A Randomized, Controlled, Open-label Short-term Study to Evaluate Changes in Exposure to Harmful and Potentially Harmful Constituents in Adult Smokers Who Completely Switch to on!® Nicotine Pouches in a Clinical Setting
Phase: NA
Conditions: Tobacco Use
Sponsor: Altria Client Services LLC

A Randomized, Controlled, Open-label Short-term Study to Evaluate Changes in Exposure to 
Harmful and Potentially Harmful Constituents in Adult Smokers Who Completely Switch to 
on!® Nicotine Pouches in a Clinical Setting 
NCT05664672 
09MAR2021 

TITLE PAGE 
Protocol 
A Randomized, Controlled, Open-label Short-term Study to Evaluate 
Changes in Exposure to Harmful and Potentially Harmful Constituents in 
Adult Smokers Who Completely Switch to on!® Nicotine Pouches in a 
Clinical Setting 
Protocol Status: Final 
Protocol Date: 09 March 2021 
Protocol Version: 1.0 
Study Product: on!® Nicotine Pouches 
Protocol Reference Number: ALCS-REG-20-15-OTDN 
Covance Study Number: 000000215511 
 
Sponsor: 
Altria Client Services LLC 
601 East Jackson Street 
Richmond, Virginia 23219, USA 
Study Sites: 
QPS  
1820 West Mount Vernon Street 
Springfield, Missouri 65802, USA 
 
 
NOCCR  
1928 Alcoa Highway, Suite 107  
Knoxville, Tennessee 37920, USA 
 
 
CKRA  
3475 Richmond Road 
3rd Floor  
Lexington, Kentucky 40509, USA 
 
Sponsor Signatories: 
 
 
 
 
 
Principal Investigators: 
  
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 

Protocol  
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Covance Study: 000000215511 
Protocol Reference: ALCS-REG-20-15-OTDN 
Final, 09 March 2021 
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SPONSOR APPROVAL 
 
I have read the protocol and approve it: 
 
 
 
 
 
 
 
 
Date 
Associate Fellow 
Altria Client Services LLC 
 
 
 
 
_______
_______________ ______________________________ 
 
Date 
Study Manager 
Altria Client Services LLC 
 
 
 
 
_______
___________________ ______________________________ 
 
Date 
Designated Medical Expert 
Altria Client Services LLC 
 
 
 
 
_______
________________ ______________________________ 
 
Date 
Biostatistician 
Altria Client Services LLC 
DocuSign Envelope ID: 2090B712-4A2A-4B88-B5CF-84E74CB70A62
3/9/2021
3/9/2021
3/9/2021
3/9/2021

Protocol  
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Covance Study: 000000215511 
Protocol Reference: ALCS-REG-20-15-OTDN 
Final, 09 March 2021 
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INVESTIGATOR AGREEMENT 
 
 
 
I have read the protocol and agree to conduct the study as described herein. 
 
 
 
 
 
 
 
Name, Qualifications 
 
Date 
Principal Investigator 
 
 

Protocol  
CONFIDENTIAL 
Covance Study: 000000215511 
Protocol Reference: ALCS-REG-20-15-OTDN 
Final, 09 March 2021 
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STUDY IDENTIFICATION 
Sponsor 
Altria Client Services LLC 
601 East Jackson Street 
Richmond, Virginia 23219, USA 
Sponsor’s Study Contact 
 
 
 
 
 
Sponsor’s Medical Contact  
 
 
 
 
 
 
 
  
Study Site 
QPS  
1820 West Mount Vernon Street  
Springfield, Missouri 65802, USA 
 
Study Site 
NOCCR  
1928 Alcoa Highway, Suite 107  
Knoxville, Tennessee 37920, USA 
Study Site 
CKRA  
3475 Richmond Road 
3rd Floor  
Lexington, Kentucky 40509, USA 
Principal Investigator 
 
  
 
 
 
Principal Investigator 
 
  
  
  
 

Protocol  
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Covance Study: 000000215511 
Protocol Reference: ALCS-REG-20-15-OTDN 
Final, 09 March 2021 
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Principal Investigator 
 
  
 
  
 
 
Sub-investigators 
Obtain information from Form FDA 1572 
Clinical Laboratories  
Obtain information from Form FDA 1572 
Bioanalytical Laboratories 
Analytischbiologisches Forschungslabor GmbH 
(ABF) 
Semmelweisstraße 5, 
82152 Planegg, Germany 
 
Celerion Inc. 
624 Peach Street 
Lincoln, Nebraska 68502, USA 
Statistician 
 
 

Protocol  
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Covance Study: 000000215511 
Protocol Reference: ALCS-REG-20-15-OTDN 
Final, 09 March 2021 
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SYNOPSIS 
Study Title 
A Randomized, Controlled, Open-label Short-term Study to Evaluate Changes in Exposure to 
Harmful and Potentially Harmful Constituents in Adult Smokers Who Completely Switch to 
on!® Nicotine Pouches in a Clinical Setting 
Objectives 
The primary objective of the study is: 
 To compare 24-hour urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
(NNAL) in subjects using nicotine pouches (NP) for 7 days versus subjects who 
continue to smoke cigarettes for 7 days. 
The secondary objectives of the study are: 
 To compare biomarkers of exposure (BOEs)1 (except total NNAL) in subjects using 
NP for 7 days versus subjects who continue to smoke cigarettes for 7 days 
 To compare BOEs in subjects using NP for 7 days versus subjects who stopped using 
any tobacco products for 7 days 
 To characterize product use behaviors (such as: number of cigarettes smoked per day, 
number of NP use per day, number of NPs per use, average duration of each NP use). 
Study Design 
This is an open-label, randomized, 5 parallel-group clinical study evaluating changes in 
exposure to selected harmful and potentially harmful constituents (HPHCs) and product use 
behavior in adult smokers who are randomly assigned to 1 of the 5 groups; continue smoking 
(Group 1), completely switch to 2 mg (Group 2), 4 mg (Group 3), or 8 mg (Group 4) on!® 
NP, or stop using any tobacco products (Group 5) for 7 days. Potential subjects will be 
screened to assess their eligibility to enter the study within 28 days prior to check-in (Day -3). 
                                                 
 
1 BOEs : Urine: total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), nicotine equivalents (NE), 
2-aminonaphthalene (2-AN), 4-aminobiphenyl (4-ABP), 2-hydroxyethyl mercapturic acid (HEMA), 
2-cyanoethylmercapturic acid (CEMA), S-phenyl mercapturic acid (S-PMA), 3-hydroxy-1-
methylpropylmercapturic acid (3-HMPMA), 3-hydroxypropylmercapturic acid (3-HPMA), 
2-hydroxypropylmercapturic acid (2-HPMA), N-acetyl-S-(2-carbamoylethyl) cysteine (AAMA), N-acetyl-S-(2-
hydroxy-2-carbamoylethyl)cysteine (GAMA), 2-hydroxybutenylmercapturic acid (2-MHBMA), 2-OH-Fluorene 
(2-OHFle), 2-Naphthol,1-OH-Phenanthrene (1-OHPhe), 3-hydroxybenzo-a-pyrene (3-HB[a]P), urine 
mutagenicity, 1-hydroxypyrene (1-OHP). Blood: carboxyhemoglobin (COHb) 

Protocol  
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Covance Study: 000000215511 
Protocol Reference: ALCS-REG-20-15-OTDN 
Final, 09 March 2021 
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Subjects will be admitted into the study site on Day -3 and be confined to the study site until 
discharge on Day 8.  
Study Groups 
 
Product Code 
Product Description 
Group 1 
A 
Subject’s Usual Brand Cigarette 
Group 2 
B 
Mint on!® 2 mg NP 
Group 3 
C 
Mint on!® 4 mg NP 
Group 4 
D 
Mint on!® 8 mg NP 
Group 5 
- 
Tobacco Cessation Group 
Number of Subjects 
Approximately 150 subjects will be enrolled in the study. 
Diagnosis and Main Criteria for Inclusion 
Healthy males and females (no more than 60% of either gender), 21-45 years of age, 
self-affirmed either menthol or non-menthol combustible cigarette smokers (average daily 
consumption between 10 and 30 factory-manufactured combustible cigarettes for at least 12 
months prior to screening). 
Study Products 
 Product A (reference): subject’s usual brand cigarette, ad libitum, from Day 1 to 
Day 7 
 Product B (test): 2 mg NP marketed as Mint on!® 2 mg nicotine pouches, at least 
3 pouches/day, from Day 1 to Day 7 
 Product C (test): 4 mg NP marketed as Mint on!® 4 mg nicotine pouches, at least 
3 pouches/day, from Day 1 to Day 7 
 Product D (test): 8 mg NP marketed as Mint on!® 8 mg nicotine pouches, at least 
3 pouches/day, from Day 1 to Day 7 
Duration of Subject Participation in the Study 
Planned screening duration: up to 28 days 
Planned study duration (screening to follow-up): approximately 5 weeks. 
 
 

Protocol  
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Covance Study: 000000215511 
Protocol Reference: ALCS-REG-20-15-OTDN 
Final, 09 March 2021 
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Endpoints 
Primary endpoint:  
 24-hour total urinary NNAL (mg/24 hours) excreted on Day 7 
Secondary endpoints: 
 24-hour urinary NE, 2-AN, 4-ABP, HEMA, CEMA, S-PMA, 3 HMPMA, 3-HPMA, , 
2-HPMA, AAMA, GAMA, 2-MHBMA, 2 OHFle, 2-Naphthol, 1 OHPhe, 3-HB[a]P, 
mutagenicity, and 1-OHP excreted on Day 7 
 COHb on Day 7 
 Product use behavior daily from Day 1 to Day 7 (ie, number of cigarettes smoked per 
day[CPD], number of NP per day [NPPD], number of NP per use [NPPU], and 
average duration of each NP use) 
Safety: 
Adverse events, clinical laboratory evaluations (hematology, clinical chemistry, urinalysis), 
12-lead electrocardiograms, vital signs measurements, and physical examinations. 
Statistical Methods 
Linear mixed models for analysis of covariance will be used to compare the Day 7 biomarker 
values between groups as described in the study objectives. In the statistical models, the 
outcome variable will be included as a dependent variable; group and gender will be included 
as fixed effects; and baseline values of corresponding biomarker will be included as 
covariates. For the NP groups compared to the continue cigarette smoking group, Dunnett’s 
method will be used for the adjustment of multiple comparisons. The SAS procedure Proc 
Mixed will be used. The least-squares means (LSM) difference and 95% confidence interval 
for the LSM difference between the test and reference groups and p-values will be provided.  
Product use behaviors and safety parameters will be analyzed using descriptive statistics.  

