Examining the Appeal of Nicotine Pouches in Ohio Appalachia
Phase: EARLY_PHASE1
Conditions: Cigarette Smoking-Related Carcinoma
Sponsor: Ohio State University Comprehensive Cancer Center

 
 
 
Examining the Appeal of Nicotine Pouches in Ohio Appalachia 
NCT Number: NCT05236894 
Protocol Date: 11/01/2022 
 
 

IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
Examining the Appeal of Nicotine Pouches in Ohio Appalachia 
Examining the Appeal of Nicotine Pouches in Ohio Appalachia Study Protocol Table of Contents 
1.
Background Information and Rationale ................................................................................. 2 
Abbreviations and Definitions of Terms .............................................................................................. 2 
Introduction .............................................................................................................................................. 3 
Abstract .................................................................................................................................. 3 
Background ............................................................................................................................ 4 
Description and Rationale of Intervention .............................................................................. 5 
Intervention Impact ................................................................................................................ 6 
Preliminary Research ............................................................................................................ 6 
Study Objectives ..................................................................................................................................... 7 
Primary .................................................................................................................................. 7 
Secondary .............................................................................................................................. 7 
Exploratory ............................................................................................................................. 7 
2.
Investigational Plan ................................................................................................................ 7 
Study Outline........................................................................................................................................... 7 
Recruitment phase ................................................................................................................. 8 
Screening and scheduling phase ........................................................................................... 8 
Clinic Visits ............................................................................................................................ 9 
Inclusion/Exclusion Criteria ................................................................................................................... 9 
3.
Study Procedures ................................................................................................................ 10 
Clinic Visits ............................................................................................................................................ 10 
Informed consent ................................................................................................................. 10 
Randomization ..................................................................................................................... 11 
Obtain baseline exhaled CO test ......................................................................................... 11 
Pregnancy Test .................................................................................................................... 11 
Pre-intervention questionnaire to be administered .............................................................. 11 
IV line insertion .................................................................................................................... 11 
Blood draw to obtain baseline plasma nicotine levels ......................................................... 11 
Administer intervention ........................................................................................................ 11 
Peri-intervention questionnaire to be administered ............................................................. 12 
Post-intervention questionnaire to be administered ............................................................. 12 

IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
 
Schedule return visit and provide gift card for participation ................................................. 12 
Procedure Manual ................................................................................................................................ 12 
4. 
Study Administration ............................................................................................................ 12 
Randomization, Blinding, and Unblinding ......................................................................................... 12 
Study Timelines, Number of Sites, and Enrollment ........................................................................ 12 
Participant Timeline ............................................................................................................. 12 
Duration of Study ................................................................................................................. 13 
Total Number of Study Sites ................................................................................................ 13 
Total Number of Subjects Projected .................................................................................... 13 
Data Collection and Management ..................................................................................................... 13 
Subject Completion, Withdrawal, and Early Termination ............................................................... 13 
Informed Consent Process ................................................................................................................. 13 
Payment to Subjects ............................................................................................................................ 13 
Confidentiality ....................................................................................................................................... 14 
Compliance Statement ........................................................................................................................ 14 
Statistical Considerations .................................................................................................................... 14 
5. 
Safety Management, Risks, and Benefits ............................................................................ 15 
Safety Management ............................................................................................................................. 15 
Clinical Adverse Events ....................................................................................................... 15 
AE Reporting ....................................................................................................................... 15 
Risks and Benefits to Participation .................................................................................................... 15 
Risk Assessment ................................................................................................................. 15 
Potential Benefits of Trial Participation ................................................................................ 16 
Risk-Benefit Assessment .................................................................................................................... 16 
6. 
References .......................................................................................................................... 17 
 
1. Background Information and Rationale 
Abbreviations and Definitions of Terms  
Term 
Definition 
Abbreviation 
Nicotine Pouches 
Nicotine pouches are white 
pouches that contain 
nicotine and are likened to 
tobacco-free snus. 
NPs 

IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
 
Appalachia, Ohio 
32 rural counties in Ohio 
that are markedly different 
when defined by poverty, 
health, education, and 
access to resources within 
the state.  
Appalachia 
Pharmacokinetics 
Study of drugs within the 
body. 
- 
Smokeless tobacco 
Also called chew, dip, or 
snuff, this tobacco product 
is chewed rather than 
smoked. 
SLT 
Adverse event 
Any mild reaction to the 
product including a 
headache, trouble sleeping, 
dizziness, or nausea.  
AE 
Serious adverse event 
A serious reaction or breach 
in confidentiality. 
SAE 
Center for Tobacco Research 
The Center for Tobacco 
Research provides 
evidence-based knowledge 
surrounding the regulation 
of tobacco products to 
inform individual health 
decisions as well as public 
health regulations.  
CTR 
Inclusion/Exclusion 
Criteria that the participant 
must meet or not meet in 
order to be considered for 
the study. 
I/E 
Early Termination 
When the participant is 
removed from the study at 
the discretion of the PI. 
ET 
 
