A Randomized, Controlled, Six-way Crossover Clinical Study To Characterize The Nicotine Pharmacokinetics And Subjective Effects Of Four Heated Tobacco Products In Adult Menthol And Nonmenthol Cigarette Smokers
Phase: NA
Conditions: Tobacco Use
Sponsor: Altria Client Services LLC

A RANDOMIZED, CONTROLLED, SIX-WAY CROSSOVER CLINICAL STUDY TO CHARACTERIZE THE 
NICOTINE PHARMACOKINETICS AND SUBJECTIVE EFFECTS OF FOUR HEATED TOBACCO 
PRODUCTS IN ADULT MENTHOL AND NON- MENTHOL CIGARETTE SMOKERS 
 
NCT06356610 
19OCT2023 

ALCS-REG-23-08-HT (Ploom® PK) 
Altria Client Services LLC 
Confidential 
Ver. 1.0 19-Oct-2023 
 
 
CLINICAL STUDY PROTOCOL 
 
A RANDOMIZED, CONTROLLED, SIX-WAY CROSSOVER CLINICAL STUDY TO 
CHARACTERIZE THE NICOTINE PHARMACOKINETICS AND SUBJECTIVE EFFECTS 
OF FOUR HEATED TOBACCO PRODUCTS IN ADULT MENTHOL AND NON- 
MENTHOL CIGARETTE SMOKERS 
Altria Client Services LLC Study No.: ALCS-REG-23-08-HT (Ploom® PK) 
Contract Research Organization Project No.: CA41312 
Version: 1.0 
Protocol Date: 19-Oct-2023 
Sponsor: 
Altria Client Services LLC 
601 E. Jackson Street 
Richmond, Virginia 23219, USA 
 
 
 
 
 
 
 
 
Sponsor Contact: 
 
 
 
 
 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Altria Client Services LLC and any 
unauthorized use or disclosure of such information without the prior written authorization of Altria Client Services 
LLC is expressly prohibited. 

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SIGNATURES 
 
SPONSOR PROTOCOL APPROVAL SIGNATURE PAGE 
Altria Client Services LLC Study No.: ALCS-REG-23-08-HT (Ploom® PK) 
 
A RANDOMIZED, CONTROLLED, SIX-WAY CROSSOVER CLINICAL STUDY TO 
CHARACTERIZE THE NICOTINE PHARMACOKINETICS AND SUBJECTIVE EFFECTS 
OF FOUR HEATED TOBACCO PRODUCTS IN ADULT MENTHOL AND NON- 
MENTHOL CIGARETTE SMOKERS 
 
 
I have read the following protocol and agreed to the conduct of the study as described herein: 
 
 
 
 
 
 
Altria Client Services LLC 
Date 
10/23/2023 
 
Altria Client Services LLC 
Date 
10/23/2023 
 
 
Altria Client Services LLC 
Date 
10/24/2023 
 
 
Altria Client Services LLC 
Date 
10/23/2023 

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INVESTIGATOR AGREEMENT AND SIGNATURE PAGE 
Altria Client Services LLC Study No.: ALCS-REG-23-08-HT (Ploom® PK) 
 
A RANDOMIZED, CONTROLLED, SIX-WAY CROSSOVER CLINICAL STUDY TO 
CHARACTERIZE THE NICOTINE PHARMACOKINETICS AND SUBJECTIVE EFFECTS 
OF FOUR HEATED TOBACCO PRODUCTS IN ADULT MENTHOL AND NON- 
MENTHOL CIGARETTE SMOKERS 
 
 
By signing below, the Investigator agrees to adhere to the protocol as outlined and agrees that 
any changes to the protocol must be approved by Altria Client Services LLC prior to seeking 
approval from the Institutional Review Board (IRB). 
 
This study will be conducted in accordance with Good Clinical Practice (GCP) based on the 
current International Council for Harmonisation (ICH) guidelines for GCP and the corresponding 
sections of the United States (US) Code of Federal Regulations (CFR) governing Protection of 
Human Participants (Title 21 CFR Part 50), IRBs (Title 21 CFR Part 56), the Basic Principles of 
the Declaration of Helsinki, and applicable legal and regulatory requirements. 
 
Principal Investigator: 
Printed Name: 
(Signature) 
Date 

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TABLE                OF                CONTENTS                           SIGNATURES ...........................2 
TABLE OF CONTENTS ............................................................................................................. 4 
STUDY OUTLINE ........................................................................................................................ 8 
SUMMARY OF EVENTS .......................................................................................................... 14 
LIST OF ABBREVIATIONS AND DEFINITIONS ............................................................... 18 
1 
INTRODUCTION AND BACKGROUND .............................................................. 21 
1.1 
Introduction ......................................................................................................... 21 
1.2 
Study Product Background ................................................................................ 22 
1.2.1 
Test Product ........................................................................................................ 22 
1.2.2 
Reference Products ............................................................................................. 22 
1.3 
Summary of Findings to Date ............................................................................ 23 
1.3.1 
Aerosol Chemistry .............................................................................................. 23 
1.3.2 
Prototype HTP Temperature ............................................................................. 23 
1.3.3 
Clinical Studies .................................................................................................... 23 
1.4 
Additional Information & Warnings ................................................................ 23 
1.5 
Study Rationale and Purpose ............................................................................. 24 
1.5.1 
Study Design Rationale ....................................................................................... 24 
2 
OBJECTIVES ............................................................................................................ 25 
2.1 
Main Objectives .................................................................................................. 25 
2.2 
Exploratory Objectives ....................................................................................... 25 
3 
STUDY DESIGN ........................................................................................................ 26 
3.1 
Study Design and Overview ............................................................................... 26 
3.1.1 
Duration of Study ................................................................................................ 28 
3.1.2 
Definition of Study Completion ......................................................................... 28 
3.1.3 
End of Study ........................................................................................................ 28 
3.2 
Clinical Procedures ............................................................................................. 28 
3.2.1 
Questionnaire Training ...................................................................................... 29 
3.2.2 
Product Use Training ......................................................................................... 29 
3.2.3 
In-Confinement Afternoon Product Use Session ............................................. 29 
3.2.4 
Daily Product Use and Accountability of Used HTS ....................................... 29 
3.3 
Test Session .......................................................................................................... 30 
3.3.1 
Pharmacokinetic Assessments ........................................................................... 30 
3.3.2 
Physiological Heart Rate Assessments .............................................................. 30 
3.3.3 
Subjective Measures ........................................................................................... 30 
3.4 
Clinical Safety Evaluations ................................................................................ 30 
4 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ................................. 32 
4.1 
Inclusion Criteria ................................................................................................ 32 

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4.2 
Exclusion Criteria ............................................................................................... 34 
4.3 
Screen Failures .................................................................................................... 36 
4.4 
Participant Discontinuation ............................................................................... 36 
5 
PARTICIPANT PRODUCT USE ............................................................................ 38 
5.1 
Identity of Study Products ................................................................................. 38 
5.2 
Products Administered ....................................................................................... 38 
5.3 
Method of Assigning Participants to Study Products ...................................... 38 
5.4 
Measurements of Product Use Compliance ...................................................... 39 
5.4.1 
At-home Product Acclimation ........................................................................... 39 
5.4.2 
Product Compliance in Confinement ................................................................ 39 
5.5 
Study Product Storage, Accountability, and Retention .................................. 39 
5.5.1 
Storage Conditions .............................................................................................. 39 
5.5.2 
Product Accountability and Retention .............................................................. 39 
5.6 
Packaging and Labeling ..................................................................................... 40 
5.6.1 
Study Product ...................................................................................................... 40 
5.6.2 
Blinding of Product Assignment ........................................................................ 40 
5.7 
Concomitant Medications and Procedures and Other Restrictions ............... 40 
5.7.1 
Concomitant Medications and Procedures ....................................................... 40 
5.7.2 
Other Restrictions ............................................................................................... 41 
5.7.3 
Dietary Considerations ....................................................................................... 41 
6 
STUDY ASSESSMENTS AND PROCEDURES .................................................... 42 
6.1 
Medical and Surgical History ............................................................................ 42 
6.2 
Demographic Characteristics ............................................................................ 42 
6.3 
Physical Measurements ...................................................................................... 42 
6.4 
Pharmacokinetic Assessments ........................................................................... 42 
6.4.1 
Plasma Nicotine Concentration Measurements ............................................... 42 
6.5 
Physiological Heart Rate Assessments .............................................................. 43 
6.6 
Subjective Measures Questionnaires ................................................................. 43 
6.7 
Product Use .......................................................................................................... 43 
6.8 
Safety Assessments .............................................................................................. 44 
6.8.1 
Adverse Experiences ........................................................................................... 44 
6.8.2 
Laboratory Tests ................................................................................................. 44 
6.8.3 
Other Tests .......................................................................................................... 45 
6.8.4 
Vital Signs ............................................................................................................ 45 
6.8.5 
Physical Examination ......................................................................................... 46 
6.8.6 
Electrocardiograms ............................................................................................. 46 
6.8.7 
Tobacco Cessation Information ......................................................................... 47 
6.8.8 
Appropriateness of Safety Assessments ............................................................ 47 
7 
ADVERSE EXPERIENCES ..................................................................................... 48 
7.1 
Recording Adverse Experiences ........................................................................ 49 
7.2 
Assessment of Adverse Experiences .................................................................. 49 
7.2.1 
Serious Adverse Experiences ............................................................................. 49 
7.2.2 
Severity ................................................................................................................. 50 
7.2.3 
Relationship to Study Product ........................................................................... 50 

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7.3 
Discontinuation due to Adverse Experiences ................................................... 51 
7.4 
Reporting Serious Adverse Experiences ........................................................... 51 
7.5 
Adverse Experiences /Serious Adverse Experience Follow-Up ...................... 51 
7.6 
Pregnancy ............................................................................................................ 52 
8 
STATISTICAL CONSIDERATIONS ..................................................................... 53 
8.1 
Sample Size Calculation ..................................................................................... 53 
8.2 
Analysis Populations ........................................................................................... 53 
8.3 
Randomization .................................................................................................... 54 
8.4 
Pharmacokinetic Analysis .................................................................................. 54 
8.4.1 
Pharmacokinetic Parameters ............................................................................. 54 
8.4.2 
Statistical Analysis .............................................................................................. 56 
8.5 
Physiological Heart Rate Assessments .............................................................. 56 
8.6 
Subjective Measures Analysis ............................................................................ 56 
8.6.1 
Product Liking, Tobacco/Nicotine Withdrawal, and Direct Effects of 
Product Questionnaires ...................................................................................... 56 
8.6.2 
Use the Product Again Questionnaire ............................................................... 57 
8.6.3 
Modified Cigarette Evaluation Questionnaires (mCEQ) ................................ 57 
8.7 
Product Use Analysis .......................................................................................... 58 
8.8 
Safety Analysis .................................................................................................... 58 
9 
ACCESS TO SOURCE DATA/DOCUMENTS ...................................................... 59 
10 
QUALITY CONTROL AND QUALITY ASSURANCE ....................................... 60 
10.1 
Conduct of Study ................................................................................................. 60 
10.1.1 
Protocol Deviations ............................................................................................. 60 
10.2 
Protocol Amendments ........................................................................................ 60 
10.3 
Monitoring of Study ............................................................................................ 61 
11 
ETHICS ....................................................................................................................... 62 
11.1 
Institutional Review Board/Independent Ethics Committee Approval ......... 62 
11.1.1 
Ethics Review Prior to Study ............................................................................. 62 
11.1.2 
Ethics Review of Other Documents ................................................................... 62 
11.2 
Written Informed Consent ................................................................................. 62 
11.3 
Confidentiality ..................................................................................................... 62 
11.4 
Ethical Conduct and Responsibility of the Investigator .................................. 63 
12 
DATA HANDLING AND RECORD KEEPING .................................................... 64 
12.1 
Data Reporting and Case Report Forms .......................................................... 64 
12.1.1 
Case Report Forms ............................................................................................. 64 
12.1.2 
Laboratory Data .................................................................................................. 64 
12.1.3 
Retention of Source Documents ......................................................................... 64 
12.1.4 
Study Report ........................................................................................................ 64 
12.2 
Retention of Essential Documents ..................................................................... 65 
12.3 
Termination of the Study ................................................................................... 65 
13 
DATA MANAGEMENT ........................................................................................... 66 

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13.1 
Medrio ePRO ....................................................................................................... 66 
14 
ADMINISTRATIVE INFORMATION ................................................................... 67 
14.1 
Financing and Insurance .................................................................................... 67 
14.2 
Publication Policy ................................................................................................ 67 
15 
REFERENCES ........................................................................................................... 68 
16 
APPENDICES ............................................................................................................ 71 
 
 
LIST OF TABLES 
Table 1: 
Overall Summary of Events .................................................................................. 14 
Table 2: 
Pharmacokinetic Sampling, Physiological Heart Rate Assessments, 
and Subjective Effects Questionnaires on Days 1 through 6 ................................ 17 
Table 3: 
Study Products ...................................................................................................... 38 
Table 4: 
Window for PK Blood Sample Collection. ........................................................... 42 
Table 5: 
Clinical Laboratory Tests ...................................................................................... 45 
 
 
LIST OF FIGURES 
Figure 1: 
Heated Tobacco Product ....................................................................................... 22 
Figure 2: 
Study Design Schematic ....................................................................................... 28 
 
 
LIST OF APPENDICES 
Appendix 1: Product Liking Questionnaire .................................................................................. 71 
Appendix 2: Tobacco/Nicotine Withdrawal Questionnaire .......................................................... 72 
Appendix 3: Direct Effects of Product Questionnaire .................................................................. 73 
Appendix 4: Use the Product Again Questionnaire ...................................................................... 74 
Appendix 5: Modified Cigarette Evaluation Questionnaires ........................................................ 75 
Appendix 6: Fagerström Test for Cigarette Dependence (FTCD) ................................................ 78 

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STUDY OUTLINE 
 
Protocol Title 
A randomized, controlled, six-way crossover clinical study to 
characterize the nicotine pharmacokinetics and subjective effects of four 
heated tobacco products in adult menthol and non-menthol cigarette 
smokers 
Brief Title 
Pharmacokinetic and abuse liability characterization of heated tobacco 
products against combustible cigarette and nicotine gum in confinement 
Purpose 
The purpose of this study is to characterize the plasma nicotine 
pharmacokinetic (PK) parameters, and subjective effects of four Ploom® 
heated tobacco products (HTPs) (two menthol and two tobacco flavor 
heated tobacco stick (HTS) varieties relative to participant’s usual brand 
combustible cigarette (UBCC) and nicotine gum (a nicotine replacement 
therapy [NRT]) in adult menthol and non-menthol combustible cigarette 
smokers. The results of this study will allow assessment of nicotine PK 
and abuse liability (AL) of the HTPs compared to UBCC and nicotine 
gum as a high and low AL reference products, respectively. 
Objectives 
Main Objectives: 
• Characterize PK parameters of nicotine in plasma during and after a 
single ad libitum use of HTP (two menthol and two tobacco flavor 
varieties) relative to UBCC and the nicotine gum. 
• Characterize Product Liking of HTP (two menthol and two tobacco 
flavor varieties) during and after a single ad libitum use relative to 
UBCC and the nicotine gum. 
• Characterize additional subjective measures of HTP (two menthol and 
two tobacco flavor varieties) during and after a single ad libitum use 
relative to UBCC and the nicotine gum. 
• Assess heart rate following the use of HTP (two menthol and two 
tobacco flavor varieties) relative to UBCC and the nicotine gum. 
• Characterize product use of HTP during a single ad libitum use. 
• Assess safety profiles of HTP (two menthol and two tobacco flavor 
varieties) compared to UBCC and nicotine gum with monitoring of 
adverse experiences, symptom-driven physical examinations, and 
relevant clinical laboratories as needed. 
Exploratory Objectives: 
• Characterize N-nitrosonornicotine (NNN) uptake and compare the 
difference during HTP and UBCC use. 
• Assess additional Product Liking parameters during each morning ad 
libitum product use. 