Protocol  
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Covance Study: 000000215511 
Protocol Reference: ALCS-REG-20-15-OTDN 
Final, 09 March 2021 
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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF TABLES AND FIGURES........................................................................................10 
LIST OF ABBREVIATIONS ..................................................................................................12 
1. 
INTRODUCTION ...........................................................................................................14 
1.1. 
Background ............................................................................................................14 
1.2. 
Study Rationale ......................................................................................................15 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................16 
2.1. 
Objectives ..............................................................................................................16 
2.2. 
Endpoints ...............................................................................................................16 
2.2.1. 
Primary Endpoints .......................................................................................16 
2.2.2. 
Secondary Endpoints ...................................................................................16 
3. 
INVESTIGATIONAL PLAN ..........................................................................................17 
3.1. 
Overall Study Design and Plan ..............................................................................17 
3.2. 
Discussion of Study Design ...................................................................................18 
3.3. 
Selection of Study Products ...................................................................................19 
4. 
SELECTION OF STUDY POPULATION .....................................................................19 
4.1. 
Inclusion Criteria ...................................................................................................19 
4.2. 
Exclusion Criteria ..................................................................................................20 
4.3. 
Subject Number and Identification ........................................................................22 
4.4. 
Subject Withdrawal and Replacement ...................................................................22 
4.5. 
Study Termination .................................................................................................23 
5. 
STUDY PRODUCTS ......................................................................................................23 
5.1. 
Description, Storage, Packaging, and Labeling .....................................................23 
5.2. 
Study Product Administration................................................................................24 
5.2.1. 
Product Trial ................................................................................................24 
5.2.2. 
Product Use from Day 1 ..............................................................................24 
5.3. 
Randomization .......................................................................................................25 
5.4. 
Blinding..................................................................................................................25 
5.5. 
Study Product Compliance ....................................................................................25 
5.6. 
Study Product Accountability, Storage, and Preparation .......................................25 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................26 
6.1. 
Concomitant Therapies ..........................................................................................26 
6.2. 
Diet .........................................................................................................................26 

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Protocol Reference: ALCS-REG-20-15-OTDN 
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6.3. 
Smoking .................................................................................................................27 
6.4. 
Exercise ..................................................................................................................27 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................27 
7.1. 
Harmful and Potentially Harmful Constituent Assessments .................................28 
7.1.1. 
Carboxyhemoglobin Assessments ...............................................................28 
7.1.2. 
Biomarkers of Exposure (other than COHb) Assessments ..........................28 
7.2. 
Product Use Behavior Assessments .......................................................................28 
7.3. 
Safety Assessments ................................................................................................29 
7.3.1. 
Adverse Events ............................................................................................29 
7.3.2. 
Clinical Laboratory Evaluations ..................................................................29 
7.3.3. 
Vital Signs ....................................................................................................30 
7.3.4. 
12-Lead Electrocardiogram .........................................................................30 
7.3.5. 
Physical Examination...................................................................................30 
7.3.6. 
COVID-19 Screening...................................................................................30 
7.3.7. 
Tobacco Cessation Information ...................................................................31 
8. 
DATA MANAGEMENT.................................................................................................31 
9. 
MONITORING OF THE STUDY...................................................................................31 
10. SAMPLE SIZE AND DATA ANALYSIS ......................................................................32 
10.1. Determination of Sample Size ...............................................................................32 
10.2. Analysis Populations ..............................................................................................32 
10.2.1. 
Biomarker of Exposure Population ..............................................................32 
10.2.2. 
Safety Population .........................................................................................32 
10.3. Biomarker of Exposure Analyses ..........................................................................33 
10.4. Product Use Behavior ............................................................................................33 
10.5. Safety Analysis ......................................................................................................33 
10.6. Interim Analysis .....................................................................................................33 
11. REFERENCES ................................................................................................................34 
12. APPENDICES .................................................................................................................36 
Appendix 1: Adverse Event Reporting ..............................................................................37 
Appendix 2: Clinical Laboratory Evaluations ...................................................................41 
Appendix 3: Contraception Guidance ................................................................................42 
Appendix 4: Regulatory, Ethical, and Study Oversight Considerations ............................43 
Appendix 5: Schedule of Assessments ..............................................................................46 
Appendix 6: Fagerström Test for Cigarette Dependence14 Questionnaire ........................50 
 
LIST OF TABLES AND FIGURES 
Table 1: 
Primary Endpoint .......................................................................................16 
Table 2: 
Secondary Endpoints – Biomarkers of Exposure ......................................16 
Table 3: 
Study Products ...........................................................................................24 

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Table 4: 
Group Allocation .......................................................................................25 
 
Figure 1:  
Study Schematic.........................................................................................18 
 

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Covance Study: 000000215511 
Protocol Reference: ALCS-REG-20-15-OTDN 
Final, 09 March 2021 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AAMA 
N-acetyl-S-(2-carbamoylethyl) cysteine  
4-ABP 
4-aminobiphenyl  
AE 
adverse event 
ALCS 
Altria Client Services 
2-AN 
2-aminonaphthalene  
BOE 
biomarker of exposure 
CC 
continue smoking cigarettes 
CEMA 
2-cyanoethylmercapturic acid  
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
COHb 
carboxyhemoglobin  
COVID 
coronavirus disease 
CPD 
number of cigarettes smoked per day 
CRO 
contract research organization 
DMP 
Data Management Plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GAMA 
N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine  
GCP 
good clinical practice 
3-HB[a]P 
3-hydroxybenzo-a-pyrene  
HEMA 
2-hydroxyethyl mercapturic acid  
HPHC 
harmful and potentially harmful constituents 
3-HMPMA 
3-hydroxy-1-methylpropylmercapturic acid 
2-HPMA 
2-hydroxypropylmercapturic acid  
3-HPMA 
3-hydroxypropylmercapturic acid 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonization 
IRB 
institutional review board 
LSM 
least-squares means 
MedDRA 
Medical Dictionary for Regulatory Activities 
2-MHBMA 
2-hydroxybutenylmercapturic acid  

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MST 
moist smokeless tobacco 
NE 
nicotine equivalents 
NNAL 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
NP 
nicotine pouch 
NP2 
2 mg nicotine pouch 
NP4 
4 mg nicotine pouch 
NP8 
8 mg nicotine pouch 
NPPD 
number of nicotine pouches used per day 
NPPU 
number of nicotine pouch per use 
NT 
no tobacco 
1-OHPhe 
1-OH-Phenanthrene  
2-OHFle 
2-OH-Fluorene  
1-OHP 
1-hydroxypyrene  
OTDN 
Oral Tobacco-Derived Nicotine 
PK 
pharmacokinetic 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAE 
serious adverse event 
SoA 
Schedule of Assessments 
S-PMA 
S-phenyl mercapturic acid  
UBC 
usual brand cigarette 
 
 

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1. INTRODUCTION 
1.1. 
Background 
The harm caused by tobacco product use is primarily attributable to cigarette smoking. 
Smoking is the primary causal factor for at least 30% of all cancer deaths, for nearly 80% of 
deaths from chronic obstructive pulmonary disease, and early cardiovascular disease and 
deaths. The scientific evidence has clearly established that smoking cessation leads to a 
significant reduction in smoking-related morbidity and mortality. 1,2,3,4 While cessation is the 
most desirable outcome for reducing the harm from smoking-related diseases, many adult 
smokers are unable or unwilling to quit. Public health authorities, including the FDA, have 
acknowledged a continuum of risk among tobacco products, with combustible cigarettes at 
the highest end and non-combustible products on the lower end of that spectrum.5,6 
The Oral Tobacco-Derived Nicotine (OTDN) products are non-combustible and intended for 
oral consumption. The OTDN category is one of the fastest growing tobacco product 
segments in the United States. 
The on!® nicotine pouches (NPs) are one such portfolio of products that belong to the OTDN 
category. The on!® NP are innovative oral tobacco products that do not contain cut, ground, 
powdered, or leaf tobacco – a point of differentiation compared to smokeless tobacco 
products in the United States. The on!® NP contain tobacco-derived nicotine and non-tobacco 
ingredients used in foods. The nicotine in the on!® products is extracted from tobacco plants 
and crystalized into nicotine salt. The on!® products do not contain any of the major food 
allergens (milk, eggs, fish, shellfish, tree nuts, peanuts, wheat, and soy). 
on!® product contains tobacco-derived nicotine, which is addictive. Nicotine can harm a baby 
for a female who is pregnant or nursing. Nicotine can increase heart rate, blood pressure and 
aggravate diabetes. Nicotine can cause dizziness, nausea and stomach pain. A burning 
sensation may be experienced while using oral nicotine products. on!® product packages have 
the following warning: “WARNING: This product contains nicotine. Nicotine is an addictive 
chemical.” 
These products have been available since 2016. The on!® NP are well tolerated and minimal 
consumer complaints have been reported. As an example of this, we received only 17 
consumer reports in a 6-month timeframe, July through December 2019, during which time 
period 2,026,251 cans had been purchased. 
Two pharmacokinetic (PK) studies were conducted with on!® NP.  
The first study (ALCS-REG-19-12-OTDN) included 6 flavor variants (Berry, Cinnamon, 
Citrus, Coffee, Original, and Wintergreen) of the 4 mg on! ® NP and the subject’s usual brand 
cigarette (UBC) as a reference product. The purpose of this PK study was to characterize the 
nicotine plasma PK profile from single use (1 pouch use for 30 minutes or 10 inhalations 
from 1 cigarette). Prior to randomization, subjects had a Product Trial period to use the NP at 
home for at least 3 days. In addition, subjects were allowed to use each of the NP ad libitum 
for 4 hours following randomization. A total of 42 (25 males, mean age 36.3 years) healthy 
adult cigarette smokers were enrolled and 41 completed the study. Starting from the first 