Introduction 
Abstract 
Nicotine pouches are novel smokeless tobacco products that are marketed as substitutes for 
cigarettes and gaining in popularity. They may have high appeal in Ohio Appalachia, a region 
with high prevalence of smoking and a population disparately impacted by tobacco-associated 
cancer. There is little research on the abuse liability of nicotine pouches (i.e., the likelihood of 
sustained patterns self-administration) in Ohio Appalachia to understand their appeal and 
potential impact on public health and tobacco-related disparities. This study is designed to 
estimate the abuse liability of nicotine pouches with varying nicotine concentrations relative to 
cigarette smoking in a clinical study with Appalachian smokers. This pilot will provide the 
foundation for a line of research that can inform policy locally and nationally. Dissemination of 

IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
 
our results through community partners will inform efforts to reduce tobacco-associated cancer 
disparities in Ohio Appalachia. 
Background 
Tobacco use is a public health threat in the United States (U.S.),12 particularly in 
Appalachian regions.1 Declines in the prevalence of tobacco use in Appalachia have not 
mirrored the rest of the country,13 leading to widening disparities in cancer.5,6 Reasons for the 
high prevalence of tobacco use in Appalachia include social norms supporting tobacco use in 
the home;14 viewing tobacco use as a rite of passage;2 a history of economic reliance on 
tobacco farming;14 promotion of smokeless tobacco (SLT) use in situations when cigarette 
smoking is unsafe (e.g., coal mining);15 and marketing that reinforces Appalachian cultural 
values of individuality and ruggedness.2,16  
Nicotine pouches (NPs; e.g., On! and Zyn) are a novel form of SLT that is rapidly gaining 
market share in the U.S.7 NPs come in containers with 15 to 20 sachets containing nicotine, 
flavoring, and other ingredients that are placed between the upper gum and lip (Figure 1). The 
one published study characterizing the contents of NPs has reported that they likely confer 
similar harm to nicotine replacement therapy.8 
Moreover, in comparison to snus, a form of 
SLT, NPs contained lower levels of metals 
(arsenic, cadmium, chromium, lead, nickel) and 
carcinogens NNK, NNN, acetaldehyde, and 
ochratoxin.8 This is notable because the Food 
and Drug Administration recently authorized 
some brands of snus to be marketed modified 
risk tobacco products because they pose less 
harm than cigarettes.17 Based on this evidence 
NPs may offer an opportunity for tobacco harm reduction in Ohio Appalachia—as long as they 
appeal to smokers and encourage complete smoking cessation. 
Key components of a tobacco product’s appeal are how it is marketed, how it is 
perceived by consumers, and how effectively it delivers nicotine. An estimated 90% of direct-
mail NP advertisements positioned NPs as a substitute for cigarettes or other tobacco products, 
70% included claims that NPs could be used anywhere, and 42% included implicit reduced 
harm claims.10 In other words, NPs are being marketed as less harmful, situational substitutes 
for cigarettes, but little is known about how smokers perceive NPs and their marketing. 
Regarding nicotine delivery, one NP brand with a high nicotine concentration has similar 
nicotine delivery to one brand of moist snuff.9 However, moist snuff has widely variable nicotine 
delivery,4 and it is unknown how nicotine delivery of NPs compares to cigarettes. The limited 
research on the abuse liability (i.e., appeal and addictiveness) of NPs suggests that they may 
be substitutes for cigarettes based on how they are marketed and deliver nicotine. However, it is 
unknown whether NPs will encourage or be perceived as useful for smoking cessation among 
smokers in Ohio Appalachia, a region with disproportionately high prevalence of smoking and 
disparately impacted smoking-related health outcomes.   
Most of the research describing tobacco use in Appalachia is at least a decade old and 
little is known about the appeal of novel tobacco products, like NPs, in this region. NPs might 
hold harm reduction potential for smokers in Ohio Appalachia if they completely switch to NPs, 
Figure 1. Example of NPs. 

IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
 
but it is also possible that NPs could increase the public health harms of smoking if they are 
used as situational substitutes for cigarettes. In this case, they could maintain or increase 
nicotine dependence and ultimately result in little change in exposure to tobacco toxicants.11  
Furthermore, synthetic “tobacco-free” nicotine products (i.e., products that use 
chemically-derived rather than tobacco-derived nicotine) are rapidly proliferating, and it is 
unclear whether there is any available regulatory action that the US FDA can take to stop it. 
FDA’s regulatory authority over tobacco products was provided by the Family Smoking 
Prevention and Tobacco Control Act of 2009 (FSPTCA), which defined tobacco products as any 
product “made or derived from tobacco.” Therefore, new tobacco-free synthetic products may 
not fall under the FDA’s purview as they are not legally tobacco products. Consequently, many 
recent FDA tobacco rulings to help curb tobacco use, especially among youth and young adults 
(Tobacco 21, e-cigarette flavoring bans, etc.), may be completely side-stepped and lead to the 
unfettered manufacture and sale of synthetic nicotine products. Making matters worse, it is 
unclear what the unregulated sale of synthetic nicotine products may mean for public health. 
The scientific evidence is severely limited as to its impact on user perceptions, behaviors, 
addiction, and health. 
 
