Conditions: Tobacco Smoking Nicotine Dependence
Keywords: Reduced nicotine cigarettes Alternative nicotine products Biomarkers of tobacco exposure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 799
Healthy volunteers: yes

Brief summary:
This project will examine the impact of very low nicotine content (VLNC) cigarettes in a complex tobacco and nicotine product marketplace. We will compare the number of cigarettes smoked and cigarette-free days in an experimental marketplace that contains VLNC cigarettes versus normal nicotine content (NNC) cigarettes.

Detailed description:
This randomized, open label, controlled, multi-site study will simulate a "real world" tobacco environment by providing participants access to an experimental marketplace where they will be given vouchers for a specified number of points that can be exchanged for study cigarettes (varying in nicotine content described below) and non-combusted tobacco/nicotine products (smokeless tobacco, snus, electronic cigarette, medicinal nicotine replacement) and at the end of the study can exchange unspent points for money.

Subjects (N=200 in each group) will be randomly assigned to: 1) very low nicotine content cigarettes (VLNC; 0.4 mg nicotine/g tobacco) along with non-combusted tobacco/nicotine products or 2) normal nicotine content cigarettes (NNC; 15.8 mg nicotine/g tobacco) along with non-combusted tobacco/nicotine products.

Smokers will undergo an orientation visit for screening and then enter a three phase experimental trial:

1. Phase 1 - Baseline: Two week baseline assessment period during usual brand cigarette smoking.
2. Phase 2 - Marketplace Adaptation: Two week period where subjects have access to the marketplace that provides their preferred usual brand cigarettes and selected non-combusted tobacco products to allow the subject to adjust to the marketplace prior to randomization;
3. Phase 3 - Intervention: Randomization to a marketplace with access to either VLNC or NNC cigarettes plus non-combusted products for a 12 week period.

Biomarker samples are collected at baseline, end of Phase 2 and end of week Phase 3 (week 12).

Arms:
arm 1: Very Low Nicotine Content Cigarettes (0.4 mg nicotine/g tobacco; 9 mg of tar): Median nicotine content, averaged across menthol and non-menthol cigarettes: arm 2: Normal (Conventional) Nicotine Content (15.8 mg nicotine/g tobacco; 9 mg of tar): Median nicotine content, averaged across menthol and non-menthol cigarettes

Interventions: intervention 1: Very Low Nicotine Content Cigarettes intervention 2: Normal Nicotine Content Cigarettes
Intervention descriptions: intervention 1: 0.4 mg nicotine/g tobacco; 9 mg tar intervention 2: 15.8 mg nicotine/g tobacco; 9 mg tar

Protocol document:
Prot_SAP_000.pdf: 
Reduced Nicotine in Cigarettes in a Marketplace with Alternative Nicotine Systems 
 
Dorothy K. Hatsukamia,b,PhD, Joni A. Jensenb,MPH, Dana Mowls Carrollc,PhD, Xianghua Luo,b,d,PhD, 
Lori G. Strayerb,MPH, Qing Caob,MS, Stephen S. Hechtb,e,PhD, Sharon E. Murphyb,f,PhD, Steven G. 
Carmellab,MS, Suzanne Colbyg,PhD, Andrew A.Strasserh,PhD, F. Joseph McClernoni,PhD, Jennifer 
Tideyg,PhD, Neal L. Benowitzj,MD and Eric C. Donnyk,PhD 
 
aDepartment of Psychiatry and Behavioral Sciences, Medical School, University of Minnesota, 
Minneapolis, Minnesota, United States of America 
bMasonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America 
cDivision of Environmental Health Sciences, School of Public Health, University of Minnesota, 
Minneapolis, Minnesota, United States of America 
dDivision of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, 
United States of America 
eDepartment of Laboratory Medicine and Pathology, Medical School, University of Minnesota, 
Minneapolis, Minnesota, United States of America 
fBiochemistry, Molecular Biology and Biophysics, Medical School, University of Minnesota, 
Minneapolis, Minnesota, United States of America 
gCenter for Alcohol and Addiction Studies, School of Public Health, Brown University, Providence, 
Rhode Island, United States of America 
h Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 
Pennsylvania, United States of America 
i Department of Psychiatry and Behavioral Sciences, School of Medicine, Duke University, Durham, 
North Carolina, United States of America 
j Department of Medicine, School of Medicine, University of California, San Francisco, California, 
United States of America 
k Department of Physiology and Pharmacology, School of Medicine, Wake Forest University, Winston 
Salem, North Carolina, United States of America 


 
 
 
 
 
 
 
 
CENIC II  PROJECT 1 
 
Impact of Very Low Nicotine Content  
Cigarettes in a Complex Marketplace*   
 
Principal Investigator:    
Dorothy Hatsukami, Ph.D. 
Department of Psychiatry and Behavioral Sciences 
612-626-2121 
hatsu001@umn.edu 
 
 
Version 7 
Date:  23NOV2022 
 
Co-Investigator: 
Sharon Allen, M.D., Ph.D. - UMN 
 
Site Leaders: 
Neal Benowitz, M.D. - UCSF 
Francis Joseph McClernon, Ph.D. – Duke 
Eric Donny, Ph.D. – Wake Forest University 
Andrew Strasser, Ph.D. – University of 
 
Pennsylvania 
Jennifer Tidey, Ph.D. – Brown University 
 
Biostatistician: 
Xianghua Luo, Ph.D.  
 
 
*Protocol title listed on clinicaltrials.gov 
 


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Revision History 
Revision 
# 
Version 
Date 
Summary Of Changes 
Consent 
Changes 
1 
7/21/17 
Original protocol to CPRC & IRB 
Original 
21JUL2017 
2 
4/4/18 
Minor corrections to grammar/spelling, clarifications of terms and 
procedures; update of study products and point exchange procedures; 
update of Statistical Analysis Plan.  
 
08FEB2018 
3 
9/27/18 
Minor corrections or clarifications 
Eligibility: CO>10 ppm or cotinine (nicotine) strip indicating regular 
 
smoking  
Removed 2nd saliva sample for genotyping 
Revised Risk: E-liquid exposure 
Baseline Point Calculations: Includes other tobacco/nicotine 
Added GAD-7 questionnaire  
Removed buccal cell collection 
Bonus ($300) will be contingent on avoiding non-study product use; or 
$100 for accurate self-report of slips 
At unanticipated visits for additional study product, CO will be done if 
CPD is >50% above baseline 
 
27SEPT2018 
4 
10/16/19 Change of N to 500 
Addition of 3 sites 
Addition of tobacco pouches to Marketplace 
Addition of risk of e-cigarette for pulmonary disease and seizures  
Exclusion criteria of suicide attempt in last 5 years has been modified  
Revised statistical analysis  
 
18NOV2019 
 
5 
1/17/20 
Increase age to 21 for eligibility 
None 
 
The COVID-19 pandemic halted subject participation in March 2020. Recruitment for the study resumed in 
September 2020 following an amendment adapting the in-person visits to telehealth with a curbside component 
for dropping off biological samples and dispensing the study products. As a result, the first 178 subjects were 
randomized under the original procedures and subsequent subjects were randomized under the telehealth-
curbside amendment procedures. Those procedures are outlined in the COVID-19 AMENDMENT_ Telehealth-
Curbside_Amenedment 1 and 2_07.01.20 and 04.08.21 (protocol and consent); document incorporated into final 
protocol. 
6 
05/04/22 Change of N to approximately 425-450 
Comments regarding the COVID-19 pandemic amendment for telehealth 
visits (discontinued BrAC, toxicology; first morning void used for 
pregnancy screen and saliva sample for compliance testing rather than 
spot urines) 
Removed statement that study cell phones provided 
Updated Statistical Analysis Plan and monitoring plan 
 
None 
7 
11/23/22 Revised the Statistical Analysis Plan; updated N to 400-450; minor edits 
or clarifications 
None 
 
 
 


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Table of Contents 
Revision History ...................................................................................................................................... 1 
Table of Contents .................................................................................................................................... 2 
Abbreviations .......................................................................................................................................... 3 
Study Synopsis ....................................................................................................................................... 5 
1. 
Study Objectives and Hypotheses ................................................................................................... 6 
2. 
Background ...................................................................................................................................... 6 
3. 
Study Endpoints / Outcomes .......................................................................................................... 10 
4. 
Intervention .................................................................................................................................... 11 
5. 
Study Plan and Procedures ........................................................................................................... 14 
6. 
Collection and Sharing of Biomarker Specimens and Data ........................................................... 31 
7. 
Sharing Results with Subjects ........................................................................................................ 33 
8. 
Study Duration ............................................................................................................................... 33 
9. 
Subject Selection ........................................................................................................................... 34 
10. Vulnerable Populations .................................................................................................................. 36 
11. Local Number of Participants ......................................................................................................... 36 
12. Local and National Recruitment Methods ...................................................................................... 36 
13. Monitoring Safety and Withdrawal of Participants .......................................................................... 38 
14. Risks to Subjects............................................................................................................................ 42 
15. Potential Benefits of Participation .................................................................................................. 46 
16. Data Management ......................................................................................................................... 46 
17. Confidentiality ................................................................................................................................ 53 
18. Provisions to Monitor the Data and Ensure Subject Safety ........................................................... 54 
19. Provisions to Protect the Privacy Interests of Participants ............................................................. 56 
20. Compensation for Research-Related Injury ................................................................................... 56 
21. Informed Consent........................................................................................................................... 56 
22. Setting ............................................................................................................................................ 58 
23. Multi-Site Research ........................................................................................................................ 58 
24. Resources Available ...................................................................................................................... 60 
25. Conduct of the Study ..................................................................................................................... 62 
26. Subject Identifier ............................................................................................................................ 63 
27. Procedure Table ............................................................................................................................ 65 
28. References ..................................................................................................................................... 68 
 
 
 


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Abbreviations 
AE: 
Adverse Events: any untoward medical occurrence in a subject administered a study product and 
which does not necessarily have a causal relationship with this treatment. 
ANDS:   
Alternative Nicotine Delivery Systems:  products such as e-cigarettes or other vaping devices, 
smokeless tobacco, medicinal nicotine replacement. 
BrAC:  
Breath Alcohol Concentration: measured by an expired breath sample is most commonly used as a 
metric of alcohol exposure.  
BDI-II:  
Beck Depression Inventory, 2nd Edition: a 21-question multiple-choice self-report inventory, used 
for measuring the severity of depression. 
BP:  
Blood Pressure: is one of the principal vital signs. 
CENIC:   
Center for the Evaluation of Nicotine in Cigarettes:  the short title selected for this program grant 
that would be easily recognized. 
CES:  
Cigarette Evaluation Scale: a 12-item questionnaire that assesses the degree to which smokers 
experience the reinforcing effects of smoking. 
CES-D:  
Center for Epidemiological Studies Depression Scale: is a self-report measure of depression 
severity. 
CO:  
Carbon Monoxide: exhaled breath carbon monoxide level reflects the level of carboxyhemoglobin 
(HbCO) in blood. 
COPD:  
Chronic Obstructive Pulmonary Disease: is a type of obstructive lung disease characterized by 
chronically poor airflow. 
CVD:  
Cardiovascular Disease: (also called heart disease) is a class of diseases that involve the heart, the 
blood vessels (arteries, capillaries, and veins) or both. 
DAST-10:  Drug Abuse Screening Test: is a 10-item, yes/no self-report instrument for clinical screening of 
drug abuse and treatment evaluation. 
DBP:  
Diastolic Blood Pressure 
DVT/PE:  
Deep Vein Thrombosis / Pulmonary Embolism: A deep vein thrombosis is a blood clot in the deep 
veins of the leg. If the thrombus breaks off (embolizes) and flows towards the lungs, it can become 
a life-threatening pulmonary embolism (PE), a blood clot in the lungs. 
ENDS:   
Electronic Nicotine Delivery Systems:  Products such as e-cigarette and other vaping devices. 
FTND:  
Fagerstrom Test for Nicotine Dependence: is a 6-item standard instrument for assessing the 
intensity of physical addiction to nicotine and includes an evaluation of cigarette consumption, the 
compulsion to use, and dependence. 
HCG:  
Human Chorionic Gonadotropin: is a hormone produced by the placenta following implantation. 
The presence of hCG is detected in pregnancy tests. 
HR:  
Heart Rate: a measure of the number of heart beats per minute (bpm) 
IVR:  
Interactive Voice Response: is a technology that allows a computer to interact with humans 
through the use of voice and input via keypad. 
MNWS:  
Minnesota Nicotine Withdrawal Scale: is a 15-item self-reported scale to evaluate the effects of 
smoking cessation. 
NIAAA:  
National Institute on Alcohol Abuse and Alcoholism: part of the National Institutes of Health that 
supports and conducts biomedical and behavioral research on the causes, consequences, 
treatment, and prevention of alcoholism and alcohol-related problems. 


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NIDA:  
National Institute on Drug Abuse: part of the National Institutes of Health whose mission is to 
"lead the Nation in bringing the power of science to bear on drug abuse and addiction.” 
NIH:  
National Institute of Health: an agency of the United States Department of Health and Human 
Services, it is the primary agency of the United States government responsible for biomedical and 
health-related research. 
NMR:  
Nicotine Metabolite Ratio: is a salivary measure of the ratio of nicotine metabolites, which 
indicates speed of nicotine metabolism. 
NNAL:  
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol: A tobacco specific nitrosamines, one of the most 
important groups of carcinogens in tobacco products, formed from nicotine during the curing and 
processing of tobacco. 
NNC: 
Normal Nicotine Content 
PATH:  
Population Assessment of Tobacco and Health: a longitudinal study national study looking at 
tobacco use and health. 
PCP:  
Phencyclidine: known colloquially as Angel Dust and many other names, is a recreational 
dissociative drug. 
PI:  
Principal Investigator: is the lead scientist for a particular well-defined research project, such as a 
laboratory study or clinical trial. 
PrimeMD:  Primary Care Evaluation of Mental Disorders: Patient Health Questionnaire (PHQ –Pfizer©), a 
multiple-choice self-report inventory that is used as a screening and diagnostic tool for mental 
health disorders of depression, anxiety, alcohol, eating, and somatoform. 
QSU:  
Questionnaire of Smoking Urges-Brief: a 10 item questionnaire to self-report smoking urges and 
cravings.  
REDCap:  
Research Electronic Data Capture (web based software): is a secure, web-based application for 
building and managing online surveys and databases. 
RNC:  
Reduced nicotine content: cigarettes with lower levels of nicotine than normal cigarettes. 
RTI:  
Research Triangle Institute: now RTI International, is a nonprofit organization, headquartered in 
the Research Triangle Park in North Carolina, that provides research and technical services. 
SAE:  
Serious Adverse Events: generally, any event which causes death, permanent damage, birth 
defects, is life-threatening or requires hospitalization is considered an SAE. 
SBP:  
Systolic Blood Pressure 
SMAST:  
Short Michigan Alcohol Screening Test: a 13 item screening tool which is derived from one of the 
oldest alcoholism screening tests in identifying dependent drinkers. 
TLFB:  
Timeline Followback: is a method that can be used as a clinical and research tool to obtain a 
variety of quantitative estimates of marijuana, cigarette, and other drug use by asking clients to 
retrospectively estimate their usage prior to the interview date. 
TNE:  
Total nicotine equivalents: a urinary measure of nicotine and its metabolite concentrations. 
VLNC:  
Very low nicotine content: cigarettes with much lower levels of nicotine than normal cigarettes 
(possibly below addictive levels). 
WISDM:  
Wisconsin Inventory of Smoking Dependence Motives (Brief): a measure of tobacco dependence. 
 
