be recorded at the Screening Visit and body-mass-index (BMI) 
will be calculated using the following formula:  
BMI = weight in kilograms
height in meters2
= 𝑘𝑔
𝑚2 
The BMI will be used to assess eligibility for enrollment. 

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7.4.5 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, respiratory rate and pulse rate) will be 
measured prior to T0M. 
All parameters will be recorded in supine position after the subject has rested for at least 5 
minutes. Subjects should have abstained from using any nicotine/tobacco containing 
products for at least 15 minutes prior to the assessment. 
For those results outside of the normal range, the Investigator will determine appropriate 
follow-up including reporting of any AEs. 
7.4.6 
Spirometry 
Spirometry without bronchodilator will be performed at the Screening visit in accordance 
with the 2019 guideline of the American Thoracic Society (ATS)/European Respiratory 
Society (ERS) Joint Task Force on the standardization of spirometry [32, 33]. Spirometry 
predicted values will be standardized to the National Health and Nutrition Examination 
Survey III predicted set [34].  
Assessed parameters will include: FEV1, FEV1 % predicted, FVC, FVC % predicted and 
FEV1/FVC. 
All personnel performing spirometry testing should have the appropriate training and 
quality control measures should be put into place and be properly documented. The testing 
will be performed in sitting position after resting for at least 15 minutes and at least 1 hour 
after smoking cigarettes (Screening Visit). 
Any printouts of Spirometry on thermo-sensitive paper must be photocopied and stapled 
together for inclusion in the source documents. 
7.4.7 
 Electrocardiogram 
A standard 12-lead ECG will be recorded after the subject has rested for at least 10 minutes 
in supine position.  
All ECGs will be reviewed on an ongoing basis by the Investigator or designee. The 
following parameters will be documented: heart rate, PR interval, QRS interval, QT 
interval, and QTc interval corrected according to Fridericia’s formula.  
For those results outside of the normal range, the Investigator will determine appropriate 
follow-up including reporting of any AEs.  
Any printouts of ECGs on thermo-sensitive paper must be photocopied and stapled together 
for inclusion in the source documents 

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7.5 
Biomarker Assessment  
All bioanalytical assays and laboratory assessments will be carried out using validated 
methods. The bioanalytical methods used will be documented in the respective 
bioanalytical plans/reports. A list of laboratories is provided in Appendix B. 
7.5.1 
Biomarkers of Exposure to Nicotine 
Venous blood samples will be collected to evaluate plasma nicotine PK profile and 
determination of terminal elimination half-life.  
The time of collection of each blood sample must be recorded on the CRF. 
7.5.2 
CYP2A6 Activity  
CYP2A6 activity drives the metabolism of nicotine to cotinine and subsequent metabolites.  
One blood sample will be collected for determination of plasma CYP2A6 activity (cotinine 
and trans-3’-hydroxy-cotinine) prior to T0 with NP 1.0. The time of collection of the blood 
sample must be recorded on the. 
7.6 
Laboratory Assessments 
7.6.1 
Clinical Chemistry, Hematology, and Urine Analysis for Safety Panel 
Hematology and clinical chemistry analysis will be assessed. Subjects should have fasted 
for at least 10 hours prior to safety laboratory assessments, except at Screening and early 
termination where non-fasting samples can be used. Tests will be conducted at a local 
laboratory (Appendix B). If during the screening period a blood sample is not suitable for 
analysis (e.g., blood clotting) a re-test should be performed for the specific parameters 
which are not available. Safety urine analysis will be also assessed.  
Parameters to be tested are listed in Table 2. 

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Table 2 
Clinical Laboratory Parameters for Safety Panel 
Hematology 
Clinical Chemistry 
Urine analysis 
• Hematocrit 
• Hemoglobin 
• Mean corpuscular 
hemoglobin 
• Mean corpuscular 
hemoglobin 
 
concentration 
• Mean corpuscular volume 
• Platelet count 
• Red blood cell count 
• White blood (WBC) cell count 
• Differential WBC count: 
- 
Neutrophils 
- 
Basophils 
- 
Eosinophils 
- 
Lymphocytes 
- 
Monocytes 
• 
Albumin 
• 
Total protein 
• 
Alkaline phosphatase 
• 
Alanine aminotransferase 
• 
Aspartate aminotransferase 
• 
Blood urea nitrogen 
• 
Creatinine 
• 
Gamma-glutamyl transferase 
• 
Glucose 
• 
Lactate dehydrogenase 
• 
Potassium 
• 
Sodium 
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Total cholesterol 
• 
Triglycerides 
• 
pH 
• 
Bilirubin 
• 
Glucose 
• 
Nitrite 
• 
Red blood cell traces 
• 
Protein 
• 
Specific gravity 
 
7.6.2 
Serology 
Tests for hepatitis B soluble antigen (HbsAg), hepatitis C virus (HCV antibody) and human 
immunodeficiency virus (anti-HIV1/2) will be performed at the Screening Visit. In case of 
positive results, the subject will be referred to appropriate medical care and the results may 
be reported to heath authorities according to local regulation. 
7.6.3 
Urine Drug Test 
A urine drug screen including testing for alcohol will be performed at the site for screening 
of:  
• amphetamine type substances,  
• barbiturates,  
• benzodiazepines,  
• cannabinoids,  
• cocaine,  
• opiates, and 
• alcohol 

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In case of a positive urine drug test, a re-test will not be allowed in order to evaluate 
eligibility. In case of an inconclusive test, a re-test can be performed but this needs to be 
done immediately after the inconclusive test. 
7.6.4 
Urine Cotinine Test  
A urine cotinine test will be performed to confirm the nicotine/tobacco use status. 
The test must detect cotinine with a threshold of  ≥ 500 ng/mL. In case of a negative cotinine 
test, a re-test will not be allowed in order to evaluate eligibility. In case of an inconclusive 
test, a re-test can be performed but this needs to be done immediately after the inconclusive 
test. 
7.6.5 
Urine Pregnancy Test  
A urine pregnancy test will be performed for all female subjects. Subjects with a positive 
urine pregnancy test or unclear results (from two repetitions) before enrollment will be 
considered as screen failures. In case of any positive pregnancy test, the Investigator or 
designee will inform the subject about the risks associated with smoking during pregnancy 
and subjects will be referred to health care facility/health care provider for pregnancy 
follow-up. 
All pregnancies detected during the study must be reported and handled as described in 
section 8.5. Pregnancies detected after enrollment will lead to discontinuation from the 
study (section 5.2). 
7.7 
Sample Handling, Storage, and Shipment 
Urine drug test including testing for alcohol, urine pregnancy tests and urine cotinine tests 
will be done by the site personnel at the site. All other blood and urine samples will be 
managed by the laboratory designated in Appendix B. 
Detailed procedures for handling of samples are described in the separate sample handling 
manual (SHM). Safety laboratory samples will be destroyed as per laboratory local 
regulations. All other samples will be destroyed post database lock or post finalization of 
the bioanalytical reports, whichever occurs last. The facility/-ies at which the samples are 
stored will be informed in writing by the Sponsor when destruction of the samples shall be 
performed. 
7.7.1 
Blood Samples  
Blood samples will be drawn by qualified and trained site personnel and according to the 
standard operating procedures (SOPs) at the investigational site. 

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Since the test for nicotine concentration is highly sensitive, precautions should be taken 
during blood sampling and processing to prevent the contamination of samples with 
environmental nicotine.  
In total, approximately 340 mL of blood will be collected for this study including samples 
for determination of plasma nicotine concentrations (approximately 296 mL), CYP2A6 
activity (5 mL), and safety laboratory including serology (approximately 37.5 mL). This 
calculation is based on an individual volume of each sample of 4.0 mL for nicotine PK, 5.0 
mL for CYP2A6 analysis, 12.5 mL per safety laboratory assessments, including serology. 
The total volume of blood drawn will not exceed the levels for a standard blood donation.  
Details on the procedures for collection, labeling, handling and shipment of samples are 
described in the SHM/ laboratory manual. 
7.8 
Questionnaires  
The questionnaires will be completed by the subjects. All subject-reported outcomes as 
well as instructions will be provided in the subject’s local language. 
7.8.1 
Fagerström Test for Nicotine Dependence (FTND, Revised Version) 
Level of nicotine dependence will be assessed using the FTND in its revised version [23] 
as updated in 2012 [35]. 
The questionnaire consists of six questions. The scores obtained on the test permit the 
classification of nicotine dependence into three levels: Mild (0 to 3 points); Moderate (4 to 
6 points); Severe (7-10 points) [35]. 
7.8.2 
Nicotine/Tobacco Product Use History 
Subjects will be asked questions about their tobacco-and/or nicotine-containing products 
use history. The questions will capture frequency and quantity of tobacco and/or nicotine-
containing product use over the past 4 weeks, number of continuous years of cigarette 
smoking, and intention to quit using tobacco and/or nicotine products within the next 3 
months. This information will be used as characteristics of the study subjects and to assess 
their eligibility to participate in the study.  
7.8.3 
Product Evaluation Scale (PES) 
Product evaluation will be assessed via a subject self-reported outcome measure, the 
Product Evaluation Scale (PES).  

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This 21 items measure consists of 4 multi-item scales and 3 single-item scales, arising from 
an adaptation of the modified cigarette evaluation questionnaire (mCEQ) [24] to conform 
to rating oral tobacco products [25]. 
The questionnaire assesses the degree to which subjects experience the reinforcing effects 
by measuring: 
• Product satisfaction (satisfying, tastes good, enjoy the product, enjoy the sensations 
in month). 
• Psychological rewards (calms down, more awake, less irritable, helps concentrate, 
reduces hunger). 
• Aversion (dizziness, nausea, too much nicotine, bothersome side effects). 
• Relief (relief craving, relief withdrawal symptoms, relief urge to smoke, enough 
nicotine, craving for a cigarette). 
• Easy to use (single-item assessment). 
• Comfortable using (single-item assessment). 
• Concerned about dependence (single-item assessment). 
Subjects will be asked to assess the items of the questionnaire on a 7-point scale, ranging 
from “not at all” to “extremely”. 
For the purpose of this study, the comfortable using in public single-item was reworded to 
a hypothetical situation, given subjects will not use the product in public in this specific 
study setting. 
7.8.4 
VAS Craving Assessment 
Cigarette craving will be assessed using a one-item self-reported craving VAS [26], asking 
subjects to rate craving for cigarettes (How strong is your craving for cigarettes?), on a 100 
mm unipolar scale, ranging from 0 (no craving) to 100 (strong craving). 
7.8.5 
VAS Liking Assessment 
Liking will be assessed using a one-item self-reported liking VAS, asking subjects to rate 
liking for product (At this moment, my liking for this product is:) on a 100 mm bipolar scale, 
ranging from 0 (strong disliking) to 100 (strong liking), with a neutral middle point, as 
recommended in the FDA guidance for industry on abuse liability assessment [27]. 
Similarly, overall liking will be assessed using a one-item self-reported liking VAS 
(Overall, my liking for this product is:) on a 100 mm bipolar scale, ranging from 0 (strong 
disliking) to 100 (strong liking), with a neutral middle point. 