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product use in the Product Trial until the time of randomization, a total of 9 mild adverse 
events (AEs) were reported by 6 (14%) subjects. The most frequent events were hiccups and 
throat irritation, experienced by 2 (5%) subjects each. The investigator considered 3 AEs 
(dyspepsia, pharyngeal paresthesia, and throat irritation) to be definitely related to study 
product, 2 AEs (hiccups and throat irritation) to be likely related, 2 AEs (hiccups and 
productive cough) to be possibly related, and the remaining 2 AEs (headache and toothache) 
not related. Of note, the investigator was unable to determine whether the AEs were related to 
NP or cigarette since both products were allowed ad libitum during the Product Trial. From 
randomization on Day -1 through study completion on Day 7, a total of 25 mild AEs were 
reported by 18 (43%) subjects, with more subjects experiencing AEs following cigarettes (8 
[19%]) compared to NP (≤ 3 [7%] subjects across flavors). Pain in extremity (due to 
venipunctures/blood draws) was the most frequently reported event, experienced by 4 (10%) 
subjects. All remaining AEs were reported by 3 or fewer (≤ 7%) subjects each. The 
investigator considered 3 AEs (dizziness [cigarette], gingival bleeding [Cinnamon NP], and 
hyperhidrosis [cigarette]) to be likely related to study product, 3 AEs (1 dyspepsia [Citrus 
NP] and 2 headaches [cigarette]) to be possibly related, and the remaining events unlikely 
related or not related. There were no serious AEs (SAEs) reported in this study and no 
subjects were discontinued due to AEs. 
The second study (ALCS-REG-19-13-OTDN) included 5 levels (1.5, 2. 3.5, 4, and 8 mg) of 
Mint on! ® NP. A total of 30 (29 males, mean age 34.9 years) healthy adult dual tobacco users 
(those who smoke cigarette and also use moist smokeless tobacco [MST]) were enrolled and 
completed the study with the similar design as the first study. During the Product Trial 
period, during which subjects were allowed to use ad libitum the supplied Mint on! ® NP, and 
their usual brands of combustible cigarettes and loose MST, a total of 9 mild AEs were 
reported by 6 (20%) subjects. The most frequent event was headache, experienced by 4 
(13%) subjects. The investigator considered all events unlikely or not related to study 
product. From the time of randomization on Day -1 until the end of study on Day 7, a total of 
61 AEs were reported by 20 (67%) subjects across study products. The majority of the events 
(59) were mild in severity and 2 (headache [cigarette] and nausea [8 mg NP]) were moderate. 
Headache was the most frequently reported event, experienced by 8 (27%) subjects, followed 
by nausea, experienced by 6 (20%) subjects. All remaining events were reported by 4 or 
fewer (≤ 13%) subjects each. The investigator considered 7 events to be likely related to 
study product and 13 events possibly related. The likely/possibly related events occurred 
across study products and included, but were not limited to, nausea, vomiting, dizziness, and 
headache. The remaining 41 events were considered unlikely/not related to study product. 
There were no SAEs reported in this study and no subjects were discontinued due to AEs. 
1.2. 
Study Rationale 
A dose-response relationship has been demonstrated between cigarette smoking and cancer of 
the lung, larynx, oral cavity, and urinary bladder (2004 SGR Report – The Health 
Consequences of Smoking7). Therefore, sustained and prolonged reduction in exposure to the 
harmful and potentially harmful constituents (HPHCs) from cigarette smoke will result in 
reduction in smoking-related disease risks. The exposure can be assessed by measuring the 
levels of constituents or metabolites in urine or blood (biomarkers of exposure - BOEs). 

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The purpose of this study is to generate evidence regarding the extent of reduction in 
exposure to selected HPHCs in adult smokers switching to on!® NPs. The study intends to 
determine changes in exposure to selected HPHCs by measuring biomarkers in adult smokers 
who completely switch from smoking to use of on!® NP compared to those who continue 
smoking cigarettes (CC) or stop using all tobacco products (NT).  
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is: 
 To compare 24-hour urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
(NNAL) in subjects using NP for 7 days versus subjects who continue to smoke 
cigarettes for 7 days. 
The secondary objectives of the study are: 
 To compare BOEs (except total NNAL) in subjects using NP for 7 days versus 
subjects who continue to smoke cigarettes for 7 days 
 To compare BOEs in subjects using NP for 7 days versus subjects who stopped using 
any tobacco products for 7 days 
 To characterize product use behaviors (such as: number of cigarettes smoked per day 
[CPD], number of NPs used per day [NPPD], number of NPs per use [NPPU], 
average duration of each NP use). 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoint is presented in Table 1. 
Table 1: 
Primary Endpoint 
2.2.2. 
Secondary Endpoints 
The secondary BOE endpoints are presented in Table 2. 
Table 2: 
Secondary Endpoints – Biomarkers of Exposure 
Biomarker of Exposure 
Abbreviation 
Associated Toxicant 
Matrix 
Nicotine equivalents (nicotine, 
cotinine, 3-hydroxycotinine and 
their glucuronide conjugates)  
NE 
Nicotine 
Urine (24 hours)  
Biomarker 
Abbreviation 
Associated Toxicant 
Matrix 
Total 4-(methylnitrosamino)-
1-(3-pyridyl)-1-butanol 
NNAL 
4-[Methyl(nitroso)amino]-1-(3-
pyridinyl)-1-butanone 
 
Urine (24-hour) 

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Biomarker of Exposure 
Abbreviation 
Associated Toxicant 
Matrix 
3-hydroxypropylmercapturic acid 
3-HPMA 
Acrolein 
Urine (24 hours)  
3-hydroxy-1-
methylpropylmercapturic acid 
3-HMPMA 
Crotonaldehyde 
Urine (24 hours)  
2-hydroxypropylmercapturic acid  
2-HPMA 
Propylene oxide 
Urine (24 hours) 
S-phenylmercapturic acid 
S-PMA 
Benzene 
Urine (24 hours)  
2-cyanoethylmercapturic acid 
CEMA 
Acrylonitrile 
Urine (24 hours)  
1-hydroxypyrene 
1-OHP 
Pyrene 
Urine (24 hours)  
2-hydroxyethylmercapturic acid 
HEMA 
Ethylene oxide 
Urine (24 hours)  
2-hydroxybutenylmercapturic acid 
(2-MHBMA) 
2-MHBMA 
1,3 butadiene 
Urine (24 hours) 
2-Naphthol 
- 
Naphthalene 
Urine (24 hours) 
4-aminobiphenyl 
4-ABP 
4-aminobiphenyl 
Urine (24 hours)  
2-aminonaphthalene 
2-AN 
2-aminonaphthalene 
Urine (24 hours)  
N-acetyl-S-(2-carbamoylethyl) 
cysteine  
AAMA 
Acrylamide 
Urine (24 hours) 
N-acetyl-S-(2-hydroxy-2-
carbamoylethyl)cysteine  
GAMA 
Acrylamide 
Urine (24 hours) 
2-OH-Fluorene 
2-OHFle 
Fluorene 
Urine (24 hours) 
Naphthol,1-OH-Phenanthrene 
1-OHPhe 
Benzo-a-pyrene 
Urine (24 hours) 
3-hydroxybenzo-a-pyrene  
3-HB[a]P 
Benzo-a-pyrene 
Urine (24 hours) 
Urine mutagenicity 
- 
- 
Urine (24 hours) 
Carboxyhemoglobin 
COHb 
Carbon monoxide 
Blood 
Additional endpoint is: 
 Product use behavior daily from Day 1 to Day 7 (ie, CPD, NPPD, NPPU, and the 
average duration of each NP use). 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This will be an open-label, randomized, 5 parallel-groups clinical study evaluating changes in 
exposure to selected HPHCs and product use behavior in adult smokers.  
Study population will be randomized into 5 groups: 
 Group 1 (n = 30): CC; subjects will be asked to continue smoking their UBCs ad 
libitum for 7 days. 
 Group 2 (n = 30): 2 mg NP (NP2); subjects will exclusively use 2 mg NP, using at 
least 3 pouches per day for 7 days. 
 Group 3 (n = 30): 4 mg NP (NP4); subjects will exclusively use 4 mg NP, using at 
least 3 pouches per day for 7 days. 
 Group 4 (n = 30): 8 mg NP (NP8); subjects will exclusively use 8 mg NP, using at 
least 3 pouches per day for 7 days. 

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 Group 5 (n = 30): No Tobacco (NT); subjects will completely stop all tobacco product 
usage for 7 days. 
The goal is to recruit approximately 150 subjects (not more than 60% of either gender) with 
the aim of at least 100 subjects completing the study (20 subjects, minimum per group).  
An overview of the study design is shown in Figure 1. 
Figure 1:  
Study Schematic 
 
Abbreviations: EOS = end of the study; NP2 = 2 mg nicotine pouches; NP4 = 4 mg nicotine pouches; NP8 = 8 
mg nicotine pouches; NT = no tobacco; UBC = usual brand cigarette. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first product administration. Subjects will be admitted into the study site on 
Day -3 and be confined to the study site until discharge on Day 8.  
The total duration of study participation for each subject (from screening through last visit) is 
anticipated to be approximately 5 weeks. 
The start of the study is defined as the date the first subject signs an informed consent form 
(ICF). The point of enrollment occurs at the time of subject check-in visit. The study 
completion is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled).  
A Schedule of Assessments (SoA) is presented in Appendix 5. 
3.2. 
Discussion of Study Design 
This is an open-label, randomized, 5 parallel-group clinical study evaluating changes in 
exposure to selected HPHCs and product use behavior in adult smokers.  
Study population will be divided into 5 groups (see Section 3.1 for details). Group 1 (subjects 
continuing to smoke their UBC) and Group 5 (NT) will serve as references, indicating 
maximum and minimum levels of BOEs. 
Collecting CPD, NPPD, NPPU, and the average duration of each NP use will help to define 
use behaviors.  
This study follows the recommendations of the Modified Risk Tobacco Product Applications 
draft FDA guidance.8 