 


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Study Synopsis 
Study 
Design: 
Phase III randomized, open label, multi-site study that will examine the impact of very 
low nicotine content (VLNC) versus normal nicotine content (NNC) cigarettes in a 
complex tobacco and nicotine product marketplace simulating a real world 
environment. 
Primary 
Aims: 
To examine the effects of cigarettes that vary in nicotine content on the number of 
cigarettes smoked, smoke-free days , extent of uptake of non-combusted alternative 
nicotine-containing products, and extent of exposure to tobacco toxicants in the context 
of a marketplace with alternative nicotine –containing products. 
We hypothesize that subjects in VLNC vs. NNC cigarette condition will experience: 1) 
fewer cigarettes smoked; 2) greater number of smoke-free days.3) greater uptake of 
alternative nicotine/tobacco products; and 4) less toxicant exposure.  
Exploratory analysis will examine whether the type (e.g., electronic nicotine delivery 
systems) and extent of use of alternative products mediates further reductions in 
cigarettes and toxicant exposure.  
Secondary 
Aim : 
Secondary Aim 1: To examine the characteristics of products alternative to cigarettes 
that are chosen and to better understand responses to these various products among 
smokers assigned to VLNC vs. NNC cigarettes. 
We hypothesize that across conditions, flavored electronic nicotine delivery systems 
with higher doses of nicotine will be preferred over other non-combustible products. 
Moreover, among subjects who try them, non-combusted products will be rated more 
positively and as providing greater withdrawal relief in the VLNC as compared to NNC 
conditions.  
Secondary Aim 2: To explore variables that predict responses to the marketplace.  
We hypothesize that a variety of factors (i.e., dependence severity, age, sex, racial 
ethnic group, SES) will impact product use patterns (e.g., the amount of non-
combusted vs. combusted products used and days smoke-free within NNC and VLNC 
cigarette conditions).  
Population: 
Cigarette smokers  
Study 
Procedures: 
Subjects will undergo two weeks of monitoring of usual brand cigarette smoking and 
then two weeks access to the experimental marketplace that includes their usual brand 
but no study cigarettes (to adapt smokers to the experimental marketplace). Subjects 
will then be randomly assigned for a period of 12 weeks to one of two marketplace 
conditions with access to:  1) VLNC study cigarettes and non-combusted tobacco and 
nicotine products; or 2) NNC study cigarettes and non-combusted tobacco and nicotine 
products.  Subjects in both conditions will be unblinded and informed that the study 
cigarettes contain very low nicotine levels or nicotine levels similar to conventional 
cigarettes currently sold on the market, respectively. The price of cigarettes and other 
products will be relative to the prices that are currently in the marketplace.  
Accrual: 
400-450; approximately 200-225 in each condition (VLNC & NNC). 
Enrollment 
Period: 
3/1/2018-9/30/2022 


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1. Study Objectives and Hypotheses 
1.1. Primary Objective  
The primary aim of this study is to examine the effects of cigarettes that vary in nicotine content 
on the number of cigarettes smoked; number of smoke-free days, extent of uptake of 
alternative non-combusted product use, and extent of tobacco-related toxicant exposure in the 
context of a marketplace containing alternative non-combusted nicotine-containing products.   
• 
We hypothesize that the very low nicotine content (VLNC) compared to normal nicotine 
content (NNC) cigarettes will lead to: 1) fewer cigarettes smoked; 2) greater number of 
smoke-free days; 3) greater number of days of non-combusted nicotine-containing product 
use; and 4) less exposure to tobacco-related toxicants. .  
Exploratory analysis will examine whether the type (e.g., electronic nicotine delivery systems 
[ENDS]) and extent of use of alternative products mediates further reductions in cigarettes and 
toxicant exposure.  We hypothesize that uptake of ENDS and greater uptake of alternative 
products will lead to lower cigarette use and toxicant exposure.  
1.2. Secondary Objectives  
1.2.a Secondary Aim 1: To examine the characteristics of products alternative to cigarettes that 
are chosen and to better understand responses to these various products among smokers 
assigned to VLNC vs. NNC cigarettes.   
• 
We hypothesize that across conditions, flavored electronic nicotine delivery systems with 
higher doses of nicotine will be preferred over other non-combustible products. Moreover, 
among subjects who try them, non-combusted products will be rated more positively and as 
providing greater withdrawal relief in the VLNC as compared to NNC conditions.  
1.2.b Secondary Aim 2: To explore variables that predict responses to the marketplace.  
• 
We hypothesize that a variety of factors will impact product use patterns (e.g., the amount 
of non-combusted vs. combusted products used and days smoke-free within NNC and 
VLNC cigarette conditions).  
 
2. Background 
2.1. Significance 
Changing the tobacco product. Over 44 million people in the United States smoke cigarettes1 
and about 1.2 billion globally.2 With about 500,000 deaths per year in the US and 6 million per 
year world-wide,2 it is critical to have strong tobacco control policies in place to minimize the 
casualties from tobacco use. 
 
The Family Smoking Prevention and Tobacco Control Act (FSPTCA), passed in 2009, provides 
the FDA with the authority to regulate tobacco products. One of the provisions in this legislative 
act empowers the FDA to assert product standards that would reduce harmful constituents in 


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tobacco products, including nicotine as long as the nicotine levels are not reduced to zero. A 
standard that has the potential to profoundly reduce the tobacco-caused mortality and morbidity 
is establishing maximum levels on nicotine to render cigarettes minimally addictive.3,4  Such a 
measure could reduce the transition of novice smokers from experimentation to becoming 
addicted, help current smokers quit smoking, and reduce the likelihood that former smokers will 
relapse. Although the proposal to reduce nicotine in cigarettes has been met with some 
skepticism because of concerns over the potential for compensatory smoking behavior5 and the 
emergence of a black market,6 this policy measure was considered to be technically feasible by 
the American Medical Association and the British Medical Association,3 and by tobacco control 
researchers, policymakers and governmental officials who were convened in a meeting on 
nicotine regulation.7 The public health impact of this approach has been estimated to be 
equivalent to the impact of sanitation efforts in reducing death and disease.8 Taking into account 
any mortality increases due to compensatory smoking or the emergence of a black market; the 
prevalence of smoking was projected to decline to 5%.9 
2.2. Existing Literature 
Reducing nicotine content in cigarettes.  Over 20 years ago, a proposal for a nationwide 
gradual reduction of nicotine levels in cigarettes was described as a means to decrease the 
development of cigarette dependence.10 Although researchers and medical organizations 
supported this approach as a potential policy measure, a number of research questions were 
raised that needed to be addressed (e.g., the impact of reduced nicotine content [RNC] 
cigarettes on smoking behavior, use of other tobacco products, toxicant exposure and 
cessation). To date, several studies have been conducted on this topic. Two studies 
conducted by Benowitz et al.11,12 examined gradual nicotine reduction approaches among 
smokers not seeking cessation treatments. These studies differed in the duration of smoking 
of each dose of RNC cigarettes: one week versus one month. The results from both of these 
studies showed minimal compensatory smoking, substantial decreases in cotinine (a 
metabolite of nicotine) levels, no increase in exposure to other tobacco toxicants, and minimal 
withdrawal symptoms. Another study conducted by Hatsukami et al.13 examined the effects of 
immediately switching to a very low nicotine content (VLNC) cigarette compared to a higher 
nicotine content cigarette and to nicotine lozenge in smokers interested in quitting smoking. In 
the VLNC cigarette condition, decreases in smoking, modest withdrawal symptoms after 
switching from usual brand cigarettes, reduction in dependence, reduction in toxicant 
exposure and a moderate cessation rate were observed. Finally, Donny et al conducted a 
large clinical trial in which cigarettes smokers (n=840) were randomly assigned to 1 of 6 doses 
of nicotine or an additional very low nicotine dose cigarette but with high tar. This study 
showed that relative to cigarettes with normal amounts of nicotine (15.8 mg/g), cigarettes with 
0.4 mg/g nicotine led to reduced smoking and dependence, reduced craving and withdrawal 
during abstinence and to increased quit attempts.14 There was no evidence of increased 
exposure to various tobacco smoke toxicants. Collectively, these studies suggest that 
reducing nicotine in cigarettes is a highly promising regulatory approach. Currently, we and 
other investigators are have analyzed data from a recently completed study to determine 
optimal approaches to reducing levels of nicotine in cigarettes (gradual vs. immediate 


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reduction to VLNC) and the impact of VLNC cigarettes in vulnerable populations (e.g. 
individuals with psychiatric diagnosis).  To date, no safety issues have been observed in either 
the immediate vs. gradual reduction 
approach or in vulnerable populations.  
2.3. 
Rationale for conducting 
current studies.   
Prior studies, while experimentally strong, 
have not fully simulated either the 
marketplace, or the consumer, in a post-
nicotine reduction policy world (Figure1).  
With respect to the marketplace, the 
aforementioned studies were/are primarily 
focused on examining the impact of RNC 
cigarettes alone under double-blind 
conditions; therefore participants were 
discouraged from using any other tobacco 
products, cigarettes were provided at no 
cost, and information about the nicotine 
content of cigarettes was withheld. These study designs, while able to evaluate the influence of 
nicotine reduction per se on relevant outcomes, do not adequately simulate a real world 
marketplace in three major ways. First, with a national nicotine reduction policy, no regular 
nicotine cigarettes would be available and alternative nicotine-containing products would be 
widely available. Therefore, the impact of such a policy on the use of other tobacco or nicotine 
products needs to be considered to fully understand public health effects. Second, providing 
cigarettes for free is likely to underestimate the degree to which RNC cigarettes might impact 
smoking behavior. If smokers were required to pay $6 to $10 for a pack of cigarettes that they 
find relatively non-rewarding, they are likely to smoke fewer cigarettes than they would if these 
products are provided at no cost.14  The importance of price on consumption is widely known 
and is the basis of increasing taxes on cigarettes to drive the prevalence of smoking down.15 
Third, with the implementation of a reduced nicotine policy, the FDA would by necessity 
provide information to consumers on the reduced nicotine content of cigarettes. The knowledge 
of nicotine content in cigarettes might influence expectancies or beliefs about the cigarettes, 
which then might affect smoking uptake or behavior. With respect to simulating the consumer, 
another limitation of prior studies is the recruitment of a relatively narrow selection of smokers 
in most studies. That is, smokers were recruited only if they were not motivated to quit smoking 
and used minimal amounts of other tobacco products. In a recent large clinical trial, about 15% 
were excluded for using other tobacco products (e.g., greater than 9 times per month) and 7% 
were excluded because they were motivated to quit in the next 30 days, thus omitting almost a 
quarter of the sample. All these limitations demonstrate the need to conduct a study that 
includes a more broadly selected sample of smokers and that better approximates the 
marketplace that is likely to occur if the policy to reduce nicotine in cigarettes is implemented.  


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Rationale for a Real World Marketplace.  The potential effects of RNC cigarettes on use of 
other tobacco products are illustrated by the findings from several studies. First, even in studies 
that required smokers to only smoke RNC cigarettes, a significant number smoked usual brand 
cigarettes, indicating the smokers needed to supplement the reduced nicotine in the study 
cigarettes with their own cigarettes. For example, in a gradual nicotine reduction study 
conducted by Benowitz et al.,12 10% (N=59) of smokers (not seeking treatment) assigned to 
RNC cigarettes withdrew during the tapering phase and 21% (N=53) of subjects who 
completed the tapering phase reported smoking some commercial cigarettes. In Hatsukami et 
al.,13 about 30.4% (N=37) of smokers (seeking smoking cessation treatment) who were 
assigned to 0.6 mg/g nicotine content cigarettes (0.05 mg machine determined nicotine yield) 
for six weeks used non-assigned tobacco products in the first week and by six weeks, about 
5.3% (N=32) reported using such products.  These rates are likely to be underestimates 
because they were not biochemically verified. For example, in the large study conducted by 
Donny et al.,14 in a secondary analysis of product non-compliance, about three-fourths of 
participants using the 0.4 mg/g nicotine content cigarettes (0.04 mg machine determined 
nicotine yield) were biochemically confirmed to be using some non-study tobacco products 
based on levels of total nicotine equivalents (TNEs).   
 
In a study conducted by Hatsukami et al.,16 smokers assigned to VLNC with access to 
alternative nicotine delivery systems (ANDS) reported greater uptake of these products 
compared to those assigned to normal nicotine content cigarette; and they also experienced 
significantly greater reductions in combusted product use, nicotine exposure, cigarette 
dependence and higher number of quit attempts.  Furthermore, the amount of non-combusted 
ANDS use was significantly, negatively associated with the amount of combusted product use 
and levels of carcinogen exposure, and positively related to number of abstinence days.  
Rationale for seeking alternative nicotine sources.  The reasons for seeking alternative 
nicotine sources among smokers assigned to VLNC cigarettes can be multi-fold. Smokers 
generally report that VLNC cigarettes are low in satisfaction/liking, enjoyable sensations, and 
psychological reward compared to NNC cigarettes.17 Therefore, smokers may be seeking 
products that have similar reinforcing value as NNC cigarettes. Smokers may also use 
alternative products in an attempt to reduce any nicotine withdrawal symptoms associated with 
smoking VLNC cigarettes. In another study conducted by Hatsukami et al.,18 smokers (seeking 
smoking cessation treatment) were provided nicotine patch in addition to VLNC (0.6 mg/g 
nicotine content) cigarettes or VLNC cigarettes alone. This study found that use of the nicotine 
patch can reduce withdrawal symptoms resulting from switching to VLNC cigarettes, 
suggesting that other nicotine-containing products may also have these effects. Other factors 
that might promote uptake and persistent use of alternative products include perceived reduced 
health risks or use as a means for cessation19-21 and for those who are assigned VLNC, more 
positive product expectancies of the alternatives than the VLNC cigarettes. Although studies 
have been conducted comparing subjective responses to VLNC with NNC cigarettes, to date, 
no studies have compared subjective responses to non-combusted nicotine-containing 
products in the context in which cigarettes with different doses of nicotine are available.  


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Predictors of use of alternative nicotine/tobacco products:  In the aforementioned study 
on the impact of nicotine content on the use of ANDS,16 predictors of greater use of these 
alternative products were being male and non-white, reporting higher dependence, and having 
higher education and income levels (all p’s < 0.0001). Some of these results are concordant 
with results from Donny et al.,14 in which indicators of dependence (cigarettes per day, urinary 
total nicotine equivalents) were associated with non-compliance with study cigarette use only, 
which could be a proxy for when smokers feel the need to seek alternative sources of nicotine. 
The predictor variables are also consistent with the literature that shows that men are more 
sensitive to nicotine than women,22,23 that dependence severity predicts the need for higher 
nicotine doses,24 and that use of alternative products, particularly electronic nicotine delivery 
systems, is greater among those with higher education.25,26 These results underscore the 
need to further investigate how different populations of smokers will respond to a national 
nicotine reduction policy.  
2.4. Summary and Rationale 
This study will examine the impact of very low nicotine content (VLNC) cigarettes in a complex 
tobacco and nicotine product marketplace.  We will compare the number of cigarettes smoked 
and smoke-free days, use of alternative nicotine-containing products, biomarkers of toxicant 
exposure and subjective responses to products in an experimental marketplace that contains 
VLNC cigarettes versus normal nicotine content cigarettes.  The results of this study would 
contribute to policy decisions on whether or not nicotine levels should be regulated in 
cigarettes.  
3. Study Endpoints / Outcomes 
3.1. Primary Endpoints 
• 
Cigarettes per day (CPD): the mean cigarettes (study and non-study cigarettes) 
smoked per day based on 7 days’ Daily Interactive Voice Response (IVR)-Revised data 
before the week 12 visit.  
• 
Smoke-free days: the number of smoke-free days during Phase 3 based on IVR-
Revised. 
 
3.2. Secondary Endpoints 
• 
Biomarker: percent change in biomarker, CEMA at the weeks 4, 8 and 12 visits during 
Phase 3 as compared to the last visit in Phase 2. 
• 
Study Cigarettes per day (CPD): the mean study cigarettes smoked per day based on 7 
days’ Daily Interactive Voice Response (IVR)-Revised data before the week 12 visit. 
• 
Seven-day abstinence and CO ≤ 6ppm for all 7 days before the week 12 visit. 
3.3. Exploratory Endpoint: 


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• 
Non-combusted tobacco/nicotine products use: the number of days using any non-
combusted tobacco/nicotine products in Phase 3. 
• 
Characteristics’ of products chosen (type, flavor, nicotine strength) 
• 
Biomarkers: percent change in biomarkers (Total Nicotine Equivalents, total NNAL, 
mercapturic acids other than CEMA) at the weeks 4, 8 and 12 visits during Phase 3 as 
compared to the last visit in Phase 2.  
• 
Product satisfaction (Product Evaluation Scale if they used the product since the last 
visit; Cigarette Evaluation Scale if they smoked cigarettes since the last visit) 
• 
Perceived health risk (Phase 1, Phase 2 and end of week 12 of Phase 3: all products 
for all subjects) 
• 
Measures of discomfort/dysfunction: MNWS-R, QSU, CESD (NNC vs VLNC cigarettes 
irrespective of use of products) 
• 
Dependence (FTND, WISDM, PATH items; monthly for study cigarettes) 
3.4. Safety Endpoints: 
• 
Potential adverse consequences:  Change in mental (CES-D) or physical health (heart 
rate, blood pressure, weight)  
• 
Increased TNE (corrected by creatinine), calculated as change from Phase 1 baseline.  
• 
Adverse events and Serious Adverse events  
4. Intervention 
4.1. Study Description 
This randomized, open label, controlled, multi-site study will simulate a “real world” tobacco 
environment by providing participants access to an experimental marketplace where they will 
be given vouchers for a specified number of points that can be exchanged for study cigarettes 
(varying in nicotine content described below) and non-combusted tobacco/nicotine products 
(smokeless tobacco, snus, nicotine pouches, electronic cigarette, medicinal nicotine 
replacement) or cash.  More specifically, subjects (N=approximately 200-225 in each group) 
will be randomly assigned to: 1) very low nicotine content cigarettes (VLNC; 0.4 mg/g) along 
with non-combusted tobacco/nicotine products or 2) normal nicotine content cigarettes (NNC; 
15.8 mg/g) along with non-combusted tobacco/nicotine products.  
 