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Endpoints 
Main Endpoints: 
• Baseline-adjusted plasma nicotine PK parameters following a single 
ad libitum HTP, UBCC, or nicotine gum use: 
• Cmax: Maximum measured plasma concentration. 
• AUC(0-180): Area under the nicotine concentration-time curve 
calculated using linear trapezoidal summation from time zero 
(defined as the start of product use) to 180 minutes. 
• Tmax: Time of the maximum measured plasma concentration. 
• Assessment of Product Liking during and following the morning 
ad libitum product use PK test session: 
• Original scores 
• Emax-PL: Maximum product liking in visual analogue scale 
(VAS) score during each morning ad libitum product use. 
• Subjective Effects (questionnaires scores during and following the 
morning ad libitum product use PK test session): 
• Tobacco/Nicotine Withdrawal Questionnaire 
• Original scores 
• Emax-TNW: For response to Tobacco/Nicotine Withdrawal 
scales, the maximum reduction in VAS score from 
baseline pre-use to post-use (i.e., VASpre-use – VASpost-use) 
for each morning ad libitum product use. 
• Direct Effects of Product Questionnaire 
• Original scores 
• Emax-DEP: For response to Direct Effects of Product, the 
largest VAS score recorded for each morning ad libitum 
product use. 
• Use the Product Again Questionnaire 
• Original scores 
• Bipolar scores 
• Modified Cigarette Evaluation Questionnaire (mCEQ) 
• Original scores 
• Factor scores 
• Physiological heart rate assessments measured during morning 
ad libitum product use PK test session 

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• Product Use 
• Number of HTS, UBCC, and nicotine gum used in the afternoon 
product use session 
• Puff count during the morning ad libitum product use PK test 
sessions for UBCC and HTP products 
• Safety 
• Physical examination (symptom driven) findings 
• Results of adverse experience (AE) monitoring 
• Clinical laboratory findings, as applicable 
Exploratory Endpoints: 
• Plasma NNN levels following HTP and UBCC use 
• Maximum change from baseline for plasma NNN levels 
• Assessment of Product Liking parameter over 180 minutes 
• AUECPL: Area under the effect curve for product liking during 
each morning ad libitum product use. 
Study Design 
This is a randomized, controlled, six-way crossover clinical study to 
characterize the nicotine PK and subjective effects of HTPs (2 menthol 
varieties, Products A and B; 2 tobacco flavor varieties, Products C and D) 
in adult menthol and non-menthol combustible cigarette smokers. The 
study will include participants’ UBCC (Product F) and a nicotine gum 
(Product E) as high and low abuse liability reference products, 
respectively, to the HTP. Results of this study will help in determining 
abuse liability of HTP products in current smokers. 
Study Events and Procedures 
Screening 
Screening will occur within 28 days prior to Day 1 and includes 
administering the Fagerström Test for Cigarette Dependence (FTCD), 
standard safety procedures, collection of baseline information, and a 5- 
day at-home HTP product trial period. 
Enrollment Visit & At-home Product Trial 
Enrollment visit (Day -6) will occur 5 days prior to Check-in (Day -1). 
Participants will receive all four varieties of HTS on Day -6 and begin the 
at-home product trial. Participants are required to use each HTS variety at 
least once a day ad libitum for a minimum of 20 HTS uses over 5 days. 
Check-in (Day -1) & Randomization 
Participants will check-in on the morning of Day -1. Participants will be 
randomized based on sex and their UBCC (menthol or non-menthol) to 

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one of six product use sequences. Once participants are randomized to a 
product use sequence, product use sessions in confinement will start. 
Participants will remain in confinement at the clinic until completion of 
all study activities on Day 6. 
Day -1 to Day 6 
Starting on Day -1 (following Check-in) through Day 5, depending on the 
randomized product use sequence, participants will use their assigned 
product (HTP, UBCC, or nicotine gum) during an afternoon product use 
session. Participants will use the same assigned product to be tested 
during the next day’s morning ad libitum product use PK test session 
(e.g., if a participant is assigned to Product A [HTP] as the product to be 
used in the morning ad libitum product use PK test session on Day 1, the 
participant will use Product A [HTP] during the afternoon product use 
session on Day -1). The afternoon product use session should be no more 
than approximately 6 hours long. Participants will be required to use the 
assigned study product at least once, but no more than six HTS, UBCC, 
or nicotine gum ad libitum per daily afternoon product use sessions. 
Participants will then be required to abstain from any tobacco- or 
nicotine-containing products for at least 12 hours prior to the start of the 
following morning’s ad libitum product use PK test session. 
Morning ad libitum product use PK test sessions will occur on the 
mornings of Days 1, 2, 3, 4, 5, and 6 (for a total of 6 morning ad libitum 
product use PK test sessions). 
During the morning ad libitum product use PK test session, participants 
will use the assigned study product per their assigned product use 
sequence. Participants will use a single UBCC or HTP for 5 minutes ad 
libitum or use the nicotine gum for 30 minutes per product use 
instruction. Blood samples for PK will be collected prior to and for 
3 hours following the start of each morning ad libitum product use PK 
test session. Heart rate measurements will be taken at specified time 
points during each morning ad libitum product use PK test session. 
In addition, participants will complete subjective effects questionnaires 
(Product Liking, Tobacco/Nicotine Withdrawal, Direct Effects of 
Product, Use Product Again, and mCEQ) at designated time points 
during each morning ad libitum product use PK test session. 
Study 
Population and 
Sample Size 
Participants will be generally healthy adult male and female combustible 
cigarette smokers between 22 and 65 years of age, inclusive, determined 
at screening. Participants must be current menthol or non-menthol 
combustible cigarette smokers with self-reported cigarette smoking 
history of at least 12 months prior to screening and have a history of 
smoking ≥ 10 to ≤ 30 combustible cigarettes per day. 
The study will recruit approximately 60 adult cigarette smokers 
(composed of approximately 30 menthol and 30 non-menthol adult 

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smokers) with the goal of obtaining approximately 48 completed 
participants (approximately 24 menthol and 24 non-menthol smokers). 
Every attempt will be made to enroll no less than 40% of either sex for 
menthol and non-menthol smokers, respectively. 
Study Products 
and Route of 
Administration 
Product 
Description 
Route of 
Administration 
A 
Ploom® 3.1 HTP - Menthol HTS; MX3 (681) 
(Test Product) 
Inhalation 
B 
Ploom® 3.1 HTP - Menthol HTS; MX5 (706) 
(Test Product) 
Inhalation 
C 
Ploom® 3.1 HTP - Tobacco HTS; R8 (120) 
(Test Product) 
Inhalation 
D 
Ploom® 3.1 HTP - Tobacco HTS; RX4 (953) 
(Test Product) 
Inhalation 
E 
Nicorette® 4 mg Mint Nicotine Gum 
(Reference Product) 
Oral 
F 
Combustible Cigarette (menthol or non-menthol), 
participant’s usual brand 
(Reference Product) 
Inhalation 
Statistical 
Analysis 
Pharmacokinetic Analysis 
A linear mixed model for analysis of variance will be performed on the 
natural log-transformed PK parameters Cmax and AUC(0-180) for nicotine 
to compare each HTP to the reference products, UBCC and nicotine gum 
(NRT), respectively. The model will include sequence, study product, 
and study day as fixed effects and participant-nested-within-sequence as 
a random effect. Sequence will be tested using participant-nested-within- 
sequence as the error term. Geometric least squares means (LSM) and 
90% confidence intervals (CIs) will be provided for the PK parameters of 
Cmax and AUC(0-180) by study product. Geometric LSM ratio, 90% CIs of 
geometric LSM ratio, and p-values will be provided for the study product 
comparisons among each of HTP products and the reference products 
(UBCC and gum [NRT], respectively) in Cmax and AUC(0-180). The above 
statistical analyses will be performed using the appropriate SAS 
procedure. Descriptive statistics will be provided as appropriate. 
Subjective Measures 
Analysis will be performed for data from the 5 questionnaires (Product 
Liking; Tobacco/Nicotine Withdrawal; Direct Effects of Product; Use 
Product Again; mCEQ). Descriptive statistics will be provided. Analysis, 
where applicable, will include use of a linear mixed model for maximum 
subjective effect score (Emax). 

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Physiological Heart Rate Assessments 
Descriptive statistics will be performed for physiological heart rate data 
collected during morning ad libitum product use PK test sessions. 
Safety Analysis 
Adverse experiences (AEs) will be summarized by product. Safety data 
will be summarized by time point of collection as appropriate and for 
available data. Descriptive statistics will be calculated for quantitative 
and frequency counts will be compiled for classification of qualitative 
safety data as appropriate. Concomitant medications will be coded using 
the World Health Organization (WHO) Drug Dictionary. 

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SUMMARY OF EVENTS 
Table 1: 
Overall Summary of Events 
 
Study Procedure 
Screening 
Study Days (Confinement) 
Study Days →
- 28 to -7 
-6 to -2 
(At-home 
Product Trial) 
-1 
1 
2 
3 
4 
5 
6 
(EOS/ET a) 
Inclusion/exclusion criteria 
X 
X b 
Verified Clinical Trials Consent 
X 
Informed consent 
X 
Demographics 
X 
Medical, surgical, tobacco/nicotine use 
history 
X 
X 
b 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FTCD 
X 
Height, body weight, BMI c 
X 
Physical examination 
X 
Symptom-driven physical examination 
X (at the discretion of the Investigator) 
Adverse experience assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP, HR, RR, oral temperature) d 
X 
X 
X 
12-lead ECG e 
X 
Clinical Labs (Hem, Chem, and UA) 
X 
Serology (HIV, Hep B, and Hep C) 
X 
Serum pregnancy test (all females) f 
X 
Urine/serum pregnancy test (all females) f 
X 
X 
FSH (post-menopausal or symptomatic 
females only) 
X 
Urine drugs of abuse and urine/breath 
alcohol screen 
X 
X 
Cotinine screen (urinary) 
X 
Exhaled carbon monoxide 
X 
At-home product acclimation g 
X 
Product use sequence randomization 
X 
Check-in 
X 
Confinement at the site 
X 
X 
X 
X 
X 
X 
X 
Questionnaire training h 
X 
Product use training i 
X 
X 
Daily afternoon product use sessions j 
X 
X 
X 
X 
X 
X 

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Study Procedure 
Screening 
Study Days (Confinement) 
Study Days → 
- 28 to -7 
-6 to -2 
(At-home 
Product Trial) 
-1 
1 
2 
3 
4 
5 
6 
(EOS/ET a) 
12- hour tobacco/ nicotine product 
abstention k 
X 
X 
X 
X 
X 
X 
Morning ad libitum product use PK test 
session l 
X 
X 
X 
X 
X 
X 
Blood collection for PK m 
X 
X 
X 
X 
X 
X 
Physiological HR assessments n 
X 
X 
X 
X 
X 
X 
Subjective effects questionnaires o 
X 
X 
X 
X 
X 
X 
Product use compliance assessment p 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: BP = blood pressure; BMI = body mass index; Chem = serum chemistry; ECG = electrocardiogram; EOS = end-of-study; ET = early termination; 
FSH = follicle-stimulating hormone; FTCD = Fagerström Test for Cigarette Dependence; Hem = hematology; Hep B = hepatitis B; Hep C = hepatitis C; 
HIV = human immunodeficiency virus; HR = heart rate; HTP = heated tobacco product; HTS = heated tobacco stick; NRT = nicotine replacement therapy; 
PK = pharmacokinetic(s); RR = respiratory rate; UA = urinalysis. 
a. 
Participants who withdraw from the study early will have end of study procedures performed at the time of discontinuation. 
b. Assessments conducted on Day -1 will be used to reconfirm a participant’s eligibility for continuation in the study and to determine if any changes have occurred 
since screening. 
c. 
The BMI will be calculated in the electronic data capture system using the height and weight obtained at screening. 
d. Blood pressure and heart rate will be measured after the participant has been resting quietly in a seated position for at least 10 minutes. 
e. 
The 12-lead ECGs will be performed after the participant has been resting quietly in a supine position or in the most recumbent position possible for at least 5 
minutes. 
f. 
Serum pregnancy test will be performed for all females at screening. At Check-in and at end of study or early termination, urine/serum pregnancy tests will be 
performed to document no-pregnancy occurred. 
g. At-home product acclimation will last for 5 days (Day -6 through Day -2) prior to check on Day -1, participants will be given an HTP device and sufficient 
HTSs to allow participants to acclimate to the products. 
h. Questionnaire training will occur at Check-in to ensure participant understands how to complete visual analogue scales on an electronic patient reported 
outcome device prior to the morning ad libitum product use PK test session. Participants will also be trained on a paper version of the questionnaires as a 
backup in case of computer issues during the study. 
i. 
Prior to sending participants home with the study HTP products on Day -6, participants must be instructed on the proper operation of the HTP device and 
how to insert/remove the HTS. Participants should receive instructions on how to use the NRT (gum) on Day -1 to ensure all participants know the proper 
use of the gum. Participants will not be provided any gum for the at-home product trial. 
j. 
Daily afternoon product use sessions will occur during study conduct in confinement; participants will use an assigned test product scheduled to be used 
during the next day’s morning ad libitum product use PK test session. 

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k. All participants will abstain from tobacco/nicotine-containing products for at least 12 hours prior to the start of the morning ad libitum product use PK test 
session scheduled on the following day. 
l. 
PK test session will start in the morning, where participants will use the assigned study product (reference and test products) ad libitum for a given amount 
of time. There will be blood collection, HR measurements, and subjective effects assessments at designated nominal time points as listed in Table 2. In 
addition, site staff will record puff counts on days when UBCC or Ploom® HTP are used. 
m. At designated time points during the morning ad libitum product use PK test sessions only. See Table 2 for the scheduled time points. 
n. Physiological HR assessments will be assessed at designated time points during the morning ad libitum product use PK test sessions. See Table 2 for the 
scheduled time points. Heart rate measurements will be performed prior to the blood draw (approximately 1 minute prior to the scheduled blood draw time point) 
when scheduled at the same time. 
o. Subjective effects will be captured via questionnaires (refer to the Appendices Appendix for a list of questionnaires to be assessed), at designated nominal 
time points. See Table 2 for the scheduled time points. 
p. Product use compliance assessment will occur at Check-in for at-home product acclimation and at each day during in-clinic confinement to ensure 
participants have met the minimum use requirements via and pharmacy log respectively. 

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Table 2: 
Pharmacokinetic Sampling, Physiological Heart Rate Assessments, and Subjective Effects Questionnaires on 
Days 1 through 6 
 
Sampling 
Times (min) a 
Blood for Nicotine 
PK 
Blood for 
NNN PK 
Heart Rate b 
Subjective effects questionnaires c 
Product 
Liking 
Tobacco/Nicotine 
Withdrawal 
Direct Effects of 
Product 
Use the Product 
Again 
mCEQ 
-5 
X 
X 
X 
X 
3 
X 
5 
X 
X 
X 
X 
X 
X 
7 
X 
X 
10 
X 
X 
15 
X 
X 
X 
X 
X 
30 
X 
X 
X 
X 
X 
45 
X 
60 
X 
X 
X 
X 
X 
X 
120 
X 
180 
X 
X 
X 
X 
 
 
Abbreviations: mCEQ = modified Cigarette Evaluation Questionnaire; min = minutes; NNN = N-nitrosonornicotine; PK = pharmacokinetic; VAS = visual 
analogue scale. 
 
a:   Nominal sampling times for PK assessments of nicotine in plasma are relative to start of the morning ad libitum product use. 
b:  Heart rate measurements will be performed prior to the blood draw (approximately 1 minute prior to the scheduled blood draw time point) when scheduled 
at the same time. 
c:   Subjective effects questionnaires will be assessed on visual analogue scale (VAS) at nominal sampling times. 