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7.8.6 
VAS Satisfaction 
Satisfaction will be assessed using a one item self-reported satisfaction VAS, asking 
subjects to rate product satisfaction (Is the product ‘satisfying’ right now?) on a 100 mm 
unipolar scale, ranging from 0 (not at all) to 100 (extremely), as recommended by Vansickel 
[28] to meet current regulatory recommendations in human abuse liability of tobacco and 
nicotine products. 
7.8.7 
VAS Intention to Use Again 
Intention to use again will be assessed using a one-item self-reported VAS, asking subjects 
to rate intention to use product again (How likely are you to use this product again) on a 
100 mm bipolar scale, ranging from 0 (very unlikely) to 100 (very likely), with a neutral 
middle point. 
7.8.8 
Sensory questionnaire 
Sensory experience will be assessed with the sensory questionnaire which consists of 9 
single items (strength of sensation in mouth, strength of sensation in throat, tingling 
sensation in gums, enjoyment of tingling sensation in gums, experience of dripping from 
the pouch, satisfaction with dripping, satisfaction with product duration,  comfort with 
pouch size, and comfort with pouch against the gums) assessed on a 7-point scale, ranging 
from “not at all” to “extremely”.  
This questionnaire was developed internally by PMP S.A. based on consumer qualitative 
insights conducted with users of nicotine pouches in PMP S.A. consumer research studies. 
The main source for AE collection in this study is the face-to-face interview between the 
subject and study site staff, using open, non-directive questions, as described in section 8.2. 
It is at the discretion of the Investigator or designee(s) to decide whether needed to 
document as AEs different symptoms reported in the questionnaires (e.g. Sensory 
questionnaire or Product Evaluation Scale). 

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8 
ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
An adverse event (AE) is defined as any health-related event which is adverse or 
unfavorable and which either starts after ICF signature or represents a worsening of a 
health–related condition that existed at the time of that signature. Careful medical judgment 
is required to establish whether a clinical finding (including an abnormal laboratory result) 
is a true AE or just a manifestation of a preexisting health–related condition. An AE may 
or may not have a causal relationship with the study procedures or with the use of 
investigational product. 
8.1.2 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an AE that: 
• results in death, 
• is life-threatening,  
• requires inpatient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity,  
• is a congenital anomaly/birth defect, or 
• is an important medical event 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate Investigator’s 
medical judgment, they may jeopardize the subject or the subject may require medical or 
surgical intervention to prevent one of the outcomes listed in the above definitions. 
"Life-threatening" means that the subject was at immediate risk of death from the event. It 
might have caused death if it had occurred in a more serious form. 
8.1.3 
Conditions Existent Before the Start of the Period of Collection (ICF 
Signature) 
Clinical conditions that existed before the start of the period of collection of AEs and are 
still ongoing at Screening (concomitant disease), and whose severity remained unchanged 
after that point, should not be considered AEs and should not be captured as such. This 
includes medical therapies or surgical interventions that had been planned before the start 
of the period of 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. 

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Otherwise, any medical condition that existed before the start of the period of collection 
and still ongoing at Screening (concomitant disease) and whose severity increased after that 
point is to be captured as an AE or SAE, depending on the seriousness criteria met.  
8.2 
Collection and Reporting of Adverse Events 
8.2.1 
Collection of Information 
AEs should be collected mainly via face-to-face interview with the subject by the use of 
consistent, open, non-directive questions from the investigator(s) or designee(s) (e.g., 
“How have you been feeling since you were last asked?”). 
Any non-serious AE occurrence during the study must be documented in the subject’s 
medical records in accordance with the Investigator’s normal clinical practice and on the 
AE page of the CRF. SAEs that occur during the study must be documented in the subject’s 
medical record, on the AE CRF, and on the SAE form for recording into the safety database. 
Information recorded for AEs/SAEs will include: verbatim description, start and stop dates 
and times, seriousness, severity (intensity), causal relationship with IP and study 
procedures, action taken with IP (e.g reduced, not changed), other action taken (e.g., 
treatment administered, if led to the subject’s discontinuation from the study),  and outcome 
(e.g., resolved, stabilized).  
Whenever a medically meaningful diagnosis is available to comprise a set of reported signs 
and/or symptoms, it should be preferentially provided as the AE or SAE term, rather than 
the individual signs and/or symptoms. 
8.2.2 
 Period of Collection 
AEs (including SAEs) will be collected from the time of ICF signature until the individual 
EOS for each subject. 
Any AEs which occur during the screening period will be captured by the investigational 
site staff and assessed by the Investigator or designee(s) in order to establish relationship 
to study procedures. 
During a 3-day Safety follow-up period new AEs/SAEs associated with IP use will be 
recorded and ongoing AEs/SAEs will be followed-up by the study site, as described in 
section 8.2.6. 
8.2.3 
Intensity of Adverse Event 
The Investigator must assess the intensity of each reported AE according to the following 
grading scale: 

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Table 3 
Intensity of Adverse Events 
Mild: 
Easily tolerated, not interfering with normal everyday activities 
Moderate: 
Interferes with normal everyday activities, but the subject is still able to 
function 
Severe: 
Incapacitating and requiring medical intervention 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures 
The Investigator must assess the causal relationship between the exposure to the IP 
(Nicotine pouch 1.0, Velo-NP and Zyn-NP) 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 (Nicotine pouch 1.0, Velo-NP, Zyn-NP) will be 
assessed for its expectedness. An AE will be regarded as “unexpected” if its nature or 
severity is not consistent with information already recorded in section 6.5 of the current 
Investigator’s Brochure [36].  
8.2.6 
Follow-up of Non-serious and Serious Adverse Events 
Any non-serious AE that is ongoing at the time of Discharge or early termination will be 
followed-up by the Investigator during the Safety follow-up period until it has been 
resolved, stabilized (i.e., no worsening of the condition), or an acceptable explanation has 
been found (e.g., a chronic condition). The follow-up of the ongoing non-serious AEs will 
be done via a phone call performed at the end of the Safety follow-up period. If the subject 
is not responding at the first phone call additional two attempts will be made, then subject 
will be declared lost to follow-up (see section 5.3).  

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At the end of the 3-day Safety FU Period, all ongoing non-serious AEs will have the 
outcome documented as “unknown” and will not be followed-up by the Investigator. At the 
discretion of the Investigator, the subject will be referred to his General Practitioner to have 
his/her ongoing AEs addressed accordingly. 
All SAEs will be followed up by the Investigator or designee after the end of the Safety 
follow-up period, until their resolution, stabilization (i.e., no worsening of the condition), 
or an acceptable explanation has been found (e.g., a chronic condition). In case the subject 
cannot be reached for additional information related to SAE(s), a total 3 attempts should be 
performed before the subject will be declared as lost to follow-up (see section 5.3). 
8.3 
Reporting of Serious Adverse Events 
Any SAE observed during the period of collection in this study must be reported within 24 
hours of first awareness to Sponsor, via email, having the SAE form attached. 
As further information regarding an already reported SAE becomes available to any of the 
parties involved in this study, such follow-up information should be reported on a new SAE 
report form, marked as a follow-up report and submitted to Sponsor according to the same 
timelines as described above. The follow-up SAE report form must include the minimum 
information required for form completion and only changed/new information needs to be 
specified. Information provided in the follow-up SAE report form supersedes any 
information that was initially reported.  
The SAE report form to be used in this study is provided as a separate document. All SAEs 
will also be recorded on the relevant CRF page, in addition to the SAE report form. 
The Investigator or designee is responsible for submitting the relevant reports of SAEs that 
occur during the study to the IEC, according to local regulations and in accordance with 
the respective safety management plan (SMP).  
8.4 
Reporting of Other Events Critical to Safety Evaluations 
The other abnormal findings discovered during different clinical assessments (e.g., ECG, 
physical examination, vital signs, body weight, safety labs results) should be evaluated for 
clinical significance by the Investigator/designee based on his/her medical judgement. All 
abnormal clinically significant test results or clinical examination findings should be 
reported as AEs and handled as described in section 8.2. 
8.5 
Reporting and Follow–Up of Pregnancies 
8.5.1 
Period of Collection and Follow-up 
Pregnancies detected between the time of signature of the ICF and the time before first 
exposure to the IP will be considered a reason for screen failure. No pregnancy form will 

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be filled in that case, however the diagnosed pregnancy must be captured in the screen 
failure page of the CRF. 
Any pregnancy detected after first exposure to the IP must be reported by the Investigator 
within 24 hours. This also includes pregnancies spontaneously reported to the Investigator 
after the end of the study for a subject. A dedicated pregnancy form will be used to report 
reportable cases of pregnancy. 
Any pregnancy that was potentially associated with exposure to IP (NP 1.0, Velo-NP, Zyn-
NP) will be followed-up until an outcome is reached (e.g., normal delivery, spontaneous 
abortion, or voluntary termination) and also until 8 weeks after delivery. Any pregnancy 
complication, adverse pregnancy outcome or maternal complications will be recorded as 
an AE accordingly. 
The procedure outlined in section 8.3 should be followed to collect pregnancy reports and 
provide any additional/follow-up information to Sponsor. 
 
8.5.2 
Reporting of Pregnancies 
The Investigator is responsible for informing the responsible IEC of any pregnancy case 
that was reported during the study, as determined by local regulations. 
8.6 
Adverse Events Leading to Discontinuation 
Subjects who are discontinued from the study because of an AE will undergo the early 
termination procedures (section 9.7), as soon as practical after discontinuation and will 
enter the 3-day Safety follow-up period.  
Any AEs or SAEs that are ongoing at the end of the Safety follow-up period will be 
managed as described in section 8.2.6. 
8.7 
Product Events 
Any occurrence of NP 1.0 product events should be actively collected during the study and 
documented by the study site. Nicotine pouch 1.0 product events will be categorized into: 
• Nicotine pouches not extractable from can/sticking together 
• Rupture of the nicotine pouch when using 
• No release of flavor when using 
• No release of nicotine when using, or  
• Other 
Furthermore, any product event that leads to an AE/SAE will follow the same processes as 
described in section 8.2. 