4.2. Investigational Products 
4.2.1. Investigational Cigarettes and Marketplace Tobacco Products: 
Study Cigarettes: Spectrum cigarettes will be ordered through NIDA (NOT-DA-14-004) and 
dispensed by Research Triangle Institute (RTI) to Wake Forest University, who holds a 


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distributer license and will distribute study cigarettes to sites. The product characteristics 
including filter ventilation and filter and paper type are the same across these two products.  
The following nicotine content and yield will be obtained from NIDA: 
Type 
Nicotine Yield 
mg/cig 
Tar Yield 
mg/cig 
NNC600  
0.8 ± 0.15* 
10 + 1.5 
NNC601 Menthol 
0.8 ± 0.15 
10 + 1.5 
VLNC102  
0.03 ± 0.01^ 
9 + 1.5 
VLNC103 Menthol 
0.03 ± 0.01 
9 + 1.5 
 
NNC= conventional nicotine; VLNC=very low nicotine content  
*This NNC dose was chosen because it is similar to commercial cigarettes and is associated with similar rates 
of smoking, nicotine levels and dependence as usual brand cigarettes. 14    
^This dose was chosen because prior studies have shown that the VLNC dose relative to NNC dose showed 
significant reductions in cigarettes smoked per day, nicotine exposure and cigarette dependence.14,17   
The selection of non-combusted tobacco/nicotine alternative nicotine delivery systems (ANDS) 
will include:  
• 
E-cigarettes or electronic nicotine delivery systems (ENDS) that are commercially available 
and of varying nicotine doses  and types (e.g., cigarette-like/pod systems such as Vuse, 
Juul and self-contained tank system such as Joytech eGo AIO or Halo Triton or similar;  
• 
Snus (e.g., Camel, Skoal );   
• 
Nicotine pouches (e.g. Zyn); 
• 
Conventional smokeless tobacco products (e.g., Copenhagen, Grizzly); 
• 
Non-prescription  medicinal nicotine (2mg and 4mg nicotine gum and lozenge; 7, 14 and 21 
mg nicotine patch).   
The most popular brands, types and flavors (no more than 4 flavors for each type of product) 
will be chosen for our marketplace. The selection of products will be based on current national 
marketing data as well as data collected from the six study site regions, but the final product 
selections will be consistent across sites. The ENDS market is dynamic and changes may 
occur during the course of the study and as a result, specific brands will not be specified. 
Although oral tobacco products and medicinal nicotine are not the most popular products 
chosen in our pilot study, the products are included to more closely simulate the products that 
are currently on the market and because we may find they are preferentially chosen at some 
sites or in a sub-sample of smokers. Products made available in the study marketplace will be 
reassessed on a yearly basis or as product availability and safety/quality issues arise).  
Experimental marketplace.  The overall goal of the experimental marketplace is to provide a 
context in which product preferences can be evaluated in a systematic way but with a high 
degree of ecological validity. Participants will exchange points for products in the marketplace. 
Points required to exchange for products will vary from site to site to reflect regional variation in 
pricing, however, points required for products within a site will be the same.  


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Product pricing. Retail market value of all products is determined by recording product prices at 
a range of retail outlets (e.g. pharmacy, grocery, gas station, corner shop, tobacco outlet, vape 
shop) at each site. The price of usual brand cigarettes and Spectrum study cigarettes, which 
are not available retail, will be equal to the site-specific average cost of cigarettes. We will 
annually assess retail prices and modify study product pricing to reflect significant changes 
(>10% difference). All products will be discounted to 66% of the regional retail market value in 
order to 1) discourage subjects from purchasing products outside the marketplace and 2) 
minimize hoarding vouchers for cash payment at the end of the study.  
Purchasing power.  Each subject will be given a point voucher at each marketplace visit that 
can be exchanged for products. Points provided at each visit are based on the subject’s points 
per day multiplied by the number of days till their next scheduled visit. Subject’s points per day 
are constant throughout the study and are calculated to allow the subject to cover their 
baseline cigarettes and other nicotine product use (e.g., vaping device, smokeless tobacco or 
nicotine replacement therapies) per day plus 1 point per day to allow for experimentation in the 
marketplace. Participants will receive a coupon that can be applied to discount e-cigarettes 
and/or medicinal nicotine products in the marketplace. This will allow for experimentation with 
the more expensive e-cigarette devices or a large box of medicinal nicotine. This coupon 
cannot be used on cigarettes or smokeless tobacco/snus/nicotine pouches. This coupon can 
only be used one time per participant. The participant cannot exchange the coupon for cash at 
the end of the study.  Although the need for higher voucher point amounts to take into account 
the possibility of compensatory smoking may be a concern, to date, the majority of people do 
not increase in smoking resulting from availability of VLNC cigarettes. In order to discourage 
needless exchange of vouchers for products, any portion of the voucher not used at each visit 
can be banked and used at later visits or converted to cash (up to $200) at the end of the 
study. Unopened products will be reimbursed for the amount of points exchanged for the 
product. 
Marketplace protocol. The marketplace will have the appearance of an on-line virtual retail 
store, with points posted on each of the product brands/types but do not have any point-of-sale 
advertisements. Subjects will be informed that they can exchange points for any amount or 
type of product up to the value of current and banked vouchers. The Marketplace website will 
allow for standardized information to be available when the participant clicks on the 
“information” option. This standardized information will include the general contents of the 
product (flavor) and the levels of nicotine content and warning labels (no more information than 
what is typically provided by the retailer). Additionally, the subject can click on the product and 
observe a video describing how to use the product.  For medicinal nicotine products, subjects 
will also be referred to consult the information/instructions provided in the package. Examples 
of the products will be available for the subject to inspect, smell and see that packaging. Post-
COVID, this procedure was not possible, but participants can ask the Research Assistant for 
additional description of the product if necessary. If the subject requests additional information, 
s/he will be directed to the product’s website. If the subject asks directly about e-cigarette risks, 
the Research Assistant will reply “The Surgeon General has said that long term risks of e-cigs 
are unknown, but it is likely less harmful than cigarettes. However, this is likely to be the case if 
the e-cigarettes and e-fluids are bought at reputable sources and not modified” If the inquiry is 


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related to smokeless tobacco or snus, the Research Assistant will reply that smokeless 
tobacco is not harmless, but it is less harmful than cigarettes.  If the inquiry is related to 
medicinal nicotine, the Research Assistant will reply that medicinal nicotine is approved by the 
FDA for the treatment of smoking cessation and has minimal risks compared to smoking.  
Outside purchases.  If subjects run out of products between visits and wish to purchase more 
with banked vouchers, they can arrange for between-visit purchases with study staff during 
office hours. At these additional visits, safety measures may be collected (e.g. adverse events, 
vital signs, CO, and product accountability measures, as warranted). CO will be obtained if the 
cigarettes smoked per day increases by 50% or more.  While subjects will be discouraged from 
making out-of-marketplace purchases of specific products offered in the marketplace, no 
penalties will be levied for such purchases in order to encourage truthful reports of 
noncompliance. 
4.2.2. Investigational Tobacco Product Handling 
Study cigarettes will be kept in locked refrigerators on site in a secured area with limited 
access. Refrigerator temperature and humidity will be documented on workdays to verify 
stability of environment. Only study staff will have access to open the refrigerator locks. 
Cartons will be pulled as needed for dispensing to subjects. Cartons will be labeled with the 
nicotine dose identified since this is not a blinded study. Cartons will be tracked by carton 
number and this number will be documented in the central Dispensing Log and in the subject 
case report form. Other tobacco and nicotine products will be kept in a secured location where 
only study staff will have access. Dispensing Logs will also be kept for these products. 
4.3. Investigational Tobacco Product 
This investigational cigarette to be used in this protocol is under FDA Submission Tracking 
Numbers: IU 0000011 (NRC600), 0000012 (NRC601), 0000126 (NRC 102), 0000127 (NRC 
103).  
This IU is held by the Project Leader, Dorothy Hatsukami, Ph.D. 
5. Study Plan and Procedures 
5.1. Study Design 
This is a randomized, open label, controlled, multi-site study simulating a “real world” tobacco 
environment. Subjects are given access to an experimental marketplace where they will be 
given vouchers that can be exchanged for study cigarettes and non-combusted tobacco/ 
nicotine products or cash. Subjects (N=~200-225 in each group) will be randomly assigned to 
either:  
1) Very low nicotine content cigarettes (VLNC; 0.4 mg/g, 0.03 nicotine yield) along 
with non-combusted tobacco/nicotine products  


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2) Normal nicotine content cigarettes (NNC; 15.8 mg/g; 0.8 nicotine yield) along 
with non-combusted tobacco/nicotine products.   
Subjects will be informed about the nicotine content in cigarettes they are assigned.  
Participants will have the option to select menthol or non-menthol cigarettes. 
 
Smokers will undergo an orientation visit for further screening and then enter a three phase 
experimental trial:  
1) Phase 1 – Baseline: a baseline assessment period during usual brand cigarette smoking.  
2) Phase 2 – Marketplace Adaptation: a marketplace with access to the preferred usual brand 
cigarettes and selected non-combusted tobacco products to allow the subject to adjust to the 
marketplace prior to randomization;  
3) Phase 3 – Intervention: randomization to a marketplace with access to either VLNC or NNC 
cigarettes and non-combusted products.   
 
 
 
5.2. Clinic Visit Procedures 
(Adaptation for COVID-19 safety precautions: In general, in-person visits converted to 
telehealth visits, including CO and vitals measurements using devices sent to participants.  
Product/biological sample drop-off and pick-up are conducted curbside. Some measures were 
discontinued including the breath alcohol test, toxicology screens for drug use, saliva samples 
were collected instead of spot urines for compliance, and first morning void was used for 
pregnancy screen.)  
ELIGIBILITY SCREENING  
5.2.1. Orientation and In-Person/Telehealth  Screening (94) 
(These 2 visits can be combined) 
Orientation: The purpose of the orientation is to inform the subjects about the study protocol. 
During this meeting, subjects will be shown a standardized presentation on the study rationale, 
description of the cigarettes and alternative nicotine products, study protocol and outcome 
measures. A copy of the consent form will be provided for review. Interested subjects will be 
asked to contact the clinic to schedule an In-Person/Telehealth Screening visit, if the 
Orientation and In-Person/Telehealth Screening are done in two separate visits. 
In-Person/Telehealth Screening:  Subjects will first present a valid photo ID prior to obtaining 
informed consent to confirm age and identity. After informed consent is obtained (See Section 
Phase 1 
Usual Brand 
Natural Marketplace 
Phase 2 
Usual Brand 
Experimental Marketplace 
Phase 3 
Study Cigarettes 
Experimental Marketplace 


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21.1 for consenting process), the following measures will be collected and documented in the 
subject’s case report form: 
A. Physiological Measures at Screening 
1) Breath alcohol concentration (BrAC) measured by an expired breath sample. 
Participants with levels over 0.010 g/210L may reschedule the interview once but will 
need to be re-consented to ensure the subject is not intoxicated while giving informed 
consent. (BrAC was discontinued due to the COVID-19 pandemic to allow for telehealth 
visits.) 
2) Expired breath carbon monoxide (CO) level to assess recent smoking. Carbon 
monoxide level must be >10 ppm to confirm regular daily smoking. 
3) Vital signs (blood pressure and heart rate). 
4) Height and weight. For Telehealth visits, weight was by self-report. 
5) Spot urine sample: 
a. Verification of smoking status: If CO is <10, a cotinine (nicotine) strip can be used to 
assess urinary cotinine quantity to verify participant is a smoker. (First morning void 
used due to COVID-19 pandemic to allow for telehealth visits.) 
b. A urine toxicological screen will be performed to assess the presence of illicit drugs 
including marijuana, cocaine, opiates, benzodiazepines, barbiturates, 
amphetamines, methadone, methamphetamines, and PCP. A failed drug screen 
(with the exception of marijuana or valid prescription for other drugs) will result in 
discontinuing the visit without compensation. The subject may reschedule the 
screening visit, but will need to be re-consented to ensure the subject is not under 
the influence while giving informed consent. They will be excluded if positive again 
at the second visit. Marijuana use, as determined by medical professional review, is 
acceptable, due to its high prevalence; however, 48 hours abstinence from smoked 
marijuana will be requested prior to biomarker collection visits. If a subject reports 
smoked marijuana within 48 hours of the visit it will be documented.  (The toxicology 
screen for eligibility was discontinued due to the COVID-19 pandemic to allow for 
telehealth visits.)  
B. Questionnaires and Assessments at Screening (See section 5.7.3 – 5.7.5 for further 
descriptions of questionnaires) 
B.0 Pen and paper forms (These forms were later completed electronically during the 
Telehealth visits) 
Pen and paper questionnaires will be completed by the subject and some of this data will 
be entered into REDCap following the visit (identified in the Schedule of Procedures Table 
on page 65). 
1) Identification Form: includes name, address, email, phone number, age and date of 
birth. This information will be stored separately from any other study data and in a 
password protected database. This information will not be shared with any study 
investigators external to the site. 


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2) Brief Medical History Questionnaire to assess current diagnoses, symptoms and past 
health problems including psychiatric and substance abuse and medication use. 
• 
Date of last menstrual period and length of cycle are included to assess pregnancy 
status. (A pregnancy test [hCG detection] will be performed for female participants 
of childbearing potential prior to accessing the Marketplace at week 92 and prior to 
randomization at week 00 and monthly thereafter).  
3) Patient Health Questionnaire (PHQ - PrimeMD). 
• 
Beck Depression Inventory 2nd Edition (BDI-II) administered for clinician review if the 
PrimeMD is positive for any diagnoses or endorsement of suicidal ideation. 
• 
GAD-7 will be administered if the PrimeMD is positive for anxiety/panic disorders.  
 
B.1 Web-based data collection completed by the subject: 
1) Demographics.  
2) Contemplation Ladder. 
3) Michigan Alcohol Screening Test Short form (SMAST). 
4) Drug Abuse Screening Test (DAST). 
5) NIAAA Alcohol Use Questionnaire (12 month version). 
6) Centers for Epidemiological Studies–Depression 20-item scale (CES-D).   
• 
BDI-II will be administered on paper if the CES-D score is 16 or greater for clinician 
review.  
B.2 Administered as an interview by the study Research Assistant (entered into REDCap): 
1) Brief Medical History Follow-up Questionnaire (not entered in REDCap) will be 
completed by study staff to further assess current medical diagnoses, symptoms or past 
health problems. 
2) Tobacco Use History and Nicotine Exposure Questionnaire.  
3) The Mini International Neuropsychiatric Interview (MINI).  
• 
Any response other than “not at all” on the suicidal ideation question of the Prime 
MD (Question 1i) or a positive response to items 2-5 on the (MINI) suicide subscale 
will not be eligible to participate in the study and will be assessed by clinician, and 
provided with information and resources and dismissed from the study. 
• 
If a subject is in immediate danger, site’s procedures for suicidal subjects will be 
followed. 
4) Recreational Drug Use Questionnaire (12 month version).   
5) End of Visit Form. 
After confirmation of eligibility criteria, subjects will be scheduled for their first baseline visit and 
medical review will be completed by the licensed medical professional (LMP) prior to the next 
visit. If upon medical review, it is determined the subject is not eligible, they will be contacted 
by phone and informed.  
C. Daily Call Recording System - Interactive Voice Response System (IVR)  
At the Screening visit, eligible subjects will be trained to use the IVR Daily Call Recording 
System, which will contact participants each day throughout the study and ask about their 


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smoking and other tobacco/nicotine product use. The questionnaire will ask for previous day’s 
use of cigarettes (study and non-study cigarettes), number of vaping puffs, number or 
alternative smokeless tobacco and nicotine products used.  
To be enrolled in the call recording system, research staff must enter subject initials, telephone 
number, subject identifier and visit dates into the HIPAA compliant website. Identifying 
information (initials and telephone numbers) will not be extracted with the data by the 
bioinformatics group. 
Any missing data due to incomplete calls or entry errors (e.g., subject entered 88 study 
cigarettes rather than 8 study cigarettes) will be reviewed at the visit via the Timeline 
Followback Method and compiled in the IVR Review Form. This data will be integrated into the 
IVR-Revised data, however initial data will be retained in the original IVR database. 
Visit Scheduling Requirements  
The scheduling window for baseline visits is 7 days + 14 days. Subjects will be required to 
schedule the Baseline 1 (93) visit within 21 days of their In-Person/Telehealth Screening (94) 
visit. If the first baseline visit is over 30 days after screening due to scheduling or eligibilitly 
criteria, the subject must be re-consented and re-screened, but will maintain the original 
assigned Subject Identifier. 
PHASE 1:  BASELINE: USUAL BRAND IN NATURAL MARKETPLACE 
5.2.2. Phase 1:  Baseline Procedures for Baseline Visits 1 (93) and 2 (92) 
During Phase 1 of baseline (screening up to access to tobacco marketplace), eligible subjects 
will continue to smoke their preferred brand as usual.  At the baseline clinic visits, subjects will 
complete several measures and provide biomarker samples as described below.  
A.  Physiological Measures at Baseline (93 and 92): 
1) BrAC, which must be below 0.03 g/210L. If over the 0.03, the visit will be delayed until 
the level drops within range or subject can be rescheduled.  If above 0.05, the visit will 
be rescheduled. Multiple baseline elevated BrAC results may result in discontinuation of 
the subject at the PI discretion. (BrAC was discontinued in conversion to telehealth 
visits.)  
2) Expired breath CO level.  
3) Vitals signs (blood pressure, heart rate).  
4) Weight.  
5) First morning void urine collected. 
6) Saliva samples: 
 
a) Saliva sample obtained with Salivette (with citric acid preparation) to be used for 
 
 
nicotine metabolite ratio (NMR) Visit 1 (93) only. 
7) Spot urine for pregnancy tests [hCG detection] will be performed for female participants 
of childbearing potential (not surgically sterilized or 2 years post-menopausal) at Week 


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92 prior to offering Marketplace. (Pregnancy tests are performed on first morning void 
after conversion to telehealth visits.) 
 