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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation Definition 
 
AE 
Adverse experience 
AL 
Abuse liability 
ALCS 
Altria Client Services LLC 
AUC(0-180) 
Area under the nicotine concentration-time curve calculated using linear 
trapezoidal summation from time zero (defined as the start of product use) to 
180 minutes (or the last quantifiable concentration during that interval) 
AUECPL 
Area under the effect curve for product liking from time zero (defined as the 
start of product use) to 180 minutes 
BLQ 
Below the lower limit of quantitation 
C0 
Pre-product administration concentration 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum measured plasma concentration over the duration of the 
measurement interval 
CRA 
Clinical Research Associate(s) 
Ct 
Corrected concentration 
Ct uncorrected 
Uncorrected concentration 
CV 
Coefficient of variation 
DEP 
Direct effects of product 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
Emax 
Maximum response score to effect 
Emax-DEP 
Maximum Direct Effects of Product response in VAS score recorded during 
each product use 
Emax-PL 
Maximum product liking response in VAS score during during each product 
use 
Emax-TNW 
Maximum reduction response in VAS score from baseline pre-use and post- 
use (i.e., VASpre-use – VASpost-use) for Tobacco/Nicotine Withdrawal 
questionnaire during each product use 
EOS 
End-of-study 

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Abbreviation   Definition 
ET 
Early termination 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HPHC 
Harmful and Potentially Harmful Constituent 
HTS 
Heated tobacco stick(s) 
HTP 
Heated tobacco product(s) 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional review board 
Kel 
Apparent first-order terminal elimination rate constant 
LSM 
Least squares means 
mCEQ 
Modified Cigarette Evaluation Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
mHCI 
Modified Health Canada Intense 
N/A 
Not applicable 
n 
Number 
NNN 
N-nitrosonornicotine 
NRT 
Nicotine replacement therapy 
OTC 
Over-the-counter 
PK 
Pharmacokinetic(s) 
PL 
Product Liking 
Q 
Quartile 
QA 
Quality assurance 
SAE 
Serious adverse experience 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SEM 
Standard error of the mean 

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Abbreviation Definition 
SOP 
Standard operating procedure 
SRM 
Study reference manual 
t 
Actual sampling time since product administration 
t1 
Actual sampling time since pre-product administration sampling 
T½ 
Terminal elimination half-life 
Tmax 
Time of the maximum measured plasma concentration over the duration of 
the measurement interval 
TNW 
Tobacco nicotine withdrawal 
UBCC 
Usual brand combustible cigarette 
VAS 
Visual analogue scale 
WHO 
World Health Organization 

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1 
INTRODUCTION AND BACKGROUND 
1.1 
Introduction 
There is an overwhelming public health consensus regarding the “continuum of risk” among 
tobacco products – with cigarettes and other combustible products posing by far the highest risk, 
and non-combustible products posing substantially lower risk (Hatsukami et al., 2007). FDA, 
through its “Comprehensive Strategy” for regulating tobacco products (FDA 2017), and Altria, 
through its 10-Year Vision (Altria), are pursuing efforts to reduce individual and population 
harm by encouraging adults who would otherwise continue to smoke combustible tobacco 
products to switch to FDA authorized, non-combustible tobacco products that are considered to 
be lower on the continuum of risk. 
Approximately half of the adult smokers in the United States are interested in less harmful 
alternatives to combustible cigarettes (Altria). To realize the optimum public health benefits of 
such products, it is important for them to be not only less harmful, but also acceptable to adult 
smokers. Nicotine pharmacokinetics is a component of adult smoker satisfaction and product 
acceptability (Jacobxon et al., 2021). Also, subjective effects evaluation such as product 
satisfaction, craving reduction, and psychological rewards inform on product use experience. 
Specifically, in FDA’s final rule on Premarket Tobacco Product Applications and Record 
keeping Requirements, FDA indicated Product Liking as a key subjective endpoint for 
assessment of abuse liability of new tobacco products (A Rule by the Food and Drug 
Administration on 10/05/2021). FDA (Gottlieb, 2017), the former Institute of Medicine (Institute 
of Medicine, 2012), and public health researchers (Abrams et al., 2018), have also indicated that 
alternatives to combustible cigarettes should deliver nicotine in an amount and manner that is 
satisfying to adult smokers. 
The test products used in this study are a type of HTP, which are also alternately referred to as 
Heat-Not-Burn Products. The non-combustible test product heats tobacco at lower temperatures 
without burning it, to produce an aerosol that delivers nicotine while significantly reducing the 
production of other Harmful and Potentially Harmful Constituents (HPHCs) (FDA 2019) 
compared to cigarette smoke. 
While there are no published data on current study product, two recent studies conducted by 
Yuki et al. (Yuki et al., 2018, Yuki et al., 2022) using earlier versions of Ploom brand of HTPs 
showed that BoE values were significantly reduced compared to combustible cigarette users in a 
5-day confinement setting (n=60). Furthermore, the magnitude of the reductions in exposure to 
HPHCs observed in the HTP users (49–94%) were close to that observed for the smoking 
abstinence group (39–95%) (Yuki et al., 2018). In a second study, significant reductions in most 
BoE relative to the combustible cigarette users after switching to heated tobacco products for 
5 days in confinement setting (n=80) were reported (Yuki et al., 2022). The magnitudes of 
reductions in exposure to most of the selected HPHCs observed in the HTP groups approached 
that observed in participants who abstained from smoking. 

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1.2 
Study Product Background 
1.2.1 
Test Product 
The test product is a prototype HTP intended for adult smokers as an alternative to combustible 
cigarettes. The HTP prototype consists of a durable hand-held battery-operated device and a 
disposable tobacco-containing stick that is inserted into the device (Figure 1). The stick consists 
of 
 
 
Upon application of electrical power by the device, the tobacco in the stick 
undergoes controlled heating and a nicotine-containing aerosol is generated. This is a new type 
of inhalable tobacco product that provides a tobacco experience by heating tobacco without 
burning it. 
Figure 1: 
Heated Tobacco Product 
A: Device 
B: HTS 
C: Cut-away view of assembled HTP 
 
Single-use tobacco-filled sticks (Figure 1) in either menthol or tobacco flavor varieties are 
inserted into the heating device (Figure 1). The stick, and therefore the tobacco, is heated and 
maintained at predetermined temperatures. As the stick is heated, an aerosol is produced, which 
is drawn through the stick and inhaled by the adult user. Each stick has a use duration of 
approximately 5 minutes, limited by the device. Once the predetermined use time is up, the stick 
is removed and disposed of. One device (Ploom® 3.1 prototype) and four HTPs, two tobacco 
flavored sticks and two menthol flavored sticks, containing different blends of tobacco will be 
tested in this study. 
1.2.2 
Reference Products 
The study will use two reference products, which are participant’s UBCC and Nicorette® Mint 
4 mg nicotine gum, which will serve as high and low abuse liability reference products, 

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respectively. Nicotine PK and subjective effects of the Ploom® HTP will be compared with these 
reference products. 
1.3 
Summary of Findings to Date 
Previous version and current Ploom HTP device and stick versions have been extensively 
evaluated over a period of approximately 24 months for collection of assessments (analytical 
aerosol data, clinical studies [PK and biomarkers], and in human expert panels assessing sensory 
experiences) in Japan and USA conducted by Altria. The functions of the device, such as 
temperature control, have been tested and verified. Both the device and sticks consistently 
performed as intended under test conditions, with no safety concerns raised.  
1.3.1 
Aerosol Chemistry 
Analysis of the aerosol chemistry was performed in Japan among prototype HTS and a market 
leading cigarette in Japan; 51 constituents (HPHCs and metals) were assessed under controlled 
conditions (modified Health Canada Intense [mHCI] regimen, 55 mL puff volume, two seconds 
duration, taken every 30 seconds without vent blocking measures). More than half of the 51 
constituents were not detected or not quantifiable. Where quantifiable, all aerosol constituents 
were lower (in most cases statistically lower) compared to market leading cigarette in Japan. 
Nicotine analysis in the aerosol of the prototype using the mHCI regimen indicated that the HTS 
deliver nicotine at a level comparable to or lower than other HTPs found in the global market 
and lower than the 1R6F reference cigarette. 
1.3.2 
Prototype HTP Temperature 
The HTP prototype to be used in this study heats the tobacco in the stick to 
 
 
These temperatures are lower than required for combustion to take place. 
1.3.3 
Clinical Studies 
Ploom® HTP and HTS being used in this study are prototypes and they are not yet available 
commercially in the US. Therefore, all studies, described earlier, were conducted using a 
previous version of the Ploom® HTP outside the US. 
1.4 
Additional Information & Warnings 
The packaging for electronically heated tobacco products (IQOS) recently marketed in the 
United States carried the following warning labels: 
 
WARNING: This product contains nicotine. Nicotine is an addictive chemical 
SURGEON GENERAL'S WARNING: Smoking Causes Lung Cancer, Heart Disease, 
Emphysema, and May Complicate Pregnancy. 
SURGEON GENERAL'S WARNING: Quitting Smoking Now Greatly Reduces Serious 
Risks to Your Health. 

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SURGEON GENERAL'S WARNING: Smoking By Pregnant Women May Result in Fetal 
Injury, Premature Birth, and Low Birth Weight. 
The participants using their own brand of combustible cigarettes will be informed of the four US 
Surgeon General’s Warnings required for cigarettes: 
 
SURGEON GENERAL'S WARNING: Smoking Causes Lung Cancer, Heart Disease, 
Emphysema, and May Complicate Pregnancy. 
SURGEON GENERAL'S WARNING: Quitting Smoking Now Greatly Reduces Serious 
Risks to Your Health. 
SURGEON GENERAL'S WARNING: Smoking By Pregnant Women May Result in 
Fetal Injury, Premature Birth, and Low Birth Weight. 
SURGEON GENERAL'S WARNING:   Cigarette Smoke Contains Carbon Monoxide. 
A copy of the nicotine gum product insert, including instructions on single use, frequency of use 
and warning labels will be provided to participants by study staff for their review. 
1.5 
Study Rationale and Purpose 
The purpose of this study is to characterize the plasma nicotine PK parameters, and subjective 
effects of four Ploom® HTPs (two menthol and two tobacco flavor HTS varieties) relative to 
participant’s UBCC and nicotine gum (NRT) in adult menthol and non-menthol combustible 
cigarette smokers. The results of this study will allow assessment of nicotine PK and AL of the 
HTPs compared to UBCC and nicotine gum as a high and low AL reference products, 
respectively. 
1.5.1 
Study Design Rationale 
This study will characterize plasma nicotine PK parameters and subjective assessments 
following HTP use with UBCC and nicotine gum as reference products (high and low abuse 
liability reference products, respectively) in healthy adult menthol and non-menthol combustible 
cigarette smokers. 
Levels of experience with new products may influence product use and subsequent exposure. For 
that reason, individuals who do not currently use any HTP products will be enrolled. Each 
participant will be provided with an equal opportunity to become accustomed to the use of the 
HTPs during the product acclimation periods. 
The subjective effects measures chosen for this study are standard measures to evaluate tobacco 
products. VAS measures of Product Liking, Tobacco/Nicotine Withdrawal, Direct Effects of 
Product, and Use the Product Again Questionnaire are included to capture the magnitude, onset, 
and offset of product effects during and after each use of the study products. The mCEQ is 
included as a measure of the overall effects of the test products. 

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2 
OBJECTIVES 
2.1 
Main Objectives 
• Characterize PK parameters of nicotine in plasma during and after a single 
ad libitum use of HTP (two menthol and two tobacco flavor varieties) relative 
to UBCC and the nicotine gum. 
• Characterize Product Liking of HTP (two menthol and two tobacco flavor 
varieties) during and after a single ad libitum use relative to UBCC and the 
nicotine gum. 
• Characterize additional subjective measures of HTP (two menthol and two 
tobacco flavor varieties) during and after a single ad libitum use relative to 
UBCC and the nicotine gum. 
• Assess heart rate following the use of HTP (two menthol and two tobacco 
flavor varieties) relative to UBCC and the nicotine gum. 
• Characterize product use of HTP during a single ad libitum use. 
• Assess safety profiles of HTP (two menthol and two tobacco flavor varieties) 
compared to UBCC and nicotine gum with monitoring of adverse experiences, 
symptom-driven physical examinations, and relevant clinical laboratories as 
needed. 
2.2 
Exploratory Objectives 
• Characterize NNN uptake and compare the difference during HTP and UBCC 
use. 
• Assess additional Product Liking parameters during each morning ad libitum 
product use. 

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3 
STUDY DESIGN 
3.1 
Study Design and Overview 
This is a randomized, controlled, six-way crossover clinical study to characterize the nicotine PK 
and subjective effects of HTPs (2 menthol varieties, Products A and B; 2 tobacco flavor 
varieties, Products C and D) in adult menthol and non-menthol combustible cigarette smokers. 
The study will include participants’ UBCC (Product F) and a nicotine gum (Product E) as high 
and low abuse liability reference products, respectively, to the HTP. Results of this study will 
help in determining abuse liability of HTP products in current smokers. 
The study will include generally healthy adult males and females who smoke factory 
manufactured combustible cigarettes. This study will recruit approximately 60 participants 
(composed of approximately 30 menthol and 30 non-menthol adult smokers) in an attempt to 
obtain approximately 48 study completed participants (approximately 24 menthol and 24 
non-menthol smokers). Every attempt will be made to enroll no less than 40% of either sex for 
menthol and non-menthol smokers, respectively. Enrolled participants will be randomized based 
on sex and their UBCC (menthol or non-menthol) to one of 6 product use sequences. 
Adult participants will be between 22 and 65 years of age at screening, inclusive. Participants 
must have a history of smoking ≥ 10 to ≤ 30 menthol or non-menthol factory manufactured 
combustible cigarettes daily for at least 12 months prior to screening. 
Screening 
Screening will occur within 28 days prior to Day 1 and includes administering the FTCD, 
standard safety procedures, collection of baseline information, and a 5-day at-home HTP product 
trial period. 
Enrollment Visit & At-home Product Trial 
Enrollment visit (Day -6) will occur 5 days prior to Check-in (Day -1). Participants will receive 
the Ploom® HTP products for at-home product acclimation to become familiar with the product 
during the next 5 days. Training on how to use the Ploom® HTP device will be provided to each 
participant at the Enrollment visit. Participants will receive all four varieties of HTS on Day -6 
and begin the at-home product trial. Participants are required to use each HTS variety at least 
once a day ad libitum for a minimum of 20 HTS uses over 5 days. 
Check-in (Day -1) & Randomization 
Participants will check-in on the morning of Day -1. Product use sequence randomization and 
assignment will also occur on Day -1. Participants will be randomized based on sex and their 
UBCC (menthol or non-menthol) to one of six product use sequences. Once participants are 
randomized to a product use sequence, product use sessions in confinement will start. 
Participants will remain in confinement at the clinic until completion of all study activities on 
Day 6. 

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Day -1 to Day 6 
Starting on Day -1 (following Check-in) through Day 5, depending on the randomized product 
use sequence, participants will use their assigned product (HTP, UBCC, or nicotine gum) during 
an afternoon product use session. Participants will use the same assigned product to be tested 
during the next day’s morning ad libitum product use PK test session (e.g., if a participant is 
assigned to Product A [HTP] as the product to be used in the morning ad libitum product use PK 
test session on Day 1, the participant will use Product A [HTP] during the afternoon product use 
session on Day -1). The afternoon product use session should be no more than approximately 
6 hours long. Participants will be required to use the assigned study product at least once, but no 
more than six HTS, UBCC, or nicotine gum ad libitum per daily afternoon product use sessions. 
Participants will then be required to abstain from any tobacco- or nicotine-containing products 
for at least 12 hours prior to the start of the following morning’s ad libitum product use PK test 
session. 
Morning ad libitum product use PK test sessions will occur on the mornings of Days 1, 2, 3, 4, 5, 
and 6 (for a total of 6 morning ad libitum product use PK test sessions). 
During the morning ad libitum product use PK test session, participants will use the assigned 
study product per their assigned product use sequence. Participants will use a single UBCC or 
HTP for 5 minutes ad libitum or use the nicotine gum for 30 minutes per product use instruction. 
Blood samples for PK will be collected prior to and for 3 hours following the start of each 
morning ad libitum product use PK test session. Heart rate measurements will be taken at 
specified time points during each morning ad libitum product use PK test session. 
In addition, participants will complete subjective effects questionnaires (Product Liking, 
Tobacco/Nicotine Withdrawal, Direct Effects of Product, Use Product Again, and mCEQ) at 
designated time points during each morning ad libitum product use PK test session. 
Participants will remain in confinement starting with Check-in on Day -1 until discharge after all 
study activities are completed on Day 6. Participants will not be forced to use the 
tobacco/nicotine products at any time during the study. 
Study products and details are shown in Table 3. 
The study schematic is presented in Figure 2. 

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Figure 2: 
Study Design Schematic 
Abbreviations: HTP: Heated tobacco product, HTS: Heated tobacco stick(s), NRT: Nicotine Replacement 
Therapy (nicotine gum), PK: pharmacokinetic, UBCC: Usual brand combustible cigarette. 
 