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3.3. 
Selection of Study Products  
on!® Nicotine pouches are available in 5 levels (1.5, 2, 3.5, 4, and 8 mg) of nicotine. The 2-, 
4-, and 8-mg levels will be assessed in this study as they represent the range of nicotine levels 
across the portfolio. The Mint flavor was chosen as it is the most widely used flavor variant. 
Subjects will be required to use NP at least 3 times per day, to ensure a minimum use of the 
product. 
4.  SELECTION OF STUDY POPULATION 
Self-affirmed adult smokers will be screened to enroll approximately 150 subjects (not more 
than 60% of either gender). Study population will be divided into 5 groups: 
 Group 1 (n = 30): CC; subjects will be asked to continue smoking their UBCs ad 
libitum for 7 days. 
 Group 2 (n = 30): 2 mg NP (NP2); subjects will exclusively use 2 mg NP, using at 
least 3 pouches per day for 7 days. 
 Group 3 (n = 30): 4 mg NP (NP4); subjects will exclusively use 4 mg NP, using at 
least 3 pouches per day for 7 days. 
 Group 4 (n = 30): 8 mg NP (NP8); subjects will exclusively use 8 mg NP, using at 
least 3 pouches per day for 7 days. 
 Group 5 (n = 30): NT; subjects will completely stop all tobacco product usage for 
7 days. 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria at the screening visit unless otherwise 
stated: 
1. Voluntary consent to participate in this study documented on the signed ICF 
2. Healthy adult males and females 21 to 45 years of age, inclusive, at screening 
3. Smoking history (self-reported at screening) of an average of at least 10 but no more 
than 30 factory-manufactured combustible cigarettes (either menthol or non-menthol) 
daily for at least 12 months prior to screening. Brief periods (ie, up to 7 consecutive 
days) of non-smoking during the 3 months prior to screening (eg, due to illness or 
participation in a study where smoking was prohibited) will be permitted 
4. Positive urine cotinine (≥ 500 ng/mL) at screening 
5. Female subjects (see Appendix 3) who are heterosexually active and of childbearing 
potential (eg, neither surgically sterile at least 6 months prior to check-in nor 
postmenopausal with amenorrhea for at least 12 months prior to check-in with 
follicle-stimulating hormone [FSH] levels consistent with postmenopausal status) 
must have been using one of the following forms of contraception for the time period 
indicated and agree to continue using it through completion of the study: 

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o Hormonal (eg, oral, vaginal ring, transdermal patch, implant, injection) 
consistently for at least 3 months prior to check-in, double barrier (ie, condom 
with spermicide or diaphragm with spermicide) consistently for at least 
4 weeks prior to check-in, an intrauterine device for at least 4 months prior to 
check-in 
o Exclusive partner who has been vasectomized for at least 6 months (inclusive) 
prior to check-in 
Female subjects of childbearing potential who are not currently engaging in 
heterosexual intercourse must agree to use one of the above methods of birth control 
through completion of study, in the event that they have heterosexual intercourse 
during the course of the study. 
6. Female subjects who are of nonchildbearing potential must have undergone one of the 
following sterilization procedures at least 6 months prior to check-in: 
o Hysteroscopic sterilization (including Essure® or similar nonsurgical 
sterilization procedures); bilateral tubal ligation or bilateral salpingectomy; 
hysterectomy; bilateral oophorectomy 
Or be postmenopausal with amenorrhea for at least 12 months prior to check-in and 
have FSH levels consistent with postmenopausal status 
7. Willing to comply with the requirements of the study 
8. Willing to use all 3 on!® NP after the Product Trial at check-in 
9. Willing and able to abstain from cigarettes from Day 1 through the end of the study 
(EOS). 
4.2. 
Exclusion Criteria 
Subjects will be excluded from the study if there is evidence of any of the following criteria 
at screening, check-in, or prior to randomization, as appropriate. 
1. Use of any type of tobacco- or nicotine-containing products other than manufactured 
cigarettes (eg, e-vapor products, roll-your-own cigarettes, bidis, snuff, nicotine 
inhaler, pipe, cigar, chewing tobacco, nicotine patch, nicotine spray, nicotine lozenge, 
or nicotine gum) in the 7 days prior to check-in 
2. Self-reported puffers (ie, adult smokers who draw smoke from the cigarette into the 
mouth and throat but do not inhale) 
3. Planning to quit smoking in the next 30 days (from screening visit) 
4. History or presence of clinically significant gastrointestinal, renal, hepatic, 
neurologic, hematologic, endocrine, oncologic, urologic, existing respiratory diseases, 
immunologic, psychiatric, lymphatic, or cardiovascular disease, or any other 
condition that, in the opinion of the investigator, would jeopardize the safety of the 
subject or impact the validity of the study results 

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5. Clinically significant abnormal findings on the vital signs, physical examination, 
medical history, electrocardiogram (ECG), or clinical laboratory results, in the 
opinion of the investigator 
6. Positive test for human immunodeficiency virus, hepatitis B surface antigen, or 
hepatitis C virus at screening 
7. History or presence of any type of malignant tumors 
8. Current evidence or any history of congestive heart failure 
9. Diabetes mellitus (fasting glucose ≥126 mg/L [7 mmol/L]) that is not controlled by 
diet/exercise alone, in the opinion of the investigator 
10. An acute illness (eg, upper respiratory infection, viral infection) requiring treatment 
with prescribed medicines within 2 weeks prior to check-in 
11. Dentition that prevents subjects from using on!® NP products 
12. Allergic to or cannot tolerate mint flavoring agents or phenylalanine 
13. Any planned surgery from the time of screening through EOS 
14. History of drug or alcohol abuse within 24 months prior to check-in 
15. Fever (ie, body temperature >100.5°F) at screening or check-in. One recheck may be 
performed at the investigator’s discretion 
16. Body mass index greater than 40.0 kg/m2 or less than 18.0 kg/m2 at screening 
17. Systolic blood pressure >150 mmHg and/or diastolic blood pressure > 90 mmHg at 
screening or check-in, measured after being seated for at least 10 minutes. One 
recheck may be performed at the investigator’s discretion 
18. Estimated creatinine clearance (by Cockcroft-Gault equation) < 80 mL/minute at 
screening 
19. Serum alanine aminotransferase ≥1.5 times the upper limit of normal and/or aspartate 
aminotransferase ≥1.5 times the upper limit of normal at screening 
20. Positive screen for alcohol (breath) or any of the following drugs of abuse (urine), 
regardless of the reason of use: amphetamines, methamphetamines, opiates, 
cannabinoids, or cocaine at screening or check-in 
21. Female subjects who are pregnant (positive serum pregnancy test at screening or urine 
pregnancy test at check-in), lactating, or intend to become pregnant from screening 
through EOS 
22. Use of prescription or over-the-counter bronchodilator medication (eg, inhaled or oral 
ß-agonists) within 12 months prior to check-in 
23. Use of medications or foods known or are suspected to interact with cytochrome P450 
2A6 (including, but not limited to, amiodarone, amlodipine, amobarbital, 
buprenorphine, clofibrate, clotrimazole, desipramine, disulfiram, entacapone, 
fenofibrate, isoniazid, grapefruit, ketoconazole, letrozole, methimazole, methoxsalen, 
metyrapone, miconazole, modafinil, orphenadrine, pentobarbital, phenobarbital, 
pilocarpine, primidone, propoxyphene, quinidine, rifampicin, rifampin, secobarbital, 

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selegiline, sulconazole, tioconazole, tranylcypromine) within 14 days or 5 half-lives 
of the drug, whichever is longer, prior to check-in or during the study 
24. Use of antibiotic treatment within 2 weeks prior to check-in 
25. Plasma donation within 7 days prior to check-in 
26. Donation of blood or blood products (with the exception of plasma as noted above), 
had significant blood loss, or received whole blood or a blood product transfusion 
within 56 days prior to check-in 
27. Participation in a previous clinical study for an investigational drug, device, biologic, 
or a tobacco product within 30 days prior to check-in 
28. Participation in 2 or more Altria Client Services (ALCS) studies within the past 
12-month period prior to check-in 
29. Subject or a first-degree relative (ie, parent, sibling, child, spouse/partner) is a current 
or former employee of the tobacco industry or a named party or class representative in 
litigation with any tobacco company 
30. Subject or a first-degree relative (ie, parent, sibling, child, spouse/partner) is a current 
employee of the study site 
31. Positive result for coronavirus disease (COVID)-19 test at screening or check-in 
32. One or more “yes” answers to any of the questions on the COVID-19 screening 
questionnaire (provided by the study site) at screening or check-in.  
4.3. 
Subject Number and Identification 
Subjects will be assigned a unique subject identification number upon signing informed 
consent. 
Subjects will be identified by subject number on all study documentation.  
4.4. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn from the study if any of the following criteria are met: 
 Change in compliance with any inclusion/exclusion criterion that is clinically relevant 
and affects subject safety as determined by the investigator (or designee) 
 Noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the investigator (or designee) 
 Any clinically relevant sign or symptom that, in the opinion of the investigator (or 
designee), warrants subject withdrawal. 
If a subject is withdrawn from product use, the sponsor will be notified and the date and 
reason(s) for the withdrawal will be documented in the subject’s electronic case report form 
(eCRF). If a subject is withdrawn from the study, efforts will be made to perform all EOS 
assessments, if possible (Appendix 5). Other procedures may be performed at the 

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investigator’s (or designee’s) and/or sponsor’s discretion. If the subject is in-house, these 
procedures should be performed before the subject is discharged from the clinic. The 
investigator (or designee) may also request that the subject return for an additional follow-up 
visit. All withdrawn subjects will be followed until resolution of all their AEs or until the 
unresolved AEs are judged by the investigator (or designee) to have stabilized. 
Subjects withdrawing from the study may be replaced at the discretion of the sponsor. 
Subjects enrolled in the Product Trial but who failed at check-in or dropped prior to 
randomization may be replaced without consultation of the sponsor. Subjects completing, 
withdrawing, or who are removed from this study cannot re-enter. 
4.5. 
Study Termination 
The study may be discontinued at the discretion of the investigator (or designee), sponsor, or 
sponsor’s medical monitor if any of the following criteria are met: 
 Adverse events unknown to date (ie, not previously reported in any similar study on 
the study products with respect to their nature, severity, and/or duration) 
 Increased frequency, severity, and/or duration of known, anticipated, or previously 
reported AEs (this may also apply to AEs defined at check-in as baseline signs and 
symptoms) 
 Medical or ethical reasons affecting the continued performance of the study 
 Difficulties in the recruitment of subjects 
 Other administrative reasons. 
5. STUDY PRODUCTS 
5.1. 
Description, Storage, Packaging, and Labeling 
Study products will be supplied by the sponsor (or designee), along with the batch/lot 
numbers and certificates of analysis.  
Details on study products can be found in Table 3. 