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9 
STUDY ACTIVITIES 
The schedule of assessment can be found in Appendix A. Measurements not conducted at 
the exact time point but conducted within the given time window (if applicable) do not 
constitute a protocol deviation but an accepted variability for the given time point. 
In general, if no start time for the procedures is provided, then the procedure can be 
performed at any time during the day. 
The main objective for this study is the evaluation of the plasma concentration-time profile 
of nicotine and derived PK parameters. Therefore, the collection of blood samples for 
determination of plasma nicotine concentration should be as close to the schedule time as 
possible and should take precedence over any other assessments required at the same time. 
9.1 
Screening Visit (Day -22 to Day -2) 
The Screening Visit will be performed within 21 days prior to enrollment at Admission 
(Day -1). Screening procedures must not be started before study information is given to the 
subject and the consent form signed by the subjects. Then, 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 4. 
Table 4 
Time Schedule – Screening Visit 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Prior to any study 
procedure 
 
Informed consent process and signature 
of ICF 
 
During the visit 
 
Information on the risks of 
smoking/advice on smoking cessation 
and debriefing on NP 1.0 
Section 7.2 
 
 
Nicotine/Tobacco product use history  
Section 7.8.2 
 
 
FTND questionnaire 
Section 7.8.1 
 
 
Demographics data 
Section 7.4.1 
 
 
Medical history/ concomitant diseases 
Section 7.4.2 
 
 
Prior (within 4 weeks prior to the 
Screening Visit) and concomitant 
medication  
Section  
 
 
Physical examination 
Section 7.4.3 
 
 
Body height, weight and calculated BMI 
Section 7.4.4 

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Time 
Blood 
Sample 
Procedures 
Additional 
Information 
 
 
Vital signs  
Section 7.4.5. 
 
 
ECG 
Section 7.4.7 
 
 
Spirometry 
Section 7.4.6 
 
X 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
Section 7.6.1 
 
 
 
 
 
 
Collection of spot urine for: 
• 
Urine analysis safety panel 
• 
Urine drug test including testing 
for alcohol 
• 
Urine cotinine test 
• 
Urine pregnancy test (all female 
subjects) 
 
Section 7.6.1 
Section 7.6.3 
 
Section 7.6.4 
Section 7.6.5 
 
X 
Serology 
Section 7.6.2 
 
 
Review of inclusion/exclusion criteria 
based on all relevant assessments 
 
 
 
AE/SAE recording 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; ECG = Electrocardiogram; HIV = Human 
immunodeficiency virus; SAE = Serious adverse event. 
If the inclusion and exclusion criteria are met, the investigational site staff will contact the 
subject to arrange Day -1 visit at site. 
 

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9.2 
Admission (Day -1) 
The assessments performed at Admission are listed in Table 5. 
Table 5 
Time Schedule – Admission (Day -1) 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Before enrollment 
 
Information on the risks of 
smoking/advice on smoking cessation 
and debriefing on NP 1.0 
Section 7.2 
 
 
Nicotine/Tobacco product use history 
Section 7.8.2 
 
 
Concomitant medication/ concomitant 
disease status  
 
 
 
Physical examination 
Section 7.4.3 
 
 
Vital signs  
Section 7.4.5 
 
 
ECG 
Section 7.4.7 
 
X 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
Section 7.6.1 
 
 
Collection of spot urine for: 
• 
Urine analysis safety panel 
• 
Urine drug test including 
testing for alcohol 
• 
Urine cotinine test 
• 
Urine pregnancy test (all 
female subjects) 
 
Section 7.6.1 
Section 7.6.3 
 
Section 7.6.4 
Section 7.6.5 
After enrollment 
X 
CYP2A6 activity 
Section 7.5.2 
After CYP2A6 
 
NP-1 product test 
Section 6.2.1 
During the visit 
 
AE/SAE recording 
Product events 
Section 8.2 
Section 8.7 
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; SAE = Serious adverse event. 
9.3 
Day 1 
The study activities performed on Day 1 are listed in Table 6.  
Table 6 
Time Schedule – Day 1 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Prior to T0M  
 
Randomization  
 

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Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Prior to T0M 
 
Vital signs  
Section 7.4.5 
Within 15 minutes prior 
to T0M 
 
VAS craving  
Section 7.8.4 
T-1 5 minutes ± 1 
minute prior to T0M 
X 
Blood sampling for baseline nicotine 
level  
Section 7.5.1 
Just before T0M 
 
Providing one NP 1.0 or Velo-NP or 
Zyn-NP 
Performed by 
investigational 
site staff 
Start of product use: T0M  
 
Placing NP 1.0 or Velo-NP or Zyn-NP 
between the upper lip and gum 
Section 6.2.2 
T1 after 5 ± 1 minutes 
T2 after 10 ± 1 minutes 
T3 after 15 ± 1 minutes 
T4 after 20 ± 1 minutes 
T5 after 25 ± 1 minutes 
T6 after 30 ± 1 minutes 
T7 after 35 ± 1 minutes 
T8 after 40 ± 1 minutes 
T9 after 1 hour ± 5 
minutes 
T10 after 3 hours ± 5 
minutes 
 
T11 after 6 hours ± 5 
minutes 
X 
Blood sampling for nicotine PK 
VAS craving, VAS liking (in the 
moment) and VAS satisfaction  
Section 7.5.1 
Section 7.8.4 
Section 7.8.5 
Section 7.8.6 
 
 
 
 
 
 
VAS craving and 
VAS satisfaction 
only 
VAS craving and 
VAS satisfaction 
only 
T10 after 3 hours ± 5 
minutes 
 
VAS liking (overall)  
Section 7.8.5 
T6 after 30 ± 1 minutes 
T10 after 3 hours ± 5 
minutes 
 
VAS intention to use again  
Section 7.8.7 
After 30 minutes of 
product use 
 
Collection of used NP 1.0, Velo-NP 
or Zyn-NP 
 
T9 after 1 hour ± 5 
minutes 
 
Product evaluation scale 
Sensory questionnaire 
Section 7.8.3 
Section 7.8.8 
Within 15 minutes prior 
to T0A 
 
VAS craving  
Section 7.8.4 
T-1 5 minutes ± 1 
minute prior to T0A 
X 
Blood sampling for baseline nicotine 
level  
Section 7.5.1 

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Philip Morris Products S.A 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Just before T0A 
 
Providing 1 NP 1.0 or Velo-NP or 
Zyn-NP 
Performed by 
investigational 
site staff 
Start of product use: T0A  
 
Placing NP 1.0 or Velo-NP or Zyn-NP 
between the upper lip and gum 
 
T1 after 5 ± 1 minutes 
T2 after 10 ± 1 minutes 
T3 after 15 ± 1 minutes 
T4 after 20 ± 1 minutes 
T5 after 25 ± 1 minutes 
T6 after 30 ± 1 minutes 
T7 after 35 ± 1 minutes 
T8 after 40 ± 1 minutes 
T9 after 1 hour ± 5 
minutes 
T10 after 3 hours ± 5 
minutes 
 
T11 after 6 hours ± 5 
minutes 
X 
Blood sampling for nicotine PK 
VAS craving, VAS liking (in the 
moment) and VAS satisfaction  
Section 7.5.1 
Section 7.8.4 
Section 7.8.5 
Section 7.8.6 
 
 
 
 
 
 
VAS craving and 
VAS satisfaction 
only 
VAS craving and 
VAS satisfaction 
only 
T10 after 3 hours ± 5 
minutes 
 
VAS liking (overall)  
Section 7.8.5 
T6 after 30 ± 1 minutes 
T10 after 3 hours ± 5 
minutes 
 
VAS intention to use again  
Section 7.8.7 
After 30 minutes of 
product use 
 
Collection of used NP 1.0, Velo-NP 
or Zyn-NP 
 
T9 after 1 hour ± 5 
minutes 
 
Product evaluation scale 
Sensory questionnaire 
Section 7.8.3 
Section 7.8.8 
During the visit 
 
AE/SAE recording 
Product events 
Section 8.2 
Section 8.7 
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; PK = Pharmacokinetic; SAE = Serious adverse event; 
VAS = Visual analogue scale 
9.4 
Day 2 
The study activities performed on Day 2 are listed in Table 7.  

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Table 7 
Time Schedule – Day 2 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
Prior to T0M  
 
Randomization  
 
Prior to T0M 
 
Vital signs  
Section 7.4.5 
Within 15 minutes prior 
to T0M 
 
VAS craving  
Section 7.8.4 
T-1 5 minutes ± 1 
minute prior to T0M 
X 
Blood sampling for baseline nicotine 
level  
Section 7.5.1 
Just before T0M 
 
Providing one NP 1.0 or Velo-NP or 
Zyn-NP 
Performed by 
investigational 
site staff 
Start of product use: T0M  
 
Placing NP 1.0 or Velo-NP or Zyn-NP 
between the upper lip and gum 
Section 6.2.2 
T1 after 5 ± 1 minutes 
T2 after 10 ± 1 minutes 
T3 after 15 ± 1 minutes 
T4 after 20 ± 1 minutes 
T5 after 25 ± 1 minutes 
T6 after 30 ± 1 minutes 
T7 after 35 ± 1 minutes 
T8 after 40 ± 1 minutes 
T9 after 1 hour ± 5 
minutes 
T10 after 3 hours ± 5 
minutes 
 
T11 after 6 hours ± 5 
minutes 
X 
Blood sampling for nicotine PK 
VAS craving, VAS liking (in the 
moment) and VAS satisfaction  
Section 7.5.1 
Section 7.8.4 
Section 7.8.5 
Section 7.8.6 
 
 
 
 
 
 
VAS craving and 
VAS satisfaction 
only 
VAS craving and 
VAS satisfaction 
only 
T10 after 3 hours ± 5 
minutes 
 
VAS liking (overall)  
Section 7.8.5 
T6 after 30 ± 1 minutes 
T10 after 3 hours ± 5 
minutes 
 