3.1.1 
Duration of Study 
Study participation for each participant is expected to last up to 34 days, including a 28-day 
screening period (that includes a 5-day at-home HTP product trial period), and a 6-day in-clinic 
confinement period (from Check-in [Day -1] through the end-of-study [EOS] visit on Day 6). 
3.1.2 
Definition of Study Completion 
End-of-study procedures will be performed as specified in the summary of events (refer to 
Table 1); participants who withdraw from the study early will have EOS/early termination (ET) 
procedures performed at the time of discontinuation. Participants with ongoing AEs will be 
followed until the AE is resolved or medically stable per Investigator’s opinion; reasonable 
attempts will be made to follow up with participants. The participant’s participation in the study 
will end once all study assessments and, if applicable, follow-up have been completed. 
3.1.3 
End of Study 
The EOS is defined as the date when the last participant has completed all study procedures up to 
and including the EOS/ET as specified in the summary of events (Table 1). 
3.2 
Clinical Procedures 
Participants will undergo screening procedures within 28 days prior to Day 1 to confirm that they 
meet study qualifications. Participants meeting all inclusion and none of the exclusion criteria 
will be selected for at home HTP acclimation and will have a product dispensing visit 
(Enrollment Visit) 5 days (Day -6) prior to Check-in at a time determined by the clinic. 
Participants will abstain from use of any nicotine- and tobacco-containing products from 

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Check-in until EOS except for the study products administered at scheduled times as defined in 
Table 1. 
3.2.1 
Questionnaire Training 
At Check-in (Day -1), participants will complete one set of the subjective effects questionnaires 
(refer to the Appendices) in order to familiarize themselves with the questions, appropriate use of 
the VAS, and use of the computerized system. Participants will also be trained on a paper version 
of the questionnaires as a backup in case of computer issues during the study. Data from the 
training session will be recorded but not reported. 
3.2.2 
Product Use Training 
Prior to sending participants home with the study HTP products on Day -6, participants must be 
instructed on the proper operation of the HTP device and how to insert/remove the HTS. 
Participants should receive instructions on how to use the NRT (gum) on Day -1 to ensure all 
participants know the proper use of the gum. Participants will not be provided any gum for the 
at-home product trial. 
Training on how to use the Ploom® HTP device will be provided to each participant prior to the 
at-home HTP acclimation to ensure that all participants are familiar with how to use the device. 
The site staff will document the number of HTS dispensed for each participant. Product use will 
be recorded (i.e., number of HTS dispensed). 
3.2.3 
In-Confinement Afternoon Product Use Session 
On the afternoon of Day -1 and on Days 1, 2, 3, 4 and 5 after the 180-minute test session, 
participants will participate in an approximately 6-hour ad libitum in-confinement afternoon 
product use session, using the product they are randomized to receive on the following morning 
during the morning ad libitum product use PK test session. During the afternoon product use 
session, each participant must use at least one but not more than 6 Ploom® HTS, pieces of 
nicotine gum, or UBCCs. Participants will abstain from all nicotine- and tobacco-containing 
products between each product use. Participants will use HTPs, combustible cigarettes and 
nicotine gum in separate rooms. 
Note: Participants will abstain from all other nicotine- and tobacco-containing products except 
for the designated use of the study products, from Check-in to EOS (confined portion of the 
study). 
3.2.4 
Daily Product Use and Accountability of Used HTS 
Daily HTP use will be tracked and recorded by the pharmacy or designated site staff and will be 
entered into the database. All used HTS will be collected and stored until the Clinical Research 
Associates (CRA) has had the opportunity to complete product reconciliation. Once the CRA has 
completed the reconciliation at the site the used HTS can be discarded per the sites’ standard 
operating procedure (SOP). All Ploom® HTPs (devices) will be returned to the Sponsor at the 
end of the study. Unused HTS will be stored at room temperature until completion of the study 

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and destroyed per site SOP or returned to the Sponsor unless required by regulations to be held 
by the study site. Study Sponsor approval should be obtained prior to returning devices or study 
product as well as prior to destroying unused study product. 
3.3 
Test Session 
3.3.1 
Pharmacokinetic Assessments 
On the morning of Days 1, 2, 3, 4, 5 and 6, depending on their assigned product use sequence, 
participants will use their assigned product (i.e., HTP, UBCC, or nicotine gum,) during the 
morning ad libitum product use PK test session. When assigned to use UBCC or HTP, PK 
assessment involves 5 minutes of ad libitum product use, during which time participants will 
smoke a single combustible cigarette without limitation on number of puffs and inter-puff 
intervals for up to 5 minutes or use one HTS without limitation on puffs or inter-puff intervals 
for up to 5 minutes (the devices automatically shut off five minutes from time of activation for 
Ploom® HTP). Study sites should ensure that the study participants only use their UBCC and any 
of the HTS for no more than 5 minutes. When assigned to use nicotine gum, participants will use 
this product for 30 minutes ad libitum, as per the manufacturer’s use instructions (chew slowly 
until taste becomes strong, then rest between gum and cheek, start to chew again when the taste 
has faded. Keep chewing like this for the 30 minutes during the morning ad libitum product use 
PK test session). Serial venous blood samples will be collected at approximately -5, 3, 5, 7, 10, 
15, 30, 45, 60, 120, and 180 minutes relative to the start of product use. 
3.3.2 
Physiological Heart Rate Assessments 
Physiological heart rate assessments will be assessed at designated time points (see Table 2) 
during the morning ad libitum product use PK test sessions. Heart rate measurements will be 
performed prior to the blood draw (approximately 1 minute prior to the scheduled blood draw 
time point) when scheduled at the same time. 
3.3.3 
Subjective Measures 
Subjective effects questionnaires (refer to the Appendices) will be administered during each 
morning ad libitum product use PK test session, concurrently with PK assessment on Days 1, 2, 
3, 4, 5 and 6 to assess the effects of product use. Participants will have a questionnaire training 
session on Day -1 (refer to Section 3.2.1). On Days 1, 2, 3, 4, 5, and 6, participants will complete 
Product Liking, Tobacco/Nicotine Withdrawal, Direct Effects of Product, Use the Product 
Again, and mCEQ at various designated nominal time points for the blood draws (refer to 
Table 2). 
3.4 
Clinical Safety Evaluations 
Clinical safety evaluations will be performed to ensure that participants meet the requirements of 
the study eligibility (Section 4) and to monitor participant safety. These evaluations will include 
physical examinations, vital sign evaluations, 12-lead ECGs, clinical laboratory assessments 
(clinical chemistry, hematology, urinalysis, and serology), urine drug and urine/breath alcohol 

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screens, and pregnancy test (all females) and follicle-stimulating hormone (FSH) tests (post- 
menopausal or symptomatic females only) at designated time points prior to and during the 
study. All reported AEs will be monitored and recorded throughout the study starting on Day -6 
upon start of the At Home Product Trial (refer to Section 7). 
Approximately 516.5 mL of whole blood will be collected from each participant during the 
course of the study. For all scheduled clinical laboratory tests, approximate blood volumes per 
sample are: 4 mL hematology and 8.5 mL chemistry (includes FSH, pregnancy, and/or serology 
when scheduled at the same time), for a total of approximately 12.5 mL for safety samples; 4 mL 
of blood for nicotine PK at each time point; and 10 mL of blood for NNN PK at each time point. 

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4 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
4.1 
Inclusion Criteria 
Participants must meet all inclusion criteria to be eligible for study participation. 
1. Participants must be informed of the nature and risks of the study and voluntarily give 
written informed consent prior to screening. 
2. Healthy adult males and females ≥ 22 and ≤ 65 years of age, inclusive, at screening. 
3. Participants must self-report currently smoking menthol or non-menthol factory 
manufactured combustible cigarettes. Participants will have a history of smoking ≥ 10 to 
≤ 30 menthol or non-menthol factory manufactured combustible cigarettes daily for at 
least 12 months prior to screening. Prior to screening, brief periods (i.e., up to 
7 consecutive days) of non-smoking within 90 days before Check-in (e.g., due to illness 
or participation in a clinical study where tobacco use was prohibited) will not be 
exclusionary at the discretion of the Investigator (other non-daily tobacco use, except for 
heated tobacco use, within 30 days prior to screening are not exclusionary). 
4. Participants must be generally healthy, free of lifetime malignant tumors, and without 
clinically significant abnormalities as assessed by the Investigator based on the review 
of medical and surgical history, physical examination, vital signs, 12-lead ECG, and 
laboratory evaluations conducted at screening and Check-in, as applicable (refer to 
Table 1). A single repeat measurement/test may be performed to confirm vital signs, 
12-lead ECG, and clinical laboratory tests abnormalities (i.e., to confirm that a 
participant is eligible). 
5. Screening and Check-in systolic/diastolic blood pressure ≤ 150/90 mmHg measured 
after being seated quietly for at least 10 minutes. Two rechecks may be performed at the 
Investigator’s discretion. 
6. Urine cotinine ≥ 500 ng/mL at screening. 
7. Exhaled carbon monoxide ≥ 10 ppm at screening. 
8. Negative pregnancy test at screening and Check-in (Day -1) for all female participants. 

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9. Female participants who are sexually active and of childbearing potential (i.e., not 
surgically sterile at least 6 months prior to Check-in nor post-menopausal with 
amenorrhea for at least 1 year prior to Check-in and FSH levels consistent with post- 
menopausal status) must not be lactating and must have been using one of the following 
forms of contraception from 3 months before first study product administration through 
30 days after the final administration of study product: 
• hormonal (e.g., oral, vaginal ring, transdermal patch, implant, injection) consistently 
for at least 3 months prior to Check-in, when used in combination with male 
condoms with spermicide (use of NuvaRing® is at the Investigator’s discretion) 
• double barrier (e.g., condom with spermicide or diaphragm with spermicide) 
consistently for at least 2 weeks prior to Check-in 
• intrauterine device or system (utilize Investigator discretion regarding use of 
hormonal or nonhormonal devices) for at least 3 months prior to Check-in 
• exclusive partner who is clinically sterile (i.e., documented infertility or surgical 
sterilization; see below for additional information on sterility) or has been 
vasectomized for at least 6 months (inclusive) prior to Check-in 
Note: Sexual abstinence, defined as refraining from intercourse, is allowed when this is in 
line with the preferred and usual lifestyle of the participant. Female participants 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. 
10. Female participants who are of non-childbearing potential must have undergone one of 
the following sterilization procedures at least 6 months prior to Check-in: 
• hysteroscopic sterilization with documentation of success with hysterosalpingogram 
• bilateral tubal ligation or bilateral salpingectomy 
• hysterectomy 
• bilateral oophorectomy 
• Essure® 
or be post-menopausal with amenorrhea for at least 1 year prior to Check-in and 
confirmed by FSH levels consistent with post-menopausal status. 
11. Able to communicate effectively with the study personnel and willing to comply with 
the requirements of the study. 
12. Willing and able to use all of the study products. This includes product use during the 
at-home product trial and the in-confinement product use sessions. If participants are 

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unwilling to use or unable to tolerate any of the study products they will not participate 
in this study. 
4.2 
Exclusion Criteria 
Participants will be excluded from the study if there is evidence of any of the following criteria 
at screening or Check-in, or at any time during the study, as appropriate. 
1. Use of any HTPs within the past 30 days prior to the screening visit; occasional use 
(i.e., not daily use) of other types of tobacco- or nicotine-containing products other than 
factory manufactured combustible cigarettes (e.g., roll-your-own cigarettes, e-cigarettes, 
bidis, snuff, nicotine inhaler, pipe, cigar, nicotine patch, nicotine spray, nicotine lozenge, 
or nicotine gum) are allowed within the past 30 days prior to screening. 
2. Any postponement of a quit attempt to participate in the study; or any attempts to quit 
smoking in the 3 months prior to Day -1 (Check-in). 
3. Self-reported puffers (i.e., smokers who draw smoke from the combustible cigarette into 
the mouth and throat but do not inhale). 
4. Poor dentition that prevents participant from using nicotine gum. 
5. History or presence of any type of malignant tumor or clinically significant 
gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, urologic, 
pulmonary, immunologic, psychiatric, or cardiovascular disease, or any other condition 
that, in the opinion of the Investigator, would interfere with the absorption, distribution, 
metabolism, or excretion of cotinine or jeopardize the safety of the participant or impact 
the validity of the study results. 
6. Current evidence or any history of congestive heart failure. 
7. Any other condition or prior therapy that, in the Investigator’s opinion, would make the 
participant unsuitable for the study, or unable or unwilling to comply with the study 
procedures. 
8. Clinically significant abnormal vital sign, physical examination (including oral cavity an 
oropharynx), medical history, or clinical laboratory finding(s), in the opinion of the 
Investigator. 
9. Positive test for human immunodeficiency virus (HIV)-1 or HIV-2; or hepatitis B 
surface antigen (HBsAg) or hepatitis C virus (HCV) consistent with current infection at 
screening. 
10. Diabetes mellitus that is not controlled by diet/exercise alone, in the opinion of the 
Investigator. Fasting plasma glucose > 126 mg/dL (7 mmol/L) is exclusionary. One 
recheck may be performed for fasting plasma glucose values > 126 mg/dL but 
< 200 mg/dL. 

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11. An acute illness (e.g., upper respiratory infection, viral infection) requiring treatment 
with prescribed medicines within 2 weeks prior to Check-in. 
12. History of surgery or major trauma within 12 weeks of screening, or surgery planned 
during the study through EOS. 
13. History of alcohol abuse or drug abuse within 24 months prior to Check-in. 
14. Consumption of alcohol-containing food or beverages within 48 hours prior to Check-in. 
15. Positive screen for alcohol (breath or urine) 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. 
16. Fever (i.e., body temperature > 100.5°F) at screening or Check-in; 1 recheck may be 
performed at the Investigator’s discretion. 
17. Body mass index (NHLBI) > 40.0 kg/m2 or < 18.0 kg/m2 at screening. 
18. Estimated glomerular filtration rate < 80 mL/minute using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula (Medscape) at screening. 
19. Serum alanine aminotransferase ≥ 1.5 times the upper limit of normal and/or aspartate 
aminotransferase ≥ 2.0 times the upper limit of normal at screening; 1 recheck may be 
performed at the Investigator’s discretion. 
20. Female participants who are pregnant (positive pregnancy test at screening or Check-in), 
lactating, or intend to become pregnant from screening through EOS. 
21. Use of prescription or over-the-counter (OTC) bronchodilator medication (e.g., inhaled 
or oral β-agonists) for treatment of any illness within 12 months prior to Check-in. 
22. Use of antibiotics within 2 weeks prior to Check-in. Also refer to Section 5.7.1. 
23. Use of medications 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, 
ketoconazole, letrozole, methimazole, methoxsalen, metyrapone, miconazole, modafinil, 
orphenadrine, pentobarbital, phenobarbital, pilocarpine, primidone, propoxyphene, 
quinidine, rifampicin, rifampin, secobarbital, selegiline, sulconazole, tioconazole, 
tranylcypromine) within 14 days or 5 half-lives of the drug, whichever is longer, prior to 
Check-in. 
24. Has taken other investigational drugs/products or participated in any clinical study for an 
investigational drug, device, biologic, or for a tobacco product within 30 days or 5 half- 
lives (if known) of the investigational product’s PK, pharmacodynamic, or biological 
activity (if known), whichever is longer, prior to first administration of study product in 

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this study or is currently participating in another clinical study; or participation in 
> 2 ALCS-sponsored studies within the past 12 month period prior to Check-in. 
25. Has received a vaccination within 14 days prior to Check-in. 
26. Plasma donation within 7 days prior to Day 1. 
27. Donation of ≥ 1 unit of blood or blood products (with the exception of plasma as noted), 
had significant blood loss > 450 mL, or received whole blood or a blood product 
transfusion within 56 days prior to Day -1. 
28. Strenuous activity (as assessed by the Investigator) within 48 hours prior to Check-in. 
29. Participant or a first-degree relative (i.e., parent, sibling, child, spouse) is a current or 
former employee of the tobacco industry or a named party or class representative in 
litigation with any tobacco company. 
30. Participant or a first-degree relative (i.e., parent, sibling, child, spouse) is a current 
employee of the study site. 
31. Unwilling or unlikely to comply with the requirements of the study. 
 