Understanding the pharmacokinetic and subjective results of tobacco-derived NPs when 
compared to cigarettes (Aim 1) and tobacco-derived vs. synthetic NPs (Aim 2) among adult 
cigarette smokers is critical in this new landscape of tobacco use.  
Description and Rationale of Intervention 
Aim 1: This study will estimate the abuse liability of NPs with varying nicotine concentrations 
relative to cigarette smoking in a clinical study with Ohio Appalachian smokers by using a 
randomized crossover experimental design. Over the course of three clinic visits, N=40 adult 
cigarette smokers who live in Ohio Appalachia will: 1) smoke a usual brand cigarette, 2) use a 
3mg nicotine concentration NP, and 3) use a 6mg nicotine concentration NP in our clinic; only 
one tobacco product will be used at each visit. We will measure nicotine pharmacokinetics, 
subjective effects, and intentions to use and switch to NPs. Our hypotheses are that (1a) both 
NPs will deliver less nicotine, and deliver it more slowly, than cigarette smoking and (1b) the 
6mg nicotine NP will have greater nicotine delivery, be rated as more appealing, and have 
greater intentions for future use than the 3mg nicotine NP. 
 
Aim 2: This study will examine the subjective and pharmacokinetic differences between 
tobacco-derived and synthetic NPs in adult cigarette smokers by using a randomized crossover 
experimental design. Over the course of three clinic visits, N=15 adult cigarette smokers who 
will: 1) use a 3mg tobacco-derived Zyn brand NP, 2) a 3mg synthetic Fre brand NP, and 3) a 
3mg Niin brand synthetic NP in our clinic; only one product will be used at each visit. We will 
measure nicotine pharmacokinetics, subjective effects, and intentions to use and switch to NPs. 
Our hypotheses are that (1) tobacco-derived NPs will deliver nicotine more quickly and 
effectively than the synthetic NP and (2) the tobacco-derived NPs will be rated as more 
appealing and have greater intentions for future use than the synthetic NPs.  
 

IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
 
Intervention Impact 
Aim 1:NPs are a novel tobacco product with potential to reduce or increase the harm of tobacco 
use in Appalachia. Evaluating NP abuse liability among Appalachian smokers will clarify the 
public health effect of NPs in Appalachian Ohio. Results will inform public health efforts, policy, 
and clinical care aimed at reducing tobacco-related disparities in Appalachia. 
Aim 2: The difference between tobacco-derived and synthetic NP on NPs’ abuse liability is 
unknown. Tobacco-derived nicotine contains >99% of the S stereoisomer of nicotine, but most 
methods of manufacturing synthetic nicotine result in a racemic mixture of R- and S-nicotine 
stereoisomers.78 NP manufacturers (as well as e-cigarette manufacturers including Puff Bar) 
that claim to use synthetic nicotine do not specify whether their nicotine solutions contain the 
racemic R-/S-nicotine mixture, or if R-nicotine is omitted. Although less studied than S-nicotine, 
it is speculated that R-nicotine produces weaker biological effects because it is a 10-fold less 
potent agonist of nicotinic receptors.78 In other words, we expect that NPs using synthetic 
nicotine vs. tobacco-derived nicotine will have a lower abuse liability—potentially making them 
less substitutable for cigarette smoking. Results from this work will provide the first evaluation of 
synthetic nicotine delivery via oral tobacco, informing public health efforts, policy, and future 
research in this emerging area of tobacco control.  
 
Preliminary Research 
For preliminary research, we evaluated characteristics of Appalachian adults enrolled in the 
Tobacco User Adult Cohort study. Compared to non-Appalachian tobacco users, Appalachian 
tobacco users initiated tobacco use and became regular users approximately one-year earlier, 
used tobacco more frequently, and had lower interest in cessation.15 Investigations into dual use 
found that a majority of Appalachian adults who used cigarettes and e-cigarettes were likely to 
transition to using cigarettes exclusively.37 In other words, it appears that e-cigarettes were 
being used unsuccessfully by smokers trying to quit and that they were an inadequate complete 
substitute for smoking. Additionally, exclusive e-cigarette users were more likely than dual users 
to report that e-cigarettes are useful for quitting smoking and that e-cigarettes feel like smoking 
regular cigarettes.38 Conclusions: (1) Tobacco use behaviors vary between Appalachian and 
non-Appalachian adults, and thus evaluation of our research objectives in Ohio Appalachia is 
warranted; (2) uptake of novel tobacco products for smoking cessation (i.e., complete 
substitution) has been largely unsuccessful in Ohio Appalachia; and (3) exclusive use of novel 
tobacco products in Appalachia is associated with beliefs that the product is appealing and aids 
in smoking cessation. 
 