VAS intention to use again  
Section 7.8.7 
After 30 minutes of 
product use 
 
Collection of used NP 1.0, Velo-NP 
or Zyn-NP 
 
T9 after 1 hour ± 5 
minutes 
 
Product evaluation scale 
Sensory questionnaire 
Section 7.8.3 
Section 7.8.8 
Within 15 minutes prior 
to T0A 
 
VAS craving  
Section 7.8.4 

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Time 
Blood 
Sample 
Procedures 
Additional 
Information 
T-1 5 minutes ± 1 
minute prior to T0A 
X 
Blood sampling for baseline nicotine 
level  
Section 7.5.1 
Just before T0A 
 
Providing 1 NP 1.0 or Velo-NP or 
Zyn-NP 
Performed by 
investigational 
site staff 
Start of product use: T0A  
 
Placing NP 1.0 or Velo-NP or Zyn-NP 
between the upper lip and gum 
 
T1 after 5 ± 1 minutes 
T2 after 10 ± 1 minutes 
T3 after 15 ± 1 minutes 
T4 after 20 ± 1 minutes 
T5 after 25 ± 1 minutes 
T6 after 30 ± 1 minutes 
T7 after 35 ± 1 minutes 
T8 after 40 ± 1 minutes 
T9 after 1 hour ± 5 
minutes 
T10 after 3 hours ± 5 
minutes 
 
T11 after 6 hours ± 
5minutes 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
Blood sampling for nicotine PK 
VAS craving, VAS liking (in the 
moment) and VAS satisfaction  
Section 7.5.1 
Section 7.8.4 
Section 7.8.5 
Section 7.8.6 
 
 
 
 
 
 
VAS craving and 
VAS satisfaction 
only 
VAS craving and 
VAS satisfaction 
only 
T10 after 3 hours ± 5 
minutes 
X 
VAS liking (overall)  
Section  
T6 after 30 ± 1 minutes 
T10 after 3 hours ± 5 
minutes 
X 
VAS intention to use again  
Section 7.8.7 
After 30 minutes of 
product use 
 
Collection of used NP 1.0, Velo-NP 
or Zyn-NP 
 
T9 after 1 hour ± 5 
minutes 
 
Product evaluation scale 
Sensory questionnaire 
Section 7.8.3 
Section 7.8.8 
T1z after 8 hours ± 5 
minutes  
X 
Blood sampling for nicotine terminal 
elimination 
 
T2z after 12 hours ± 5 
minutes 
X 
Blood sampling for nicotine terminal 
elimination 
 
During the visit 
 
AE/SAE recording 
Product events 
Section 8.2 
Section 8.7 
 

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Abbreviations: AE = Adverse event; ECG = Electrocardiogram; PK = Pharmacokinetic; SAE = Serious adverse event; 
VAS = Visual analogue scale 
9.5 
Day 3 
The study activities performed on Day 3 prior to the time of discharge are listed in Table 
8.  
Table 8 
Time Schedule – Day 3 (Discharge) 
Time 
Blood 
Sample 
Procedures 
Additional 
Information 
 
X 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
Section 7.6.1 
 
 
Vital signs  
Section 7.4.5 
Within 15 minutes prior 
to T0M 
 
VAS craving  
Section 7.8.4 
T-1 5 minutes ± 1 
minute prior to T0M 
X 
Blood sampling for baseline 
nicotine level  
Section 7.5.1 
Just before T0M 
 
Providing one NP 1.0 or Velo-NP or 
Zyn-NP 
Performed by 
investigational site 
staff 
Start of product use: T0M  
 
Placing NP 1.0 or Velo-NP or Zyn-
NP between the upper lip and gum 
Section 6.2.2 
T1 after 5 ± 1 minutes 
T2 after 10 ± 1 minutes 
T3 after 15 ± 1 minutes 
T4 after 20 ± 1 minutes 
T5 after 25 ± 1 minutes 
T6 after 30 ± 1 minutes 
T7 after 35 ± 1 minutes 
T8 after 40 ± 1 minutes 
T9 after 1 hour ± 5 
minutes 
T10 after 3 hours ± 5 
minutes 
 
T11 after 6 hours ± 5 
minutes 
X 
Blood sampling for nicotine PK 
VAS craving, VAS liking (in the 
moment) and VAS satisfaction  
Section 7.5.1 
Section 7.8.4 
Section 7.8.5 
Section 7.8.6 
 
 
 
 
 
 
VAS craving and 
VAS satisfaction 
only 
VAS craving and 
VAS satisfaction 
only 
T10 after 3 hours ± 5 
minutes 
 
VAS liking (overall)  
Section 7.8.5 
T6 after 30 ± 1 minutes 
 
VAS intention to use again  
Section 7.8.7 

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Time 
Blood 
Sample 
Procedures 
Additional 
Information 
T10 after 3 hours ± 5 
minutes 
After 30 minutes of 
product use 
 
Collection of used NP 1.0, Velo-NP 
or Zyn-NP 
 
T9 after 1 hour ± 5 
minutes 
 
Product evaluation scale 
Sensory questionnaire 
Section 7.8.3 
Section 7.8.8 
Within 15 minutes prior 
to T0A 
 
VAS craving  
Section 7.8.4 
T-1 5 minutes ± 1 
minute prior to T0A 
X 
Blood sampling for baseline 
nicotine level  
Section 7.5.1 
Just before T0A 
 
Providing 1 NP 1.0 or Velo-NP or 
Zyn-NP 
Performed by 
investigational site 
staff 
Start of product use: T0A  
 
Placing NP 1.0 or Velo-NP or Zyn-
NP between the upper lip and gum 
Section 6.2.2 
T1 after 5 ± 1 minutes 
T2 after 10 ± 1 minutes 
T3 after 15 ± 1 minutes 
T4 after 20 ± 1 minutes 
T5 after 25 ± 1 minutes 
T6 after 30 ± 1 minutes 
T7 after 35 ± 1 minutes 
T8 after 40 ± 1 minutes 
T9 after 1 hour ± 5 
minutes 
T10 after 3 hours ± 5 
minutes 
 
T11 after 6 hours ± 5 
minutes 
X 
Blood sampling for nicotine PK 
VAS craving, VAS liking (in the 
moment) and VAS satisfaction  
Section 7.5.1 
Section 7.8.4 
Section 7.8.5 
Section 7.8.6 
 
 
 
 
 
 
VAS craving and 
VAS satisfaction 
only 
VAS craving and 
VAS satisfaction 
only 
 
 
 
 
After 30 minutes of 
product use 
 
Collection of used NP 1.0, Velo-NP 
or Zyn-NP 
 
T9 after 1 hour ± 5 
minutes 
 
Product evaluation scale 
Sensory questionnaire 
Section 7.8.3 
Section 7.8.8 
Between 2 hours after 
T0A and Discharge 
 
Collection of spot urine for: 
• 
Urine analysis safety panel 
• 
Urine pregnancy test (all 
female subjects) 
 
Section 7.6.1 
Section 7.6.5 

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Time 
Blood 
Sample 
Procedures 
Additional 
Information 
 
 
Concomitant 
medication/concomitant disease 
status 
 
 
 
Physical examination 
Section 7.4.3 
 
 
ECG 
Section 7.4.7 
During the visit 
 
Information on the risk of 
smoking/advice on smoking 
cessation and debriefing on 
Nicotine pouch 1.0 
Section 7.2 
During the visit 
 
AE/SAE recording 
Product events 
Section 8.2 
Section 8.7 
 
 
Discharge 
 
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; PK = Pharmacokinetic; SAE = Serious adverse event; 
VAS = Visual analogue scale 
9.6 
Safety Follow-Up Period 
After discharge at Day 3, the subjects will enter a 3-day Safety follow-up period during 
which AE/SAEs associated with IP use reported by the subjects will be collected and the 
follow-up of AEs/SAEs will be conducted by the study investigational site as described in 
section 8.2.6. 
9.7 
Early Termination Procedures 
When a subject is discontinued from the study, all early termination procedures listed in 
Table 9 are performed unless the subject refuses to perform the assessments or the 
procedures have already been performed during that study day. Early termination 
procedures are to be performed only for subjects who have been exposed to investigational 
products. After the date of termination, the subject will enter into the 3-day Safety follow-
up period.  

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Table 9 
Early Termination 
Blood 
Sample 
Procedures 
Additional Information 
X 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
Section 7.6.1 
 
Urine analysis safety panel 
Section 7.6.1 
 
Urine pregnancy test (all female 
subjects) 
Section 7.6.5 
 
Vital signs  
Section 7.4.5 
 
ECG  
Section 7.4.7 
 
Physical examination 
Section 7.4.3 
 
Information on the risks of 
smoking/advice on smoking 
cessation and debriefing on NP 1.0 
Section 7.2 
 
AE/SAE, concomitant medication 
recording 
Section 8.2 
 
Product events 
Section 8.7 
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 any new information relevant to the performance of this study is forwarded in a timely 

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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/IRB may 
perform audits or inspections, including source data verification. The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data was recorded, 
analyzed, and accurately reported according to the protocol, ICH GCP guidelines and any 
applicable regulatory requirements. The Investigator or designee will contact the Sponsor 
or the authorized representative immediately if contacted by a regulatory agency about an 
inspection at their investigational site.  
The Investigator and study staff are responsible for maintaining a comprehensive and 
accurate filing system of all study-related documentation that will be suitable for inspection 
at any time by the Sponsor, its authorized representative and/or regulatory agencies. By 
signing this protocol, the Investigator or designee understands and agrees to provide access 
to the necessary documentation and files. 