 
4.3 
Screen Failures 
Participants who are discontinued from the study prior to study product administration will be 
considered screen failures. 
If a qualified participant, including an alternate participant, leaves the study prior to first test 
product use (at home product trial), the participant may be enrolled into a subsequent cohort (at 
Investigator’s discretion) if the enrollment is within 28 days of screening and the required at 
home product trial is completed prior to Check-in. 
Screen failures will be recorded in the electronic data capture (EDC) system. 
4.4 
Participant Discontinuation 
Participants will be advised that they are free to discontinue from the study at any time and/or 
withdraw consent. The Investigator may discontinue a participant if they feel this action is in the 
best interest of the participant. At the discretion of the Investigator, and in consultation with the 
Sponsor, a participant may be discontinued for failure to adhere to the requirements of the 
protocol. 
If a participant discontinues early from the study and has used any study product provided by the 
Sponsor, all of the safety data normally required at the EOS should be obtained, unless the 
participant refuses or withdraws consent. Participants with AEs will be followed to a final 
outcome. Final outcome may be classified as resolved, improved, unchanged, worse, fatal, or 
unknown (participant is lost to follow-up). 

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Participants discontinuing from the study will not be replaced. Participants enrolled in the 
Product Trial but failed at Check-in or dropped prior to randomization will not be replaced. 
Participants completing, discontinuing, or removed from this study cannot re-enter. Reasons for 
discontinuation may include: 
• AE 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Study terminated by Sponsor 
• Withdrawal by participant 
• Death 
• Noncompliance with study product 
• Other (reasons other than the above should be noted) 
In the event of a participant’s discontinuation, the Investigator will promptly notify the Sponsor 
and Medical Monitor and will make every effort to complete the EOS assessments. All 
discontinued participants with ongoing clinically significant clinical or laboratory findings will 
be followed until the finding is resolved or medically stable; reasonable attempts will be made to 
follow up with participants. 
In addition, the Sponsor reserves the right to discontinue this study at any time. The Investigator, 
in collaboration with the Sponsor, reserves the right to discontinue the study for safety reasons at 
any time. 

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5 
PARTICIPANT PRODUCT USE 
5.1 
Identity of Study Products 
A description of the study products is presented in Table 3. 
Table 3: 
Study Products 
 
Study 
Product 
Description 
Route of 
Administration 
Manufacturer 
Device 
Sticks 
A 
Ploom® 3.1 HTP - Menthol HTS; MX3 (681) 
(Test Product) 
Inhalation 
PT. Pegatron 
Technology 
JTI 
B 
Ploom® 3.1 HTP - Menthol HTS; MX5 (706) 
(Test Product) 
Inhalation 
PT. Pegatron 
Technology 
JTI 
C 
Ploom® 3.1 HTP - Tobacco HTS; R8 (120) 
(Test Product) 
Inhalation 
PT. Pegatron 
Technology 
JTI 
D 
Ploom® 3.1 HTP - Tobacco HTS; RX4 (953) 
(Test Product) 
Inhalation 
PT. Pegatron 
Technology 
JTI 
E 
Nicorette® 4 mg Mint Nicotine Gum 
(Reference Product) 
Oral 
N/A 
N/A 
F 
Combustible Cigarette (menthol or non- 
menthol), participant’s usual brand 
(Reference Product) 
Inhalation 
N/A 
Various 
The HTP (devices and sticks; Products A, B, C, and D) and nicotine gum (Product E) will be 
sourced by Altria Client Services LLC. HTS for Products A, B, C, and D were manufactured by 
Japan Tobacco International (JTI). Participants’ UBCC (Product F) will be sourced by the 
participant prior to Check-in. 
5.2 
Products Administered 
The HTPs consist of a portable device and disposable HTS that contains approximately 254 – 
261 mg of material consisting of tobacco (cut-filler), water, flavors and humectants (propylene 
glycol and vegetable glycerin). The device is used to hold the stick and provide power to heat 
tobacco in the stick. Four HTS (i.e., four Ploom® device sticks) will be tested in the study along 
with nicotine gum and the participant’s menthol or non-menthol UBCC will be used as the 
reference product for menthol and tobacco groups, respectively. Refer to Table 3 for test product 
and reference product information. 
5.3 
Method of Assigning Participants to Study Products 
ALCS will generate the randomization schedule and the Medrio system will be utilized to 
randomize participants. Refer to Section 8.3 for a description of randomization methods. Eligible 
participants will be assigned to a product sequence according to the list of participant 
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5.4 
Measurements of Product Use Compliance 
5.4.1 
At-home Product Acclimation 
Study participants will be provided with a Ploom® HTP device and the HTS’s for at-home 
product acclimation. Product use compliance will be assessed and unused product (HTS) at 
Check-in by site staff and will be recorded. 
5.4.2 
Product Compliance in Confinement 
The study products will be administered by delegated and trained site staff. All product uses will 
be under the supervision of the study site staff. Details regarding product administration, 
including the product administered and the date and time of administration, will be recorded. 
5.5 
Study Product Storage, Accountability, and Retention 
5.5.1 
Storage Conditions 
All study products will be stored in a locked, limited-access area in the study site and kept at 
controlled room temperature (defined as 15° to 25°C [59° to 77°F], with excursions permitted to 
30°C [86°F]). A sufficient supply of all products for each participant may be transferred and kept 
in a secure area in the clinic (e.g., locked drawer or cupboard) each day as necessary, with 
appropriate documentation of transfer noted as above. 
5.5.2 
Product Accountability and Retention 
The Principal Investigator must ensure that all study product supplies are kept in a secure locked 
area with access limited to those authorized by the Investigator. The Investigator must maintain 
accurate records of the receipt of all study product shipped by Altria Client Services LLC or their 
representative, including but not limited to the date received, lot number, expiration date, amount 
received, and the disposition of all study product. Current dispensing records will also be 
maintained including the date and amount of study product dispensed and the participant 
receiving the study product. All remaining study products not required by regulations to be held 
by the study site will be destroyed per site SOP or returned to Altria Client Services LLC or their 
representative after the study is completed. 
Participants will supply one unopened pack of their UBCC at Check-in to be used during the 
study. The storage and accountability of the cigarettes will be handled in the same way, as 
applicable, as the study product supplied by Altria Client Services LLC. In addition, site staff 
will verify participants’ UBCC and document/label accordingly for each participant for use 
during the study. Site staff will make a color copy of the package of each participant’s UBCC. 
Each participant will only be provided the UBCC supplied by that participant. 
Site staff will coordinate shipping of the HTPs and nicotine gum from the Sponsor. Site staff will 
document the date each shipment was received and recorded in the inventory records. Site 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 

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the end of clinical conduct. The site pharmacy where randomization is completed will retain and 
store 1 pack of each HTP type at the site until the final study report is completed. 
All used HTS will be collected and stored until the CRA has had the opportunity to complete 
product reconciliation. Once the CRA has completed the reconciliation at the site the used HTS 
can be discarded per the sites SOP. All Ploom® HTPs (devices) will be returned to the Sponsor at 
the end of the study. Unused HTS will be stored at room temperature until completion of the 
study and destroyed per site SOP or returned to the Sponsor. Sponsor approval should be 
obtained prior to returning devices or study product as well as prior to destroying unused study 
product. 
5.6 
Packaging and Labeling 
5.6.1 
Study Product 
 
All product preparation will be performed by the pharmacist or qualified and trained study staff. 
 
5.6.2 
Blinding of Product Assignment 
 
Study participants will know when they are using their UBCC and the nicotine gum. However, 
participants will not be informed of which Ploom® HTS product they are using. Participants will 
not see the stick or device packaging. 
5.7 
Concomitant Medications and Procedures and Other Restrictions 
5.7.1 
Concomitant Medications and Procedures 
 
Any concomitant medications taken from 30 days prior to Check-in (Day -1) through EOS/ET 
will be recorded. 
 
Prohibited medications are included in the exclusion criteria (Section 4.2). 
 
Stable doses (i.e., no dosage adjustments within 30 days prior to Check-in) of prescription or 
OTC medications required to treat an Investigator-approved disease or condition are permitted at 
the discretion of the Investigator. Hormonal contraceptives (e.g., oral, vaginal ring, transdermal 
patch, implant, injection) and hormonal replacement therapy are permitted. Occasional use of 
OTC analgesics (e.g., acetaminophen, ibuprofen), Milk of Magnesia®, antihistamines, and nasal 
decongestants are permitted as needed to treat AEs experienced by participants at the discretion 
of the Investigator. Note: acetaminophen dosage up to 650 mg/day will be permitted. Note that 
some decongestants might cause a positive drug screen result and therefore their use should be 
discouraged within five to seven days of those tests. 
 
No concomitant procedures will be performed during the study unless approved by the 
Investigator. Medications taken for a procedure will also be included on the concomitant 
medication eCRF, as well as the procedure itself. 

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5.7.2 
Other Restrictions 
 
Participants will be instructed to adhere to the following restrictions: 
 
• No tobacco- or nicotine-containing product use from Check-in until EOS except at the 
designated time when only the study products are allowed. 
• No strenuous exercise is allowed for 48 hours prior to Check-in or during confinement. 
Participants will be instructed to refrain from strenuous physical activity that could cause 
muscle aches or injury, including contact sports. 
• No food or beverages containing alcohol for 48 hours prior to screening or Check-in or 
during confinement. 
• No food or beverages containing grapefruit for 14 days prior to Check-in or during 
confinement. 
• No beverages or liquids of any kind (including water) are allowed during the morning ad 
libitum product use PK test session five-minute ad libitum product use or 30-minute 
nicotine gum use. An exception can be made if a participant starts coughing 
uncontrollably while smoking their combustible cigarettes or using the HTPs, in which 
case they will be allowed to drink water. Water will be provided as desired at all other 
times. 
• On each of the study days, participants will be required to shower and will receive clean 
articles of clothing following the completion of study events that day. 
5.7.3 
Dietary Considerations 
 
Starting on Day -1, meals and snacks will be served at appropriate times as determined by the 
clinic based on the time of Check-in. 
 
Participants will be served a standard breakfast each morning and must complete breakfasts on 
the mornings of Days 1 - 6 at least one hour prior to the start of each test session. Participants are 
not allowed snacks during the 180-minute test session. Participants are not required to consume 
the entire breakfast. The breakfast menu should be consistent (same menu items) throughout 
confinement (Days 1 - 6). A standard lunch, dinner, and snack will be served at approximately 
the same time on each of Days -1-5. 

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6 
STUDY ASSESSMENTS AND PROCEDURES 
Participants will undergo study procedures and assessments at time points specified in the 
summary of events in Table 1 and Table 2. Additional information on procedures is presented in 
Section 3.2. 
6.1 
Medical and Surgical History 
 
At screening, the Investigator or designee will collect each participant’s complete medical and 
surgical history in the EDC system. Histories will be confirmed at Check-in to determine if any 
changes have occurred since screening. Tobacco use history (UBCC only) will be captured in the 
EDC system, but other tobacco use will be kept in the participants’ source documents. 
6.2 
Demographic Characteristics 
 
Demographic characteristics including sex, age, race, and ethnicity will be recorded at screening. 
 
6.3 
Physical Measurements 
 
Height (cm) and body weight (kg) without shoes will be recorded. Body mass index will be 
calculated using the height and weight obtained at screening. 
6.4 
Pharmacokinetic Assessments 
6.4.1 
Plasma Nicotine Concentration Measurements 
Plasma PK samples (total whole blood volume of approximately 504 mL from Days 1 through 6) 
will be collected at time points specified in the PK sampling schedule (Table 2). Blood sample 
collection, processing, and shipping details will be outlined in a separate Study Reference 
Manual (SRM). 
The allowed window for PK blood sampling is indicated in Table 4. 
Table 4: 
Window for PK Blood Sample Collection 
 
Nominal Time 
Allowed Window 
< 0 minute 
≤ ± 2 minutes 
> 0 - 30 minutes 
≤ ± 30 seconds 
> 30 - < 45 minutes 
≤ ± 1 minute 
≥ 45 - < 120 minutes 
≤ ± 2 minutes 
≥ 120 - ≤ 180 minutes 
≤ ± 5 minutes 
Plasma nicotine concentrations will be analyzed by the validated procedure “The Determination 
of Nicotine, Cotinine, Trans-3’-Hydroxycotinine Concentrations in Human Plasma by 
LC-MS/MS” by (
 Sample analysis shall be conducted in compliance with the agreed 
upon protocol, analytical plan, and 
 Bioanalytical Laboratory’s SOPs. The ICH 

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Harmonised Guideline M10, Bioanalytical Method Validation and Study Sample Analysis (24 
May 2022) will be used as a reference for sample conduct. 
6.5 
Physiological Heart Rate Assessments 
 
At the time points indicated in Table 2, seated heart rate will be measured (see Section 6.8.4 for 
additional details). When scheduled at the same time, heart rate measurements will be performed 
prior to the blood draw (approximately 1 minute prior to the scheduled blood draw time point). 
6.6 
Subjective Measures Questionnaires 
At the time points indicated in Table 1 and Table 2, participants will complete the following 
questionnaires (using VAS, as applicable) on an electronic device: 
• Product Liking Questionnaire (Appendix 1) 
• Tobacco/Nicotine Withdrawal Questionnaire (Appendix 2) 
• Direct Effects of Product Questionnaire (Appendix 3) 
• Use the Product Again Questionnaire (Appendix 4) 
• Modified Cigarette Evaluation Questionnaire (HTP, Cigarette, NRT/Gum) (Appendix 5) 
 
All relevant software and staff training specific to the electronic questionnaires will be provided 
by the Sponsor. Data will be captured in the Medrio system, as supplied by the Sponsor or 
designee (Section 13.1). Paper data collection may also be used if necessary and data entry will 
be performed through Medrio. Details will be provided in the Data Management Plan. Any 
electronic device and any electronic data collection/recording used must meet all regulatory 
requirements, including 21 CFR Part 11. 
6.7 
Product Use 
 
For UBCC use, the cigarette dispensed, the number of puffs per combustible cigarette, and the 
start time of the first puff and end time of the last puff will be documented for the 5-minute ad 
libitum product use during the morning ad libitum product use PK Test Session (manually 
documented). During the afternoon product use session (no more than approximately 6 hours 
afternoon ad libitum product use), the number of cigarettes used will be documented (manually). 
 
For HTP use, the HTS dispensed, the number of puffs per stick, and the start time of the first puff 
and the stop time of the last puff, will be documented for the 5-minute ad libitum product use 
period during the morning ad libitum product use PK test session (manually documented). 
During the afternoon product use session (no more than approximately 6 hours ad libitum 
product use), the number of sticks used will be documented (manually). 

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For nicotine gum, the product dispensed, the start time of use (when participant places the gum 
in the mouth) and the use stop time (when participant takes the gum out of the mouth) will be 
documented for the 30-minute ad libitum product use during the morning ad libitum product use 
PK test session (manually documented). During the afternoon product use sessions (no more than 
approximately 6 hours ad libitum product use), the number of pieces of gum used will be 
documented (manually). 
6.8 
Safety Assessments 
6.8.1 
Adverse Experiences 
Participants will be monitored for AEs according to Section 7. 
6.8.2 
Laboratory Tests 
 
All clinical laboratory tests listed in Table 5 will be conducted by a laboratory accredited by 
Centers for Medicare and Medicaid Services (Clinical Laboratory Improvement Amendments of 
1988 [CLIA-88]) or at the clinic study site using CLIA-waived kits or procedures. The baseline 
laboratory test results for clinical assessment for a particular test will be defined as the last 
measurement prior to the administration of a first study product. 
 
Participants will fast a minimum of 8 hours prior to clinical laboratory sample collection at 
screening. 
 
At screening, if a participant has an out-of-range value for a clinical laboratory parameter that the 
Investigator believes is not clinically significant or the Investigator does not believe is correct 
(e.g., lab or specimen processing error), but the Investigator wants to confirm with a repeat 
laboratory test, a single repeat is allowed to confirm the initial result. 
 
Additional safety laboratory tests may be conducted as needed by the Investigator to evaluate 
participant safety. 