B. Questionnaires and Assessments at Baseline (93 and 92): 
 
B.1 Web-based data collection program completed by the subject: 
1) Minnesota Nicotine Withdrawal Scale (MNWS).  
2) Questionnaire of Smoking Urges- Brief - Usual Brand Cigarette (QSU). 
3) Cigarette Evaluation Scale – Baseline (CES – Usual Brand). 
4) Respiratory and Global Health Questionnaire. 
5) If monitored for psychiatric illness: Beck Depression Inventory 2nd Edition (BD-II) 
(paper only).  
6) Cigarette Dependence Measures (Usual Brand - Visit 93 only). 
7) Environmental Tobacco Smoke Exposure Questionnaire (Visit 93 only).   
8) Social and Environmental Influences on Tobacco Use (Visit 93 only). 
9) Dietary Intake (e.g., charred and smoked meats and fish) (Visit 93 only). 
10) NIAAA Alcohol Use Questionnaire - 1 month version (Visit 93 only). 
11) Expected Utility (ANDS) (Visit 93 only). 
12) Perceived Health Risk of no tobacco use, usual brand cigarettes, very low nicotine 
cigarettes, smokeless tobacco/snus/nicotine pouches, medicinal nicotine, ENDS (Visit 
92 only).   
13) Product Expectancy Questionnaire (Visit 92 only). 
14) Cigarette (Usual Brand)/Product Purchase Task (Week 92 only). 
 
B.2. Administered as an interview by the Research Assistant (entered into REDCap): 
1) Health Changes Questionnaire. 
2) Adverse Events.  
3) Concomitant Medications. 
4) IVR Review of Daily Call and follow-up on missing and unusual reports. 
5) Timeline Followback Questionnaire (14 days for Visit 93 or since last visit for Visit 92). 
6) Recreational Drug Use Questionnaire (1 month version at Visit 93).  
7) Study Product (see C.1-3: Visit 92 only) and Procedure Compliance Review. 
8) End of Visit Evaluation. 
C. Introduction to Experimental Marketplace with Usual Brand Cigarettes:   
Upon completion of V92 (end of Baseline), subjects will have access to the web-based 
experimental marketplace that includes their usual brand cigarettes and non-combusted 
tobacco and nicotine products. This phase is instituted to allow the participant to adjust to 
the experimental marketplace while smoking usual brand cigarettes prior to randomization 


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to study cigarettes. In addition, exploratory comparisons will be made between Phases 1 
and 2 to assess purchasing and product use patterns when participants are purchasing 
their own cigarettes in the natural environment versus when purchasing products in the 
experimental market.  
C.1 Present marketplace web page 
Subjects will be presented with the Marketplace web page containing their usual brand 
cigarettes and the other study tobacco and nicotine products (no study cigarettes). These 
products include: smokeless tobacco, snus, nicotine pouches, electronic nicotine delivery 
systems (ENDS) and medicinal nicotine. The point exchange system will be reviewed and 
the subjects are shown how to access product information on the webpage. They will then 
choose their preferred products and are instructed to only use the products they put in their 
“cart” in exchange for their points.  
C.2 Dispense Study Product 
After subject has selected their desired products (usual brand cigarettes and alternative 
nicotine products) from the Marketplace website, those products will be provided to the 
subject with instruction on how to track the use of their products for the Daily Call 
Recording System.  
C.3 Product Accountability (Dispensing Log) 
Any products obtained by the subject will be documented in the Product Accountability Log 
in the subject’s case report form. Subjects will be asked to return used and unused product 
packaging and empty vaping device cartridges/e-liquid containers. Number of products 
dispensed, used and unused items will be documented at each visit. If smokeless tobacco 
products are chosen, the tins will be weighed before dispensing and after return. A similar 
procedure will be followed for vials of e-fluids that are dispensed. Review compliance 
counseling with the study product use and procedures. 
(Refer to Section 4.2.1:  Marketplace protocol. for additional information) 
 
PHASE 2: USUAL BRAND IN EXPERMENTAL MARKETPLACE (MP91 AND MP00) 
Scheduling window at baseline is 7 days + 4 days. 
During the 2 weeks of Phase 2 (MP 91 and MP 00), eligible subjects will have access to the 
marketplace products that contains their usual brand cigarettes and other tobacco 
products. At this visit, subjects will complete several measures and provide biomarker 
samples as described below.  
 
5.2.3. Phase 2: Marketplace Adaptation Visit MP (91) Procedures 
A.  Physiological Measures at MP 91: 


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1) BrAC (discontinued at telehealth visits).  
2) Expired breath CO level.  
3) Vitals signs (blood pressure, heart rate).  
4) Weight.  
B.  Questionnaires and Assessments at MP 91:  
B.1 Web-based data collection program completed by the subject: 
1) Minnesota Nicotine Withdrawal Scale (MNWS).  
2) Questionnaire of Smoking Urges-Brief -Usual Cigarette (QSU).  
3) Cigarette & Product Evaluation Scale – (Baseline Usual Brand CES/PES). 
4) Respiratory and Global Health Questionnaire. 
5) If monitored for psychiatric illness: Beck Depression Inventory 2nd Edition (BD-II) 
(paper only).  
 
B.2  Administered as an interview by the study Research Assistant (entered into REDCap): 
1) Health Changes Questionnaire.  
2) Adverse Events.  
3) Concomitant Medications. 
4) Review of Daily Call and follow-up on missing and unusual reports. 
5) Timeline Followback Questionnaire (since last visit).  
6) Product Accountability: Complete Product Dispensing Log. 
7) Study Product and Procedure Compliance Review. 
8) End of Visit Questionnaire. 
5.2.4. Phase 2: Marketplace Adaptation Visit (00) Procedures 
A.  Physiological Measures at MP 00: 
1) BrAC (discontinued at telehealth visits).  
2) Expired breath CO level.  
3) Vitals signs (blood pressure, heart rate).  
4) Weight.  
5) First morning void urine. 
6) Spot urine for pregnancy tests [hCG detection] will be performed for female participants 
of childbearing potential (not surgically sterilized or 2 years post-menopausal) at Week 
00. (Pregnancy tests are performed on first morning void after conversion to telehealth 
visits.) 
B.  Questionnaires and Assessments at MP 00:  
 
B.1 Web-based data collection program completed by the subject: 


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1) Minnesota Nicotine Withdrawal Scale (MNWS).  
2) Questionnaire of Smoking Urges-Brief -Usual Cigarette (QSU). 
3) Cigarette & Product Evaluation Scale – (Baseline Usual Brand CES/PES). 
4) Respiratory and Global Health Questionnaire. 
5) CES-D: 
Beck Depression Inventory 2nd Edition (BD-II) will be administered on paper if the CES-D 
score is 16 or greater of if monitored for psychiatric illness.  
6) Cigarette Dependence Measures (Usual brand) 
7) Environmental Tobacco Smoke Exposure Questionnaire  
8) Dietary Intake. 
9) NIAAA Alcohol Use Questionnaire (1 month). 
10) Perceived Health Risk of no tobacco use, usual brand cigarettes, very low nicotine 
cigarettes, smokeless tobacco, medicinal nicotine and ENDS.   
11) Contemplation Ladder.  
12) Cigarette (Usual Brand and All Products) Purchase Task. 
 
B.2 Administered as an interview by the study Research Assistant (entered into REDCap): 
1) Health Changes Questionnaire.  
2) Adverse Events.  
3) Concomitant Medications. 
4) Review of Daily Call and follow-up of missing and unusual reports. 
5) Timeline Followback Questionnaire. 
6) Recreational Drug Use Questionnaire (1 month version). 
7) Product Accountability: Complete Product Dispensing Log. 
8) Study Product and Procedures Compliance Review. 
9) End of Visit Questionnaire. 
Randomization and Marketplace with study cigarettes  
At the end of Visit 00, subjects will be randomized to one of the two experimental conditions 
(VLNC vs. NNC cigarettes) for 12 weeks. Twelve weeks was chosen because experimentation 
with or use of other tobacco/nicotine products is most likely to occur during the first weeks of 
intervention and stabilization is likely to occur thereafter. However, the time course of 
stabilization of product use is not clearly known, a 12 week duration of intervention was 
selected to allow sufficient time to observe any smoking cessation behaviors.   
Subjects will be informed of the general nicotine content of the Spectrum cigarettes. Subjects 
assigned to the VLNC Spectrum cigarette condition will be informed they contain minimal 
amounts of nicotine to reduce their addictiveness and those assigned to the NNC Spectrum 
cigarettes will be informed that they contain levels of nicotine that are similar to the 


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conventional cigarettes that are currently on the market. Research cigarettes are provided 
under non-blind conditions because if a reduced-nicotine policy were to be implemented, the 
FDA would by necessity provide information to the public on the reduced nicotine content of 
cigarettes.  
PHASE 3:  INTERVENTION: STUDY CIGARETTES IN EXPERIMENTAL 
MARKETPLACE 
Scheduling window at baseline is 7 days -3/+ 4 days and 14 days -6/+ 7 days for bi-weekly 
visits. 
 
During the Phase 3 visits (Weeks 1-12), subjects will continue to acquire the study cigarettes 
and alternative nicotine products via the Marketplace website (no access to usual brand 
cigarettes). At the clinic visits, subjects will complete several measures and provide biomarker 
samples as described below.  
5.2.5. Procedures for Phase 3 - Weeks 1, 2, and 3 (Week 3 was discontinued following 
telehealth procedure changes)  
At these visits, the procedures will only involve access to products and checking records of 
product use and safety checks.   
A.  Physiological Measures at Weeks 1, 2 and 3: 
1) BrAC (discontinued at telehealth visits).  
2) Expired breath CO level. 
3) Vitals signs (blood pressure, heart rate).  
4) Weight.  
5) Spot urine sample for compliance testing. (Saliva samples for compliance testing are 
collected at telehealth visits.) 
B.  Questionnaires and Assessments at Weeks 1, 2, and 3:  
 B.1 Web-based data collection program completed by the subject: 
1) Minnesota Nicotine Withdrawal Scale (MNWS).  
2) Questionnaire of Smoking Urges-Brief - Study Cigarette (QSU). 
3) Cigarette & Product Evaluation Scale – (Study Cigarettes CES/PES). 
4) Respiratory and Global Health Questionnaire. 
5) If monitored for psychiatric illness: Beck Depression Inventory 2nd Edition (BD-II) 
(paper only).  
B.2  Administered as an interview by the study Research Assistant (entered into REDCap): 
1) Health Changes Questionnaire.  
2) Adverse Events.  


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3) Concomitant Medications. 
4) Review of Daily Call and follow-up on missing and unusual reports. 
5) Timeline Followback Questionnaire (since last visit).  
6) Study Product Accountability: Complete product dispensing log.  
7) Study Product and Procedures Compliance Review.  
8) End of Visit Questionnaire. 
 
5.2.6. Procedures for Phase 3 - Weeks 4, 8 and 12 
A.  Physiological Measures at Weeks 4, 8 and 12: 
1) BrAC (discontinued at telehealth visits).  
2) CO level.  
3) Vitals signs (blood pressure, heart rate).  
4) Weight.  
5) First morning void urine sample. 
6) Spot urine for pregnancy tests [hCG detection] will be performed for female participants 
of childbearing potential. (Pregnancy tests are performed on first morning void after 
conversion to telehealth visits.) 
7) Spot urine sample for compliance testing. (Saliva samples for compliance testing are 
collected at telehealth visits.) 
8) Drug screen (Week 12 only). (Discontinued at telehealth visits.) 
B.  Questionnaires and Assessments at Weeks 4, 8 and 12:  
B.1 Web-based data collection program completed by the subject: 
1) Minnesota Nicotine Withdrawal Scale (MNWS).  
2) Questionnaire of Smoking Urges-Brief-Study Cigarette (QSU). 
3) Cigarette & Product Evaluation Scale – (Study Cigarettes CES/PES). 
4) Respiratory and Global Health Questionnaire. 
5) CES-D:   
Beck Depression Inventory 2nd Edition (BD-II) will be administered on paper if the CES-D 
score is 16 or greater or if monitored for psychiatric illness.  
6) Cigarette Dependence Measures (Study Cigarettes).  
7) Environmental Tobacco Smoke Exposure Questionnaire. 
8) Dietary Intake. 
9) NIAAA Alcohol Use Questionnaire (1 month). 
10) Social and Environmental Influences on Tobacco Use (Week 12 only).  


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11) Perceived Health Risk of no tobacco use, usual brand cigarettes, study cigarettes, 
smokeless tobacco, medicinal nicotine and ENDS (Week 12 only).   
12) Cigarette/Product Purchase Task (Week 12 only). 
13) Vaping/Product Dependence Scale (week 12 only) 
 
B.2 Administered as an interview by the Research Assistant (entered into REDCap): 
1) Health Changes Questionnaire. 
2) Adverse Events.  
3) Concomitant Medications. 
4) Review of Daily Call and follow-up of missing and unusual reports. 
5) Timeline Followback Questionnaire (since last visit). 
6) Recreational Drug Use Questionnaire (1 month version).  
7) Study Product Accountability: Complete Product Dispensing Log. 
8) Study Product and Procedures Compliance Review. 
9) End of Visit Questionnaire. 
5.2.7. Procedures for Phase 3 - Weeks 6 and 10 
At these visits, the procedures will only involve access to products and checking records of 
product use and safety checks.   
A.  Physiological Measures at Weeks 6 and 10: 
1) BrAC (discontinued at telehealth visits). 
2) Expired breath CO level.  
3) Vitals signs (blood pressure, heart rate).  
4) Weight.   
5) Spot urine sample for compliance testing. (Saliva samples for compliance testing are 
collected at telehealth visits.) 
 
B.  Questionnaires and Assessments at Weeks 6 and 10:  
 B.1 Web-based data collection program completed by the subject: 
1) Minnesota Nicotine Withdrawal Scale (MNWS).  
2) Questionnaire of Smoking Urges-Brief-Study Cigarette (QSU). 
3) Cigarette & Product Evaluation Scale – (Study Cigarettes CES/PES). 
4) Respiratory and Global Health Questionnaire. 
5) If monitored for psychiatric illness: Beck Depression Inventory 2nd Edition (BD-II) 
(paper only).  
 


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B.2  Administered as an interview by the study Research Assistant (entered into REDCap): 
1) Health Changes and Menstrual Cycle Questionnaire.  
2) Adverse Events.  
3) Concomitant Medications. 
4) Review of Daily Call and follow-up on missing and unusual reports. 
5) Timeline Followback Questionnaire (since last visit).  
6) Study Product Accountability: Complete product dispensing log. 
7) Study Product and Procedures Compliance Review. 
8) End of Visit Questionnaire. 
5.3. Study Product and Procedures Compliance Review Sessions  
At each study product visit, subjects will be counseled about use of only products obtained 
through the experimental Marketplace website. Subjects will be asked about any concerns or 
obstacles associated with use of the study products. The importance of honest reporting will be 
stressed. Subjects will be told that it is crucial for them to report any use of products obtained 
from outside the experimental marketplace, even though it is discouraged. If difficulties using 
only study products are encountered, they will be asked why they are experiencing difficulties 
(e.g., taste, withdrawal symptoms) and problem-solve how to deal with these difficulties in order 
to meet the protocol requirements. Additionally, compliance counseling will include daily diary 
call completion, visit attendance and accurate product accountability. These review sessions 
should be about 5-10 minutes in length. 
5.4. Quit Attempts During the Study Protocol:  
At each session, we will ask if the subject is currently abstaining from smoking and/or has the 
intention of quitting or planning to quit smoking or tobacco use prior to the next scheduled visit. 
If the subject chooses to quit during the study, they will be encouraged to do so and will 
continue to receive vouchers. 
If Currently Abstinent from Smoking:  
• 
Encourage continued abstinence from smoking.  
• 
Provide the cessation manual and local smoking cessation resources.  
• 
Remind the subject that medicinal nicotine is available in the Marketplace and may aid in 
their cessation efforts. 
• 
Schedule normal weekly or bi-weekly visits.  
If a Participant is Planning to Quit Smoking, But Has Not Initiated the Quit Attempt 
• 
Ask if a target quit date has been chosen and document the target quit date. 
• 
Provide the participant with the cessation manual and local smoking cessation resources. 
• 
Remind the subject that medicinal nicotine is available in the Marketplace and may aid in 
their cessation efforts. 


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• 
Recommend that on the target quit date he/she puts any tobacco products “away” so as to 
avoid unwanted cues to smoke  
At the end of the 12 week experimental period, all subjects will be strongly encouraged to stop 
smoking and if possible, using all tobacco products, and set a quit date. A treatment manual for 
cessation will be provided and subjects will be encouraged to call the state telephone quit line. 
If the subject has a quit date planned or intends to set a quit date they may obtain medicinal 
nicotine from Marketplace with any remaining points. No additional points are given at this visit. 
5.5. Tobacco/nicotine use measures: Consistency and product compliance 
The importance of honest reporting will be stressed. Consistency across data collection will be 
examinined by comparing: a) daily call records; b) timeline follow-back; and c) product 
accountability logs where the amount of products dispensed are recorded and any unused 
products and packages/ cartridges from used products returned to the clinic are recorded. For 
smokeless tobacco, we will weigh tins prior to distribution and after use. A similar procedure will 
be followed for vials of e-fluids that are dispensed. Participants will be allowed to keep any of the 
unused products until the follow-up visit. Participants will be provided feedback regarding the 
consistencies across data collected and encouraged to be more accurate if the data is 
inconsistent. In the event that subjects purchased a study product outside our experimental 
market or obtained product by other means (e.g., provided by a friend), they will be asked to 
report the type and amount of product to us without penalty. (Purchase  of combustible products 
would be penalized; see compliance section.) Several biochemical methods will be used to 
confirm product self-report: 1) urinary anatabine < 0.01 nmol/ if a subject is assigned to VLNC 
cigarettes and reports use of only VLNC cigarettes, medicinal nicotine and/or ENDS; and  2) CO 
< 6 ppm if a subject reports use of only non-combusted products. The level for urinary anatabine 
was determined by a study in which smokers were confined to a residential living situation and 
asked to only smoke VLNC study cigarettes.27 Data will be analyzed with and without this 
biochemical verification. Unfortunately, biochemical analysis is not available to confirm use of 
VLNC cigarettes when other tobacco products are also used (i.e., smokeless tobacco) nor to 
distinguish usual-brand cigarettes from NNC study cigarettes. But non-compliance is less likely 
in the NNC condition given that rates of usual-brand and NNC smoking were nearly identical in 
our prior study.14 Reports of use of non-study cigarettes will be considered as an outcome 
variable in this study and as a potential indicator of a need to supplement nicotine via another 
source.  
5.6. Follow-up 
5.6.1. Procedures for Week 16  
Follow-up will occur 4 weeks (-7 and + 30 days) after the end of the experimental period. Tobacco 
use status (amount and type of tobacco product use) will be determined and first void urine 
samples assessed for various biomarkers of exposure, partially as a safety assessment. Quitting 
smoking or staying quit will continue to be strongly encouraged.  