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11 DATA MANAGEMENT ACTIVITIES 
All data management activities will be described in detail in the data management plan 
(DMP) and documents specified therein. 
11.1 Data Capture 
11.1.1 
Case Report Forms and Study Records 
CRFs are produced by the CRO responsible for Data Management activities (DM-CRO), 
stored electronically, and are available to the designated study team members. Each CRF 
is reviewed and signed by the Investigator. The final signed CRFs are provided to the 
Sponsor in the format as decided upon between DM-CRO and the Sponsor (e.g., CD, flash 
drive, SFTP). This will be documented in the DMP). The subject questionnaires will be 
completed directly by the subject. Trained study personnel will be responsible for capturing 
the data from the observations, tests, and assessments specified in the protocol in the source 
documents and DM-CRO will enter the data into the CRF, in accordance with the CRF 
Completion Guidelines.  
The Investigator has ultimate responsibility for the collection and reporting of all data 
related to the clinical study and ensuring that the data are accurate, authentic/original, 
legible, timely (contemporaneous), enduring, and available when required. The CRF must 
be signed by the Investigator to attest that the data contained in the CRF are true and 
accurate. Any correction made to source documents must be clearly recorded, without 
obscuring the original values and be accompanied by the date of change, reason for change, 
and identification of the person making the change. The CRF for each subject will be 
checked against the source documents at the investigational site by the Monitor. Instances 
of missing or unclear data will be discussed with the Investigator for resolution. A CRF 
will be generated for all subjects that sign the ICF. 
11.1.2 
Protocol Deviations 
Protocol deviations are defined as any departure from the procedures defined in this 
document, including, but not limited to, any violation of inclusion/exclusion criteria, mis-
randomization, use of any nicotine or tobacco-containing product other than the assigned 
product during the exposure period, assessments not performed or performed outside the 
scheduled time windows, or use of medications that are known to affect study endpoints.  
Protocol deviations will be entered into the clinical trial management system (CTMS) or 
other approved format. The data collected in the CRF may be used to assess protocol 
deviations from the data programmatically. Protocol deviations will be reconciled and 
categorized prior to locking the clinical database as described in the DMP.  

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Information from the source documents will represent the primary source of protocol 
deviations. Information following investigational site monitoring and other manual reviews 
will be documented in the investigational site visit reports, follow-up letters, audit 
documentation, or other manual review and will be recorded and tracked in the CTMS or 
other approved format. Telecommunications and other verbal communications regarding 
deviations will be considered and handled as important communication, documented and 
tracked as protocol deviations, as necessary.  
Individual entries for protocol deviations that are recorded in the CTMS, or other approved 
format, following investigational site monitoring and other manual reviews, will be 
reviewed against the individual data points in the database. The overall procedure for 
managing protocol deviations are defined in the SOPs and study specific procedures of the 
DM-CRO. All deviations will be reviewed, as defined at study start, to identify trends to 
improve monitoring and/or potential impact on the statistical analysis. 
11.2 Data Handling 
All study data will be managed by the DM-CRO. The overall procedures for quality 
assurance of clinical study data are described in the SOPs of the DM-CRO. The DM-CRO 
will prepare the DMP that will be approved by the Sponsor, prior to the start of the study, 
i.e., First Subject Screened. This document will describe, in detail, the procedures and 
processes related to data management.  
All data of all subjects that are enrolled will be captured and stored in the study database. 
For screen failures, only the following information should be captured: date/time of ICF 
signature, date of birth, sex, race, AEs, date and reason for screen failure. 
All data collected during the study is property of the Sponsor, irrespective of the location 
of the database and the DM-CRO. 
The sponsor should ensure that the Investigator has control of and continuous access to the 
CRF data reported to the sponsor. The sponsor should not have exclusive control of those 
data. 
The Investigator should have control of all essential documents and records generated by 
the Investigator/investigational site before, during and after the study. 
Additional details are covered in the DMP. 
11.2.1 
Data Verification 
The data will be verified as defined in the DMP and data validation plan (DVP). Data 
clarification forms (DCFs) will be issued to the investigational site for discrepant or missing 
data.  
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 
medication:  
WHO Drug Dictionary Enhanced and Anatomical 
Therapeutic and Chemical classification system 
11.2.3 
Database Lock  
When all outstanding data management issues have been resolved and all validation, quality 
review and cleaning activities are complete as defined in the DMP, the Sponsor organizes 
a data review and ensures that the resolution of all raised queries and quality control of the 
changed data are performed by the CRO before approving the database locked.  
Any changes to the database after that time can only be made by written agreement between 
the Sponsor and the data management and statistical teams at the CRO. Any changes must 
be documented in the database log file and if these impact the study analysis the PMP S.A. 
process for a database unlock may be requested.  
The study database will be transformed into a Clinical Data Interchange Standards 
Consortium (CDISC) compliant format and transferred to the Sponsor as specified in the 
DMP and defined in the data transfer agreement. The clinical data will adhere to the CDISC 
Study Data Tabulation Model (SDTM) Data Structure Specifications. 
 
 
 
 
 
 

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12 PLANNED STATISTICAL METHODS 
12.1 General Considerations 
Full details of the statistical analysis will be described in the Statistical Analysis Plan 
(SAP). The following statistical analyses will not be performed prior to the finalization of 
the SAP. Any changes to the planned statistical methods will be documented in the SAP 
and CSR. The statistical evaluation will be performed using SAS®, version 9.2 or higher. 
12.1.1 
Stratification Criteria 
The sample enrollment will enforce at least 25% of each sex, therefore demographics, 
baseline characteristics, PK and PD parameters analyses will be stratified by sex, as well 
as unstratified, as detailed in the SAP. 
12.1.2 
Definitions for Statistical Data Analysis 
For PK and PD analyses, baseline will be defined as the last assessment prior to T0 (5 
minutes prior to T0) for each study day of exposure. 
Nicotine PK parameters (e.g., Tmax, Cmax, …will be derived from background-corrected 
nicotine concentrations. 
12.1.3 
Descriptive Statistics 
All data will be presented in listings, ordered by randomized sequence, subject, and time 
point unless otherwise specified. 
Continuous endpoints will be summarized with descriptive statistics including number of 
subjects (n), number and percent of subjects with missing data, arithmetic means and 
standard deviations (mean and SD), median, first and third quartiles, minimum and 
maximum, and change from baseline.  
For log normally distributed endpoints, geometric mean, geometric CV, confidence interval 
of the geometric mean, and percent change from baseline will be presented additionally.  
Nominal categorical variables will be summarized by frequency statistics (number and 
percentage), including the number of missing data as a category.  
Ordinal categorical data (e.g., Tmax) will be summarized by number of subjects (n), number 
and percent of subjects with missing data, median, first and third quartiles, and minimum 
and maximum. 

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12.1.4 
Handling of Missing Values and of Values outside the Detection Limits 
In general, missing data will not be imputed 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. 
Nicotine concentrations outside detection limits will be substituted using the following 
rules: 
• BLOQ values before T0 will be imputed by LLOQ/2. 
• BLOQ values after the last quantifiable value are not included in the analysis (e.g., 
for the calculation of AUC). 
• Any BLOQ value (after T0 and before the last quantifiable value) would need to be 
queried and, if confirmed, it will be imputed by LLOQ/2.  
Handling of missing answers to questionnaires will be described in the SAP. 
12.2 Analysis Sets 
The following analysis sets will be used for the data analyses. 
12.2.1 
Screened Population 
The screened population consists of all subjects who underwent screening. 
12.2.2 
Safety population (SAF) 
The safety population (SAF) will consist of all the subjects who signed ICF consent and 
have at least one exposure to NP 1.0 (including the product test with NP-1 at Admission 
regardless of whether or not they are enrolled in the study). 
12.2.3 
PK Population 
The PK Population is a subset of the Safety population and consists of all randomized 
subjects for whom at least one nicotine PK parameter can be derived. Only subjects without 
major protocol deviations, as defined in the SAP, which have an impact on evaluability of 
the main objective will be included in the PK population. 

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12.3 Disposition of Subjects 
Disposition of subjects will be summarized in the SAF population by reporting the number 
of subjects screened, enrolled, enrolled, and exposed to NP, randomized, completed, and 
discontinued the study with discontinuation reasons. 
12.4 Protocol Deviations 
Protocol deviations will be summarized in the SAF population by reporting the number and 
percent of subjects with protocol deviations, and the number of protocol deviations, will be 
summarized. Summaries will be broken down by main deviation category (major/minor), 
sub-categories, and evaluability impact. Subjects will be counted once per deviation 
category and can be counted for more than one deviation category. 
12.5 Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the SAF and PK 
populations using the appropriate summary statistics as described in section 12.1.3.  
Summaries will include sex, age, height, weight, BMI, nicotine/tobacco product use 
history, FTND, CYP2A6 activity and other endpoints that are only captured prior to product 
use.  
12.6 Exploratory Analysis 
12.6.1 
Descriptive Statistics 
Descriptive statistics will be performed on Background-Corrected Plasma Nicotine 
Concentrations, Observed Plasma Nicotine Concentrations, and PK, PD parameters in the 
PK population, by NP product and for all the planned timepoints, as described in section 
12.1.3.  
Summaries will be produced overall and stratified as described in section 12.1.1. 
12.6.2 
Primary Estimand Analysis 
The primary estimand is defined as following: 
Product Use Under Evaluation: 30 minutes product use period. 
Target Population: Healthy adult smokers, who:   
• Satisfy all inclusion/exclusion criteria (see section 5.1) 
• Tolerate NP, based on a 30-minute product test at Admission (Day -1) after which 
subject have not, or have not been, discontinued.  

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Variables of Interest: Cmax, Tmax, AUC0-5min, AUC0-10min, AUC0-15min, AUC0-20min, AUC0-
25min, AUC0-30min, AUC0-35min, AUC0-40min, AUC0-1h, AUC0-3h, AUC0-6h, AUC0-infinity. 
Intercurrent Events: 
• Subject’s non-adherence with 30 minutes (± 1 minute) IP use: If the subject uses 
other tobacco or nicotine product than the planned IP, or if the subject does not 
adhere with the planned IP use of 30 minutes (± 1 minute), the variables of interest 
from the related sequence’s period will be set to missing and handled as MAR. 
• Subject’s non-adherence with abstinence periods: If the subject has used any 
nicotine or tobacco product during an abstinence period, the subject’s variable of 
interest data from the related sequence’s period will be set to missing and handled 
as MAR. 
• Subject’s discontinuation. The corresponding subject’s variable of interest missing 
data will be handled as MAR. 
Population-Level Summary Statistic:  
• Geometric means ratios for Cmax, AUC0-5min, AUC0-10min, AUC0-15min, AUC0-
20min, AUC0-25min, AUC0-30min, AUC0-35min, AUC0-40min, AUC0-1h, AUC0-3h, AUC0-
6h, AUC0-infinity. 
• Median differences for Tmax. 
12.6.2.1 Main Analysis 
Missing Data Strategy 
The outcome data that will be missing or set to missing following an intercurrent event, 
will be assumed to be missing at random (MAR) and will be handled through model-based 
restricted maximum likelihood (REML) estimates. 
Statistical Model 
A mixed model analysis of variance (ANOVA) will be conducted on AUCs, and Cmax 
endpoints in the natural logarithmic scale.  
The model will include terms for sequence, period, product exposure as fixed effects and 
subject as a categorical random effect modeling the within subject correlations.  
An heterogeneous Compound Symmetry matrix will be used to model the variance-
covariance structure within subjects. If this model fails to converge, then the following 
variance-covariance matrix will be used (in this order) until one converges. Variance 
Components, Compound Symmetry, and finally no repeated statement. 