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Table 5: 
Clinical Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
 
 
 
Hematocrit 
Hemoglobin 
Red blood cell count 
White blood cell count 
Neutrophils (absolute and percent) 
Lymphocytes (absolute and 
percent) 
Monocytes (absolute and percent) 
Basophils (absolute and percent) 
Eosinophils (absolute and percent) 
Platelet count (estimate not 
acceptable) 
 
 
 
 
 
a. 
Fasting for at least 8 hours 
6.8.3 
Other Tests 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Total bilirubin 
Total protein 
Blood urea nitrogen 
Creatinine 
Estimated glomerular filtration rate 
per the CKD-EPI (Medscape) 
Sodium 
Potassium 
Carbon dioxide 
Chloride 
Glucose a 
Uric acid 
Specific gravity 
Ketones 
pH 
Protein 
Blood 
Glucose 
Leukocyte esterase 
Nitrite 
Bilirubin 
Urobilinogen 
Microscopic analysis (performed if 
blood, leukocytes, nitrites, or 
protein are present) 
 
The following tests will be performed: 
 
• Exhaled carbon monoxide 
• Urine drugs of abuse (see Section 4.2 for minimum evaluation) and urine/breath alcohol 
screens 
o During the screening period, drugs of abuse and alcohol screens may not be 
repeated for eligibility 
• Quantitative urine cotinine test 
• Serology tests (i.e., HIV-1 and HIV-2 antibodies, HBsAg, and HCV with current 
infection 
• Pregnancy test (all females): serum testing at screening and urine/serum testing at 
Check-in 
• FSH (post-menopausal or symptomatic females only) 
6.8.4 
Vital Signs 
 
Seated screening and Check-in vital sign assessments will include oral temperature (°C), 
respiratory rate (breaths per minute), systolic and diastolic blood pressure (mmHg), and heart 

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rate (beats per minute). Blood pressure and heart rate will be measured after the participant has 
been resting quietly in a seated position for at least 10 minutes. Any clinically significant 
abnormal vital sign assessments requires at least 1 repeat measurement. 
 
If assessed, a vital signs abnormality that is considered clinically significant initially and on 
confirmation, requires a participant to be discontinued from the study, requires a participant to 
receive treatment, or requires a change or discontinuation from the study product (if applicable) 
will be recorded as an AE. 
6.8.5 
Physical Examination 
 
Comprehensive physical examinations (excluding genital, rectal, and breast examinations [unless 
indicated]) will be performed per Table 1; timing, and abnormal findings will be documented in 
the participant’s eCRF. All comprehensive physical examinations will include, at a minimum, 
assessment of the following systems: skin, head, ears, eyes, nose and throat (including oral cavity 
and oropharynx), respiratory system, cardiovascular system, gastrointestinal system, blood and 
lymphatic systems, and the musculoskeletal system. 
 
Symptom-driven physical examinations will be performed per Table 1 timing and will focus on 
any AEs ongoing at the time of the examination. 
 
An abnormal physical examination finding that is considered clinically significant and requires 
the participant to be discontinued from the study, requires the participant to receive treatment, or 
requires a change or discontinuation of the study product (if applicable) will be recorded as an 
AE. 
6.8.6 
Electrocardiograms 
 
Participants must be resting quietly in a supine position or in the most recumbent position 
possible for at least 5 minutes before the screening 12-lead ECG is obtained. 
 
The ECGs will be documented as normal, having a clinically insignificant abnormality, or 
having a clinically significant abnormality, by the Investigator or medically qualified designee. 
 
Electrocardiogram assessment may include automated interpretation of the tracings (e.g., rhythm, 
presence of arrhythmia or conduction defects, morphology, any evidence of myocardial 
infarction, or ST segment, T-wave, and U-wave abnormalities). The Investigator or designee is 
responsible for reviewing and over-reading the ECG interpretation, for assessing whether the 
ECG machine interpretation findings are accurate, appropriate, normal or abnormal, and for 
providing corrected interpretations as appropriate. In addition, any abnormal ECGs will be 
assessed for clinical significance. 

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6.8.7 
Tobacco Cessation Information 
 
The Investigator or his/her designee, at screening and at the EOS/ET, will advise all participants 
that to reduce the health effects of tobacco, the best thing to do is to quit. The Investigator or 
his/her designee will refer all adult tobacco smokers to the Quit Assist® website (using 
information cards, participant handouts, etc.), which contains citations to a number of third-party 
information sources, including websites, telephone resources, and other organizations with 
additional information. 
6.8.8 
Appropriateness of Safety Assessments 
 
Safety evaluations selected for this study are typical of those for this participant population and 
utilize widely accepted measures. 

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7 
ADVERSE EXPERIENCES 
An AE is defined as any untoward medical occurrence in a participant administered a study 
product during the course of a clinical investigation. An AE can therefore be any unfavorable 
and unintended sign, symptom, or disease temporally associated with the use of a study product, 
whether or not thought to be related to the study product (E6[R2] 2018). This includes a newly 
developed, worsened preexisting, recurring intermittent or intercurrent illness, injury, or 
condition. For this study, a laboratory AE is defined as an abnormal laboratory finding that is 
determined by the Investigator to be clinically significant for that participant. 
 
Events captured between screening and the first study product use (i.e., Product Trial) will be 
documented as baseline signs and symptoms (in medical history) and not AEs. All AEs 
occurring during this clinical study after the first use of the HTP during the Product Trial and 
through Day 6 or EOS/ET 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 products during the product study will be documented as baseline signs and symptoms 
in the 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. 
 
The subjective measures questionnaires are not designed for identifying or documenting AEs. 
Therefore, responses to any items in the subjective measures questionnaires will not be used for 
AE identification or evaluation. 
 
No causal relationship with the study products or with the clinical study itself is implied by the 
use of the term “adverse experience.” 
 
The procedures specified in Section 7.4 are to be followed for reporting SAEs. 

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7.1 
Recording Adverse Experiences 
Adverse experiences are to be recorded on the AE page of the eCRF. The following information 
will be recorded: 
Assessment of whether or not the AE is an SAE (Section 7.2.1) 
Assessment of AE severity (Section 7.2.2) 
Assessment of AE relationship to study product (Section 7.2.3) 
Action taken - categorized as study product use not changed, study product use reduced, study 
product interrupted, study product withdrawn, not applicable 
Outcome - recorded as fatal, not recovered/not resolved, recovered/resolved, recovered/resolved 
with sequelae, recovering/resolving, or unknown, as applicable 
7.2 
Assessment of Adverse Experiences 
The Investigator will assess each AE for seriousness, severity, and relationship to study product. 
7.2.1 
Serious Adverse Experiences 
The Investigator is responsible for determining whether an AE meets the definition of an SAE. 
An SAE is any AE that results in any of the following outcomes (ICH 1995, 21CFR312.32): 
• Death 
• A life-threatening adverse study experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
“Life-threatening” means that the participant was at immediate risk of death at the time of the 
SAE; it does not refer to a SAE that hypothetically might have caused death if it were more 
severe. 
“Persistent or significant disability/incapacity” means that there is a substantial disruption of a 
person’s ability to carry out normal life functions. 
Important medical events that may or may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse experience when, based upon appropriate 
medical judgment, it may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. An example is allergic 
bronchospasm requiring intensive treatment in an emergency room or at home. 
Note: SAEs require immediate reporting to the Sponsor and Medical Monitor. Refer to 
Section 7.4 for details. 

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7.2.2 
Severity 
The severity of an AE will be graded according to the following definitions (ICH 1995): 
• Mild: The AE is easily tolerated and does not interfere with daily activity. 
• Moderate: The AE interferes with daily activity, but the participant 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. 
7.2.3 
Relationship to Study Product 
The relationship of an AE to the study product should be determined by the Investigator 
according to the following criteria (E6[R2] 2018, ICH 1995, Nebeker et al., 2004, Edwards and 
Aronson, 2000) (the strength of a causal association may be revised as more information 
becomes available): 
Not related: 
Clearly and definitely due to extraneous cause (e.g., disease, environment). 
Unlikely: 
a Does not follow a probable temporal (i.e., time) sequence from use of study product. 
b Does not follow a known pattern of response to the study product. 
c 
Could plausibly have been produced by the participant’s clinical state/underlying disease 
or other drugs or chemicals the participant received. 
d Does not reappear or worsen when the study product is re-administered. 
Possible: 
a. Follows a reasonable temporal (i.e., time) sequence from use of study product. 
b. Follows a known pattern of response to the study product. 
c. Could also have been produced by the participant’s clinical state/concurrent disease or 
other drugs or chemicals the participant received. 
Likely: 
a 
Follows a reasonable temporal (i.e., time) sequence from use of study product. 
b Follows a known pattern of response to the study product. 
c Could not readily have been produced by the participant’s clinical state/concurrent 
disease or other drugs or chemicals. 
d Follows a clinically reasonable response on withdrawal (de-challenge), i.e., disappears or 
decreases when the study product is stopped or reduced. 

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e Rechallenge information is not required to fulfill this definition. 
Definitely: 
a Follows a reasonable temporal (i.e., time) sequence from use of study product. 
b Follows a known pattern of response to the study product. 
c Cannot be explained by the participant’s clinical state/concurrent disease or other drugs 
or chemicals. 
d Follows a clinically reasonable response on withdrawal (de-challenge), i.e., 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 
participant is NOT required, but the “certainly/definitely related” category may only be 
used when recurrence is observed. 
7.3 
Discontinuation due to Adverse Experiences 
Any participant who experiences an AE may be discontinued at any time from the study at the 
discretion of the Investigator. Participants discontinued from the study due to an AE, whether 
serious or non-serious, should be followed by the Investigator until the clinical outcome of the 
AE is determined. The AE(s) should be noted on the appropriate eCRFs and the participant’s 
progress should be followed until the AE is resolved or medically stable as determined by the 
Investigator. The Sponsor and Medical Monitor must be notified. 
7.4 
Reporting Serious Adverse Experiences 
In the event of any SAE reported or observed during the study, whether or not attributable to the 
study product, site personnel will report it immediately (within 24 hours) by telephone and by 
fax or e-mail to the Sponsor and Medical Monitor in accordance with procedures described in the 
SRM and/or SAE study-specific procedure. Site personnel will follow up with a written report on 
the next working day. The Investigator must also inform the IRB, in compliance with GCP 
reporting guidelines, and the site monitor of an SAE, whether or not considered study related. 
The initial report must be as complete as possible, including an assessment of the causal 
relationship between the event and the study product. Information not available at the time of the 
initial report (e.g., end date, laboratory values) must be documented on a follow-up SAE form. 
All SAEs should be followed to their resolution, with documentation provided to the Sponsor 
and Medical Monitor on a follow-up SAE Report Form. 
7.5 
Adverse Experiences /Serious Adverse Experience Follow-Up 
Each AE, including clinically significant laboratory abnormalities, whether serious or 
non-serious, will be followed until resolved, determined that follow-up is no longer required (at 
the discretion of the Investigator) or the participant is lost to follow-up. Final outcome may be 
classified as fatal, not recovered/not resolved, recovered/resolved, recovered/resolved with 

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sequelae, recovering/resolving, or unknown, as applicable. Where appropriate, medical tests and 
examinations will be performed to document the outcome of the AE. 
7.6 
Pregnancy 
Pregnancies will be captured if they occur in female participants from the time the participant is 
first exposed to the study product until EOS/ET. 
A positive pregnancy test prior to enrollment will be documented as a screen failure. Pregnancy 
occurring in a female participant (after first HTP use during the Product Trial through Day 6 or 
EOS/ET) will be documented in a pregnancy form (provided separately by the Sponsor) and as a 
protocol deviation to the IRB. 
Pregnancy itself is not an AE. The Investigator or designee will discontinue the pregnant 
participant from the study and will advise her to seek prenatal care and counseling from her 
primary care provider. The Investigator 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 
participant’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 participant notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the study site staff will follow up 
with the participant until the end of pregnancy, if in compliance with the site’s SOPs and with 
the participant’s consent. This request and the participant’s response will be documented in the 
participant’s source document. A final report of pregnancy outcome will be sent to the Medical 
Monitor and Sponsor. 

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8 
STATISTICAL CONSIDERATIONS 
The statistical analysis will be conducted following the principles specified in ICH Topic E9 
(CPMP/ICH/363/96). 
Details of the statistical analysis will be provided in the Statistical Analysis Plan (SAP). 
SAS software (Version 9.4 or higher, Cary, North Carolina) will be used for all data presentation 
and summarization including statistical analyses, summary tables, figures, and data listings. 
Statistical methods will be discussed in detail in the SAP. 
8.1 
Sample Size Calculation 
The purpose of this study is to characterize the nicotine PK and subjective effects of four Ploom® 
HTPs in healthy adult menthol and non-menthol combustible cigarette smokers. Assuming an 
intra-subject variability of 60% for plasma nicotine Cmax and AUC (Picavet et al., 2016) as well 
as a true geometric mean ratio of 100%, a sample size of 48 participants would result in a 90% 
CI of (83%, 121%). If true geometric mean ratio of 105% is assumed, a sample size of 
48 participants would result in a 90% CI of (87%, 127%). Based on previously published 
literature, typical sample sizes range from 10 to 32 participants for studies examining the PK and 
subjective effects of tobacco/nicotine-containing product use (Carter et al., 2009, Cobb et 
al., 2010, Cox et al., 2001, Gray et al., 2008, Hardie et al., 2022, Hatsukami et al., 2004, 
Kotlyar et al., 2007, McDermott et al., 2023). Therefore, a sample size of approximately 
48 participants (24 completed participants per each of the menthol and non-menthol groups) is 
considered adequate for the current study design. 
8.2 
Analysis Populations 
Enrolled Population: All participants who signed the ICF. This population will include all screen 
failure participants. 
Pharmacokinetic Population: All participants who used any study product and have baseline 
pre-use and at least one plasma nicotine concentration value after product use has started. 
Subjective Measures Population: All participants who used any study product and have pre-use 
(Tobacco/Nicotine Withdrawal) and at least one post-use (Product Liking, Tobacco/Nicotine 
Withdrawal, Direct Effects of Product, Use the Product Again, and mCEQ) score. 
Physiological Heart Rate Population: All participants who used any study product and have 
pre-use and at least one post-use physiological heart rate measurement during the morning 
ad libitum product use PK test session. 
Product Use Population: All participants who used any study product and have at least one puff 
count value. 
Safety Population: All participants who used any study product. 
Additional details describing the analysis data sets will be provided in the SAP. 

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For any participant who is pregnant during the study, that participant’s data will only be listed 
but will be excluded from all analyses. 
8.3 
Randomization 
ALCS will prepare the randomization schedule. Participants will be randomized at 1:1:1:1:1:1 
ratio into 1 of 6 sequences as listed below. At least 60 participants will be randomized to ensure 
approximately 48 completed participants, with approximately 24 menthol and 24 non-menthol 
cigarette smokers. Every attempt will be made to enroll no less than 40% of either sex for each 
cigarette flavor (menthol or non-menthol). Participants will be stratified by sex and cigarette type 
for each of the sequences. 
A 6x6 Latin Square with the following sequences will be used for the randomization: 
Sequence 1 = ABFCED 
Sequence 2 = BCADFE 
Sequence 3 = CDBEAF 
Sequence 4 = DECFBA 
Sequence 5 = EFDACB 
Sequence 6 = FAEBDC 
Participants will be randomized to the above sequences on the day of Check-in (Day -1). 
8.4 
Pharmacokinetic Analysis 
8.4.1 
Pharmacokinetic Parameters 
 
Pharmacokinetic parameters for nicotine will be computed from the individual baseline-adjusted 
plasma concentrations applying non-compartmental methods using appropriate validated PK 
software (Phoenix WinNonlin Version 8.0.0.3176 or higher). Concentration values below the 
lower limit of quantitation will be set to one half of the limit of quantification. 
 
The following PK parameters will be determined for each product following the morning PK 
ad libitum Product Use: 
 
Cmax: 
Maximum measured plasma concentration over the duration of the 
measurement interval. 
 
Tmax: 
Time of the maximum measured plasma concentration over the duration of 
the measurement interval. If the maximum value occurs at more than one time 
point within the time span specified, Tmax is defined as the first time point 
with this value. 

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AUC(0-180): 
Area under the nicotine concentration-time curve calculated using linear 
trapezoidal summation from time zero (defined as the start of product use) to 
180 minutes (or the last quantifiable concentration during that interval). 
 
Kel: 
Apparent first-order terminal elimination rate constant calculated from a 
semi-log plot of the plasma concentration time curve. The parameter will be 
calculated by linear least-squares regression analysis using the maximum 
number of points in the terminal log linear period (e.g., three or more non- 
zero plasma concentrations). 
 
T½ 
Apparent first-order terminal elimination half-life will be calculated as 
0.693/Kel. 
 