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A. Physiological Measures at Week 16: 
1) BrAC (discontinued at telehealth visits).  
2) Expired breath CO level. 
3) Vitals signs (blood pressure, heart rate).  
4) Weight. 
5) First morning void urine sample. 
6) Collect vaping device and smokeless tobacco products, if obtained from the 
experimental marketplace during study. 
B. Questionnaires and Assessments at Week 16: 
B.1 Web-based data collection program completed by the subject: 
1) Cigarette Evaluation Scale - Usual Brand. 
2) Respiratory and Global Health Questionnaires. 
3) CES-D;  
Beck Depression Inventory 2nd Edition (BD-II) will be administered on paper if the CES-D 
score is 16 or greater or if monitored for psychiatric illness.  
4) Cigarette Dependence Measures (Usual Brand).  
5) End of Study Questionnaire. 
B.2  Administered as an interview by the study Research Assistant (entered into REDCap): 
1) Health Changes Questionnaire.  
2) Adverse Events.  
3) Concomitant Medications. 
4) Timeline Followback Questionnaire (since last visit) Follow-up version.   
5) End of Visit Questionnaire. 
5.6.2. Procedures for Post-Follow-up  
If urinary biomarker levels from the Phase 3 Week 16 visit are substantially elevated over 
baseline levels and it is determined by the PI that this may be a safety issue, subjects will be 
sent a letter to alert them of their nicotine exposure, advise them to try to reduce their 
tobacco/nicotine use, and they will be strongly encouraged to quit smoking and provided 
tobacco cessation resources. If subjects have any questions, they are free to contact us.  
5.6.3. Study Completion 
Any Adverse Event or Concomitant Medications that remain open from the last study session 
will be assessed and closed or indicated as ongoing at end of study. Once a participant has 
completed all study procedures and all open events have been closed or indicated as ongoing 


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at end of trial, the Site Leader will review the participant’s binder and sign off indicating study 
completion for that participant.  
5.7. Data Collection Measures 
5.7.1. Individually Identifiable Health Information  
No information will be collected from medical records. Identifiable information will be retained at 
each site and will only be available to the local study and regulatory staff.  The only exception 
is subject telephone numbers provided to a HIPAA compliant vendor for our Interactive Voice 
Response System.  
5.7.2. Data Collection Platforms 
Data will be collected and entered into multiple platforms including the REDCap, which will be 
used by RAs to enter data and by subjects to directly enter their responses to questionnaires, 
and the Daily Call Interactive Voice Response System (IVR) on a HIPAA secured website. In 
the event that internet access is not functioning, the assessments will be printed out and 
administered on paper. The source documents will be kept in the participant’s case report form 
binder and the interviewer will enter the data into the software when it resumes functioning 
properly.  Biosamples will be entered into a biomarker tracking database as they are collected. 
The following questionnaires and other measures will be collected throughout the study. Some 
forms are administered only at baseline to assess history and eligibility criteria and others are 
repeated measures: 
5.7.3. Screening Questionnaires 
1) Tobacco Use History and Nicotine Exposure, derived from the Population Assessment of 
Tobacco and Health (PATH) allowing comparisons with a nationally representative sample 
of smokers which measures variables such as smoking rate (current and maximum), 
cigarette brand, age of initiation of smoking, number of quit attempts, duration of quit 
attempts and duration of smoking and history of use of other tobacco and nicotine products. 
2) Demographics asks about age and gender, race, ethnicity, current occupation and usual 
occupation, and income.  
3) Brief Medical History Questionnaire to assess medical history and current health 
diagnoses, symptoms and past health problems including psychiatric and substance abuse 
and medication use. 
• 
Medical History Follow-up Questionnaire will be completed by study staff to further 
assess current diagnoses, symptoms or past health problems.  
4) Concomitant Medications lists medications (prescription, over-the-counter and 
supplements) and doses that are taken 30 days prior and during the study. 
5) PrimeMD - Patient Health Questionnaire (PHQ), a brief multi-choice questionnaire 
developed as a screening and diagnostic tool for mental health disorders of depression and  
anxiety (somatoform, alcohol and eating disorder questions are not used in this study) and 
developed for use by  primary care physicians.28 


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6) Centers for Epidemiological Studies-Depression 20-item scale (CES-D) which measures 
current symptoms of depression.29 
7) Mini International Neuropsychiatric Interview (MINI) suicide subscale (43) to evaluate 
suicide risk.30 
8) Beck Depression Inventory 2nd Edition (BD-II) is a severity measure assessing symptoms of 
depression.31 
9) Michigan Alcohol Screening Test Short form (SMAST) is a widely used measure for 
assessing lifetime alcohol abuse.32 
10) Drug Abuse Screening Test (DAST) is a brief instrument for population screening 
assessing lifetime drug abuse.33 
5.7.4. Biomarker Modifier Questionnaires 
Measures of factors that may moderate biomarkers of exposure and effect:  
1) Environmental Tobacco Smoke Exposure Questionnaire consists of 1 question related to 
tobacco smoke exposure at home, work and socially.34 
2) Dietary Intake assesses intake of specific foods high in polycyclic aromatic hydrocarbons 
(e.g., charred and smoked meats and fish). 
5.7.5. Subjective Outcome Measures 
1) Interactive Voice Response – Daily Call Recording System to record amount of product 
use, cigarettes, and other nicotine containing products on a daily basis (estimated ENDS 
puffs per day will be recorded),.  
2) Timeline followback for tobacco35 will be used as another measure of non-cigarette tobacco 
and nicotine intake), alcohol and marijuana use assessed at each clinic visit.   
3)  IVR Review Form will assess study and non-study use of cigarette and other products 
missing from the IVR calls, correct errors in IVR entries or clarify any discrepancies or 
unusual IVR reports.  
4) Cigarette/Vaping Dependence Measures includes:  Fagerstrom Test for Nicotine 
Dependence (FTND),36 Penn State Cigarette Dependence Scale,37 Brief Wisconsin 
Inventory of Smoking Motives (WISDM) primary dependence motives subscales38 and 3 
items from PATH. 
5) Severson Smokeless Tobacco (SLT) Dependence Questionnaire is an 8 item measure to 
assess tobacco dependence.39 
6) Minnesota Nicotine Withdrawal Scale (MNWS) is an 8 item assessing symptoms of tobacco 
withdrawal.40 
7) Questionnaire of Smoking Urges-Brief 10 item measures the urge to smoke.41 
8) Adverse Events to assess the nature, severity, duration, action taken, and outcome of 
adverse events related to tobacco/nicotine product use.  
9) Health Changes Questionnaire queries for any health care visits or circumstances that 
would indicate any change since last visits. 
10) Respiratory and Global Health Questionnaire rates overall health (1-10 scale) and 
respiratory symptoms such as cough, phlegm production, shortness of breath on a scale 


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ranging from 0 = none up to 10 = severe with a total respiratory score determined by 
adding the scores of each of these items. 
11) NIAAA Alcohol Use Questionnaire (1 and 12 month) assesses frequency and quantity of 
alcohol use.42 
12) Recreational Drug Use History (1 and 12 month) assesses amount, frequency in past year, 
and past month and date of last use of illicit drugs.  
13) Perceived Health Risks assesses perceived health risks of no tobacco use, usual brand of 
cigarettes and study products that are provided.43 
14) Modified Cigarette Evaluation Scale44-46 and/or Product Evaluation Scale47 assesses 
different dimensions of responses to cigarettes or other tobacco/nicotine products, (e.g., 
psychological reward, satisfaction, aversiveness, and additional oral and respiratory 
sensation items).  
15) Cigarette/Product Purchase Task assesses demand curves of products that are 
chosen.48,49  This task will be used to generate demand curves by asking the subject to 
report the number of units of a tobacco product that they would consume in a day if the 
units cost various amounts of money.  
16) Product Expectancy Questionnaire to assess attitudes and beliefs about the products 
provided.  
17) Expected Utility (Alternative Nicotine Products) Questionnaire assesses the situations or 
expected uses of the study products. 
18) Contemplation Ladder50 assesses intention to quit smoking including next 30 days and 6 
months and overall readiness to quit.51 
19) Social and Environmental Influences on Tobacco Use assesses tobacco/nicotine situational 
use and subject’s opinion on potential tobacco control policies. 
20) End of Study Questionnaire, administered at follow-up to assess subject responses to 
study products and study experience.  
6. Collection and Sharing of Biomarker Specimens and Data 
6.1. Storage and Access 
Biomarker specimens described below will be collected and stored at study sites until shipment 
to the Masonic Cancer Center’s Drs. Stephen Hecht, Irina Stepanov and Sharon Murphy 
laboratories for analysis or long term storage. Shipments will be requested at approximately 
quaterly intervals. Samples that are not used for the primary analysis of study biomarkers will 
be banked for future use. The banked samples will be stored until requested by a qualified 
investigator and used up or destroyed if it is determined they are no longer needed. The 
samples, including DNA or RNA, may be stored up to a maximum of 20 years from the study’s 
end. A subject has the right to withdraw consent at any time by informing the Principal 
Investigator by following the instructions provided in the consent document. If this occurs, any 
remaining identifiable research sample(s) will be destroyed. 
6.2. Data Storage 


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Local data will be stored on the Tobacco Research AHC server at the University of Minnesota.  
Upon completion of the trial, this data will be housed on the CENIC II portal which will be 
maintained by Clinical Informatics Shared Services at the University of MN.  Shared data will 
be de-identified and includes demographics, tobacco/nicotine exposure history and current 
use, health and medications, subjective questionnaire data, biomarkers analyses, and visit 
number and intervention arm.   
Biomarker samples that are banked after the completion of the primary analyses will be stored 
at the Masonic Cancer Center Hecht, Stepanov and Murphy laboratories located at the Cancer 
and Cardiovascular Research Building and Diehl Hall for future use.     
6.3. Release/Sharing of samples 
Access to the de-identified samples and data will be controlled by the Project 1 and the 
Biomarker Core investigators. Qualified researchers must submit an application request to 
access the samples and data to the Principal Investigator who will determine if the request is 
appropriate, in consultation with the other investigators.  
6.4. Analysis of Biomarkers 
The following panel of biomarkers has been selected to represent exposures to relevant 
toxicants.  
Biomarkers of Carcinogen Exposure:  Biomarkers include urinary NNAL (metabolite of NNK, a 
potent lung cancer carcinogen), mercapturic acid metabolites of acrolein, benzene, 
crotonaldehyde, and acrylonitrile. These biomarkers have shown good laboratory 
reproducibility, have clear differences in levels between smokers and nonsmokers and/or 
decrease upon tobacco cessation, and reflect differences in toxicants in the various 
tobacco/nicotine products.52,53    
 
Oxidative damage: Urine samples will be banked for analysis of 8-iso-PGF2α and will be 
conducted if supplemental funding is received. If no funding is available the samples will be 
banked for sharing. 
Total nicotine equivalents (TNEs):  This is the molar sum of nicotine and its metabolites. TNE 
accounts for 73-96% of the nicotine dose and is a useful measure of daily nicotine exposure. 
Nicotine metabolite ratio (NMR): NMR will be assessed from saliva as an indicator of CYP2A6 
enzymatic activity and is the ratio between two nicotine metabolites, free cotinine and trans-3’-
hydroxycontinine (3-HC). Because CYP2A6 is the primary enzyme associated with nicotine 
metabolism and also catalyzes the conversion of cotinine to 3-HC, the 3-HC:cotinine ratio is 
considered to reflect the enzymatic activity of CYP2A6 and therefore the extent of nicotine 
clearance rate (higher the ratio, the faster the clearance rate). This metabolite ratio has been 
observed to be moderately correlated to CYP2A6 genotype and highly correlated with the rate 
of nicotine metabolism.54-59  


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Genotyping sample: A saliva sample will be collected for potential genotyping for genes related 
to metabolism of tobacco constituents, behavior, mood, brain functioning and harmful effects of 
tobacco exposure. Subjects may opt out of this collection and still be allowed to participate in 
the study.  If the subject decides to withdraw their samples during or after the study, the 
samples will be destroyed immediately. 
Biobank:  Other tobacco-related validated biomarkers for assessment in saliva or urines may 
be developed over time and these additional assays may be completed as appropriate using 
samples stored in the Biobank. Also, in the future, samples may be analyzed for genetic 
predisposition for tobacco toxicant metabolism, tobacco use behavior and tobacco-related 
harm. All samples remaining after the primary analyses will be biobanked.  
7. Sharing Results with Subjects  
No individual research or biomarker data will be shared with the subjects. Data that is collected 
at visits such as vital signs, carbon monoxide level, breath alcohol concentration test, drug 
screen results, will be evident to the subjects during the visits. If study medical staff believes 
that any of these measures are of clinical significance, such as observed worsening of 
psychiatric symptoms or subject reports of adverse events experienced during the trial that 
require further follow up, the subject will be referred to their primary care physician. Information 
will be released to the primary care physician or other health professional upon request of the 
subject.  
No genetic testing information will be shared with subjects. 
After data collection from all participants is complete and results are analyzed, participants may 
be mailed a letter telling them the general results of the study.   
8. Study Duration  
• 
A subject’s direct study involvement is approximately 21 weeks. There may be some 
variation due to scheduling constraints. Baseline and intervention clinic visits are weekly for 
9 weeks and bi-weekly for 8 weeks.  
 
o Screening - 1 week 
o Phase 1:  Baseline - 2 weeks 
o Phase 2:  Usual Brand Experimental Marketplace - 2 weeks  
o Phase 3:  Study Cigarettes in Experimental Marketplace (Intervention) - 12 weeks 
o Follow-up: 1 visit 4 weeks post-intervention 
 
• 
The duration of the study recruitment period will be approximately 47 months. (54 months 
with 7 month recruitment hiatus due to COVID-19.) 
• 
The duration to complete all study procedures and initial data analysis is estimated to be 50 
months. (55 months to complete the intervention and follow-up; an additional 5 months for 
primary data analysis and an additional 12 months for other analysis.) 