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The procedure will use the restricted maximum likelihood method and the Kenward-Roger 
method to compute the degrees of freedom.  
The results of this analysis will be presented in terms of geometric least square mean ratios 
and 95% confidence intervals (95% CI) for the 4 respective variants of NP 1.0, Velo-NP 
and Zyn-NP ratios. The pairwise comparisons which will be performed are listed in Table 
10. 
Table 10 List of pairwise comparisons 
 
NP-2 
NP-3 
NP-4 
Velo-NP  
Zyn-NP 
NP-1 
X 
X 
X 
X 
X 
NP-2 
 
X 
X 
X 
X 
NP-3 
 
 
X 
X 
X 
NP-4 
 
 
 
X 
X 
 
The model described above will be implemented in the SAS® language as: 
PROC MIXED data=dataset method=reml; 
    class Subject Sequence Period Product Sex; 
    model Log(Parameter) = Sequence Period Product / ddfm=KR; 
    repeated Product / subject=Subject type=csh; 
    lsmeans Product / pdiff=LIST_OF_PAIRWISE_COMPARISONS cl; 
RUN; 
The analysis of Tmax will be performed by conducting a Wilcoxon signed rank test and 
calculating the median Tmax for each product along with the Hodges-Lehmann estimate of 
the median difference between products, and the related 95% CI. 
12.6.2.2 
Sensitivity Analysis 
In case the plasma concentrations cannot be background-corrected in 2 or more subjects in 
a sequence a sensitivity analysis will be performed similarly to the main analysis, whereby: 
• If the subject’s terminal elimination rate cannot be estimated it will be substituted 
by the average terminal elimination rate of the subjects having the same sex, 
• If the uncorrected nicotine concentration at baseline is not available for the period 
2 or 3, it will be substituted by the extrapolation of the previous concentrations 
using the terminal elimination rate. 

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12.6.2.3 
Supplementary Analysis 
In case of any uncorrected nicotine concentration at T0 [uC0] greater than 25% of their 
uncorrected maximum value, a supplementary analysis of the endpoints will be performed 
similarly to the main analysis, whereby data of these subjects for this specific study day 
will be excluded from the analysis. 
An analysis of covariance (ANCOVA) will be conducted by product use. The PK 
parameters will be transformed in the natural logarithmic scale. The model will include 
terms for sequence, period and a PD parameters mentioned in the objective 4. The results 
of this analysis will be presented by product in terms of: 
• The percentage of variance explained by the PD parameter  
• The standardized effect of the PD parameter, defined as the mean effect divided by 
the square root of its variance.  
Another analysis of covariance (ANCOVA) will be conducted similarly at the exception 
that it will be performed overall using mixed effects ANCOVA where the model will 
include additionally the subject as a categorical random effect to model the within subject 
correlations. 
A multivariate analysis will be performed to analyze the joint effect of nicotine 
concentration, PH and moisture. The PK parameters will be transformed in the natural 
logarithmic scale. The model will include be adjusted for product use, sequence, period, 
and covariates encoded as low and high for nicotine concentration, PH level and moisture 
percentage. The results of this analysis will be presented for all products. The output will 
contain regression coefficients and their confidence intervals for factors of interests. 
Further details will be provided in the SAP. 
12.7 Safety Analysis 
In general, all safety data will be listed and tabulated in the Safety population using the 
approach described in section 12.1.3. Safety variables collected during exposure period will 
also be reported by sequence. 
AE data will serve for the assessment of safety. Other safety variables monitored in this 
study include: incidence of  NP 1.0 product events including malfunction/misuse; vital 
signs (systolic and diastolic blood pressure, pulse rate, respiratory rate); ECG data; clinical 
chemistry, hematology, and urine analysis safety panel; concomitant medication.  
The number and percentage of subjects with AEs, SAEs, and product events will be 
tabulated by system organ class and preferred term. Summaries will also be presented for 
AEs leading to product discontinuation, AEs leading to study discontinuation, AEs by 
relatedness to product exposure (including expectedness) and relatedness to study 
procedures, AEs by severity, and AE by action taken related to the product.Tabulations will 
include the number of subjects experiencing an event and the number of events. 

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Safety laboratory assessments are performed on Day -1 and Day 3 in the morning prior to 
product use (). Any lab related AEs on Day 3 will be assigned to the product used on the 
previous day. 
Summary tables showing actual values and change from baseline of clinical findings will 
be provided for ECGs, vital signs, and laboratory parameter. Descriptive statistics will be 
summarized by period for ECG and vital signs and by Day for laboratory parameters, ECG 
and vital signs.  
12.8 Interim Analysis 
No interim analysis will be done. 
12.9 Measures to Control Bias 
12.9.1 
Method for Assigning Subjects to Study sequences 
The study will be conducted with 6-period and 6 sequences in a cross-over Williams design 
[37]. A Williams design is an orthogonal Latin squares design with balanced property [38]. 
On day -1, subjects will be randomized to one of the six study sequences. Details about the 
randomization process will be included in the Data Management Plan (DMP). 
A minimum quota of each sex will be applied to ensure they represent at least 25% of the 
total study randomized population. 
12.9.2 
Blinding 
This is an open-label study. However, the subjects will be blinded to the randomized 
sequence. Subjects will be blinded to the products they will receive. 
The PMP study statistician and the PMP clinical scientist will be blinded up to the end of 
the data review process as summarized in Table 11.  
Table 11 
Description of Blinded Study Personnel 
Blinded Study Personnel 
End of Blinding Period 
PMP and CRO Study 
Statisticians 
After the SAP finalizationa.  
PMP Clinical Scientist 
After the SAP finalizationa. Can be actively un-
blinded when appropriate. 
a. 
As part of the PMP S.A. quality control (QC) activity, a data review will be performed before database 
lock. Data listings will be reviewed by the CRO and PMP S.A., with no access to the product 
information for blinded data review team members. Full details will be available in the data review plan. 

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12.9.3 
Study Significance Level 
Not applicable 
12.9.4 
Multiple Testing Procedures 
It is an exploratory study thus no adjustment for multiplicity will be done. When inference 
will be performed, point estimate and 95% confidence interval (95% CI) will be computed.  
12.9.5 
Determination of Sample Size and Power Consideration 
The sample size is empirically based as there are no considerations for statistical 
hypothesis.  
A total of 24 subjects is expected to be sufficient to obtain a precision of 15% or less on 
the NP-1: Velo-NP Cmax ratio. 
The precision has been determined using the following geometric coefficient of variation 
(GCV) and within subjects correlation assumptions for Cmax: 
• For all products the GCV of Cmax is assumed to be 40%. [1] 
• The correlation within subjects on log-transformed data is assumed to be 0.7. It has 
been derived as the correlation that would explain the width of the confidence 
interval of the Cmax difference between the Zyn and Velo-NP product, as compared 
to the confidence interval of the Cmax of Zyn-NP and Velo-NP product as described 
in [16]. 
The precision has been determined using 10,000 simulations performed with SAS®.  
 
 
 

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13 ADMINISTRATIVE CONSIDERATIONS 
13.1 Investigators and Study Administrative Structure 
13.1.1 
Investigator 
Investigator: 
, MD 
 
 
 
13.1.2 
Sponsor 
The list of sponsor personnel will be provided as a separate document. 
13.1.3 
Other Responsibilities 
Project Management: 
 
 
 
 
 
 
Monitoring: 
 
 
 
 
 
Data Management: 
 
 
 
Pharmacokinetic Analyses: 
 
 
 
Statistical Analyses: 
 
 
 
 
 

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All duties and responsibilities transferred by the Sponsor to the above listed CROs will be 
defined in an agreement signed between the relevant two parties. 
Any SAEs or pregnancies will be handled as described in section 8.3. 
Details of the laboratories conducting the clinical safety laboratory services and bioanalyses 
are shown in Appendix B.  
13.2 Subject Recruitment 
Subjects will be recruited from the volunteers’ database maintained by the CRO. This 
database contains a pool of volunteers that are contacted whenever necessary to enroll 
subjects in a new study. Before the start of the new study, the Investigator and other relevant 
staff discuss with the volunteers’ recruiter the study recruitment needs and specific 
requirements. On the basis of this information, the volunteers’ recruiter queries the 
database, contacts potential volunteers to propose the study and evaluate their interest and 
availability. In addition to the volunteer’s database, IEC-approved advertisement will be 
used. New subjects often call or email the CRO asking to become a research volunteer, 
after hearing of the clinical site activities from other volunteers or friends or after checking 
the company web site. The CRO and its clinical site have detailed SOPs on the recruitment 
process. 
13.3 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects' state 
of health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subject in writing and signed by the subject, in compliance with all local 
and national data protection and privacy legislation. 
The name of the subjects participating in this study will be kept confidential. Subjects will 
be identifiable by the Sponsor (or Sponsor’s authorized representative) on CRFs and other 
documents by their subject (or randomization) number/code, sex, and age, but not by name, 
initial, or any other details relating to identifiable person (e.g., address, social security 
number, medical chart number, etc.). The assignment of a subject number/code for subject 
identification will be based on the appropriate data protection rules. 
Any documents that allow full identification of the subject (e.g., the subject’s signed ICF) 
must be maintained in confidence by the Investigator. If any document relating to this study 
shows a subject’s name or any other details relating to an identifiable person (e.g., address, 
social security number, medical chart number, etc.), the name or other identifiable details 
must be obscured before a copy of that document is supplied to the Sponsor or the Sponsor’s 
authorized representative. 