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Table 3: 
Study Products 
Study 
Product 
Product 
Code 
Format 
Product  
Nicotine 
Yield/Content 
1 
B 
Pouch 
Mint on!® 2 mg nicotine pouches 
2 mg/pouch 
2 
C 
Pouch 
Mint on!® 4 mg nicotine pouches 
4 mg/pouch 
3 
D 
Pouch 
Mint on!® 8 mg nicotine pouches 
8 mg/pouch 
The study products will be packaged in the original commercial packs in sealed pre-
packaging. Each product pack contains 20 pouches. To open the packages, the sealed 
pre-packaging will have to be broken and the lid opened.  
Study products will be stored at the study site in a location that is locked with restricted 
access. 
The study product containers will be labeled in accordance with applicable laws and 
regulations.  
5.2. 
Study Product Administration 
5.2.1. 
Product Trial 
At Day -3, subjects will engage in a brief Product Trial using 1 Mint on!® 8 mg NP for 
10 minutes to allow them to become accustomed to the product and to confirm their ability to 
tolerate the study product. Subjects will be instructed to place the pouch between the upper 
lip and gum, on either side of the mouth, per subject’s choice. Subjects will be informed that 
these products are spit-free. 
5.2.2. 
Product Use from Day 1 
Subjects will begin using the assigned study products or completely stop using tobacco 
products on the morning of Day 1 and continue through Day 7 according to the 
randomization: 
 Subjects in Group 1 will be allowed to smoke their UBCs ad libitum (ie, no restriction 
on the duration of use or the number of CPD) from 07:00 through 23:00. Subjects will 
be allowed to smoke upon request to the clinic staff but will only be allowed 1 
cigarette at a time. 
 Subjects in Groups 2, 3, and 4 will use the assigned NPs ad libitum (ie, no restrictions 
on the NPPU, the NPPD, or the duration of use) except for 3 specific NP use 
opportunities at approximately 11:00, 15:00, and 19:00 each day during which 
subjects will be asked to keep the assigned NP in their mouth for at least 10 minutes. 
Subjects will be allowed to use the NPs upon request.  
 Subjects in Group 5 will not be allowed to smoke or use NPs. 

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Study product use will not be permitted from 23:00 to 07:00 each day during the study from 
check-in (Day -3) until Day 7. Study products and cigarettes will not be allowed on Day 8 
(discharge day). 
5.3. 
Randomization 
On Day 1, the subjects will be randomized to 1 of the following 5 groups in a 1:1:1:1:1 ratio, 
with not more than 60% of either gender. Subjects will be stratified by gender and screening 
visit self-reported CPD (≤16; >16). 
Table 4: 
Group Allocation 
Group number 
Intervention 
Number of subjects 
Group 1 
Continue Smoking (CC) 
30 
Group 2 
2 mg NP (NP2) 
30 
Group 3 
4 mg NP (NP4) 
30 
Group 4 
8 mg NP (NP8) 
30 
Group 5 
No Tobacco (NT) 
30 
5.4. 
Blinding 
This is an open-label study. 
5.5. 
Study Product Compliance 
For study integrity, all smoked cigarette butts and all used NPs will be collected throughout 
the study (from Day -3 to Day 7). 
The following measures will be employed to ensure study product use compliance: 
 Subjects from Group 1 will request a cigarette from the clinic staff, each time they 
want to smoke a cigarette. They will be instructed to return each cigarette butt upon 
completion. Only 1 cigarette will be dispensed for use at a time and subjects will be 
instructed to return the cigarette butt before being allowed to obtain another UBC 
 Subjects from Groups 2, 3, and 4 will request NPs from the clinic staff, each time they 
want to use a NP. At approximately 11:00, 15:00, and 19:00, they will use their 
assigned NP in the presence of a clinical staff member. Subjects will be instructed to 
return each used NP upon completion. 
5.6. 
Study Product Accountability, Storage, and Preparation 
All study products will be provided by the sponsor, except UBCs. The study staff at the site 
will coordinate shipping of the study products from the sponsor. The study staff will 
document the date each shipment was received and record it in the inventory records. The 
study staff will document and reconcile the total number of products shipped to the site, the 
total number of study products used during the study, and the total number of unused study 
products remaining at the EOS. The site pharmacy will retain and store 2 cans/packages of 
each study product at the site until finalization of the final study report. 

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All subjects will be required to provide a sufficient supply of their UBC to the study site for 
use from check-in through Day 7 (10 days) in case they are randomized to continue smoking 
their UBC. This supply will be calculated from the number of CPD reported at screening plus 
an additional 20% rounded up to the next pack. For example, a subject reporting to smoke 
15 CPD would bring 9 packs (15 CPD x 10 days = 150 cigarettes + an additional 30 
cigarettes = 180 cigarettes total [9 packs]). The clinical site will purchase additional cigarettes 
if subjects run out of cigarettes during the study. 
All study products will be stored in a locked, limited-access area at the study site and kept at 
controlled room temperature (defined as 15°C – 25°C [59°F – 77°F], with excursions 
permitted to 30°C [86°F]). A sufficient supply for each subject may be transferred and kept in 
a secure area in the clinic (eg, locked drawer or cupboard) each day as necessary, with 
appropriate documentation of transfer noted as above. 
Any unused packs of cigarettes will be returned to the study subjects upon their completion 
or withdrawal from the study. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Any medications, and the reason for its use, taken from 30 days prior to check-in through 
check-in will be recorded as prior medications. 
Any concomitant medications, and the reason for its use, taken from check-in through the 
EOS (or upon early termination) will be recorded as concomitant medication. 
Prohibited medications are included in the exclusion criteria (Section 4.2).  
Stable doses (ie, no dosage adjustments within 30 days prior to check-in) of prescription or 
over-the-counter medications required to treat an investigator-approved disease or condition 
are permitted at the discretion of the investigator. Hormonal contraceptives (eg, oral, vaginal 
ring, transdermal patch, implant, injection) and hormonal replacement therapy are permitted. 
Use of over-the-counter analgesics (eg, acetaminophen, ibuprofen), milk-of-magnesia, 
antihistamines, and nasal decongestants are permitted as needed to treat AEs experienced by 
subjects, at the discretion of the investigator. Note that some decongestants might cause a 
positive urine/saliva drug screen result and therefore their use should be discouraged within 
5 to 7 days of those tests.  
The administration of any other concomitant medications during the study is prohibited 
without prior approval of the investigator (or designee), unless its use is deemed necessary 
for the treatment of an AE. 
6.2. 
Diet 
While confined at the study site, subjects will receive a standardized diet at scheduled times 
that do not conflict with other study-related activities.  

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No foods or beverages containing alcohol will be allowed for 48 hours prior to screening, 
check-in, and during confinement at the study site. 
Consumption of broiled or pan-fried meat, pre-cooked meats (eg, tuna, ham, corned beef, 
smoked lunchmeats), bacon, or sausage will not be allowed for 48 hours prior to check-in and 
during the confinement at the study site. 
Caffeinated beverages (up to 1 cup per meal) may be served while subjects are confined at 
the study site. 
Subjects will be fasted overnight (at least 8 hours) before collection of blood samples for 
clinical laboratory evaluations. 
 
6.3. 
Smoking 
Following Product Trial on Day -3, subjects will continue to smoke their UBC through 23:00 
on Day -3 and from 07:00 to 23:00 on Days -2 and -1.  
Subjects from Groups 2, 3, 4, and 5 will not be allowed to smoke from Day 1 to the EOS 
Smoking will be limited to a designated area of the clinic. Subjects permitted to smoke 
(Group 1) will be housed separately from the subjects from Groups 2, 3, 4, and 5.  
Any illicit use of any tobacco- or nicotine-containing products or sharing of study products 
will be strictly prohibited and will be grounds for immediate termination from the study at the 
discretion of the investigator. 
6.4. 
Exercise 
Strenuous exercise will be forbidden for 48 hours prior to check-in and while the subject is 
confined at the study site. 
7. STUDY ASSESSMENTS AND PROCEDURES 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and the other procedures to be performed at the same timepoint. 
The highest priority procedures will be performed closest to the nominal time. The order of 
priority for scheduling procedures around a timepoint is (in descending order of priority): 
 24-hour urine sampling 
 Vital signs 
 ECG 
 Physical examination including an oral exam 

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 Blood samples. 
7.1. 
Harmful and Potentially Harmful Constituent Assessments 
7.1.1. 
Carboxyhemoglobin Assessments 
7.1.1.1. 
Blood Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times indicated in the 
SoA in Appendix 5.  
Procedures for collection, processing, and shipping of blood samples will be detailed in a 
separate document.  
The maximum blood volume for the entire study, including samples taken for safety 
evaluation, will not exceed 450 mL. 
7.1.1.2. 
Analytical Methodology 
Blood concentrations of COHb will be determined using a validated analytical procedure. 
Specifics of the analytical method will be provided in a separate document.  
7.1.2. 
Biomarkers of Exposure (other than COHb) Assessments 
Biomarkers of exposure other than COHb (see list in Table 1 and Table 2) will be assessed in 
24-hour urine. 
7.1.2.1. 
Urine Sample Collection and Processing 
A 24-hour urine collection will be performed at the times indicated in the SoA in Appendix 5.  
All urine voids over a 24-hour period (24-hour urine) will be collected for BOE analysis. The 
24-hour urine collection begins on each scheduled day after the first morning void and any 
void prior to 07:00, and finishes the following morning with the last void collected at 
approximately 07:00 (including first morning void).  
Procedures for collection, processing, and shipping of urine samples will be detailed in a 
separate document.  
7.1.2.2. 
Analytical Methodology 
Urine concentrations of BOEs will be determined using validated analytical procedures. 
Specifics of the analytical methods will be provided in a separate document.  
Urine creatinine will be measured in each 24-hour collection and may be used to adjust the 
concentration values of urine BOEs.  
7.2. 
Product Use Behavior Assessments 
The following parameters will be collected to assess product use behavior: 

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 Number of CPD: number of cigarettes smoked from 07:00 to 23:00, each day 
 NPPD: number of NP used from 07:00 to 23:00, each day 
 NPPU: number of NPs that could be used at once will not be limited 
 Average duration of each NP use: time of NP placement in the subject’s mouth and 
time it was removed from the subject’s mouth.  
 