Baseline adjustment of plasma nicotine concentrations will be performed by using the following 
equation: Ct = Ct uncorrected – [C0 × e-kel t1], where: 
Ct 
Corrected concentration 
Ct uncorrected 
Uncorrected concentration 
C0 
Pre-product administration concentration 
 
Kel £ 
Apparent elimination rate constant obtained from each participant’s 
uncorrected concentrations (for this estimation, values below the lower limit 
of quantitation [BLQ] are set to zero pre-administration and prior to the first 
measurable concentration and as missing thereafter) 
 
t 
Actual sampling time since product administration 
 
t1 
Actual sampling time since pre-product administration sampling 
 
£ Note: the adjustment is participant- and product-specific. If a Kel cannot be estimated for a 
participant, the mean Kel value from other participants for that product will be used. 
 
After correction for pre-product administration values, some concentrations may be BLQ and 
some may be negative values. Negative values will be assigned a value of 0 in the analyses and 
all other values obtained will be reported as is even if these values are BLQ. 
 
Maximum change from baseline for plasma NNN levels will also be reported following HTP and 
UBCC use. 

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8.4.2 
Statistical Analysis 
A linear mixed model for analysis of variance will be performed on the natural log-transformed 
PK parameters Cmax and AUC(0-180) for nicotine to compare each HTP to the reference products, 
UBCC and nicotine gum (NRT), respectively. The model will include sequence, study product, 
and study day as fixed effects and participant-nested-within-sequence as a random effect. 
Sequence will be tested using participant-nested-within-sequence as the error term. Geometric 
LSM and 90% CIs will be provided for the PK parameters of Cmax and AUC(0-180) by study 
product. Geometric LSM ratio, 90% CIs of geometric LSM ratio, and p-values will be provided 
for the study product comparisons among each of HTP products and the reference products 
(UBCC and gum [NRT], respectively) in Cmax and AUC(0-180). The above statistical analyses will 
be performed using the appropriate SAS procedure. Descriptive statistics will be provided as 
appropriate. 
Details of the statistical methods will be provided in the SAP. 
8.5 
Physiological Heart Rate Assessments 
Descriptive statistics will be performed for physiological heart rate data collected during 
morning ad libitum product use PK test sessions. 
8.6 
Subjective Measures Analysis 
8.6.1 
Product Liking, Tobacco/Nicotine Withdrawal, and Direct Effects of Product 
Questionnaires 
Responses to Product Liking, Tobacco/Nicotine Withdrawal and Direct Effects of Product 
questionnaires recorded as VAS scores, will be treated as continuous variables and summarized 
by study product and time point for each questionnaire item. For each questionnaire item, 
descriptive statistics including n, mean, standard deviation (SD), percent coefficient of variation 
(CV%), minimum, median, maximum, first quartile (Q1), and third quartile (Q3) will be 
reported. For Tobacco/Nicotine Withdrawal, the above-mentioned descriptive statistics for the 
difference from pre-use to post-use scores at each time point will also be reported. 
The following subjective effects parameters will be determined: 
 
Emax-PL 
Maximum product liking response in VAS score during each morning 
ad libitum product use. 
Emax-TNW 
Maximum reduction response in VAS score from baseline pre-use to post-use 
(i.e., VASpre-use – VASpost-use) for Tobacco/Nicotine Withdrawal questionnaire 
during each morning ad libitum product use. 
Emax-DEP 
Maximum Direct Effects of Product response in VAS score recorded during 
each morning ad libitum product use. 

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As an exploratory endpoint, the area under the effect curve from time zero (defined as the start of 
product use) to 180 minutes for Product Liking response (AUECPL) during each morning 
ad libitum product use will be determined. 
For the maximum response score to Product Liking questionnaire (Emax-PL), the maximum 
reduction response to each question item in the Tobacco/Nicotine Withdrawal questionnaire 
(Emax-TNW), and the maximum response score to each question item in the Direct Effects of 
Product questionnaire (Emax-DEP) following each product use, a linear mixed model for analysis of 
variance will be performed. The model will include sequence, study product, and study day as 
fixed effects and participant-nested-within-sequence as a random effect. Sequence will be tested 
using participant-nested-within-sequence as the error term. The LSM, 90% CIs, and p-values 
will be provided for the study products in each response. For exploratory purposes, the LSM 
difference, 90% CIs for the difference, and p-values will be provided for the study product 
comparisons among each of HTP products and the reference products UBCC and gum (NRT), 
respectively. 
8.6.2 
Use the Product Again Questionnaire 
Responses on the Use the Product Again questionnaire will be recorded as VAS scores and 
converted to categorical variables (-50 to < 0, 0, > 0 to 50). These categorical data will be 
summarized by study product using frequency count tables. The categorical score for the Use the 
Product Again questionnaire is calculated by subtracting 50 from the original VAS score 
(0 to 100). Both the original VAS scores and bipolar scores in each category will also be treated 
as continuous variables and summarized using descriptive statistics (n, mean, SD, CV%, 
standard error of the mean [SEM], minimum, median, maximum, Q1, Q3, and 90% CIs). 
8.6.3 
Modified Cigarette Evaluation Questionnaires (mCEQ) 
The appropriate mCEQ (Appendix 5) will be administered on study days when the participant 
uses either HTP, nicotine gum, or UBCC. The mCEQ will be administered using a 7-point 
Likert-type scale and treated as a continuous variable. Responses on the mCEQ will be presented 
individually and as the following item domains (Cappelleri et al., 2007): 
a Product use satisfaction: average of the response scores from items 1, 2, and 12; 
b Psychological reward: average of the response scores from items 4 to 8; 
c Aversion: average of the response scores from items 9 and 10; 
d Enjoyment of the sensation: response score from item 3; 
e Craving reduction: response score from item 11. 
Descriptive statistics (n, mean, SD, CV%, SEM, minimum, median, maximum, Q1, Q3, and 
90% CIs) of the subscale factor scores will be provided by sex and by study product. Individual 
responses will be listed. 
Details of the statistical analyses will be described in a separate SAP. 

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8.7 
Product Use Analysis 
Descriptive statistics will be provided for the product use: 
• Afternoon product use sessions (no more than approximately 6 hours): number of HTS, 
UBCC, and nicotine gum used 
• Start time of the first puff and stop time of last puff for each product use during a 
morning ad libitum product use PK test session. 
• Puff count during the morning ad libitum product use PK test sessions for UBCC and 
HTP products 
8.8 
Safety Analysis 
AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA®) and summarized by study product for the number of participants 
reporting the product-emergent AE and the number of product-emergent AEs reported. An AE 
listing, including verbatim term, preferred term, study product, severity, and relationship to study 
product, will be provided. 
The number of participants experiencing AEs and the number of AEs will be summarized by 
study product using frequency counts. 
Safety data, including laboratory evaluations, and vital signs assessments will be summarized by 
time point of collection as appropriate and for available data. 
Descriptive statistics will be calculated for quantitative safety data and frequency counts will be 
compiled for classification of qualitative safety data as appropriate. 
Changes in physical examination findings and/or symptom-driven findings will be described in 
the text of the clinical study report. 
Concomitant medications will be coded using the WHO Drug Dictionary. 
For any participant who enrolled into the study and test positive for pregnancy, that participant’s 
data will only be listed but will be excluded from all analyses. 

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9 
ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator will provide direct access to source data and documents for individuals 
conducting study-related monitoring, audits, IRB review, and regulatory review. The Investigator 
must inform the study participant that his/her study-related records may be reviewed by the 
above individuals without violating the participant’s privacy of personal health information in 
compliance with Health Insurance Portability and Accountability Act of 1996 regulations. 
Attention is drawn to the regulations promulgated by the FDA under the Freedom of Information 
Act providing, in part, that information furnished to Clinical Investigators and IRBs will be kept 
confidential by the FDA only if maintained in confidence by the clinical Investigator and IRB. 
By signing this protocol, the Investigator affirms to the Sponsor that the Investigator will 
maintain, in confidence, information furnished to him or her by the Sponsor and will divulge 
such information to the IRB under an appropriate understanding of confidentiality with such 
board. 

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10 
QUALITY CONTROL AND QUALITY ASSURANCE 
Sponsor and 
 will implement and maintain quality control and quality assurance (QA) 
procedures with written SOPs to ensure the study is conducted and data are generated, 
documented, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirements. 
10.1 
Conduct of Study 
This study will be conducted in accordance with the provisions of the Declaration of Helsinki 
and all revisions thereof (Tokyo 2004), and in accordance with FDA CFR governing Protection 
of Human Participants (Title 21 CFR Part 50), IRBs (Title 21 CFR Part 56), and the ICH E6 
Guidelines on GCP (CPMP/ICH/135/95) The study will be conducted under a protocol reviewed 
by an IRB; the study will be conducted by scientifically and medically qualified persons, and 
each participant will give his or her written, informed consent before any protocol driven tests or 
evaluations are performed. 
The Investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IRB, except when necessary to eliminate 
immediate hazards to the participant or when the change(s) involve only logistical or 
administrative aspects of the study and are approved by the Sponsor. 
10.1.1 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result from the action or 
inaction of the participant, Investigator, or site staff. 
At the outset of the study, a process for defining and handling protocol deviations will be 
established. This will include determining which violations will be designated “important,” 
requiring immediate notification to the Sponsor and Medical Monitor. The Investigator is 
responsible for ensuring that any known protocol deviations are recorded and handled as agreed. 
All protocol deviations/violations that occur during the study will be evaluated prior to database 
lock for their severity and impact on participant safety and data integrity and will be taken into 
consideration when participants are assigned to analysis population. 
10.2 
Protocol Amendments 
No deviations from this protocol will be permitted, except in a medical emergency. The 
Investigator and the Sponsor will discuss any amendment to this study. If agreement is reached 
concerning the need for modification, this agreement will be made in a formal amendment to the 
protocol. 
All revisions and/or amendments to the protocol must be reviewed and approved, if applicable, 
in writing by the IRB. 
All persons who are affected by the amendment to the protocol will be retrained. 

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10.3 
Monitoring of Study 
The responsible study monitor will contact and visit the Investigator as necessary, and they will 
be allowed, upon request, to inspect and verify all records of the study (e.g., source document, 
ICFs, eCRFs, regulatory documents) in a manner consistent with 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 participant has consented in writing prior 
to any study procedures being performed. Where the terms of the Informed Consent, GCP, and 
all other applicable state and federal law permit, the monitor should have access to laboratory 
test reports and other participant 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 oversight monitors, internal auditors (or designee), 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). 

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11 
ETHICS 
11.1 
Institutional Review Board/Independent Ethics Committee Approval 
11.1.1 
Ethics Review Prior to Study 
This protocol and ICFs will be reviewed and approved in writing by the IRB prior to 
commencement of the study. The study will not be initiated without the approval from the IRB. 
As applicable, any amendments after protocol approval will be reviewed and approved by the 
IRB prior to implementation. The IRB operations are in compliance with Title 21 CFR Part 56. 
Notice that the IRB approved the protocol, ICF, and any applicable amendments to the protocol 
and ICF updates will be in the final study report. 
11.1.2 
Ethics Review of Other Documents 
The IRB will approve all protocol amendments (except for Sponsor-approved logistical or 
administrative changes), written informed consent documents and document updates, participant 
recruitment procedures, written information to be provided to the participants, available safety 
information, information about payment and compensation available to participants, the 
Investigator’s curriculum vitae and/or other evidence of qualifications, and any other documents 
requested by the IRB and regulatory authority as applicable. 
11.2 
Written Informed Consent 
The nature and purpose of the study will be fully explained to each participant. The participants 
must be given ample time and opportunity to inquire about details of the study, to have questions 
answered to their satisfaction, and to decide whether to participate. Written informed consent 
must be obtained from each participant prior to any study procedures being performed. All 
prospective participants will also sign the verified clinical trial consent form and will be checked 
to verify they are not enrolled in another clinical study prior to the remaining screening 
procedures. 
11.3 
Confidentiality 
All study sites and vendors will have signed confidentiality agreements with 
 
will regard all information provided to the Investigator dealing with the study and information 
obtained during the course of the study as confidential. 
 and the clinical site(s) will not supply to the Sponsor any participant names, initials, 
date of birth (except year), or other personal identifiers. All such information appearing on any 
study document must be redacted before a copy of the document is supplied to the Sponsor or 
 Study findings stored on a computer will be stored in accordance with local data 
protection laws. The participants will be informed during the consenting process that 
representatives of the Sponsor (or designee), IRB, or regulatory authorities may inspect their 
medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in the strictest confidence and in accordance with local 
data protection laws. 

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11.4 
Ethical Conduct and Responsibility of the Investigator 
The Investigator is responsible for ensuring that the clinical study is performed in accordance 
with GCP based on the current ICH Guideline for GCP, the corresponding sections of the US 
CFR governing Protection of Human Participants (Title 21 CFR Part 50), Institutional Review 
Boards (Title 21 CFR Part 56), the Basic Principles of the Declaration of Helsinki, and other 
applicable legal and regulatory requirements. 
The Investigator should ensure that all persons assisting with the study are qualified for the 
duties assigned, adequately informed and trained on the protocol and amendments to the 
protocol, the study products, and their study related duties and functions. 
The Investigator will maintain a list, including signatures, of sub-investigators and other 
appropriately qualified persons to whom significant study-related duties are delegated. Any 
personnel changes in this list during the course of the study will be documented. All study- 
related training will be documented. 

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12 
DATA HANDLING AND RECORD KEEPING 
12.1 
Data Reporting and Case Report Forms 
12.1.1 
Case Report Forms 
The Investigator will be provided with eCRFs, and will ensure all data from participant visits are 
promptly entered into the eCRFs in accordance with the specific instructions given. The eCRFs 
will be completed for each screened participant whether or not they have completed the study. 
The Investigator will assure complete and accurate entries on the forms. The Investigator must 
review and sign the eCRFs to verify the integrity of the data recorded. 
12.1.2 
Laboratory Data 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to study start. If a central laboratory has been selected to 
conduct any or all tests, it is essential all samples be analyzed at that laboratory. The Investigator 
must maintain source documents such as laboratory reports and complete history and physical 
examination reports. 
12.1.3 
Retention of Source Documents 
Investigator-specific essential documents and all primary data and copies thereof (e.g., source 
documents, eCRFs, laboratory records, data sheets, correspondence, photographs, computer 
records, etc.), which are a result of the original observations and activities of the study and are 
necessary for the reconstruction and evaluation of any study report will be retained in the 
investigative site’s archives for a minimum of 20 years after the completion or termination of the 
study. It is the responsibility of the Sponsor to inform the Investigator as to when these 
documents no longer need to be retained. The study report and final database will be retained in 
 archives for a minimum of 20 years after the completion or termination of the study 
and will be available for inspection at any time by the Sponsor. At completion of the study 
(i.e., at issuance of final study report), the final data will be transferred to the Sponsor. 
Participant initials, serology results, date of birth (except year), and other personal identifiers will 
be redacted from this data transfer file; any such information removed will be documented at the 
time of transfer. 
12.1.4 
Study Report 
A study report written consistent with ICH guidelines will be provided by 
 to the 
Sponsor. The report will include a description of the clinical conduct of the study, safety 
evaluation, analytical methods and results, and the statistical analysis described in the statistical 
methodology section of the protocol and the SAP. 
At the time the draft study report is completed, 
 QA unit will audit the report against 
the SAS data and the raw data. At the completion of the audit, a QA report will be issued 
internally allowing any findings to be addressed before report finalization. 

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12.2 
Retention of Essential Documents 
The study essential documents must be maintained as specified in the ICH guidelines for GCP 
and the applicable regulatory requirements. The Investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents should be retained until at least two years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least two years have elapsed since the formal 
discontinuation of clinical development of the study product. These documents should be 
retained for a longer period; however, if required by the applicable regulatory requirements or by 
an agreement with the Sponsor. It is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained. 
12.3 
Termination of the Study 
The Sponsor reserves the right to discontinue this study at any time. The Investigator, in 
collaboration with the Sponsor, reserves the right to discontinue the study for safety reasons at 
any time. 