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13.4 Access to Source Documentation 
Subjects will be informed that, during the study, the Sponsor, any authorized 
representatives of the Sponsor, IEC/IRB or regulatory authorities may inspect their medical 
records and source documentation to verify the information collected and ensure that all 
personal information made available for inspection is handled in the strictest confidence 
and in accordance with national and local data protection and privacy legislation. 
The Investigator and all investigational site staff involved with the study must permit direct 
access to source data/documents for study related monitoring, audits, IEC/IRB review and 
regulatory inspection(s). 
13.5 Record Retention 
All records of data, source data and source documents (original records or certified copies), 
in any form (including, but not limited to, written, electronic, magnetic, optical records and 
scans and ECGs) that describe or record the methods, conduct, and/or results of the study, 
the factors affecting the study and the actions taken will be maintained by the 
investigational site for the study, as required by ICH GCP [1] and any other applicable local 
or national regulations. 
Essential study documents/records, which individually and collectively permit evaluation 
of the conduct of a study and the quality of the data produced, are described in section 8 of 
the ICH GCP Guideline [1]. 
Essential documents must be retained by the Investigator for a minimum of:  
• At least 15 years after completion or discontinuation of the study.  
However, these documents should be retained for a longer period if required by the 
applicable regulatory requirements or by agreement with the Sponsor.  
Examples of essential records/documents include, but are not limited to:  
• Signed informed consent documents for all subjects and master ICF.  
• Subject identification code list, Screening log and Enrollment log (if applicable).  
• Record of all communications between the Investigator and the IEC/IRB, composition 
of the IEC/IRB.  
• 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). 

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• AE reports and details of follow-up investigations, details of concomitant medication. 
• All other source documents (e.g., ECGs, consultation reports, physical examination 
and laboratory records) or any electronically captured study source data. 
• Clinical laboratory reports, laboratory normal ranges. 
• Original medical/hospital records, if applicable (the medical files of study subjects must 
be retained in accordance with local legislation and in accordance with the maximum 
period of time permitted by the hospital or study site). 
• Record of any body fluids or tissue samples collected and retained. 
• IP Accountability Logs, dispensing records. 
• Information regarding subjects’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the Investigator/study site as to when these 
documents no longer need to be retained. 
The Investigator/study site must take measures to prevent accidental or premature 
destruction of these documents. 
If an Investigator wishes to assign the study records to another party or move them to 
another location, the Sponsor must be notified in advance. The Investigator must obtain 
written approval from the Sponsor before destruction of any records. Normally, these 
records will be held in the Investigator’s archives. If an Investigator is unable to meet this 
obligation, they must ask the Sponsor for permission to make alternative arrangements. 
Details of these arrangements must be documented. 
The Sponsor or Sponsor’s authorized representative will maintain documentation relating 
to the study as long as the IP is on the market, and/or for 15 years after the CSR has been 
finalized. 
13.6 Clinical Study Report 
The Sponsor must ensure that a CSR for this study is prepared regardless of whether the 
study is completed or prematurely terminated.  
The CSR will be written based on standards of the ICH Guideline for the “Structure and 
Content of Clinical Study Reports” [39]. In certain circumstances, an abbreviated CSR may 
be acceptable. Submission of the CSR to the IEC/IRB will be complied with as requested 
by local requirements. 
13.7 Financial Disclosure 
Investigators and any designees are required to provide financial disclosure information to 
the Sponsor. In addition, the Investigators and designees must provide the Sponsor with a 

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commitment to promptly update this information if any relevant changes occur during the 
study and for one year following the completion of the study. 
13.8 Publication and Disclosure Policy 
This document contains information that is confidential and proprietary to the Sponsor. 
This information is being provided solely for the purpose of evaluation and/or conducting 
this study for the Sponsor. Disclosure of the content of this document is allowed only to 
study personnel, IEC/IRB, or duly authorized representatives of regulatory agencies for this 
purpose under the condition that confidentiality is maintained. The contents of this 
document may not be used in any other study, disclosed to any other person or entity 
without the prior written permission of the Sponsor. The foregoing shall not apply to 
disclosure required by any regulations; however, prompt notice must be given to the 
Sponsor prior to any such disclosure.  
The study will be registered and published in a WHO primary register or at 
www.clinicaltrials.gov. 
13.9 Insurance 
The Sponsor is responsible for AEs and health damage of the subjects that are associated 
with the investigational products which are used during the study, except for AEs and health 
damage of the subjects caused by a negligent or an intentional misconduct and/or 
significant deviation to the protocol of the Investigator or the clinical investigational site or 
the subjects. The Sponsor has taken out insurance to cover any bodily injury and property 
damage caused by the operations carried out by the insured. 

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REFERENCE LIST 
1. 
ICH E6 (R2), Integrated addendum to ICH E6 (R1): guideline for good clinical 
practice - Current Step 4 version dated 9 November 2016. 2016. Available from: 
https://database.ich.org/sites/default/files/E6 R2 Addendum.pdf 
(Accessed 
on 17 January 2020). 
2. 
World Medical Association (WMA), Declaration of Helsinki - Ethical principles 
for medical research involving human subjects. 2013. Available from: 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-
principles-for-medical-research-involving-human-subjects/ (Accessed on 12 
July 2018). 
3. 
U.S. Department of Health and Human Services, The health consequences of 
smoking - 50 years of progress: a report of the Surgeon General. 2014. 
4. 
WHO Study Group, et al., WHO study group on tobacco product regulation - 
Report on the scientific basis of tobacco product regulations: fifth report of a WHO 
study group. 2015. 
5. 
Royal College of Physicians, Harm reduction in nicotine addiction: helping people 
who can’t quit. A report by the Tobacco Advisory Group of the Royal College of 
Physicians. London: RCP. 2007. 
6. 
Etter, J.F., E-cigarettes: methodological and ideological issues and research 
priorities. BMC Med, 2015. 13(1): p. 264. 
7. 
FDA (Food and Drug Administration), Guidance for industry - Modified risk 
tobacco product applications - Draft Guidance. 2012. Available from: 
https://www.fda.gov/media/83300/download (Accessed on 27 September 2019). 
8. 
Bullen, C., et al., Study protocol for a randomised controlled trial of electronic 
cigarettes versus nicotine patch for smoking cessation. BMC Public Health, 2013. 
13: p. 210. 
9. 
Farsalinos, K.E., et al., Nicotine absorption from electronic cigarette use: 
comparison between first and new-generation devices. Sci Rep, 2014. 4: p. 1-7. 
10. 
Farsalinos, K.E. and R. Polosa, Safety evaluation and risk assessment of electronic 
cigarettes as tobacco cigarette substitutes: a systematic review. Ther Adv Drug Saf, 
2014. 5(2): p. 67-86. 
11. 
Patwardhan, S. and K. Fagerström, The new nicotine pouch category: A tobacco 
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nicotine pouches: A survey of people with experience of smoking and/or vaping in 
the UK. International Journal of Environmental Research and Public Health, 2021. 
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13. 
Thornley, S., et al., A single-blind, randomized, crossover trial of the effects of a 
nicotine pouch on the relief of tobacco withdrawal symptoms and user satisfaction. 
Nicotine & Tobacco Research, 2009. 11(6): p. 715-721. 

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Data and information contained in this document are considered to constitute trade secrets 
and confidential commercial information, and the legal protections provided to such trade 
secrets and confidential information are hereby claimed under the provisions of applicable 
law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
14. 
Rensch, J., et al., Nicotine pharmacokinetics and subjective response among adult 
smokers using different flavors of on!® nicotine pouches compared to combustible 
cigarettes. Psychopharmacology, 2021: p. 1-10. 
15. 
McEwan, M., et al., A Randomised Study to Investigate the Nicotine 
Pharmacokinetics of Oral Nicotine Pouches and a Combustible Cigarette. 
European Journal of Drug Metabolism and Pharmacokinetics, 2021: p. 1-11. 
16. 
Lunell, E., et al., Pharmacokinetic comparison of a novel non-tobacco-based 
nicotine pouch (ZYN) with conventional, tobacco-based Swedish snus and 
American moist snuff. Nicotine and Tobacco Research, 2020. 22(10): p. 1757-1763. 
17. 
Lunell, E. and M. Lunell, Steady-state nicotine plasma levels following use of four 
different types of Swedish snus compared with 2-mg Nicorette chewing gum: a 
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18. 
Pickworth, W.B., et al., Nicotine absorption from smokeless tobacco modified to 
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Marchand, M., et al., Nicotine population pharmacokinetics in healthy adult 
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of the Fagerström Tolerance Questionnaire. Br J Addict, 1991. 86(9): p. 1119-27. 
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cigarette evaluation questionnaire. Addictive Behaviors, 2007. 32: p. 912–923. 
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validation. Nicotine Tob Res, 2013. 15(7): p. 1259-64. 
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device: part 2-effect on craving and smoking urges. Nicotine Tob Res, 2015. 17(1): 
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potential of drugs. 2017. 
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Products: Approaches for Meeting Current Regulatory Recommendations. 
Nicotine & Tobacco Research, 2021. 
29. 
FDA (Food and Drug Administration), Food-effect bioavailability and fed 
bioequivalence studies. 2002. 

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Document ID: VV-TMF-00821 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets 
and confidential commercial information, and the legal protections provided to such trade 
secrets and confidential information are hereby claimed under the provisions of applicable 
law. No part of this document may be publicly disclosed without the written consent of 
Philip Morris Products S.A 
30. 
American Pharmacists Association, Cytochrome P450 enzymes: substrates, 
inhibitors, and inducers, in Drug information handbook. 2014. p. 2316-2324. 
31. 
Raw, M., et al., WHO Europe evidence based recommendations on the treatment of 
tobacco dependence. Tob Control, 2002. 11(1): p. 44-6. 
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Miller, M.R., et al., Standardisation of spirometry. Eur Respir J, 2005. 26(2): p. 
319-38. 
33. 
Graham, B.L., et al., Standardization of spirometry 2019 update. An official 
American Thoracic Society and European Respiratory Society technical statement. 
Am J Respir Crit Care Med, 2019. 200(8): p. e70-e88. 
34. 
Hu, G. and P.A. Cassano, Antioxidant nutrients and pulmonary function: the Third 
National Health and Nutrition Examination Survey (NHANES III). Am J Epidemiol, 
2000. 151(10): p. 975-81. 
35. 
Fagerstrom, K., et al., The Fagerstrom Test for Nicotine Dependence as a predictor 
of smoking abstinence: a pooled analysis of varenicline clinical trial data. Nicotine 
and Tobacco Research, 2012. 14(12): p. 1467-73. 
36. 
Philip Morris Products S.A., Unpublished on file data: Investigator's Brochure for 
Mesh 2.0. Edition 3. 2020. 
37. 
Chow, S.C. and J.P. Liu, Crossover designs, in Design and analysis of clinical 
trials: concepts and methodologies. 2013, Wiley. 
38. 
Chow, D., et al., Short-term ezetimibe is well tolerated and effective in combination 
with statin therapy to treat elevated LDL cholesterol in HIV-infected patients. Aids, 
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39. 
ICH E3, Structure and content of clinical study reports - Guideline. 1995. Available 
from: 
http://www.ich.org/fileadmin/Public Web Site/ICH Products/Guidelines/Eff
icacy/E3/E3 Guideline.pdf (Accessed on 17 July 2014). 
 