7.3. 
Safety Assessments 
7.3.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to final 
discharge from the study.  
Subjects will be observed for any signs or symptoms and asked about their condition by open 
questioning, such as “How have you been feeling since you were last asked?”, at least once 
each day while resident at the study site and at each study visit. Subjects will also be 
encouraged to spontaneously report AEs occurring at any other time during the study. 
All nonserious AEs, whether reported by the subject voluntarily or upon questioning, or 
noted on physical examination, will be recorded from initiation of study product until study 
completion. Serious AEs will be recorded from the time the subject signs the ICF until study 
completion. The nature, time of onset, duration, and severity will be documented, together 
with an investigator’s (or designee’s) opinion of the relationship to the use of the study 
product. 
Adverse events recorded during the course of the study will be followed up, where possible, 
to resolution or until the unresolved AEs are judged by the investigator (or designee) to have 
stabilized. This will be completed at the investigator’s (or designee’s) discretion. 
7.3.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations at the times 
indicated in the SoA in Appendix 5. Clinical laboratory evaluations are listed in Appendix 2. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test 
and will undergo an alcohol breath test at the times indicated in the SoA in Appendix 5. For 
female subjects, a pregnancy test will be performed at the times indicated in the SoA in 
Appendix 5.  
All clinical laboratory tests will be conducted by a laboratory accredited by Centers for 
Medicare and Medicaid Services (Clinical Laboratory Improvement Amendments [CLIA] of 
1988) or at the clinical study site using CLIA-waived kits or procedures.  

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An investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
Values for the laboratory parameters are to be within the laboratory normal ranges or deemed 
not clinically significant in the opinion of the investigator (or designee) or otherwise meet the 
specified values (ranges) in the protocol. One recheck may be performed at the investigator’s 
discretion for all clinical laboratory tests except for the urine/saliva drug screen, urine/breath 
alcohol screen, and urine cotinine test.  
7.3.3. 
Vital Signs 
Seated blood pressure, seated pulse rate, and oral body temperature will be assessed at the 
times indicated in the SoA in Appendix 5. Vital signs may also be performed at other times if 
judged to be clinically appropriate. 
All measurements will be performed singly and repeated once if outside the relevant clinical 
reference range. 
Subjects must be seated for at least 5 minutes before blood pressure and pulse rate 
measurements. 
Product use is to be stopped 15 minutes prior to vital sign measurement. 
7.3.4. 
12-Lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at 
least 5 minutes at the times indicated in the SoA in Appendix 5. Single 12-lead ECGs will be 
repeated twice, and an average taken of the 3 readings, if either of the following criteria 
apply: 
 QT interval corrected for heart rate using Fridericia’s method (QTcF) is >500 ms 
 QTcF change from the baseline (pre study product exposure) is >60 ms. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate. The investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG. 
7.3.5. 
Physical Examination 
A full physical examination will be performed at screening. Symptom-directed physical 
examination will be performed at the other timepoints specified in the SoA (Appendix 5).  
7.3.6. 
COVID-19 Screening 
All subjects will be tested for COVID-19 at the times indicated in the SoA (Appendix 5). 
Details of the testing will be provided separately. 
Throughout confinement, daily temperature will also be measured prior to any product use as 
part of the site’s COVID-19 measures/mitigation and will be captured separately from safety 
vital signs assessment. 

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7.3.7. 
Tobacco Cessation Information 
The investigator (or designee), at screening and at the EOS or 
upon early termination, will advise all adult tobacco product users that to reduce 
the health effects of tobacco, the best thing to do is to quit. The investigator (or 
designee) will refer all adult tobacco product users to the Quit Assist® 
website (using information cards, subject handouts, etc.), which contains citations 
to a number of third-party information sources, including websites, telephone 
resources, and other organizations with additional information. 
8. DATA MANAGEMENT 
Data management activities will be detailed in the Data Management Plan (DMP). All data 
for this study will be captured in the Medrio system, supplied by ALCS or designee. Medrio 
is 21 Code of Federal Regulations (CFR) Part 11 compliant. Electronic case report forms 
(eCRF) will be developed according to the study protocol specifications and will follow 
ALCS data standards. Analytical data will be collected externally to the database. 
Data will be captured on paper source and will be entered into the electronic data capture 
(EDC) system by the site. All data captured will have an audit trail. 
Programmed edits checks will be used to ensure the accuracy and integrity of the database. 
Edit checks will be programmed within the system to check for errors and discrepancies, such 
as missing data, data inconsistencies, and inappropriate date ranges. Corrections will be made 
by the site as necessary prior to database lock. Database lock will occur after all reviews are 
completed, all queries are resolved, and there are no outstanding issues. Any changes to the 
data following database lock will be documented and approved by the sponsor prior to 
unlocking the database to make the required changes. 
Adverse events will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Concomitant medications will be coded using the most 
current version of World Health Organization Drug Dictionary. The versions will remain the 
same throughout the study. Coding will be completed by ALCS Data Management and will 
be reviewed by the medical monitor at ALCS and Covance. 
All casebooks (eCRFs) will be signed by the investigator prior to database lock. Submission 
casebooks will be extracted after database lock and provided to the site. 
9. MONITORING OF THE STUDY 
The responsible study monitor will contact and visit the investigator as necessary, and he/she 
will be allowed, upon request, to inspect and verify all records of the study (eg, source 
document, ICFs, eCRFs, regulatory documents) in a manner consistent with good clinical 
practice (GCP) and all other applicable state and federal law. 
It will be the study monitor’s responsibility to inspect the source documents to verify the 
adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered in the eCRF. The monitor will verify that each subject has consented in writing prior 
to any study procedures being performed. Where the terms of the ICF, GCP, and all other 

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applicable state and federal law permit, the monitor should have access to laboratory test 
reports and other subject records needed to verify the entries on the eCRF. The investigator 
(or designee) agrees to cooperate with the monitor to ensure that any issues detected in the 
course of these monitoring visits are resolved. 
In addition, the sponsor’s internal auditors (or designee), institutional review board (IRB) 
reviewers, and government inspectors may evaluate the study and must be allowed access to 
eCRFs, source documents, and other study files. 
The investigator must notify the sponsor (or designee) promptly of any inspections of the 
study or activities related to the study conducted by regulatory authorities, allow the sponsor 
(or designee) to be present during the inspection, and promptly forward copies of inspection 
reports to the sponsor (or designee). 
10. SAMPLE SIZE AND DATA ANALYSIS 
Full details of the statistical analysis methods for the study will be specified in the Statistical 
Analysis Plan. 
10.1. Determination of Sample Size 
Up to 150 subjects will be enrolled in order that 20 subjects per group complete the study.  
This study is being conducted to assess the differences in BOE values after adult smokers 
switched to on!® NP with the total NNAL (ng/24 h, measured at Day 7) as the primary 
endpoint. The sample size estimation is based on total NNAL data, assuming a two-sided test, 
85% power and α =0.017 Type I error rate to account for the multiplicity adjustment for the 
comparisons (each of the 3 NP groups versus CC group), a sample size of approximately 
20 subjects per group is needed to detect a statistically significant difference between the NP 
groups and CC group. Thirty subjects will be randomized to make sure 20 subjects per group 
complete the study. The sample size calculation used to derive the sample size for this study 
was based on summary statistics data of total NNAL from a previous study with a similar 
study design,9 where the mean ± standard deviation of total NNAL at Day 7 were 476.1 ± 
296.58 ng/24 h for the CC group and 167.3 ± 100.17 ng/24 h and 176.9 ± 135.17 ng/24 h for 
the groups that used a chewable OTDN product with 2 flavors, respectively. 
10.2. Analysis Populations 
10.2.1. 
Biomarker of Exposure Population 
The BOE population will include all subjects from Groups 1, 2, 3, and 4 who used at least 1 
of the assigned study products and all Group 5 subjects. To be included in the BOE 
population, subjects must have baseline (Day 1) and at least 1 postbaseline evaluable BOE 
data.  
10.2.2. 
Safety Population 
The safety population will include all subjects from Groups 1, 2, 3, and 4 who used at least 1 
of the assigned study product and Group 5 subjects. 

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10.3. Biomarker of Exposure Analyses 
Urinary biomarkers: 
Linear mixed models for analysis of covariance will be used to compare the Day 7 biomarker 
values between groups as described in the study objectives. In the statistical models, the 
outcome variable will be included as a dependent variable; group and gender will be included 
as fixed effects; and baseline values of corresponding biomarker will be included as 
covariates. For the NP groups compared to the CC group, Dunnett’s method will be used for 
the adjustment of multiple comparisons. The SAS procedure Proc Mixed will be used. The 
least-squares means (LSM) difference and 95% confidence interval for the LSM difference 
between the test and reference groups and p-values will be provided. 
10.4. Product Use Behavior 
The number of each product used per day (cigarettes or NPs), NPPU, and the duration of each 
NP used during each product use period will be listed and summarized by study product 
using descriptive statistics, as appropriate.  
10.5. Safety Analysis 
All AEs will be listed and summarized using descriptive methodology. Each AE will be 
coded using MedDRA. Frequency counts of AEs will be provided by body system, preferred 
term, and study product. Frequency counts of AEs will also be summarized by severity and 
relationship to study product. 
Observed values for clinical laboratory test data, 12-lead ECGs, vital signs, and physical 
examination findings will be listed.  
10.6. Interim Analysis 
No interim analyses are planned for this study.  
 