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9. Subject Selection  
Study entry is open to adults who are healthy volunteers regardless of gender, race or ethnic 
background. While there will be every effort to seek out and include females and minority 
patients, the participant population is dependent upon the characteristics of the population at 
the sites where enrollment is occurring.   
9.1. Inclusion Criteria 
a) Male or female;  
b) At least 21 years of age (legal age to buy tobacco; prior to 1/2021 at least 18 years of age 
at sites where legal age was 18); 
c) Smoking at least 5 and no more than 40 cigarettes per day for the past month; 
d) Biochemically confirmed regular smoking status by a carbon monoxide level of >10 ppm or 
if CO <10 ppm, a nicotine test strip that confirms smoking status. 
9.2. Exclusion Criterion 
a) Unstable health conditions (any significant serious, unstable medical condition including, 
but not limited to, cardiovascular disease, unstable COPD, seizure disorder (seizure within 
the last year), blood pressure, heart rate and cancer) as determined by the licensed 
medical professional at each site; 
b) Unstable mental health (to be determined by medical history, CES-D, Prime-MD after 
review by the licensed medical professional at each site);  
c) Suicidal Ideation in the past month.  History of suicide attempts will be reviewed by the 
licensed medical professional to determine current risk; 
d) Excessive drinking or problems with drinking or drugs (e.g., binge drinking more than nine 
days in the past 30 days) as assessed by PI or licensed medical professional;  
e) Breath alcohol concentration (BrAC)> 0.01 as measured by breath sample at screening: 
Participants failing the BrAC screen will be allowed to re-screen once (discontinued due to 
COVID-19 pandemic when procedures were adapted for telehealth visits); 
f) Positive toxicology screen for any of the following drugs: cocaine, opiates, methadone, 
benzodiazepines, barbiturates, amphetamines, methamphetamines, and PCP. Failing 
temperature strip for the sample. Marijuana use will be tested, but will only be an 
exclusionary criterion if the licensed medical professional decides that use will interfere with 
study results.  Participants with valid prescriptions for opiates, benzodiazepines, 
barbiturates, amphetamines or methadone will not be excluded. Participants failing the 
toxicology screen will be allowed to re-screen once. (Toxicology screen was discontinued 
due to COVID-19 pandemic when procedures were adapted for telehealth visits); 
g) Currently pregnant, breast feeding or intending to become pregnant for the duration of the 
study or unwilling to agree to use adequate protection to avoid pregnancy; 
h) Currently taking any one of the following medications: 
1) Phenytoin [Brand Name: Dilantin] (if unstable) 
2) Carbamazepine [Brand Name: Tegretol, Carbatrol, Equetro, Epitol] (if unstable) 
3) Oxcarbazepine [Brand Name: Trileptal] (if unstable) 


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4) Primidone [Brand Name: Mysoline] (if unstable) 
5) Phenobarbital (if unstable) 
6) Bendamustine [Brand Name: Treanda] 
7) Erlotinib [Brand Name: Tarceva] 
8) Flecainide [Brand Name: Tambocor] 
9) Irinotecan [Brand Name: Camptosar]; 
i) 
Vital signs outside of the following range (participants failing for vital signs will be allowed to 
re-screen once): 
1) Systolic BP greater than or equal to 160 mm/hg 
2) Diastolic BP greater than or equal to 100 mm/hg 
3) Systolic BP below 90 mm/hg and symptomatic (dizziness, extreme fatigue, difficulty 
thinking, inability to stand or walk, feeling faint) 
4) Diastolic BP below 50 mm/hg and symptomatic (dizziness, extreme fatigue, difficulty 
thinking, inability to stand or walk, feeling faint) 
5) Heart rate greater than or equal to 105 bpm 
6) Heart rate lower than 45 bpm and symptomatic (dizziness, extreme fatigue, difficulty 
thinking, inability to stand or walk, feeling faint); 
j) 
Expired air carbon monoxide (CO) level greater than 80 ppm; 
k) Allergy to propylene glycol or vegetable glycerin; 
l) 
Household member enrolled in the study concurrently; 
m) Participated in prior study that involved reduced nicotine content cigarettes within the last 
24 months; 
n) Having participated in a research study during the past three months that would impact 
baseline smoking or response to study products; 
o) Inability to independently read and comprehend the consent form and other written study 
materials and measures because participants are required to complete parts of the protocol 
at home independently; 
p) Unstable living environment that would compromise the ability to attend visits, sequester 
study products to prevent use by other people or complete study procedures outside of 
visits. 
9.3. Screening Procedure 
Subjects will contact the clinics by telephone or through an online interest form. A telephone 
screening questionnaire will then be administered. If eligible based on initial screening, the 
subject will be invited to an Orientation visit to describe the protocol and then scheduled for the 
In–Person/Telehealth Screening visit (Orientation and In-Person/Telehealth Screen visits can 
be combined). Procedures conducted for screening are described in section 5.2.1. The data 
collected at this visit will be reviewed for further eligibility assessment and health forms will be 
reviewed by the medical professional to confirm stable physical and mental health.   
9.4. Justification for Inclusion/Exclusion Criteria  
Children under age 21 are excluded because they cannot legally buy tobacco products. 
Requirement of 5 cigarettes daily for the past month ensures changes will be observed in our 


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exposure biomarkers for the VLNC condition. Those subjects with unstable medical or 
medication conditions will be determined by the site’s licensed medical professional and are 
excluded if these symptoms are believed to render the subject unable to fully participate in the 
study or pose a safety issue. Examples include but are not limited to the following: angina, 
stroke, heart attack, blood clots in the arms or legs for which the individual is undergoing active 
medical treatment, cancer requiring active chemotherapy or radiation therapy, severe arthritis, 
severe shortness of breath (caused by conditions such as uncontrolled asthma, COPD, or 
arrhythmia), active untreated infection such as pneumonia, active untreated endocrine disorder 
such as hyperthyroidism, suicidal ideation or any other condition which is likely to impair the 
individual’s ability to attend and fully participate in study visits and procedures. Pregnant and 
nursing women are excluded as tobacco use is detrimental to the fetus or infant. Current or 
recent (3 month) alcohol or drug abuse problems will be excluded as these factors could 
independently affect smoking behavior and may affect the subject’s participation in the study. 
Unstable living situations, such as homelessness, could compromise the subject’s ability to 
control access to the investigational study cigarettes. Medical or psychiatric conditions (to be 
determined by medical history, CES-D, Prime-MD) may be deemed to pose a safety issue to 
the subject. 
10. 
Vulnerable Populations 
Vulnerable populations will not be recruited into this study. 
11. 
Local Number of Participants 
The total number of subjects to be randomized for this trial is 400-450. The intent is to recruit 
subjects across the six sites:  University of Minnesota, Duke University, University of California, 
San Francisco, Wake Forest University, Brown University and University of Pennsylvania. If 
equal recruitment across sites is not possible, a site with faster recruitment may over recruit. 
Local and National Recruitment Methods 
12. 
Recruitment Process 
Once IRB approval is received and recruitment begins, cigarette smokers will contact the local 
study clinic in response to advertisements or word of mouth and receive information about the 
study. Interested potential subjects will be screened for initial eligibility over the telephone. If a 
site maintains a waitlist for potential subjects who have requested to be contacted if new 
studies begin, they will be called and screened for eligibility. If subjects meet the initial 
screening eligibility criteria for the study, they will be asked to attend an orientation meeting.  
12.1. 
Source of Participants 


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Subjects will self-select into the screening process for the study.  No medical chart review or 
direct patient solicitation will occur. 
12.2. 
Identification of Participants 
Self-identified subjects will contact the local research clinic in response to advertisements.  
12.3. 
Recruitment Materials 
Recruitment venues will include advertisement in local print media, internet (e.g. banner ads, 
Craigslist), social media (e.g. Facebook, snapchat, twitter), radio, television, and posted flyers 
and site’s web page and waitlists. The verbiage in advertisements in print or verbal text is the 
following: 
 
 
 
SMOKERS wanted for a study that provides research cigarettes with different  
nicotine levels and access to other tobacco, e-cigarette and vaping devices or nicotine 
products.  
Joining the study is free and you will receive compensation for your time  
Please call xxx-xxx-xxxx or go to [local website]  
for more information and to see if you are eligible. 
[local site institutional logo] 
  
12.4. 
Compensation 
Subjects will either receive cash, a gift card or a monthly check, depending on the site’s 
institututional policies for providing compensation. Compensation includes $30 for screening, 
$40 per clinic visit for the participant’s time ($520), $10 for travel ($140) for each of the 14 clinic 
visits, and an additional $15 for the 7 visits during which biomarker samples are collected 
($105).  After the follow up visit, they will receive a bonus for compliance with the study 
protocol requirements ($300 for avoidance of non-study combusted products; $100 for 
accurate self-report of slips using non-study products) and the amount earned for the daily call. 
The compensation for the completion of the daily calls will be $10 per week if they have not 
missed any calls ($160 total). The maximum earned will be $1,255 ($520 for visits; $140 for 
travel, $105 for first void sample collection; $300 for bonus; up to $160 for daily calls).  (The 
maximum earned after converting to telehealth visits is $1240: $520 for visits; $130 for travel; 
$120 for biomarker collections; $300 for bonus; up to $170 for daily calls). They will also 
receive a voucher for a specified number of points per week (the amount is dependent on site 
and baseline smoking rate) to exchange for study products and at the end of the study will 
receive the amount that was not exchanged for products (1 point = $1 with a maximum of 
$200). Subjects must complete the study to be eligible to exchange their remaining vouchers at 
week 16 (unless withdrawn by PI for safety concerns). 


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13. 
Monitoring Safety and Withdrawal of Participants  
13.1. 
Adverse Event Reporting and Safety Monitoring 
Identifying Adverse Events 
While participating in the trial, adverse events and concomitant medications will be assessed at 
every study visit and vital signs and carbon monoxide will be obtained. Adverse events typically 
will be identified during the administration of the Health Changes Questionnaire and 
Respiratory and Global Health Questionnaire, and in some cases during the administration of 
the CES-D. Other events may be identified from physiological study measures or by 
spontaneous reports during non-scheduled assessments. Withdrawal symptoms are 
considered an adverse event if the symptom had a significant impact on the participant’s daily 
life, caused a major disruption of functioning, or took any medication for it. 
 
Questionnaire items that will be reviewed: 
• 
Health Changes Questionnaire: If the participant answers ‘YES’ to Questions 1, 2, or 3 the 
interviewer should assess for adverse events. 
1) Have you had any negative changes in your physical or mental health since your last visit?  
2) Have you received any form of medical care? 
3) Have you had any changes in medication since your last visit?  
• 
Respiratory and Global Health Questionnaire: If the participant indicates ‘YES’ to Question 
6 regarding having a cold or flu, the interviewer should assess for adverse events  
• 
CES-D: If the participant scores 16 or higher and is not already being monitored for 
depression, an Adverse Event for Elevated CES-D should be completed and the licensed 
medical professional will provide information regarding follow-up. If there is already an open 
event, information will be added to the existing form.  
Physiological data that will be reviewed: 
• 
CO level: The ‘Adverse Event Log’ should be completed if the average CO within a visit is: 
a. CO is greater than 50 ppm if CO at Baseline is < 20 ppm. 
b. CO is greater than 60 ppm if CO at Baseline is 20 – 34 ppm. 
c. CO is greater than 70 ppm if CO at Baseline 35 – 49 ppm. 
d. CO is greater than 80 ppm if CO at Baseline 50 – 64 ppm. 
e. CO is greater than 90 ppm if CO at Baseline 65 – 80 ppm.  
 
• 
Blood Pressure:  
o The ‘Adverse Event Log’ and ‘Blood Pressure and Heart Rate Symptom Checklist’ 
should be completed if an automatic and subsequent manual blood pressure 
measurement during the same visit is at or above 160 SBP or 100 DBP. 
o The ‘Adverse Event Log’ and ‘Blood Pressure and Heart Rate Symptom Checklist’ 
should be completed if an automatic and subsequent manual blood pressure 
measurement during the same visit is below 90 SBP or 50 DSP and the participant is 
experiencing symptoms listed on the ‘Blood Pressure and Heart Rate Symptom 
Checklist.’ 


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• 
Heart Rate:  
o The ‘Adverse Event Log’ and ‘Blood Pressure and Heart Rate Symptom Checklist’ 
should be completed if an automatic and subsequent manual heart rate measurement 
during the same visit is at or above 105 bpm or below 45 and symptomatic. 
• 
Since converting to telehealth visits, if vital signs are elevated during telehealth visits, the 
second reading will be conducted with the study supplied home monitoring device rather 
than a manual reading. 
 
The site licensed medical professional will review all AEs. A study participant may be 
discontinued from the study if the medical professional and/or PI determine it is the best 
decision in order to protect the safety of a participant (see below).  In the event that a 
participant either withdraws from the study or the investigator decides to discontinue a 
participant due to an AE/SAE, the participant will be followed, and if necessary referred to their 
physician, until the problem resolves, stabilizes, or is clearly unrelated to the study cigarettes. 
Any AE that remains open will be reviewed and closed at the 30-day follow-up interview.   
13.2. 
Withdrawal of Subjects and Medical Monitoring 
For the safety concerns, subjects will be withdrawn immediately from the study if any of the 
following occur: 
1) Cardiovascular disease (CVD) event: Typically includes MI (heart attack), PTCA 
(angioplasty/stenting), bypass surgery, stroke, peripheral vascular disease (arterial 
blockages in arms or legs leading to procedure or surgery). Less common CVD problems 
would be new cardiac arrhythmias (e.g., new atrial fibrillation) or new valvular disease (e.g., 
mitral or aortic regurgitation). 
2) DVT/PE (deep vein thrombosis/pulmonary embolism, i.e., blood clots in the venous 
system). 
3) Suicide Attempt:  A subject will be withdrawn if he/she attempts suicide at any time during 
participation in the study. 
4) Psychiatric Hospitalization: A subject will be withdrawn if he/she is hospitalized for 
psychiatric reasons at any time during participation in the study. 
5) Pregnancy: If subject indicates she is pregnant or has a positive pregnancy test after 
receipt of study products, she will be withdrawn from the study if she is continuing to use 
any tobacco or ENDS product (oral medicinal nicotine use will be acceptable if approved by 
the LMP), and the pregnancy will be documented as an adverse event that will remain open 
until delivery. At that time the licensed medical professional will contact the participant to 
ask a few questions about the baby’s health and will update the open Adverse Event. A 
positive pregnancy test at Week 12 or follow-up will trigger an Adverse Event to be 
documented but will not result in withdrawal since she is no longer receiving study product. 
6) Expired breath carbon monoxide increase: A subject will be withdrawn from the study if the 
average of the 2 CO readings is 100 ppm or greater.   
The following will be monitored and can lead to withdrawal by the PI or licensed medical 
professional: 


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1) Blood pressure (BP) or heart rate (HR) changes: If any of the following occur post-
enrollment: 1) BP is at or above 160 SBP or 100 DBP, 2) BP is below 90 SBP or 50 DBP 
and the participant is experiencing symptoms listed on the ‘Blood Pressure and Heart 
Rate Symptom Checklist,’ 3) HR is at or above 105 bpm, 4) or below 45 bpm and the 
participant is experiencing symptoms listed on the ‘Blood Pressure and Heart Rate 
Symptom Checklist.’  
2) Expired breath Carbon Monoxide increase:  An adverse event will be documented and the 
subject will be monitored by the medical professional if the average of the 2 (or 3) CO 
readings is: 
a. CO is greater than 50 ppm if CO at Baseline is < 20 ppm. 
b. CO is greater than 60 ppm if CO at Baseline is 20 – 34 ppm. 
c. CO is greater than 70 ppm if CO at Baseline 35 – 49 ppm. 
d. CO is greater than 80 ppm if CO at Baseline 50 – 64 ppm. 
e. CO is greater than 90 ppm if CO at Baseline 65 – 80 ppm.  
3) Changes in tobacco product use: if during the weekly visits, participants’ self-report a 
greater than 100% increase in cigarette per day (total cigarettes, including study and non-
study cigarettes) relative to baseline, or a 50% increase in cigarettes per day relative to 
baseline that is accompanied by daily use of alternative nicotine products. 
4) Medication changes: If a subject begins taking any of the exclusionary medications or other 
medications that could potentially have a smoking-drug interaction post-enrollment, the 
LMP will determine how best to monitor and minimize potential risks (including withdrawal if 
warranted). We will provide a letter to the participant that can be given to the prescribing 
physician and that lists potential medications that can be affected by changes in smoking 
that could occur as a result of participation in the study.   
5) Any hospitalization or debilitation in which participation in the study could be detrimental to 
the recovery process. This will be self-reported by the subject and will be reviewed by the 
site PI and LMP to determine whether continued participation in the study is appropriate.  
6) If a subject is behaving in an inappropriate or threatening manner, admits to lying about 
eligibility criteria, including omitting previous medical diagnoses and medications, is 
participating in other smoking research studies that could affect the primary outcome 
measures, does not follow study instructions, etc., then the PI can withdraw him/her from 
the study at the PI’s discretion.  
7) If a participant fails to attend his/her Randomization Visit within the 21-day allowable visit 
window, he/she may not be eligible to reschedule this visit or continue participation in the 
study without PI approval. 
8) If there is reason to believe the participant is sharing large quantities of the study product 
with other people. 
13.3. 
Withdrawal Procedures 


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If the decision to withdraw a subject occurs at a study visit, regular clinic visit procedures will be 
conducted as well as the additional termination procedures described in 13.4. If it is determined 
via a phone call that withdrawal is appropriate or if the subject is dropping out, we will ask the 
subject to attend an exit visit to return study product and equipment, complete questionnaires, 
product accountability and safety assessments and to receive their final study payment.  
If the subject refuses an exit visit, we will request that at the minimum, study investigational 
product be returned and product accountability be completed. We will also stress the 
importance of being able to assess safety measures for the subject’s safety.  
13.4. 
Procedures for Early Termination Visits 
If a Phase 2 and 3 subject decides to withdraw from the study prior to completion or if they are 
withdrawn by the PI/LMP due to safety concerns, they will be scheduled for an early 
termination visit. If the participant is seen within the window of a regularly scheduled visit, all 
measures for that visit will be collected. If the early termination visit occurs at Weeks 1, 2, 3, 6, 
or 10, additional questionnaires and safety measures will be obtained (urine sample for 
biomarkers and pregnancy screen, CES-D and BDI-II if appropriate) since these measures are 
not scheduled at those visits. If the subject is seen outside of a regularly scheduled visit 
window, the following measures will be obtained. 
A. Physiological Measures at Early Termination: 
1) Expired breath CO level. 
2) Vitals signs (blood pressure, heart rate).  
3) Weight.  
4) First morning void, (or if missing collect a spot urine) for biomarkers analysis.  
5) Spot urine for pregnancy tests [hCG detection] for females (first morning void used at 
telehealth visits). 
6) Spot urine sample for compliance testing (first morning void used at telehealth visits). 
B. Questionnaires and Assessments at Early Termination: 
 
The following additional assessments will be completed by all early termination participants, if 
not part of the usual measures scheduled for the regularly scheduled visit:  
1) Cigarette & Product Evaluation Scale – (Study Cigarettes and Usual Brand CES/PES) 
2) CES-D:  
Beck Depression Inventory 2nd Edition (BD-II) will be administered on paper if the CES-D 
score is 16 or greater or if monitored for psychiatric illness.  
3) Cigarette Dependence Measures (Study Cigarettes).  
4) Vaping/Product Dependence Scale. 
5) Environmental Tobacco Smoke Exposure Questionnaire. 
6) Dietary Intake. 
7) NIAAA Alcohol Use Questionnaire (1 month). 