We are also conducting a pilot observational study examining awareness of NPs, NP use, and 
exposure to NP marketing in Ohio adults. To date, we have enrolled 294 participants (32% 
smokers, 45% SLT users, 23% non-users) to complete a brief, online survey. Of the sample, 
92% have agreed to be re-contacted for future studies—providing a source of recruitment for 
our proposed pilot. In preliminary analyses, nearly two-thirds (66%) of participants were aware 
of NPs, 38% had tried NPs, and 31% reported current NP use. Among smokers, awareness 
(65%) and trial (33%) of NPs were similar to the overall sample, and 25% reported current use. 
NP marketing exposure among smokers was also high (65% in the past year), with the most 
common sources of exposure being point of sale (35%), online/social media (29%), and 

IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
 
television (20%). Conclusions: 1) Awareness and trial of NPs is growing among Ohio adults, 
including cigarette smokers; and 2) marketing exposure is common, supporting our rationale to 
extend this line of investigation to understand NP appeal and addictiveness in smokers in 
Appalachia. 
Aim 1 Study Objectives 
Primary 
• 
To estimate the abuse liability of NPs with varying nicotine concentrations relative to 
cigarette smoking. 
Secondary 
• 
To clarify the public health effect of NPs in Appalachian Ohio. 
Exploratory 
• 
To estimate the abuse liability of NPs with varying nicotine concentrations relative to 
cigarette smoking by measuring nicotine pharmacokinetics. 
• 
To estimate the abuse liability of NPs with varying nicotine concentrations relative to 
cigarette smoking by measuring subjective effects. 
• 
To estimate the abuse liability of NPs with varying nicotine concentrations relative to 
cigarette smoking by measuring intentions to use and switch to NPs.  
 
Aim 2 Study Objectives 
Primary 
• 
To understand the pharmacokinetic difference between tobacco-derived and synthetic 
NPs. 
Secondary 
• 
To clarify the public health effect of NPs on adult smokers 
Exploratory 
• 
To understand the differences in abuse liability between tobacco-derived and synthetic 
NPs by measuring nicotine pharmacokinetics. 
• 
To understand the differences in abuse liability between tobacco-derived and synthetic 
NPs by measuring subjective effects. 
• 
To estimate the abuse liability of tobacco-derived vs. synthetic NPs by measuring 
intentions to use and switch to NPs.  
 
2. Investigational Plan 
Study Outline 
This study will recruit 40 adult cigarette smokers from Ohio Appalachia and surrounding rural 
areas (Aim 1) and 20 adult cigarette smokers from Ohio (Aim 2) for a randomized crossover 
study. Subjects will be recruited through social media advertisements; through our nicotine 
pouch pilot study, where participants agreed to future contact regarding other studies; and 
through outreach to our community partners: the OSUCCC’s Community Outreach and 

IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
 
Engagement team and the Tobacco Free Ohio Alliance. Subjects will have an initial phone 
screen to confirm interest and eligibility and will then be invited to participate in 3 study visits in 
person visits at the Center for Tobacco Research.  
Aim 1: Order of study clinic visits will be randomized. In random order, participants will 1) smoke 
one usual brand cigarette, 2) use one 3mg NP, and 3) use one 6mg NP. Research staff will 
measure nicotine pharmacokinetics, subjective effects, and intentions to use and switch to NPs 
through physiological data, lab values, and questionnaires.  
Aim 2: Order of study clinic visits will be randomized. In random order, participants will use 1) 
Zyn wintergreen 3mg (tobacco-derived nicotine) 2) a Fre wintergreen 3mg (synthetic nicotine), 
and 3) a Niin wintergreen 3mg (synthetic nicotine). Research staff will measure nicotine 
pharmacokinetics, subjective effects, and intentions to use and switch to NPs through 
physiological data, lab values, and questionnaires. 
Recruitment phase 
Aim 1: We will recruit daily cigarette smokers who live in Ohio Appalachia and surrounding rural 
areas using social media advertisements, by re-contacting participants from our preliminary 
studies who agreed to take part in future studies, and through outreach via our community 
partners.  
Geographically, recruitment advertising will be targeted to Ohio Appalachia counties (32 in 
total), surrounding rural counties close to Ohio Appalachia, with efforts focused on counties 
within one hour of Columbus. 
Aim 2:  We will recruit daily cigarette smokers using social media advertisements, by re-
contacting participants from our preliminary studies who agreed to take part in future studies, 
and through outreach via our community partners.  
Participants in Aim 2 may reside anywhere in Ohio, though recruitment efforts will be focused 
within one hour of Columbus.  
 
Screening and scheduling phase 
Interested participants will fill out a brief questionnaire to confirm eligibility either online or over 
the phone with research staff. Participants will be asked a series of questions regarding their 
tobacco product usage, health status, willingness to travel to Columbus for study visits, and brief 
demographic and contact information. Research staff will review the screener questionnaire for 
eligibility and inform participants if they are eligible for this study or not. Research staff will  
provide a study overview, discuss study procedures, and ascertain participant interest. Should 
the participant wish to proceed, research staff will schedule the first visit and communicate IRB-
approved guidance, such as the CTR address and the need for subjects to abstain from tobacco 
products for 12 hours prior to the study visit. Participants will be advised that each research visit 
must be scheduled 2 or more days apart and that they must bring their own brand of cigarettes 
to the study visits in case they are randomized to smoke cigarettes at a particular visit. 

IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
 
Clinic Visits 
Aim 1: Participants will be invited to the CTR to complete study procedures. At visit 1, informed 
consent will be collected. During visits 1-3, participants will complete an exhaled CO test, take a 
pregnancy test if applicable, a line will be placed for IV blood draw by the staff research nurse 
for IV blood draws throughout the course of the study visit, and be asked to either smoke their 
usual brand or insert a 3mg or 6mg NP and then sit in the room for 60 minutes. At each visit, 
participants will be randomly assigned to use 3mg Wintergreen pouches, 6mg Wintergreen 
pouches or their own brand of cigarettes. Participants will be asked a series of 3 questionnaires 
before, during, and after each product is used. Blood draws will be collected from the line at 0 5, 
15, 30, 60, and 90-minutes. 3mLs, or a little less than 1 teaspoon, of blood will be drawn at each 
timepoint.    
Measures of craving and withdrawal relief will be assessed at each blood draw (see attached 
surveys). If a collection interval is not met there will be no draw retroactively. Participants will be 
assessed for AE throughout procedures and prior to leaving the visit.  
 
Aim 2: Participants will be invited to the CTR to complete study procedures. At visit 1, informed 
consent will be collected. During visits 1-3, participants will complete an eCO test, take a 
pregnancy test if applicable, a line will be placed for IV blood draw by the staff research nurse 
for IV blood draws throughout the course of the study visit, and be asked to either try a 3mg NP 
or a synthetic NP and then sit in the room for 60 minutes. Participants will be asked a series of 3 
questionnaires before, during, and after each product is used. Blood draws will be collected 
from the line at 0 5, 15, 30, 60, and 90-minutes. 3mLs, or a little less than 1 teaspoon, of blood 
will be drawn at each timepoint.    
Measures of craving and withdrawal relief will be assessed at each blood draw (see attached 
surveys). If a collection interval is not met there will be no draw retroactively. Participants will be 
assessed for AE throughout procedures and prior to leaving the visit.  
 
Inclusion/Exclusion Criteria 
Aim 1: Adults aged 21 and older who reside in an Ohio Appalachian county and smoke at least 
5 cigarettes per day will be considered for this project. Smokers who use other tobacco products 
(e.g., SLT, electronic cigarettes) > 10 days a month will be ineligible because our goal is to 
characterize the abuse liability of NPs among those who exclusively or primarily smoke 
cigarettes.  
Inclusion 
Exclusion 
Age 21 years or older 
Use tobacco products other than cigarettes 
>10 days per month. 
Reside in an Ohio Appalachian county or 
surrounding rural area 
Use NP in the past 3 months 
Willing to complete study procedures, 
including abstaining from all tobacco, 
Unstable or significant psychiatric conditions 
(past and stable conditions will be allowed) 

IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
 
nicotine, and marijuana for 12 hours before 
clinic visits 
Ability to read and speak English 
Pregnant, planning to become pregnant, or 
breastfeeding  
Smoke at least 5 cigarettes per day for the 
past 30 days 
History of cardiac event or distress within the 
past 3 months 
 
Currently attempting to quit all tobacco use 
 
Self-reported diagnosis of lung disease 
including asthma (if uncontrolled or worse 
than usual), cystic fibrosis, or chronic 
obstructive pulmonary disease 
 
 
Aim 2: Adults aged 21 and older who reside in any Ohio county and smoke at least 5 cigarettes 
per day will be considered for this project. Smokers who use other tobacco products (e.g., SLT, 
electronic cigarettes) > 10 days a month will be ineligible because our goal is to characterize the 
abuse liability of NPs among those who exclusively or primarily smoke cigarettes.  
Inclusion 
Exclusion 
Age 21 years or older 
Use tobacco products other than cigarettes 
>10 days per month. 
Willing to complete study procedures, 
including abstaining from all tobacco, 
nicotine, and marijuana for 12 hours before 
clinic visits 
Use NP in the past 3 months 
Ability to read and speak English 
Unstable or significant psychiatric conditions 
(past and stable conditions will be allowed) 
Smoke at least 5 cigarettes per day for the 
past 30 days 
Pregnant, planning to become pregnant, or 
breastfeeding  
 
History of cardiac event or distress within the 
past 3 months 
 
Currently attempting to quit all tobacco use 
 
3. Study Procedures 
Clinic Visits 
Informed consent 
The participant will arrive at the CTR and meet a member of the research staff in the lobby. The 
research staff member will escort the subject to a private lab room and review the informed 
consent form (including a description of the nature, purpose, risks, and benefits of the study). 
The subject will receive an oral and written explanation of the study. The voluntary nature of the 
study and the participant’s right to withdraw at any time will be stressed during the consent 
process; a copy of the informed consent will be provided to the participant either electronically 
or physically at the time of consent for them to keep. Informed consent will be collected by IRB-
approved study personnel and stored electronically in the secure database, REDCap.  

IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
 
Recruitment scripts and materials, consent forms, and all study procedures will be approved by 
the OSU Institutional Review Board. All participants will provide written consent before any 
study procedures are performed. 
Randomization 
After participants consent to the study, their visit order will be randomized. Randomization will 
be counterbalanced and cannot be changed once it is completed. Randomization in Aim 1 
involves the 3mg, 6mg, or regular brand of cigarettes while Randomization in Aim 2 involves the 
3mg tobacco-derived NP and 2 synthetic NPs.  
Obtain baseline exhaled CO test 
Participants will need to abstain from tobacco and nicotine products for >12 hours prior to their 
study visit. To check for abstinence from tobacco, participants will perform exhaled carbon 
monoxide testing (eCO<10ppm) and confirm via self-report that they have not used any other 
nicotine products over the last 12 hours.  
Pregnancy Test 
All subjects capable of becoming pregnant will need to take and produce a negative pregnancy 
test in order to proceed further.    
Pre-intervention questionnaire to be administered 
This questionnaire will assess sociodemographics, tobacco use history, NP use history, and 
nicotine dependence. These questionnaires will be administered during Visit 1.  
IV line insertion 
Because blood draws will occur at set intervals, an IV line will be inserted by a trained staff 
nurse.  
Blood draw to obtain baseline plasma nicotine levels   
Next, participants will be reminded that in addition to the exhaled CO test, their abstinence will 
be confirmed at the time of visit via blood plasma nicotine analysis. 3 mL venous blood sample 
will be collected for later analysis to confirm abstinence. This blood draw will also be used to 
establish baseline plasma nicotine levels to estimate total nicotine delivery. 
Administer intervention 
Aim 1: The participant will receive a 3mg NP, 6mg NP, or be asked to smoke one cigarette of 
their usual brand depending on the randomization assignment. If smoking a cigarette, 
participants will be asked to smoke one cigarette following a standardized puffing protocol: they 
will take one puff every 30 seconds for 5 minutes.  If using an NP, participants will be asked to 
place the pouch between their upper lip and gum and leave it in place for 30 minutes. 
Aim 2: The participant will receive a 3mg tobacco-derived NP or a 3mg synthetic NP on 
randomization assignment. Participants will be asked to place the pouch between their upper lip 
and gum and leave it in place for 30 minutes. 
 

IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
 
Peri-intervention questionnaire to be administered 
The QSU and MNWS surveys will be administered while at each blood draw interval of 0, 5, 15, 
30, 60, and 90 minutes.  
Post-intervention questionnaire to be administered  
Measures of product appeal and behavioral intentions will be assessed after the participant has 
the cigarette or NP (Aim 1) or the tobacco-derived vs. synthetic NP (Aim 2). 
Schedule return visit and provide gift card for participation 
Schedule return visit per subject and interviewer availability that is >2 days after the current 
visit. Provide $100 via Clincard for their participation out of the up to $350 possible. If it is their 
last visit has been completed within 1 month from consent, they will receive $150 during their 
last visit.  
  
Post-Enrollment Survey 
6 months after enrolling, participants from Aims 1 and 2 will be recontacted via phone, text, and 
email for the opportunity to participate in a short online REDCap survey. Participants will 
complete a short consent addendum and respond to survey questions regarding their current 
tobacco product use and opinions surrounding nicotine pouches. For their time, they will receive 
a $10 Amazon gift code.  
Procedure Manual 
Study procedures, including conducting pregnancy tests, blood draws, blood processing and 
analysis, gift card administration, and other procedures will be thoroughly explained in the study 
procedure manual.  
 
4. Study Administration 
Randomization, Blinding, and Unblinding 
Participants will be randomized within the secure database, REDCap. The randomization piece 
involves at which of the 3 visits they are to use each product (Aim 1: 3mg NP, 6mg NP, or their 
own usual brand cigarette and Aim 2: the tobacco-derived 3mg tobacco-derived NP or the 3mg 
synthetic pouches). Participants will be blinded during study visits and at the end of their third 
visit will be informed which product they had at each visit.  
Study Timelines, Number of Sites, and Enrollment 
Participant Timeline  
There will be a total of 3 study visits and 1 online survey opportunity 6 months after the 
completion of the final study visit. The study timeline for each participant will vary. Clinic visits 
can be completed in as little as a week and a half or as long as 2 months, but will ideally be 
completed within 3 week’s timeframe for retention and administrative purposes. The study visits 
will take approximately 3 hours each. The online survey will take approximately 10 minutes to 
complete and will be offered 6 months after completing the final visit. 

IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
 
Duration of Study 
We anticipate the clinical trial to take six months to complete. After that, we anticipate that it will 
take 1-1.5 years to clean and analyze data and disseminate results. 
Total Number of Study Sites 
All recruitment and enrollment activities will be completed within the CTR. 
Total Number of Subjects Projected 
55 subjects will be enrolled and each subject must meet I/E criteria.  
Data Collection and Management 
Data will be collected and stored electronically in the secure database, REDCap. Data will only 
be accessible to approved study personnel and will be secured through multiple firewalls. 
Subjects’ first and last names will be deidentified and not linked with the data. The consent 
forms with first and last names will be databased electronically in REDCap but will not be 
downloaded with any study data.  
Subject Completion, Withdrawal, and Early Termination 
Participants will be invited to complete 3 study visits (i.e., participants cannot participate in both 
Aim 1 and Aim 2) and a supplemental, online survey opportunity to be completed once 6 
months after the third clinic visit. The participant timeline will be complete once the 3 study visits 
are complete. Participants have the option to withdraw at any point by expressing their desire to 
withdraw to study staff orally or in writing. Study staff will complete a Withdrawal form to 
document this event. If at any point a participant becomes unable to complete study tasks per 
protocol (e.g., repeated violations of nicotine abstinence; inconsistent responses reported on 
questionnaires; showing up to a clinic visit impaired; injury, illness, or medications that impair 
ability to accurately complete study measures; or inappropriate behavior toward study staff), Dr. 
Keller-Hamilton reserves the right to ET a participant.  
 