 

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11. REFERENCES 
1. IARC. Tobacco Control: Reversal of Risk after Quitting Smoking [Internet]. [cited 
2019 Mar 29]. Available from: http://publications.iarc.fr/Book-And-Report-
Series/Iarc-Handbooks-Of-Cancer-Prevention/Tobacco-Control-Reversal-Of-Risk-
After-Quitting-Smoking-2007 
2. World Health Organization / WHO report on the global tobacco epidemic 2011 
[Internet]. [cited 2019 Mar 29]. Available from: 
http://www.who.int/tobacco/global_report/2011/en/ 
3. The Health Consequences of Smoking—50 Years of Progress: A Report of the 
Surgeon General, 2014 [Internet]. [cited 2019 Mar 29]. Available from: 
https://www.ncbi.nlm.nih.gov/books/NBK179276 
4. Doll R, Peto R, Wheatley K, Gray R, Sutherland I. Mortality in relation to smoking: 
40 years’ observations on male British doctors. BMJ. 1994; Oct 
8;309(6959):901-911. 
5. Zeller M, Hatsukami D. The Strategic Dialogue on Tobacco Harm Reduction: A 
Vision and Blueprint for Action in the US. Tob Control. 2009;18(4):324-332. 
6. Hatsukami DK, Joseph AM, Lesage M, et al. Developing the Science Base for 
Reducing Tobacco Harm. Nicotine Tob Res. 2007;9 Suppl 4(0 4):S537-553. 
7. Centers for Disease Control and Prevention. 2004 Surgeon General’s Reports: The 
Health Consequences of Smoking. Available from: 
https://www.cdc.gov/tobacco/data_statistics/sgr/2004/complete_report/index.htm 
8. Food and Drug Administration. Draft Guidance for Industry: Modified Risk 
Tobacco Product Applications [Internet]. 2012. Available from: 
.https://www.fda.gov/media/135135/download. 
9. Altria; Study Report No: ALCS-RDS-18-04-VRV.  
10. ICH Guideline for Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting (E2A). Federal Register. 1995;60:11284. 
11. E6(R2) Good Clinical Practice: Integrated Addendum to E6(R1); International 
Council for Harmonisation; Guidance for Industry. Federal Register. 
2018;83:8882-8883. 
12. Nebeker JR, Barach P, Samore MH. Clarifying Adverse Drug Events: A Clinician’s 
Guide to Terminology, Documentation, and Reporting. Ann Intern Med. 2004; 
140:795-801. 
13. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and 
management. Lancet. 2000; 356:1255-1259. 

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14. Fagerström K, Russ C, Yu CR, Yunis C, Foulds J. The Fagerström Test for 
Nicotine Dependence as a Predictor of Smoking Abstinence: A Pooled Analysis of 
Varenicline Clinical Trial Data. Nicotine Tob Res. 2012;14:1467-1473.  

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12. APPENDICES 

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Appendix 1: Adverse Event Reporting 
Definitions 
The following is the definition for an AE:  
Any unfavorable and unintended sign (including an abnormal laboratory finding10), symptom, 
or disease10 temporally associated with the use of a study product, whether or not related to 
the study product.10, 11 
All AEs occurring during this study after the subject has signed the ICF and after the first use 
of the study product during the Product Trial and through Day 8 or EOS/Early Termination 
must be recorded in the eCRF, including the date and time of onset and outcome of each 
event. Events occurring between signing of the ICF and prior to the first use of study product 
during the Product Trial will be documented as medical history.  
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned 
surgery permitted by the clinical study protocol and the condition(s) leading to this surgery 
are not AEs.  
No causal relationship with the study products or with the clinical study itself is implied by 
the use of the term “adverse event.” 
Assessment of Severity 
The investigator (or designee) will review each event and rate each reported sign or symptom 
on a 3-point severity scale. The following definitions for rating severity10 will be used:  
 Mild: The AE is easily tolerated and does not interfere with daily activity  
 Moderate: The AE interferes with daily activity, but the subject is still able to function  
 Severe: The AE is incapacitating and requires medical intervention. Note: This is not 
the same as “serious,” which is based on the outcome or action criteria usually 
associated with events that pose a threat to life or functioning. 
Relationship to Study Product 
Each AE will also be assessed by the investigator (or designee) for relationship to study 
product (causality) using the following grades of certainty12, 13 (the strength of a causal 
association may be revised as more information becomes available):  
Not related: Clearly and definitely due to extraneous cause (eg, disease, environment)  
Unlikely:  
a. Does not follow a probable temporal (ie, time) sequence from the use of 
study product.  

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b. Does not follow a known pattern of response to the study product.  
c. Could plausibly have been produced by the subject’s clinical 
state/underlying disease or other drugs or chemicals the subject received.  
d. Does not reappear or worsen when the study product is re-administered.  
Possible:  
a. Follows a reasonable temporal (ie, time) sequence from the use of study 
product.  
b. Follows a known pattern of response to the study product.  
c. Could also have been produced by the subject’s clinical state/concurrent 
disease or other drugs or chemicals the subject received.  
Likely:  
a. Follows a reasonable temporal (ie, time) sequence from the use of study 
product.  
b. Follows a known pattern of response to the study product.  
c. Could not readily have been produced by the subject’s clinical 
state/concurrent disease or other drugs or chemicals.  
d. Follows a clinically reasonable response on withdrawal (dechallenge), ie, 
disappears or decreases when the study product is stopped or reduced.  
e. Rechallenge information is not required to fulfill this definition.  
Definitely:  
a. Follows a reasonable temporal (ie, time) sequence from the use of study 
product.  
b. Follows a known pattern of response to the study product.  
c. Cannot be explained by the subject’s clinical state/concurrent disease or 
other drugs or chemicals.  
d. Follows a clinically reasonable response on withdrawal (dechallenge), ie, 
disappears or decreases when the study product is stopped or reduced.  
e. Recurs with re-exposure to study product (rechallenge). NOTE: 
Re-exposure of the subject is NOT required, but the “definitely related” 
category may only be used when recurrence is observed.  
 

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Follow-up of Adverse Events 
Every reasonable effort will be made to follow up with subjects who have ongoing AEs at the 
EOS visit. Any subject who has an ongoing AE that is possibly related or related to the study 
product or study procedures at the EOS visit will be followed up, where possible, until 
resolution or until the unresolved AE is judged by the investigator (or designee) to have 
stabilized. This will be completed at the investigator’s (or designee’s) discretion. Any subject 
who has an ongoing AE that is not related or unlikely related to the study product or study 
procedures at the EOS visit can be closed out as ongoing at the investigator’s discretion.  
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that either: 
 Results in death 
 Is life-threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
 Results in a congenital anomaly/birth defect 
 Results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
Instances of death or congenital abnormality, if brought to the attention of the investigator at 
any time after cessation of the study product and considered by the investigator to be possibly 
related to the study product, will be reported to the sponsor. 
Definition of Life-threatening 
An AE is life-threatening if the subject was at immediate risk of death from the event as it 
occurred (ie, does not include a reaction that might have caused death if it had occurred in a 
more serious form). For instance, drug-induced hepatitis that resolved without evidence of 
hepatic failure would not be considered life-threatening even though drug-induced hepatitis 
can be fatal. 
Definition of Hospitalization 
Adverse events requiring hospitalization should be considered serious. In general, 
hospitalization signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the study site. When in doubt as to whether hospitalization occurred or 
was necessary, the AE should be considered as serious. 

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Hospitalization for elective surgery or routine clinical procedures, which are not the result of 
an AE, need not be considered AEs and should be recorded on a clinical assessment form and 
added to the eCRF. If anything untoward is reported during the procedure, this must be 
reported as an AE and either ‘serious’ or ‘nonserious’ attributed according to the usual 
criteria. 
Serious Adverse Event Reporting 
AEs that are associated with the use of the study product and are serious and unexpected will 
be reported by the study site to the sponsor, medical monitor assigned by the sponsor, and the 
responsible IRB. 
The sponsor and medical monitor will be notified in writing (eg, facsimile) within 24 hours of 
when a serious, unexpected AE that is associated with use of the study product associated is 
first recognized or reported. 
Subsequently, a written confirmation or summary of the AE (using FDA Form 3500A or 
equivalent) will be sent to the sponsor within 3 working days of the original notification.  
The IRB will be notified of any serious, unexpected AE that is associated with the use of the 
study product in accordance with the IRB’s procedures.  
Pregnancy 
A positive pregnancy test prior to enrollment will be documented as a screen failure. 
Pregnancy occurring in a female study subject (after check-in through EOS/Early 
Termination) will be documented in a pregnancy form (provided separately) and as a protocol 
deviation to the IRB.  
Pregnancy itself is not an AE. The investigator or designee will discontinue the pregnant 
subject from the study and will advise her to seek prenatal care and counseling from her 
primary care provider. The investigator (or designee) will refer her to the Quit Assist® 
website, which contains citations to a number of third-party information sources, including 
websites, telephone resources, and other organizations with additional information. Advice 
given will be documented in the subject’s source document. 
All pregnancies must be reported by telephone and by fax or email to the sponsor and the 
medical monitor within 24 hours of the site’s learning of the pregnancy or, at the latest, on 
the following workday. 
The study site staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (ie, birth, loss, or termination). To help ensure this, the study site staff will follow 
up with the subject until the end of pregnancy, if in compliance with the site’s standard 
operating procedures and with the subject’s consent. This request and the subject’s response 
will be documented in the subject’s source document. A final report of pregnancy outcome 
will be sent to the medical monitor. 
 

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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate  
Blood urea nitrogen  
Chloride 
Creatininec 
Glucose 
Potassium  
Sodium  
Total bilirubina 
Total protein 
Uric acid 
Hematocrit  
Hemoglobin 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC differential: 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
 
Bilirubin  
Blood 
Color and appearance  
Glucose 
Ketones 
Leukocyte esterase  
Nitrite  
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examinationd (RBCs, 
WBCs, casts, and bacteria)  
Serology: 
Drug screen: 
Hormone panel - females 
only: 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency virus 
(HIV-1 and HIV-2) antibodies 
Including but not limited to:  
Amphetamines/methamphetamines 
Cocaine (metabolite) 
Opiates 
Tetrahydrocannabinol/cannabinoids 
Alcohol 
Cotinine teste 
Follicle-stimulating hormonef 
(postmenopausal females only) 
Serum pregnancy testg (human 
chorionic gonadotropin) 
Urine pregnancy testb  
a Direct and indirect bilirubin will be analyzed if total bilirubin is elevated.  
b Performed for all females at check-in. A positive urine pregnancy test will be confirmed with a serum pregnancy test. 
c At screening, estimated glomerular filtration rate will be calculated. 
d Microscopic examination will be conducted if protein, leukocyte esterase, nitrite, and/or blood are abnormal. 
e A positive qualitative test (≥ 500 ng/mL) will be required for participation in the study. 
f To confirm postmenopausal status. 
g Performed for all females at screening.  
 
 
In addition, COVID-19 testing will be performed at screening and check-in. 