 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, 
and the legal protections provided to such trade secrets and confidential information are hereby claimed under the provisions of 
applicable law. No part of this document may be publicly disclosed without the written consent of Philip Morris Products S.A 
APPENDIX A 
SCHEDULE OF EVENTS 
 
Study Day 
Day -22 to -2 
Screening 
Day -1 
Admission 
Day 1  
 
Day 2 
Day 3 
Discharge/ 
Early 
termination 
Day 4 to 6 
Safety 
Follow-Up 
Informed consent 
● 
 
 
 
 
 
Information on the risks of 
smoking/advice on smoking 
cessation and debriefing on 
Nicotine pouch 1.0 
● 
● 
 
 
● p 
 
Inclusion/exclusion criteria a 
● 
● 
 
 
 
 
Nicotine/Tobacco product use 
history 
● 
● 
 
 
 
 
Demographics b  
● 
 
 
 
 
  
Medical history, concomitant 
diseases 
● 
●c 
●c 
●c 
●c 
 
Prior medication/ Concomitant 
medication d 
● 
● 
● 
● 
● p 
● q 
Physical examination 
● 
● 
 
 
● p 
 
Body height, weight and related 
BMI 
● 
 
 
 
 
 
Vital signs e 
● 
● 
● 
● 
● p 
 

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and the legal protections provided to such trade secrets and confidential information are hereby claimed under the provisions of 
applicable law. No part of this document may be publicly disclosed without the written consent of Philip Morris Products S.A 
Study Day 
Day -22 to -2 
Screening 
Day -1 
Admission 
Day 1  
 
Day 2 
Day 3 
Discharge/ 
Early 
termination 
Day 4 to 6 
Safety 
Follow-Up 
ECG f 
● 
● 
 
 
● p 
 
Spirometry 
● 
 
 
 
 
 
Blood and urine sample for 
hematology, clinical chemistry, 
urine analysis safety panel g 
● 
● 
 
 
● p 
 
Blood sample for serology h  
● 
 
 
 
 
 
Urine sample for drug test  
● 
● 
 
 
 
 
Urine sample for cotinine test  
● 
● 
 
 
 
 
Urine pregnancy test (females) 
● 
● 
 
 
● p 
 
Blood sample for trans-3’-
hydroxycotinine and cotinine 
(CYP2A6 activity) in plasma i 
 
● 
 
 
 
 
Fagerström Test for Nicotine 
Dependence 
● 
 
 
 
 
 
NP-1 product test j 
 
● 
 
 
 
 
Enrollment 
 
● 
 
 
 
 
Randomization 
 
● 
 
 
 
 
30 min product use periods in the 
morning and in the afternoon 
 
 
● 
● 
● 
 
Blood sample collection for 
plasma nicotine l 
 
 
● 
● 
● 
 

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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, 
and the legal protections provided to such trade secrets and confidential information are hereby claimed under the provisions of 
applicable law. No part of this document may be publicly disclosed without the written consent of Philip Morris Products S.A 
Study Day 
Day -22 to -2 
Screening 
Day -1 
Admission 
Day 1  
 
Day 2 
Day 3 
Discharge/ 
Early 
termination 
Day 4 to 6 
Safety 
Follow-Up 
Product Evaluation Scale (PES) m 
 
 
● 
● 
● 
 
VAS craving assessment n 
 
 
● 
● 
● 
 
VAS liking (in-the-moment) 
assessment n 
 
 
● 
● 
● 
 
VAS liking (overall) assessment n 
 
 
● 
● 
● 
 
VAS satisfaction assessment n 
 
 
● 
● 
● 
 
VAS intention-to-use-again 
assessment n 
 
 
● 
● 
● 
 
Sensory questionnaire m 
 
 
● 
● 
● 
 
AE/SAE recording 
● 
● 
● 
● 
● p 
● 
Product events 
 
● 
● 
● 
● p 
 
Support during periods of 
abstinence from any tobacco and 
nicotine containing products (as 
required) 
 
● 
● 
● 
● 
 
Collection of used products o  
 
 
● 
● 
● 
 
Abbreviations: AE = Adverse event; BMI = Body mass index; ECG = Electrocardiogram; SAE = Serious adverse event  
a. 
Prior to enrollment at Admission on Day -1, the following inclusion and exclusion criteria will be re-checked: Inclusion Criteria: (4) Subject has smoked ≥ 10 commercially 
available cigarettes per day for 4 weeks prior to Screening Visit and Admission. Smoking status will be verified based on a urinary cotinine test (cotinine ≥ 500 ng/mL), (5) 
Subject does not plan to quit smoking or using other nicotine/tobacco-containing products in the next 3 months. Exclusion criteria: (10) Subject has a positive urine drug 
including alcohol test, (15) For women only: subject is pregnant (does not have negative pregnancy tests at Screening Visit and at Admission) or is breastfeeding, (16) For 
women of childbearing potential only: subject does not agree to use an acceptable method of effective contraception, (17) Use of estrogen-containing hormonal contraception 
or hormone replacement therapy. 

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and the legal protections provided to such trade secrets and confidential information are hereby claimed under the provisions of 
applicable law. No part of this document may be publicly disclosed without the written consent of Philip Morris Products S.A 
The following eligibility criteria will only be checked at Admission: (7) Subject has received medication within 14 days or within 5 half-lives of the drug prior to Admission, 
whichever is longer, which has an impact on CYP2A6 activity.  
b. 
Sex, date of birth/age, race and ethnicity. 
c. 
Concomitant disease status. 
d. 
All medication taken within 4 weeks prior to the Screening Visit will be documented. Prior medication which has an impact on CYP2A6 activity taken within 14 days or within 
5 half-lives of the drug (whichever is longer) prior to Day -1 is an exclusion criterion. 
e. 
Systolic and diastolic blood pressure, pulse rate and respiratory rate. On Day 1 to Day 3 in the morning, vital signs will be assessed prior to T0M. 
f. 
At Screening an ECG will be performed after signed ICF and at least 1 hour after smoking cigarettes, on Day -1 an ECG will be performed prior to enrollment, on Day 3 an 
ECG will be performed 60 minutes ± 10 minutes after T0. 
g. 
Blood samples should be taken in the morning of the Screening visit, Admission (Day -1) and Discharge (Day 3) or at Early termination. Subjects should have fasted for at least 
10 hours prior to safety laboratory assessments except at the Screening visit and Early termination where non-fasting samples will be used.  
h. 
Tests for hepatitis B (HbsAg), hepatitis C (HCV antibody) virus and human immunodeficiency virus (anti-HIV1/2) will be performed at the Screening Visit. 
i. 
Sample taken prior to NP-1 product test. 
j. 
On Day -1, after enrollment, subjects will perform a product test using NP-1 for 30 minutes (± 1 minute).  
k. 
On Day 1 to Day 3 in the morning and in the afternoon, subjects will use one product for 30 minutes (± 1 minute) according to the randomized product use sequence. 
l. 
On Day 1 to Day 3, 24 blood samples will be taken for determination of nicotine concentration: one blood sample will be taken prior to the start of product use in the morning 
(T0A) 5 minutes ± 1 minute (T-1). Thereafter in relation to T0A, blood will be drawn at the following time points: T1 after 5 minutes ± 1 minute, T2 after 10 minutes ± 1 
minute, T3 after 15 minutes ± 1 minute, T4 after 20 minutes ± 1 minute, T5 after 25 minutes ± 1 minute, T6 after 30 minutes ± 1 minute, T7 after 35 minutes ± 1 minute, T8 
after 40 minutes ± 1 minute, T9 after 1 hour ± 5 minutes, T10 after 3 hours ± 5 minutes, T11 after 6 hours ± 5 minutes. 
On Day 2, 2 additional blood samples will be taken for determination of the terminal elimination half-life (t1/2z). Blood samples will be taken in relation to T0A from Day 2 at 
the following time points: T1z after 8 hours ± 5 minutes and T2z after 12 hours ± 5 minutes. 
m. On Day 1 to Day 3 in the morning and in the afternoon, the PES and the Sensory questionnaire  will be answered at T9 after 1 hour ± 5 minutes, after T0M and T0A. 
n. 
On Day 1 to Day 3 in the morning and in the afternoon, VAS craving, VAS liking (in the moment) and VAS satisfaction assessments at: Within 15 minutes prior to T0M and 
T0A (VAS craving only), and at T1 after 5 minutes ± 1 minute, T2 after 10 minutes ± 1 minute, T3 after 15 minutes ± 1 minute, T4 after 20 minutes ± 1 minute, T5 after 25 
minutes ± 1 minute, T6 after 30 minutes ± 1 minute, T7 after 35 minutes ± 1 minute, T8 after 40 minutes ± 1 minute, T9 after 1 hour ± 5 minutes, T10 after 3 hours ± 5 
minutes (VAS craving and VAS satisfaction only), T11 after 6 hours ± 5 minutes (VAS craving and VAS satisfaction only) after T0M and T0A. On Day 1 to Day 3 in the 
morning and in the afternoon, VAS liking (overall) assessment at: T10 after 3 hours ± 5 minutes, after T0M and T0A. On Day 1 to Day 3 in the morning and in the afternoon, 
VAS intention to use again assessment at: T6 after 30 minutes ± 1 minute, and T10 after 3 hours ± 5 minutes, after T0M and T0A. 
 
o. 
On Day 1 to Day 3 in the morning and in the afternoon, used product will be collected for analysis of residual nicotine. 
p. 
Early termination assessments to be conducted in subjects who withdraw consent / are discontinued from the study. 
q. 
Only medication administered as treatment for an adverse event 

 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
APPENDIX B 
PARTICIPATING LABORATORIES  
Bioanalytical laboratory (Plasma Nicotine and CYP2A6 analyses): 
 
 
 
 
Safety Laboratory: 
 
 
  
 
 
 
 

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