Informed Consent Process 
Informed consent will be collected in person by a trained study staff member at the beginning of 
the initial study visit. Signatures will be documented electronically in REDCap and subjects will 
be offered an email or printed copy of the consent for their records.  
For the 6-month follow on survey, an online consent addendum will be completed prior to the 
online survey. Signatures will not be collected for the consent addendum and instead the online 
framework of clicking “next page” will suffice.  
Payment to Subjects 
Participant compensation will be administered in two tiers: clinic visits and completion bonus.  
Aim 1: For each clinic visit, subjects will receive $150. If participants complete all three visits 
within a month, they will receive a $50 bonus for their participation. Participants could earn up to 
$500 for their participation. Compensation will be offered in the form of Clincard.  

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Date Protocol Updated: 11/01/2022 
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Aim 2: For each clinic visit, subjects will receive $100. If participants complete all three visits 
within a month, they will receive a $50 bonus for their participation. Participants could earn up to 
$350 for their participation. Compensation will be offered in the form of Clincard.  
If any part of the visit is not possible to complete, participants will be given $50 to thank them for 
their time. 
Aims 1 & 2: 6 months after the final visit is complete, participants from Aim 1 and 2 will be 
offered participation in a short, 10-minute online survey via email. For their time, participants will 
receive a $10 Amazon gift code within 2 business days via email.  
 
Confidentiality 
Confidentiality will be maintained by all study staff along with the use of a secure study 
database.  
All lab personnel and study staff will complete HIPAA and CITI trainings, human subjects 
protection training, responsible conduct of research training, and good clinical practices training. 
Phone scripts will be developed to ensure the subject is in an isolated environment where they 
are comfortable sharing personal information during the phone screen. During the study visit, 
participants will be taken to a private lab environment.  
The secure databasing platform, REDCap, will store participant data. A subject ID will be 
assigned to each participant in order to deidentify study data. Multiple levels of security 
clearance are required before entering the REDCap system and only approved study personnel 
will have access to this data.  
Compliance Statement 
Research will be conducted in accordance with CTR policies and IRB regulations. Questions will 
be directed to OSU IRB representatives and S/AEs will be reported per IRB policy.  
Statistical Considerations 
Data will be summarized descriptively. For hypothesis testing, we will use linear or logistic 
mixed effects regression models (with a random subject effect) to assess the main effects of 
product on plasma nicotine delivery, subjective effects, and behavioral intentions. Model 
assumptions will be checked, and variables will be transformed as needed. Missing data will not 
be imputed as likelihood-based linear mixed models will yield valid inference under missing at 
random assumptions. Models will control for age, sex, and other tobacco use if these features 
are not balanced by randomization. The same analysis strategy will be used for both aims. We 
calculated power for Aim 1 based on a repeated measures ANOVA comparing mean total 
nicotine delivery and maximum plasma nicotine concentration across 3 conditions; existing 
literature on differences in nicotine delivery across SLT products, including NPs, facilitates the 
use of this outcome for a power analysis.9 With a total sample size of only 20 participants and a 
Bonferroni-adjusted alpha of 0.017, we would have 84% power to detect a mean difference in 
total nicotine delivery of 25.7 ng/mL and 99% power to detect a mean difference of maximum 
nicotine concentration of 7.0 ng/mL between products.9 To account for attrition and the potential 
need for a larger sample size to detect differences in more subjective outcomes, we will recruit a 

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Date Protocol Updated: 11/01/2022 
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sample of 40 participants. For Aim 2, there are no known data to estimate effect sizes and thus 
to conduct power analyses. The sample size of 15 participants is intended to provide these data 
for future research.  
 