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Appendix 3: Contraception Guidance 
Definitions 
Women of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche. 
Women of Nonchildbearing Potential:  
1. Surgically sterile: females who are permanently sterile via hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy by reported medical 
history and/or medical records. Surgical sterilization to have occurred a minimum 
of 6 months, or at the investigator’s discretion, prior to screening. 
2. Postmenopausal: females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory FSH levels of 
≥40 mIU/mL. The amenorrhea should not be induced by a medical condition such 
as anorexia nervosa, hypothyroid disease, or polycystic ovarian disease or by 
extreme exercise. It should not be due to concomitant medications that may have 
induced the amenorrhea such as oral contraceptives, hormones, 
gonadotropin-releasing hormones, anti-estrogens, or selective estrogen receptor 
modulators.  
Contraception Guidance 
Female Subjects 
Female subjects who are heterosexually active and of childbearing potential (eg, not 
surgically sterile at least 6 months prior to check-in nor postmenopausal with amenorrhea for 
at least 12 months prior to check-in and FSH levels consistent with postmenopausal status) 
must have been using one of the following forms of contraception and agree to continue 
using it through completion of the study: 
 Hormonal (eg, oral, vaginal ring, transdermal patch, implant, injection) consistently 
for at least 3 months prior to check-in 
 Double barrier (eg, condom with spermicide or diaphragm with spermicide) 
consistently for at least 4 weeks prior to check-in 
 Intrauterine device for at least 4 months prior to check-in 
 Exclusive partner who has been vasectomized for at least 6 months (inclusive) prior to 
check-in. 
Female subjects of childbearing potential who are not currently engaging in heterosexual 
intercourse must agree to use one of the above methods of birth control through completion 
of study, in the event that they have heterosexual intercourse during the course of the study. 

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Appendix 4: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
 Applicable International Conference on Harmonization (ICH) GCP Guidelines. 
 Applicable laws and regulations. 
The protocol, protocol amendments, ICF, and other relevant documents must be submitted to 
an IRB by the investigator and reviewed and approved by the IRB before the study is 
initiated.  
Any amendments to the protocol will require IRB approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to 
study subjects.  
The investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB. 
 Notifying the IRB of SAEs or other significant safety findings in accordance with the 
IRB’s procedures. 
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines and all other applicable regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study products, procedures, and potential risks of the study. Subjects 
will be instructed that they are free to obtain further information from the investigator (or 
designee) and that their participation is voluntary and they are free to withdraw from the 
study at any time. Subjects will be given an opportunity to ask questions about the study prior 
to providing consent for participation. 
Following discussion of the study with study site personnel, subjects will sign the ICF in the 
presence of a suitably trained member of staff to indicate that they are freely giving their 
informed consent. A copy of the ICF will be given to the subjects. 

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If the ICF is amended at any time after subjects have started participating in the study, those 
subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in eCRFs, 
study-related forms, study reports, or any related publications. Subject and investigator 
personal data will be treated in compliance with all applicable laws and regulations. In the 
event the study protocol, study report, or study data are included in a public registry, all 
identifiable information from individual subjects or investigators will be redacted according 
to applicable laws and regulations.  
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. The subject must also be informed that his/her study-related data 
may be examined by sponsor or contract research organization (CRO) auditors or other 
authorized personnel appointed by the sponsor, by appropriate IRB members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
 All relevant subject data relating to the study will be recorded on eCRFs unless 
directly transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF.  
 The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
 The investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections and provide direct access to source data documents.  
 The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Predefined agreed risks, monitoring thresholds, 
quality tolerance thresholds, controls, and mitigation plans will be documented in a 
risk management register. Additional details of quality checking to be performed on 
the data may be included in a DMP.  
 A study monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 

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verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for a minimum of 20 years after the completion or 
termination of the study. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to another 
location or party without written notification to the sponsor.  
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR 
Part 11-compliant EDC system on an eCRF in a timely fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and 
transmitted to the sponsor or designee electronically, will be integrated with the subject’s 
eCRF data in accordance with the DMP.  
An eCRF must be completed for each enrolled subject who undergoes any screening 
procedures, according to the eCRF completion instructions. The sponsor, or CRO, will 
review the supporting source documentation against the data entered into the eCRFs to verify 
the accuracy of the electronic data. The investigator will ensure that corrections are made to 
the eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the investigator reviewed and approved the data 
on the eCRF, data queries, and site notifications. 

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Appendix 5: Schedule of Assessments 

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Protocol Reference: ALCS-REG-20-15-OTDN 
Final, 09 March 2021  
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Study Procedures 
Screening 
Days -3 to -1f 
Days 1 (Baseline) to 7 
EOS (Day 8) or Early Termination 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X (Day -3) 
 
 
Demographic data 
X 
 
 
 
Medical history 
X 
X (Day -3)a 
 
 
Tobacco use historyb 
X 
 
 
 
Fagerström Test for Cigarette 
Dependence (Appendix 6) 
 
 
X (Day 1, only) 
 
Urinary drug screen 
X 
X (Day -3) 
 
 
Cotinine test 
X 
 
 
 
Alcohol breath test 
X  
X (Day -3) 
 
 
Serologyc 
X 
 
 
 
Pregnancy testd 
X 
X (Day -3) 
 
 
FSHe 
X 
 
 
 
Height, body weight, and 
BMI 
X 
 
 
 
COVID-19 test 
X 
X (Day -3) 
 
 
Study residency: 
 
 
 
 
Check-in 
 
X (Day -3) 
 
 
Check-out 
 
 
 
X (after last Day 7 urine collection) 
Study product 
administrationg: 
 
 
 
 
Product trial 
 
Xh (Day -3, only) 
 
 
Randomizationi 
 
 
Day 1 
 
2 mg NP (Group 2) 
 
 
Xj (ad libitumk) 
 
4 mg NP (Group 3) 
 
 
Xj (ad libitumk) 
 
8 mg NP (Group 4) 
 
 
Xj (ad libitumk) 
 
UBC (Group 1) 
 
 
Xl (ad libitumm) 
 
No Tobacco (Group 5) 
 
 
X 
 
Pharmacokinetics: 
 
 
 
 
Blood samplingn 
 
X (Day -1, only) 
X (Day 7, only) 
 

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Protocol Reference: ALCS-REG-20-15-OTDN 
Final, 09 March 2021  
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Study Procedures 
Screening 
Days -3 to -1f 
Days 1 (Baseline) to 7 
EOS (Day 8) or Early Termination 
24-hour urine samplingo 
 
X (Day -1, only) 
X (Day 7, only) 
 
Urine creatininep 
 
X (Day -1, only) 
X (Day 7, only) 
 
Safety: 
 
 
 
 
Adverse event recording 
 
X 
Ongoing 
X 
Prior/concomitant medication 
monitoring 
X 
X 
Ongoing 
X 
Clinical laboratory 
evaluationsq 
X 
 
 
 
Vital signsr 
X 
X  
X 
X 
12-lead ECG 
X 
 
 
 
Physical examinations 
X 
X (Day -3) 
 
X 
Abbreviations: BMI = body mass index; BOE = biomarker of exposure; COHb = carboxyhemoglobin; COVID = coronavirus disease; CPD = cigarettes smoked per day; ECG = 
electrocardiogram; EOS = end of the study; FSH = follicle-stimulating hormone; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV= human immunodeficiency virus; NP = 
nicotine pouch; UBC = usual brand cigarettes.  
a Interim medical history. 
b The following characteristics of the subject’s usual brand will be documented: brand, brand style, and flavor. The number of uses per day (single number, not a range) will also be documented. 
Subjects will bring with them a new pack of their most commonly used cigarettes. The pack will be color photocopied and the copy will be placed in the source documents at screening and at 
any time during the study in which the subject changes cigarette brand. 
c HIV, HBsAg, HCV tests. 
d Serum pregnancy test for all females at screening; urine pregnancy test for all females at check-in. A positive urine pregnancy test will be confirmed with a serum pregnancy test. 
e To confirm postmenopausal status in self-reported postmenopausal females only. 
f Following Product Trial on Day -3, subjects will continue to smoke their UBCs through 23:00 on Day -3 and from 07:00 to 23:00 on Days -2 and -1.  
g Product use will not be permitted from 23:00 to 07:00 each day during the study from check-in (Day -3) until Day 7. Product use and cigarette smoking will not be allowed at Day 8 (EOS). 
h Subjects will engage in a brief Product Trial using one 8 mg NP for 10 minutes to allow subjects to become accustomed to the products. 
i Subjects will be randomized into each group on Day 1 based on gender and CPD. 
j Subjects will be allowed to use the NPs upon request and they will be instructed to return each used NP upon completion. 
k No restrictions on the number of NP used at once, the number of NP used per day, or the duration of use except for 3 specific NP use opportunities at approximately 11:00, 15:00, and 19:00 
each day during which subjects will be asked to keep the assigned NP in their mouth for at least 10 minutes. 
l Subjects will be allowed to smoke upon request to the clinic staff but will only be allowed 1 cigarette at a time and will be instructed to return each cigarette butt upon completion. 
m No restriction on the duration of use or the number of CPD. 
n At approximately 21:30. The sample will be used for COHb analysis, and banked for biomarker of potential harm analysis. 
o All urine voids over a 24-hour period (24-hour urine) will be collected for BOE analysis. The 24-hour urine collection begins on each scheduled day after the first morning void and any void 
prior to 07:00, and finishes the following morning with the last void collected at approximately 07:00 (including first morning void). 
p Urine creatinine will be measured in each 24-hour collection and may be used to adjust the concentration values of urine BOEs. 
q Hematology, clinical chemistry, routine urinalysis (see Appendix 2) at screening.  

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r Blood pressure, pulse rate, oral temperature. All vital signs assessed at screening, Day -3 and EOS. From Day -2 to Day 7: daily oral temperature only.  
s Full physical examination at screening; symptom-directed physical examinations at other timepoints.

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Appendix 6: Fagerström Test for Cigarette Dependence14 Questionnaire 
 
 
1. How soon after you wake up do you smoke your first cigarette? 
 
Within 5 minutes (3) 
 
6-30 minutes (2) 
 
31-60 minutes (1) 
 
After 60 minutes (0) 
 
2. Do you find it difficult to refrain from smoking in places where it is 
forbidden? 
 
Yes (1) 
 
No (0) 
 
3. Which cigarette would you hate most to give up? 
 
The first one in the morning (1) 
 
All others (0) 
 
4. How many cigarettes/day do you smoke? 
 
10 or less (0) 
 
11-20 (1) 
 
21-30 (2) 
 
31 or more (3) 
 
5. Do you smoke more frequently during the first hours after waking than during 
the rest of the day? 
 
Yes (1) 
 
No (0) 
 
6. Do you smoke if you are so ill that you are in bed most of the day? 
 
Yes (1) 
 
No (0)