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8) Perceived Health Risk of no tobacco use, usual brand cigarettes, study cigarettes, 
smokeless tobacco, medicinal nicotine and ENDS).   
9) Cigarette/Product Purchase Task. 
10) End of Study Questionnaire.  
B.2 Administered as an interview by the study Research Assistant (entered into REDCap): 
1) Health Changes Questionnaire.  
2) Adverse Events.  
3) Concomitant Medications. 
4) Review of Daily Call and follow-up on missing and unusual reports. 
5) Timeline Follow Back Questionnaire (since last visit).  
6) Recreational Drug Use Questionnaire (1 month version). 
7) Drug accountability: Complete study Product Dispensing Log. 
8) End of Visit Questionnaire. 
The data collected during the termination visit will be used as appropriate given the days 
outside of visit window, subject use of study product, measures of safety or other 
considerations to be determined in the data analysis. 
14. 
Risks to Subjects 
14.1. 
Study Related Risk 
Potential risks of participation are minimal and include the following:  
1) Survey Questionnaires: The interviews will include questions about medical history, drug 
and alcohol use, and questionnaires about mood. Answering these personal questions 
could make the subject feel uncomfortable. 
2) Breach of Confidentiality: The risk of the interview is loss of privacy if other people find out 
the results from individual subjects. 
3) Drug Testing: A breach of confidentiality could occur and other people could learn of the 
subject’s drug use. (Discontinued since conversion to telehealth visits.) 
4) Obtaining blood pressure: The blood pressure cuff may cause minimal discomfort. In 
obtaining blood pressure, researchers may find out the subject has abnormal blood 
pressure and must refer them to their primary care physician. 
5) Smoking Cigarettes: All cigarettes are detrimental to a person’s health and can lead to 
severe or fatal medical problems including: 
a. Cardiovascular Diseases: Coronary heart disease, heart attack, stroke, peripheral 
vascular disease, reduced blood circulation, abdominal aortic aneurysm 


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b. Respiratory Diseases: Emphysema, bronchitis, tuberculosis and chronic airway 
obstruction  
c. Cancers: Lung, bladder, liver, colon, cervical, esophageal, kidney, larynx, mouth, 
pancreatic, throat, stomach cancers and acute myeloid leukemia  
d. Diabetes 
e. Immune function, rheumatoid arthritis 
f. Other Health Risks Associated with Smoking: Including but not limited to infertility, 
ectopic pregnancy, miscarriage, lower bone density in postmenopausal women, hip 
fracture in women, male sexual dysfunction; age-related macular degeneration, 
blindness and cataracts 
6) Smoking VLNC Study Cigarettes (NNC are similar to commercial cigarettes): In addition to 
the above medical problems, subjects may experience some minor adverse health effects 
such as headaches or experience withdrawal symptoms, which are listed below. Due to the 
altered nicotine levels, there could be a change in their cigarette use including the manner 
in which they inhale the smoke or increase in the number of cigarettes smoked per day. 
This increased rate of smoking may persist after completing the study. Smoking the study 
cigarettes does not provide any less risk than their usual brand cigarette and could pose 
increased health risks. Participants may also experience increases in levels of carbon 
monoxide, a gas from smoke. The study cigarettes are made from genetically modified 
tobacco plants. A recent toxicological analysis of these cigarettes showed that the 
concentrations of many harmful tobacco constituents, including polycyclic aromatic 
hydrocarbons, ammonia, and toxic metals, were similar to the concentrations of these 
constituents in commercial cigarettes 60. 
7) ENDS: ENDS can expose users to several chemicals, including nicotine, carbonyl 
compounds, and volatile organic compounds, known to have adverse health effects. The 
health effects and potentially harmful doses of heated and aerosolized constituents of 
ENDS liquids, including solvents, flavorants, and toxicants, are not completely understood. 
ENDS aerosol is not harmless although it generally contains fewer toxicants and at lower 
levels than combustible tobacco products. Specific potential known risks include: 
a. ENDS contain nicotine, which may contribute to some of the disease associated with 
smoking. 
b. The most common side effects related to ENDS use are changes in taste, mucus in 
throat/sinus, dry mouth, dry cough, throat irritation, sore throat, mouth ulcers, dizziness, 
headache, and nausea. 
c. While uncommon, the batteries from ENDS have exploded/ignited and injured users.  
d. ENDS can overheat and present a minor burn risk if the button is turned on repeatedly. 
Subjects are told to be careful if storing the device in a place where the button might be 
accidentally pressed often. In rare cases the cartridge or pod containing the e-liquid has 
cracked or leaked e-liquid. Refilling of the tanks may also result in e-liquid spills. 
Subjects are instructed to immediately wash any exposed skin with soap and water.  


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e. Ingestion of ENDS liquids containing nicotine can cause acute toxicity and possible 
death if the contents of refill cartridges containing nicotine are consumed. Subjects are 
told to keep study ENDS and all e-liquid cartomizers away from pets and children.  
f. 
Nicotine is an addictive chemical. It is possible that this experience could lead to long-
term use of ENDS after the trial is over. 
g. Allergic reactions to propylene glycol, vegetable glycerin or flavorants have been 
reported. If a subject reports a medical history of these allergies after randomization 
they will not be offered the vaping products in the marketplace. Chemicals used to 
flavor foods are also a risk for allergic reactions. We will ask subjects if they have had 
allergic reactions to specific nuts, fruits, and other flavors and advise them not to use e-
liquids/cartridges that may contain or be labeled with those flavors. 
h. Recent reports of seizure associated with vaping are being evaluated by the CDC and 
the FDA.  While collection of evidence for seizure is not conclusive of causality, it is 
prudent to inform potential subjects of this investigation. 
i. 
Reports of severe lung disease and deaths are being investigated by the CDC and the 
FDA. These incidents have been predominantly attributed to vaping THC and vitamin E 
acetate.  Participants will be alerted to the symptoms of lung disease including: cough, 
shortness of breath, chest pain, nausea, vomiting, abdominal pain, fever. Participants 
are advised to discontinue use and promptly seek medical attention for any health 
concerns. Participants will also be advised to use only the study product we have 
provided to them and to not alter the device or add any substances to e-fluids. We will 
keep the participants informed as the additional information is provided by the CDC and 
FDA. 
8) Use of Smokeless Tobacco or Snus:  Smokeless tobacco products could increase risk for 
mouth sores, gum disease and tooth loss, nausea or upset stomach, vomiting, high blood 
pressure and nicotine addiction. Smokeless tobacco products may increase the risk of 
cancer, particularly oral, esophageal and pancreatic cancer. However, these risks are less 
than the health risks of smoking combustible cigarettes.  
9) Use of Medicinal Nicotine (nicotine polacrilex and transdermal patch) or nicotine pouches:  
Most common adverse effects for medicinal nicotine include irregular 
heartbeat/palpitations, high blood pressure, mouth sores, mouth or throat irritation, 
heartburn, upset stomach, vomiting, diarrhea, dizzy or lightheadedness, and hiccups or 
belching. Additional adverse effects associated with nicotine gum include teeth or jaw 
problems. Additional adverse effects associated with nicotine patch are erythema, pruritus, 
edema and sleep disturbance. There may also be a risk of nicotine toxicity including 
symptoms such as nausea, dizziness, vomiting, diarrhea, and weakness.  
10) Dual use of tobacco or nicotine products:  There is also the chance of use of more than one 
product that may result in symptoms of nicotine toxicity and/or continued use of the 
products.  However, cessation of all tobacco products will be strongly recommended to the 
subjects both at the end of the experimental phase and at follow-up with referrals to local 
cessation treatments or state quit line.  


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11) Smoking Withdrawal: Participants may experience smoking withdrawal symptoms during 
this study. The symptoms can be uncomfortable but are typically of minimal risk. Smoking 
withdrawal symptoms include: 
a. Anger, irritability, frustration 
b. Anxiousness, nervousness 
c. Depressed mood or sadness  
d. Desire or craving to smoke 
e. Difficulty concentrating 
f. 
Increased appetite, hunger or weight gain 
g. Insomnia, problems sleeping or awakening at night 
h. Restlessness 
i. 
Impatience 
j. 
Constipation 
k. Dizziness 
l. 
Coughing 
m. Dreaming or nightmares 
n. Nausea 
o. Sore Throat 
12) Returning to Regular Smoking: It is possible that if participants return to smoking their usual 
brand of cigarette at the end of the study they may experience mild and transient nausea, 
dizziness, and lightheadedness. 
13) Changes in Blood Pressure and/or Heart Rate: Smoking and nicotine can affect the 
cardiovascular system, which may result in changes in blood pressure and/or heart rate. 
14) Changes in Mood, Emotions and Psychiatric Symptoms: Smoking and nicotine can affect a 
person’s mood and emotions and are associated with psychiatric disorders including major 
depressive disorder, general anxiety disorder, bipolar disorder and eating disorders. Any 
changes in nicotine use or cigarette consumption could adversely affect mood, emotions 
and the symptoms related to psychiatric conditions in some individuals. 
15) Smoking and Oral Contraceptives in Women: Women who smoke and are over the age of 
35 should not take oral contraceptives that contain estrogen without consulting their 
physician. Smoking while using oral contraceptives can increase the risk of having a 
cardiovascular event such as a heart attack or stroke. Additionally, there is a potential risk 
of thrombosis associated with hormonal therapy (including contraceptives) and smoking.  
16) Smoking and Medications: Quitting smoking can greatly benefit participants’ health. 
However, changes in smoking can lead to changes in how well some medications work. 
Participants are asked to disclose all medications they are taking. We also recommend that 
participants discuss any planned or actual changes in how much they smoke with their 
doctor, especially if they are taking any medications for psychiatric, cardiovascular, or other 
serious diseases. 
14.2. 
Reproductive Risks 


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Risk to Fetus: Smoking during pregnancy can lead to miscarriage, preterm delivery, stillbirth, 
low birth weight, problems with the placenta, birth defects such as cleft palate, sudden infant 
death syndrome (SIDS), and early childhood behavioral problems. Smokeless 
tobacco/snus/nicotine pouches use increases risks for preterm delivery, preeclampsia or 
stillbirth and may have a negative effect on birth weight. Although unknown, similar effects 
could occur with the use of ENDS.  
Avoiding Risks to Fetus 
If female participants choose to be sexually active, they are asked to use an appropriate 
“double barrier” method of birth control (such as female use of a diaphragm, intrauterine device 
(IUD), or contraceptive sponge in addition to male use of a condom), or should be using 
prescribed “birth control” pills, injections, or implants. Female participants with child-bearing 
potential will be tested for pregnancy at the first Marketplace visit and the randomization visit 
and monthly thereafter. If a participant becomes pregnant during the study, she will be 
withdrawn from the study if using tobacco or ENDS products. Approximately 30 days after 
being withdrawn or having a positive pregnancy test, the research staff will call the participant 
to confirm her due date. The licensed medical professional will follow-up with the participant 
after delivery to ask questions about the baby’s health. 
14.3. 
Risks to Others 
Tobacco products in the home can be toxic to children and pets.  Smoking can lead to second 
hand exposure that can increase risk for disease.  All participants will be informed to keep 
products not accessible to children and pets and informed about the harms of second hand 
smoke and vapor exposures in the home or in cars.   
15. 
Potential Benefits of Participation 
There are no immediate benefits from participating in the study.   
The information obtained from this study may ultimately help the Food and Drug Administration 
decide how best to regulate tobacco products with the goal of improving public health.  
16. 
Data Management 
16.1. 
Data analysis plan 
For complete statistical detail, please see Statistical Analysis Plan.  
16.2. 
Randomization 
Subjects will be randomized at the end of Phase 2 with a 1:1 ratio to the two studied conditions 
described above. Randomization will be stratified by site (6 study sites) using a blocked 


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randomization scheme with random block sizes of 2, 4, and 6. We anticipate no or less than 
minimal block effects in our data based on previous studies with similar design.  
16.3. 
Sample Size 
We will enroll 400-450 subjects (approximately 200-225 per group) to the study and assume a 
20% attrition rate over the 12-week post randomization period. Power analysis was performed 
for two of the primary outcomes in the primary aim: CPD smoked at the end of Phase 3 and 
smoke-free days during Phase 3. The effect sizes and the distribution of population 
demographics were projected from a pilot study (U19CA157345; Hatsukami et al., 2017) and 
Donny et al. (2015)16,14. The two-sided type-I error rate for each outcome (CPD and smoke-free 
days) was set at α=0.025 (=0.05/2 outcomes by the Bonferroni method) for the overall sample. 
Powers for two independent subgroup analyses, by sex or by age, are also presented in Table 
1, with type I error rate equal to α divided by the number of subgroups (=2) for each factor. T-
test was used for the CPD outcome. For the smoke-free days outcome, we first calculated the 
rate of smoke-free days by dividing the number of smoke-free days by the total number of days 
in Phase 3 (approximately 84 days) and then used z-test for the Poisson rate difference. PASS 
13 was used for power calculations.  
Table 1: Power Analysis for Total Enrolled (randomized) N=450 and 400 
Primary outcomes 
 VLNC  NNC 
 Overall 
sample 
  3Subgroup 
analysis  
   by sex 
4Subgroup analysis  
by age 
  F 
  M 
  18-24 
  25-44 
45+ 
N enrolled = 450  
1Cigarettes (study or non-study) per 
day smoked at the end of Phase 3 
(calculated as mean CPD based on 
7 days’ IVR data before the week 12 
visit) 
7 
15 
>.99 
>.99 
>.99 
- 
>.99 
>.99 
2Number of smoke-free days during 
Phase 3 (12 weeks or 84 days) 
11 days 
difference 
.92 
.49 
.56 
- 
.67 
.37 
N enrolled = 400 
1Cigarettes (study or non-study) per 
day smoked at the end of Phase 3 
(calculated as mean CPD based on 
7 days’ IVR data before the week 12 
visit) 
Same as 
above 
>.99 
>.99 
>.99 
- 
>.99 
>.99 
2Number of smoke-free days during 
Phase 3 (12 weeks or 84 days) 
.88 
.43 
.50 
- 
.61 
.32 
1We assumed an equal SD for the two treatment arms. See Table 1 (left panel) in SAP for SD for the overall group, 
by gender and by age.   
2 The NNC arm’s rate of abstinence was based on the interim analysis result (see Table 1 in SAP, right panel).  
344.7% female and 55.3% male, based on the interim data (see Table 1 in SAP).  


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40.2%, 53.4%, and 44.7% for 18-24, 25-44, and >= 45 years old, respectively, based on the interim data (see Table 1 
in SAP).  
16.4. 
Study Populations 
16.4.1. Intent-to-Treat  
The primary analysis of all endpoints will adhere to the intent-to-treat principle. Under this 
principle, all randomized subjects will be included in the analysis in the group to which they 
were randomized regardless of protocol violations and compliance to treatment assignment.  
16.4.2. Definition of Sub-Group Population in Different Analyses 
We intend to complete pre-planned subgroup analyses by sex, age groups (18-44, and 45+), 
and whether the participant was recruited pre- or post-COVID. Subgroup analysis will allow us 
to evaluate the consistency of the effect of VLNC vs. NNC across important subgroups. 
16.5. 
Trial Endpoints 
16.5.1. Primary Endpoints 
• Cigarettes per day (CPD): the mean cigarettes (study and non-study cigarettes) 
smoked per day based on 7 days’ Daily Interactive Voice Response (IVR)-Revised data 
before the week 12 visit. 
• Smoke-free days: the number of smoke-free days during Phase 3, based on IVR-Revised 
during Phase 3. 
 
16.5.2. Secondary Endpoints 
• Biomarker: percent change in biomarker, CEMA, at the weeks 4, 8 and 12 visits during 
Phase 3 as compared to the last visit in Phase 2. 
• Study Cigarettes per day (CPD): the mean study cigarettes smoked per day based on 7 
days’ Daily Interactive Voice Response (IVR)-Revised data before the week 12 visit. 
• Smoke-free point prevalence:  Smoke-free days based on IVR-Revised and 
biochemical verification of smoke-free status (CO < 6ppm) 7 days prior to the end of the 
12 week. 
 
16.5.3. Exploratory Endpoint 
• Non-combusted tobacco/nicotine products use: the number of days using any non-
combusted tobacco/nicotine products in Phase 3. 
• Characteristics of products chosen (type, flavor, nicotine strength). 


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• Biomarkers: percent change in other biomarkers (Total Nicotine Equivalents, total 
NNAL, other mercapturic acids) at the weeks 4, 8 and 12 visits during Phase 3 as 
compared to the last visit in Phase 2. 
• Product satisfaction (Product Evaluation Scale if they used the product since the last 
visit; Cigarette Evaluation Scale if they smoked cigarettes since the last visit). 
• Perceived health risk (Phase 1, Phase 2 and end of week 12 of Phase 3: all products 
for all subjects). 
• Measures of discomfort/dysfunction: MNWS, QSU, CES-D, (NNC vs VLNC cigarettes 
irrespective of use of products). 
• Dependence (FTND, WISDM, PATH items, monthly for study cigarettes) 
16.5.4. Safety Endpoints 
• Potential adverse consequences: Change in mental (CES-D) or physical health (heart 
rate, blood pressure, weight). 
• Increased TNE (corrected by creatinine), calculated as change from Phase 1 baseline. 
• Adverse events and Serious Adverse Events 
16.6. 
Statistical Analysis 
16.6.1. General Approach 
All statistical analyses will be performed using SAS or R. All statistical tests will be two-tailed. 
A Bonferroni multiple-comparisons adjustment will be used to account for multiple 
comparisons for each of the two primary endpoints (α = 0.025). Analyses of the secondary 
and exploratory endpoints will not be adjusted for multiple comparisons (α = 0.05). All 
analyses will be completed using the intent-to-treat principle unless otherwise noted. Methods 
for handling missing data will be specified below.   
16.6.2. Describing the Study Population 
Descriptive statistics will be performed for data collected at different visits. Daily Interactive 
Voice Response (IVR)-Revised data will be summarized by phase and by visit (according to 
the actual visit dates or scheduled visit dates if a visit is missed). Baseline data will be 
compared between the two studied conditions with t test or Wilcoxon rank sum test for 
continuous variables and chi-square test or Fisher’s exact test for categorical variables, which 
include sex, age, race, education, menthol status, dependence (FTND), CPD, nicotine 
metabolite ratio (NMR) and TNE. Baseline CPD and TNE are based on Phase 2. 
16.6.3. Primary Endpoint Analysis 
The primary endpoints are (1) the mean cigarettes (study and non-study cigarettes) smoked 
per day based on 7 days’ Daily Interactive Voice Response (IVR)-Revised data before the 
week 12 visit; and (2) the number of smoke-free days out of the total number of days in Phase 
3. 