 
5. Safety Management, Risks, and Benefits 
Safety Management 
Clinical Adverse Events  
Clinical AE will be assessed by study staff at each study visit via participant self-report and 
managed immediately. Clinical AE may be related to nicotine overdose or the blood draw. Signs 
of nicotine overdose include nausea, vomiting, headache, presyncope, tachycardia, and 
disrupted sleep. With the blood draw, there is a slight risk of bruising, discomfort, and infection 
with blood draw. Study staff will be trained to recognize these signs and subjects will be 
encouraged throughout the visit to self-report any AE. In the event of a medical emergency, 
study staff will be advised to call 911 on the subject’s behalf. 
AE Reporting 
All adverse events will be reported to the OSU IRB. We will monitor for risks associated with 
smoking and nicotine pouch use by screening participants for general medical precautions 
(pregnancy, cardiovascular disease). Any adverse events, breaks of confidentiality, or any other 
data or safety issues that arise will be discussed immediately between study personnel and Dr. 
Keller-Hamilton. Dr. Keller-Hamilton will be responsible for completing an Adverse Events Form 
should an event occur. Dr. Keller-Hamilton will report potential unanticipated problems involving 
risks to subjects or others (UPIRSOs) to the OSU IRB within 24 hours of having received notice 
of the event. Dr. Keller-Hamilton will gather any information needed to investigate the event and 
to determine subsequent action. Any subsequent action will be documented and reported to the 
OSU IRB and the Program Officer at NIH. Adverse event reports will be reviewed annually with 
the OSU IRB to ensure participant safety. 
Risks and Benefits to Participation 
Risk Assessment 
Every attempt will be made to reduce risk to the participant. The research protocol calls for 
current smokers who do not plan to quit smoking to try a NP at 3mg or 6mg or smoke their 
regular cigarette brand (Aim 1) or try a 3mg tobacco-derived NP or 3mg synthetic NP (Aim 
2) during a supervised study visit. NPs are no more harmful than conventional cigarettes, 
and there is some evidence that they may offer reduced harm. Questionnaires and exhaled 
breath collection procedures are all non-invasive and involve minimal risk to study 
participants. Potential risks are as follows: a) risk of using NPs, b) use of cigarettes (Aim 1 
only), c) loss of confidentiality or privacy, d) potential for undermining smoking cessation, 
and e) slight risk of discomfort, bruising and infection with blood draw. 
  

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Potential Benefits of Trial Participation 
Participants are not expected to directly gain any benefits from this study. Participants may 
indirectly consider quitting tobacco products or choosing a harm reduction product as a result of 
their involvement with this investigation though this is not a study objective. Through their 
contributions to science, subjects provide insight into a novel tobacco product that has potential 
to reduce or increase the harm of tobacco use in Appalachia (Aim 1) or Ohio in general. 
Moreover, data collected will inform public health efforts, policy, and clinical care aimed at 
reducing tobacco-related disparities in Appalachia. 
Risk-Benefit Assessment 
While this trial is not without risk, every effort will be taken to reduce risk and undue burden on 
participants.  
Efforts to reduce risk are as follows: 
1. Risk of using NP: The risk of side effects and adverse events are very low. Whether 
using tobacco-derived or synthetic nicotine, these products are sold online, and at 
specialty stores and convenience stores nationwide, without a prescription. 
Nevertheless, all participants will be screened for general medical precautions 
(pregnancy, cardiovascular disease) and monitored for adverse events during the 
study period. Study personnel will assess for adverse events via self-report at all 
follow-up visits. Subjects will also be provided a study phone line to report an adverse 
event between follow-up visits. Any serious adverse events will be reported to the PI 
and then to the OSU IRB and potentially to the NIH. We will withdraw participants 
who have a serious adverse event, or become pregnant or begin to breastfeed. The 
most likely adverse (potential for nicotine overdose) event is anticipated to be rare 
(<5% in our previous studies) and mild (nausea, headache, disrupted sleep) event will 
be handled quickly (i.e., advice to participant to reduce or stop NP use). Our on-site 
research nurse will also be available to escalate issues as needed and to handle any 
questions regarding reported adverse events. Lab studies of toxin exposure suggest 
that NPs incur no greater risk to health than do conventional cigarettes. Moreover, 
these are all over the counter products and are not significantly different from what 
the participant typically uses.  
2. Loss of Confidentiality and Privacy: Confidentiality will be maintained by numerically 
coding all data, disguising identifying information, and keeping data locked in file 
drawers or in a secure, password protected database. All biospecimen samples are 
kept in a locked freezer and also will be deidentified. Names of participants will be 
kept separate from participant data. Only study research personnel and the PI will 
have the information that connects participants’ names and ID numbers. All electronic 
data will be numerically coded and stored in a password-protected database, on a 
password-protected computer in a secure research space. Participant information will 
be accessible only to research staff, who are pledged to confidentiality and have 
completed training in the ethical conduct of research (i.e., both HIPAA and CITI 
trainings). Identifying information will not be reported in any publication. 
3. Potential for Undermining Cessation: The study sample is comprised of smokers with 
no plan to quit in the next three months. Therefore, we are not asking smokers who 
want to quit to continue smoking. The PI will be available for any questions that 
participants may have about NPs, smoking, or smoking cessation. It is important to 
note that the use of NPs incurs no greater harm than if the participant decided on 

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his/her own to use the product. Among those screened and ineligible/uninterested, 
referral resources for smoking cessation will be provided for those who inquire. 
Among study participants, information on cessation resources will be provided at the 
final visit and if at any time during the study participants are interested in smoking 
cessation services, a list of smoking cessation resources will be provided. 
4. Slight risk of bruising, discomfort and infection with blood draw: Blood will be 
collected by trained research staff. Sterile instruments will be used and for blood 
draws, the participants skin will be cleaned with an alcohol wipe at the venipuncture 
site. 
 
 
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IRB Protocol Number: 2021C0199 
IRB Approval Original Date: 1/10/2022 
Date Protocol Updated: 11/01/2022 
Version: 4 
 
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