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13 
DATA MANAGEMENT 
Data management activities will be detailed in the Data Management Plan and carried out by the 
 data management team according to its internally established SOPs. All data for this 
study will be captured in the Medrio system, as supplied by the Sponsor or designee. Medrio is a 
21 CFR Part 11 compliant. Electronic CRF’s will be developed according to the study protocol 
specifications and will follow ALCS Data Standards. Analytical data will be collected external to 
the database. 
Data can be captured as either paper source or using the Medrio InClinic ePRO system for 
participant -complete data. Data captured on paper will be entered into the EDC system by the 
site. The participant completed InClinic ePRO data will be completed by the participant. All 
subjective measures questionnaire data will be captured directly via the Medrio InClinic ePRO 
system and will be treated as source data. All data captured will have an audit trail. 
Programmed edit 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 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. 
The AEs will be coded using the most current version of MedDRA®. Concomitant medications 
will be coded using the most current version of the WHO Drug Dictionary. The versions will 
remain the same throughout the study. Coding will be reviewed by the Medical Monitor at 
 and ALCS. 
All casebooks will be signed by the Investigator prior to database lock. Submissions casebooks 
will be extracted after database lock and provided to the site. 
Upon completion of the study, the clinical data will be transferred to the Sponsor in SAS format 
with supporting SAS documentation according to the specifications of the Sponsor. Participant 
names, initials, date of birth (except year), and other personal identifiers will be removed from 
this data transfer file; any such information removed will be documented at the time of transfer. 
13.1 
Medrio ePRO 
The subjective measures questionnaire data will be captured in the Medrio system, as supplied 
by the Sponsor or designee. Paper data collection may also be used if necessary and data entry 
will be performed through Medrio. Details will be provided in the Data Management Plan. 

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14 
ADMINISTRATIVE INFORMATION 
14.1 
Financing and Insurance 
Financing and insurance will be addressed in a separate agreement between the Sponsor and the 
Investigator. 
14.2 
Publication Policy 
The Sponsor will retain ownership of all data. All proposed publications based on this study will 
be subject to Sponsor’s approval requirements. 

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15 
REFERENCES 
21CFR312.32. Available at: 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=312.32. 
 
Abrams DB, Glasser AM, Pearson JL, Villanti AC, Collins LK, Niaura RS. Harm 
Minimization and Tobacco Control: Reframing Societal Views of Nicotine Use to Rapidly 
Save Lives. Annu Rev Public Health. 2018;39:193-213. 
 
Altria. Our Approach to Harm Reduction. Available at: https://www.altria.com/harm- 
reduction/our-approach-to-harm-reduction. 
 
Cappelleri JC, Bushmakin AG, Baker CL, Merikle E, Olufade AO, Gilbert DG. 
Confirmatory factor analyses and reliability of the modified cigarette evaluation 
questionnaire. Addict Behav. 2007;32(5):912-23.Carter LP, Stitzer ML, Henningfield JE, 
O’Connor RJ, Cummings KM, Hatsukami DK. Abuse liability assessment of tobacco 
products including potential reduced exposure products. Cancer Epidemiol Biomarkers Prev. 
2009;18(12):3241-62. 
 
CKD-EPI, Creatinine Clearance Estimate by Cockcroft-Gault Equation. Available at: 
https://reference.medscape.com/calculator/creatinine-clearance-cockcroft-gault. 
 
Cobb CO, Weaver MF, Eissenberg T. Evaluating the acute effects of oral, non-combustible 
potential reduced exposure products marketed to smokers. Tob Control. 2010;19(5):367-73. 
 
Cox LS, Tiffany ST, Christen AG. Evaluation of the brief questionnaire of smoking urges 
(QSU-brief) in laboratory and clinical settings. Nicotine Tob Res. 2001;3(1):7-16. 
 
E6(R2) Good Clinical Practice: Integrated Addendum to E6(R1); International Council for 
Harmonisation; Guidance for Industry. Federal Register. Vol. 83, March 1, 2018, p. 8882-3. 
Available at: https://www.fda.gov/media/93884/download. 
 
Edwards IR and Aronson JK. Adverse drug reactions: definitions, diagnosis, and 
management. Lancet. 2000;356(9237):1255-9. 
 
FDA Guidance for Industry. Bioanalytical Method Validation, 2018 May. Available at: 
http://www.fda.gov/downloads/Drugs/Guidances/ucm070107.pdf. 
 
FDA Guidance for Industry. Harmful and Potentially Harmful Constituents (HPHCs). 2019. 
Available at: https://www.fda.gov/tobacco-products/products-ingredients- 
components/harmful-and-potentially-harmful-constituents-hphcs. 

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FDA Press Release. FDA announces comprehensive regulatory plan to shift trajectory of 
tobacco-related disease, death. 27-Jul-2017. Available at: 
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm568923.htm. 
 
FDA Remarks by Scott Gottlieb. Protecting American Families: Comprehensive Approach to 
Nicotine and Tobacco. Speeches by FDA Officials. 28-Jul-2017. Available at: 
https://www.fda.gov/news-events/speeches-fda-officials/protecting-american-families- 
comprehensive-approach-nicotine-and-tobacco-06282017. 
 
Gray JN, Breland AB, Weaver M, Eissenberg T. Potential reduced exposure products 
(PREPs) for smokeless tobacco users: clinical evaluation methodology. Nicotine Tob Res. 
2008;10(9):1441-8. 
 
Hardie G, Gale N, McEwan M, Oscar SM, Ziviani L, Proctor CJ, Murphy J. An abuse 
liability assessment of the glo tobacco heating product in comparison to combustible 
cigarettes and nicotine replacement therapy. Sci Rep. 2022;12(1):14701. 
 
Hatsukami DK, Joseph AM, Lesage M, Jensen J, Murphy SE, Pentel PR, Kotlyar M, Borgida 
E, Le C, Hecht SS. Developing the science base for reducing tobacco harm. Nicotine Tob 
Res. 2007;9 Suppl 4(0 4):S537-53. 
 
Hatsukami DK, Lemmonds C, Tomar SL. Smokeless tobacco use: harm reduction or 
induction approach? Prev Med. 2004;38(3):309-17. 
 
ICH Guideline for Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting (E2A). Federal Register. Vol. 60, March 1, 1995, p. 11284. 
 
Institute of Medicine, 2012. Scientific Standards for Studies on Modified Risk Tobacco 
Products. Washington, DC: The National Academies Press. 
 
Jacobxon K, Martinez J, Larroque S, Jones IW, Paschke T. Nicotine pharmacokinetics of 
electronic cigarettes: A pooled data analysis from the literature. Toxicology Reports. 2021; 
Volume 8:84-95. 
 
Kotlyar M, Mendoza-Baumgart MI, Li ZZ, Pentel PR, Barnett BC, Feuer RM, Smith EA, 
Hatsukami DK. Nicotine pharmacokinetics and subjective effects of three potential reduced 
exposure products, moist snuff and nicotine lozenge. Tob Control. 2007;16(2):138-42. 
 
McDermott S, Reichmann K, Mason E, Fearon IM, O'Connell G, Nahde T. An assessment of 
nicotine pharmacokinetics and subjective effects of the pulze heated tobacco system 
compared with cigarettes. Sci Rep. 2023;13(1):9037. 

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National Heart, Lung, and Blood Institute, Calculate Your Body Mass Index. Available at: 
https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmi-m.htm. 
 
Nebeker JR, Barach P, Samore MH. Clarifying adverse drug events: a clinician's guide to 
terminology, documentation, and reporting. Ann Intern Med. 2004;140(10):795-801. 
 
Picavet P, Haziza C, Lama N, Weitkunat R, Lüdicke F. Comparison of the Pharmacokinetics 
of Nicotine Following Single and Ad Libitum Use of a Tobacco Heating System or 
Combustible Cigarettes. Nicotine Tob Res. 2016;18(5):557-63. 
 
Yuki D, Kikuchi A, Suzuki T, Sakaguchi C, Huangfu D, Nagata Y, Kakehi A. Assessment of 
the exposure to selected smoke constituents in adult smokers using in-market heated tobacco 
products: a randomized, controlled study. Sci Rep. 2022;12(1):18167. 
 
Yuki D, Takeshige Y, Nakaya K, Futamura Y. Assessment of the exposure to harmful and 
potentially harmful constituents in healthy Japanese smokers using a novel tobacco vapor 
product compared with conventional cigarettes and smoking abstinence. Regul Toxicol 
Pharmacol. 2018;96:127-34. 

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16 
APPENDICES 
Appendix 1: Product Liking Questionnaire 
 
Product Liking Questionnaire 
VAS Product Liking questionnaire is adopted from Drug Liking questionnaire. 
 
Note: This question is paired with a VAS. The VAS is anchored with ‘Strongly Dislike’ on the 
left, ‘Neither Like nor Dislike’ in the center and ‘Strongly Like’ on the right. Participants place a 
vertical line at a place along the VAS based on how he/she feels in the moment. 
 
 
 
 
 
 
 
Please respond to the question with how you feel right now in relation to the study product you 
are using today. 
 
 
At this moment, how much do you like the product? 
 
 
 
 
 
 
 
 
 
 
 
Product Liking Questionnaire Final v1.0 
Effective Date: 14SEP2023 

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Appendix 2: Tobacco/Nicotine Withdrawal Questionnaire 
 
 
Tobacco Nicotine Withdrawal Questionnaire 
VAS Tobacco/Nicotine Withdrawal Scale (items on these scales have been adapted from 
Hughes & Hatsukami1) 
 
Note: Each question will be paired with a VAS. The VAS is anchored with “Not at All” on the 
left and “Extremely” on the right. Participants place a vertical line at a place along the VAS 
based on how he/she feels in the moment. 
 
 
 
These phrases may or may not describe how you feel right now. Please respond to each word 
or phrase with how you feel RIGHT NOW by drawing a vertical mark anywhere along the 
horizontal line. 
 
1. Urges to smoke 
2. Craving a Cigarette 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Hughes JR, Hatsukami D (1986). Signs and symptoms of tobacco withdrawal. Archives of 
General Psychiatry. 43(3):289-94. 
 
Tobacco Nicotine Withdrawal Questionnaire v1.0 
Effective Date: 01FEB2022 

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Appendix 3: Direct Effects of Product Questionnaire 
 
 
Direct Effects of Product Questionnaire 
 
VAS Direct Effects of Product Questionnaire (Items were selected based on measures of 
product effects used in previous trials with conventional cigarettes and other tobacco products.) 
Note: Each question will be paired with a VAS.  The VAS is anchored with “Not at ALL” on 
the left and “Extremely” on the right. Participants place a vertical line at a place along the VAS 
based on how he/she feels in the moment. 
 
 
1. Is the product “Pleasant” right now? 
2. Is the product “Satisfying” right now? 
3. Is the product making you feel “Calm” right now? 
4. Is the product helping you “Concentrate” right now? 
5. Is the product making you feel more “Awake” right now? 
6. Is the product making you feel “Sick” right now? 
7. Is the product reducing your “Hunger” for food right now? 
8. Would you like “More” of the product right now? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Direct Effects of Product Questionnaire v1.0 
Effective Date: 01FEB2022 

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Appendix 4: Use the Product Again Questionnaire 
 
 
Use the Product Again Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Use the Product Again Questionnaire v1.0 
Effective Date: 01FEB2022 

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Appendix 5: Modified Cigarette Evaluation Questionnaires 
 
 
Modified Cigarette Evaluation Questionnaire - HTP 
 
Modified Cigarette Evaluation Questionnaire further modified for heated tobacco product (mCEQ-HTP) 
Thinking about the study product that you used today, please mark the number that best represents 
how using the heated tobacco product made you feel (1- not at all, 2- very little, 3-a little, 4- 
moderately, 5-a lot, 6-quite a lot, 7-extremely) 
 
1. Was using the heated tobacco product satisfying? 
2. Did the heated tobacco product taste good? 
3. Did you enjoy the sensations in your throat and chest? 
4. Did using the heated tobacco product calm you down? 
5. Did using the heated tobacco product make you feel more awake? 
6. Did using the heated tobacco product make you feel less irritable? 
7. Did using the heated tobacco product help you concentrate? 
8. Did using the heated tobacco product reduce your hunger for food? 
9. Did using the heated tobacco product make you dizzy? 
10. Did using the heated tobacco product make you nauseous? 
11. Did using the heated tobacco product immediately relieve your craving for a cigarette? 
12. Did you enjoy using the heated tobacco product? 
 
 
 
 
 
 
 
 
 
 
Modified Cigarette Evaluation Questionnaire for Heated Tobacco Product v1.0 01FEB2022 

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Modified Cigarette Evaluation Questionnaire (mCEQ) - Cigarette 
 
Please mark the number that best represents how using the product made you feel (1 – not at all, 2 – very 
little, 3–a little, 4–moderately, 5-a lot, 6-quite a lot, 7-extremely) 
 
Modified Cigarette Evaluation Questionnaire (mCEQ) 
 
1. Was smoking satisfying? 
2. Did the cigarette taste good? 
3. Did you enjoy the sensation in your throat and chest? 
4. Did smoking cigarettes calm you down? 
5. Did smoking cigarettes make you feel more awake? 
6. Did smoking cigarettes make you feel less irritable? 
7. Did smoking cigarettes help you concentrate? 
8. Did smoking cigarettes reduce your hunger for food? 
9. Did smoking cigarettes make you dizzy? 
10. Did smoking cigarettes make you nauseous? 
11. Did smoking cigarettes immediately relieve your craving for a cigarette? 
12. Did you enjoy smoking cigarettes? 
 
 
 
 
 
 
 
 
 
 
 
Modified Cigarette Evaluation Questionnaire v1.0 01FEB2022 

ALCS-REG-23-08-HT (Ploom® PK) 
Altria Client Services LLC 
Confidential 
Ver. 1.0 19-Oct-2023 
Page 77 
HIGHLY CONFIDENTIAL 
 
 
 
 
Modified Cigarette Evaluation Questionnaire-NRT 
 
Modified Cigarette Evaluation Questionnaire further modified for oral TDN products 
Please mark the number that best represents how using the product made you feel (1-not at all, 2-very 
little, 3-a little, 4-moderately, 5-a lot, 6-quite a lot, 7-extremely) 
 
1. Was using the product satisfying? 
2. Did the product taste good? 
3. Did you enjoy the sensations in your mouth? 
4. Did using the product calm you down? 
5. Did using the product make you feel more awake? 
6. Did using the product make you feel less irritable? 
7. Did using the product help you concentrate? 
8. Did using the product reduce your hunger for food? 
9. Did using the product make you dizzy? 
10. Did using the product make you nauseous? 
11. Did using the product immediately relieve your craving for a cigarette? 
12. Did you enjoy using the product? 
 
 
 
 
 
 
 
 
 
 
 
 
 
Modified Cigarette Evaluation Questionnaire for OTDN v1.0 Effective Date: 01FEB2022 

ALCS-REG-23-08-HT (Ploom® PK) 
Altria Client Services LLC 
Confidential 
Ver. 1.0 19-Oct-2023 
Page 78 
HIGHLY CONFIDENTIAL 
 
 
 
Appendix 6: Fagerström Test for Cigarette Dependence (FTCD) 
 
Fagerström Test for Cigarette Dependence (FTCD) 
For each question, enter the answer choice which best describes your response. 
 
1. How soon after you wake up do you smoke your first cigarette 
o Within 5 minutes (3) 
o 6 – 30 minutes (2) 
o 31 – 60 minutes (1) 
o After 60 minutes (0) 
 
2. Do you find it difficult to refrain from smoking in places where it is forbidden (e.g., in church, at the library, 
in the cinema, etc.)? 
o No (0) 
o Yes (1) 
 
3. Which cigarette would you most hate to give up? 
o The first one in the morning (1) 
o Any other (0) 
 
4. How many cigarettes per day do you smoke? 
o 10 or less (0) 
o 11 to 20 (1) 
o 21 to 30 (2) 
o 31 or more (3) 
 
5. Do you smoke more frequently during the first hours after waking than during the rest of the day? 
o No (0) 
o Yes (1) 
 
6. Do you smoke if you are so ill that you are in bed most of the day? 
o No (0) 
o Yes (1) 
 
Total Score:   
 
 
Level of Nicotine Dependence: 
 
o 0 – 2 = very low dependence 
o 3 – 4 = low dependence 
o 5 = moderate dependence 
o 6 – 7 = high dependence 
o 8 – 10 = very high dependence 
 
Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO (1991). The Fagerstrom Test for Nicotine Dependence: a revision of the Fagerstrom 
Tolerance Questionnaire. Br J Addict 86:1119-27. 
 
Fagerstrom, Karl (2011): Determinants of Tobacco Use and Renaming the FTND to the Fagerstrom Test for Cigarette Dependence. Published by 
Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 
 
 
Fagerstrom Test for Cigarette Dependence 
ALCS Standard v1.0 Effective Date 19JUL2023 

 
 
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