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Primary Analysis 
We expect the two groups to, on average, be balanced for important baseline 
characteristics due to randomization, so the primary analyses will be regressions for the 
difference in CPD and the number of smoke-free days between two conditions, adjusting 
for only the baseline value (the mean CPD and the percent of smoke-free days during 
Phase 2, respectively).  Specifically, for the CPD outcome at week 12, we will use linear 
regression; for the number of smoke-free days, we will use Poisson regression or negative 
binomial regression when there is over-dispersion in the count data. 
Secondary Analysis 
For the Week 12 CPD and total number of smoke-free days, we will perform an adjusted 
analysis, adjusting for baseline value, study site (the randomization stratification factor), 
whether the Week 12 visit is pre-COVID or not, and any baseline characteristics (listed in 
Section 16.6.2), which are different at p<0.20, in multivariable regressions to improve 
efficiency.  
For the CPD outcome measured repeatedly, we will use linear mixed effects models.61 
Fixed effects in the model will include: treatment group, visit, treatment group by visit 
interaction, baseline CPD, study site, whether the visit time is pre-COVID or not (as a time-
dependent covariate), and any baseline characteristics (listed in Section 16.6.2) which are 
different at p>0.20. A random intercept for each subject will also be included in the model to 
account for within subject correlation. 
16.6.4. Secondary Endpoint Analysis 
The secondary endpoints will first be summarized by treatment group using mean and standard 
deviation. We will use similar adjusted regression methods for the secondary endpoints as for 
the primary endpoints described in Secondary Analysis Section. Details are described as 
follows. 
• 
For the percent change (relative to the measure at the end of Phase 2) of the 
biomarkers measured repeatedly (weeks 4, 8, 12), we will use linear mixed effects 
models.61 Fixed effects in the model will include: treatment group, visit, treatment group 
by visit interaction, and study site, whether the visit time is pre-COVID or not (as a time-
dependent covariate), and any baseline characteristics (listed in Section 16.6.2) which 
are different at p>0.20. A random intercept for each subject will also be included in the 
model to account for within subject correlation. 
• 
Study cigarettes per day will be similar to the Primary Endpoint analyses for total 
cigarettes per day.  
• 
For the smoke-free point prevalence outcome, we will use logistic regression. 
16.6.5. Exploratory Endpoint Analysis 
We will conduct the following exploratory endpoint analysis: 


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• 
For the number of days of non-combusted tobacco/nicotine products use, we will use 
Poisson or negative binomial regression, adjusting for baseline value, study site, 
whether the visit is pre-COVID or not, and any baseline characteristics which are 
different at p<0.20. 
• 
Descriptively examine the characteristics of the various products that are chosen (type, 
nicotine strength, flavor).  
• 
Other biomarkers will be analyzed similar to the Secondary Endpoint analysis.  
• 
Product satisfaction (Product Evaluation Scale, Cigarette Evaluation Scale) at the first 
time a participant tried a product will be summarized using mean and standard 
deviation and compared between two treatment arms using linear regression.  
• 
Repeated measure of perceived health risk will be analyzed using the mixed effects 
model as described in the Secondary Analysis Section.  
• 
Discomfort as assessed by MNWS-R, QSU, and CES-D will be compared between the 
VLNC vs. NNC cigarette conditions. The methods for comparing discomfort measures 
between VLNC and NNC cigarettes will be the same as for those described for the 
Primary Endpoints. 
• 
Repeated measures of dependence of study cigarettes will be analyzed using mixed 
effects model described in the Secondary Analysis Section. 
• 
Examine the cross-sectional associations of non-combusted products use with 
cigarettes smoked and biomarkers at different visits using marginal generalized 
estimating equations (GEE) model62 (Chapter 12) with the non-combusted product use 
as the independent variable. 
• 
We will explore baseline predictors of responses. We will use multivariable regressions 
to determine predictors of product use patterns, e.g., non-combusted product use, 
combusted product use, and smoke-free days.  Predictor variables (depending on the 
responses measured) will include baseline CPD, total nicotine equivalents, FTND, age, 
sex, racial ethnic group, SES, perceived risk of products, product expectancy, product 
utility, social and environmental influences, contemplation ladder, menthol cigarette use 
and nicotine metabolite ratio (NMR, reflecting rate of nicotine metabolism).  Similar 
regression models as described in Primary and Secondary Endpoint Analyses will be 
used. 
16.6.6. Subgroup Analyses 
Subgroup analyses will play an important role in understanding the effect of nicotine reduction 
for different subpopulations. We will explore the effect of VLNC vs. NNC within subgroups 
defined by age (18-44, and 45+) or sex. We will also conduct subgroup analysis by the time of 
the subject being recruited, pre- or post-COVID. Subgroup analysis will follow the same 
approach described above as for the overall sample, but significance will be assessed by a 


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Bonferroni-adjusted type-I rate (α/2 for a sex group or an age group, where α is the type-I error 
pre-specified for a specific outcome variable for the overall sample; see Section 16.6.1 for the 
values of α).  
Formal testing of the interaction between subgroup and treatment effect is not the primary 
concern of our subgroup analyses. Instead, subgroup analyses will provide information about 
the consistency of the treatment effect across subgroups, which will provide supplementary 
information for full understanding of the relationship between the studied interventions and the 
study endpoints. 
16.6.7. Safety 
The distinction between the primary/secondary outcomes and safety outcomes is not as clear 
in this trial as it would be in a typical clinical trial of a novel therapeutic agent. Many outcomes 
that would typically be considered potential adverse consequences or safety outcomes will be 
analyzed similarly as the secondary outcomes. For example, the other tobacco product use will 
be analyzed using similar statistical methods as for the other continuous primary/secondary 
endpoints.  
AEs and SAEs will be recorded as described in the Adverse Event SOP. AEs and SAEs will be 
tabulated and compared across treatment groups.  Count of AEs will be analyzed using 
Poisson regression or negative binomial regression as described in Secondary Endpoint 
Analysis.  
16.6.8. Missing Data 
Every effort will be made to limit the amount of missing data in this trial. Study participants will 
be incentivized to attend study sessions and complete the daily IVR-Revised as detailed in the 
study protocol (Compensation subsection 12.5). However, some level of missing data is 
inevitable in a study of this kind. We will compare subjects who do and do not complete the 
study in order to identify baseline covariates associated with the study completion. 
We will use multiple imputation with the Markov Chain Monte Carlo (MCMC) method,63,64 
carried out in PROC MI in SAS. If the treatment group is associated with missing, we will 
conduct multiple imputation for each treatment group separately.65 At least 10 imputed data will 
be generated, with the treatment effect being assessed in each imputed data set. A final single 
assessment of treatment arm difference will be obtained from combining the results across the 
imputed datasets using PROC MIANALYZE in SAS. 
We will then conduct sensitivity analyses of primary and secondary endpoints by baseline 
imputation and the last observation carried forward (LOCF) method. Specifically, for the 
baseline imputation method, for a day with missing IVR-Revised data, the Phase 2 mean CPD 
will be imputed and non-abstinence will be assumed. For the outcome of biomarkers, missing 
data will be replaced by baseline values (i.e., no change in biomarkers). This will serve as a 
“worse-case scenario” as treatment group will be, on average, balanced at baseline. The 


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results of these analyses will be compared to the primary analysis to evaluate the robustness 
of our conclusions.  
16.6.9. Interim Analyses 
Interim analyses were conducted for re-estimation of sample size and will be conducted 
(blinded to investigators) for providing preliminary results to FDA if rulemaking for reducing 
nicotine in cigarettes to non-addictive or minimally addictive levels is proposed (see SAP for 
details).  
 
16.7. 
Data Integrity 
Adherence to protocol procedures, training and data integrity.   
Standard operating procedures for all visits and procedures will be provided. Face-to face 
training for research personnel will occur at a site initiation visit prior to the study start, where 
the protocol and procedures will be carefully described. Case Report Form books will be 
created to maximize parallel recording of data across studies. Each visit will have a checklist of 
all the measures that need to be administered and the order by which these measures are 
administered. Additionally, conference calls will be held regularly with lead site, PIs and 
coordinators. 
17. 
Confidentiality 
17.1. 
Data Security 
Subjects will be told their participation in the project will be strictly confidential, that any 
identifying information will be available to the project investigators or institutional or federal 
regulatory groups only, and that no identifying information concerning the data and results will 
otherwise be made known. Identifying information (initials and telephone numbers) entered in 
the Daily Call system will not be shared nor extracted with the data by the Biostatistics and 
Data Management Core. 
Subjects will have written assurance that while de-identified individual subject data may be 
available to other internal researchers for research purposes, only a summary of the results will 
ever be published or otherwise publicly released. They will also be informed that all raw data 
will be coded with numbers and any form with identifying information (e.g., consent forms) will 
be kept separately in locked files. If subjects would like their information on vitals or other 
findings released to another party, they will be asked to sign a release form.   
All electronic data will be de-identified, housed on the University of Minnesota AHC secured 
server. In–house access will be password protected. De-identified outcome data will be posted 
on a secure, password-protected website that is only available to research investigators (both 


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inside and outside the institutions affiliated with this U54 due to data sharing requirements; 
subjects will be informed of this during the informed consent process). All identifying 
information will be kept separate from the data in a locked cabinet in a secure place at the local 
site.  Research study staff are required to complete site specific data security training through 
their institutions. There will be no data or consent forms will be placed in subject’s medical 
records. 
17.2. 
Certificate of Confidentiality 
To help protect the participant’s privacy, a Certificate of Confidentiality from the National 
Institutes of Health will be in place.  With this certificate, the researchers cannot be forced to 
disclose information that may identify the participants, even by a court subpoena, in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings.  The 
researchers will use the Certificate to resist any demands for information that would identify the 
participants, except as explained below. The Certificate cannot be used to resist a demand for 
information from personnel of the United States Government that is used for auditing or 
evaluation of federally funded projects or for information that must be disclosed in order to 
meet the requirements of the Federal Food and Drug Administration (FDA). 
The Certificate of Confidentiality does not prevent the participant or a member of their family 
(e.g. guardian) from voluntarily releasing information about themselves and their involvement in 
the research. If an insurer, employer or other person obtains the participant’s written consent to 
receive research information, then the researcher may not use the Certificate to withhold that 
information. 
The Certificate of Confidentiality does not prevent the researchers from disclosing voluntarily, 
without consent, information that would identify the individual as a participant of the research 
project in instances such as evidence of child or elder abuse or a participant's threatened harm 
to self or others. 
18. 
Provisions to Monitor the Data and Ensure Subject Safety 
18.1. 
Data Integrity Monitoring 
The Project Manager will oversee the day-to-day operation of the study. We will obtain IRB 
approval from all institutions prior to beginning the study. All personnel will be trained on study 
procedures, human protection issues and regulatory requirements. This will be conducted via 
an initial Start-up Meeting for all research Coordinators and site Principal Investigators. Prior to 
starting recruitment at the sties, an Initiation Visit will be conducted. At this visit, all research 
staff will attend to ensure that they possess adequate knowledge of the protocol and 
procedures.  Standard Operating Procedures for all visit procedures, use of equipment, 
collection and entry of data will be reviewed at this visit. Any new staff will undergo training in 
these areas. To ensure correct data entry, outcome variable data will be double entered into 
REDCap and compared for discrepancies. 


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As another measure to ensure data collection integrity, the project manager from the University 
of Minnesota will make a visit to each site after they have started enrollment to make sure that 
the protocol is being followed carefully (and will include review of signed consent forms) and all 
the data is being collected properly. (The additional three sites (Wake, UPenn and Brown) did 
not have a site visit at the start of enrollment due to COVID-19 travel restrictions. Monthly 
quality checks monitoring the data and procedures were conducted through REDCap during 
this time.) Thereafter, these monitoring visits will occur every 12 months. (Annual monitoring 
visits were halted during COVID-19, however close-out visits will be conducted at all sites.) All 
subjective forms will be entered into REDCap including the telephone screening. Data on 
REDCap will be monitored remotely at the lead site (U of MN) for missing data or any unusual 
values or issues related to safety (adverse events and serious adverse events). This review will 
be provided to the respective sites in real time.   
An external monitor through each of the institution’s Clinical and Translational Science Award 
and/or the University of Minnesota Project Manager will review the study records to make sure 
that regulatory requirements are met. At this time, the consent forms will be reviewed (this 
would mean that the monitor will see the names of the participants; however no record of this 
identifying information will leave the premises), Delegation and Training Logs and IRB approval 
will be confirmed. On-site review of 5-10% of case report forms will be conducted unless there 
is cause for increased oversight.   
The University of Minnesota NCI designated Cancer Center also has a Cancer Protocol 
Review Committee that meets on a monthly basis to review all cancer-related protocols. This 
study will be subjected to review by this committee. Progress reports to this committee are 
submitted on a yearly basis.  
18.2. 
Data Safety Monitoring Plan 
The DSMB for this project will begin by reviewing the protocol and establishing guidelines for 
data and safety monitoring. This will include developing standard procedures for day-to-day 
monitoring by the internal monitors, investigators and study staff. This Board will meet at 
regular intervals (at least once a year) to evaluate the progress of the trial, review data quality, 
patient recruitment, study retention, and examine other factors that may affect study outcome.  
They will also review the participant’s ability to achieve the study requirements and the rates of 
adverse events to determine whether there has been any change in participant risk. Their 
review will ensure that subject risk does not outweigh the study benefits. A brief report will be 
generated from each of these meetings for the study record and forwarded to the Institutional 
Review Boards (IRB). 
The DSMB will be available to convene outside of the regular meetings, if necessary, if 
concerns should arise regarding a particular subject, or any troublesome trends in the subject 
experiences. They will make appropriate recommendations for changes in protocol, if needed. 
All product-related adverse events of a non-serious nature will be reported to the IRB at the 
time of renewal. Reportable serious adverse events will be submitted promptly. The DSMB will 
review all serious or unexpected adverse events and provide recommendations.  


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We will inform IRB and NIH of any significant action taken as a result of the DSMB’s findings. 
We will inform the subjects of any changes in risk.  
The study coordinator at each of the sites will be responsible for the daily oversight of subject 
safety. At each of the sites, the site PI and licensed medical professional (LMP) will meet 
regularly with the study staff to review patient’s progress and their experiences with the 
tobacco products, including any adverse events. Entrance criteria will be reviewed following 
screening. Medical history will be reviewed by the LMP for any contraindications for the use of 
the study products and vital signs are checked at each clinic visit. Patients will be under 
medical supervision while in the study and seen on an ongoing basis by our research staff who 
will assess adverse events and make appropriate referrals to the LMP. The Data and Safety 
Monitoring Board (DSMB) and other regulatory bodies will be informed of any adverse events 
either at the regularly convened meetings or in the annual report, or if necessary, immediately.  
19. 
Provisions to Protect the Privacy Interests of Participants 
19.1. 
Protecting Privacy 
Privacy will be maintained by meeting in a private room with subjects, they will be informed 
they may refuse to answer questions if they chose, but this may impact their eligibility. Subjects 
will be reminded that we have obtained a Certificate of Confidentiality to protect their data from 
being subpoenaed, particularly related to illegal drug use. Subjects are told that their 
identifiable information is not shared with any others outside of the research team. 
19.2 Access to Subjects:  There is no access to subjects’ medical records or other private 
information. 
20. 
Compensation for Research-Related Injury 
There will not be any compensation for research related injury in this NIDA sponsored trial. The 
consent form will state:  “In the event that this research activity results in an injury, treatment 
will be available, including first aid, emergency treatment and follow-up care as needed. Care 
for such injuries will be billed in the ordinary manner to you or your insurance company. If you 
think that you have suffered a research related injury, let the study physicians know right 
away.” 
21. 
Informed Consent  
21.1. 
Consent Process 
Potential subjects will attend an orientation visit at the local clinic site where they will receive a 
copy of the consent form to read and be shown a standardized PowerPoint presentation 
showing the study purpose, procedures and responsibilities of participation. If the subject is to 


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return for the In-person/Teleheath Screening visit at a later date, they will take the consent 
home for review and signatures will be obtained at the In-person Screen. If the Orientation and 
In-Person/Telehealth Screen are combined, the process of obtaining informed consent will be 
obtained during Orientation and then the In-Person/Telehealth Screen will commence. Upon 
converting to Telehealth visits due to COVID-19 safety precautions, the orientation visit and 
PowerPoint presentation was conducted remotely and the consent forms were signed 
electronically.  
The subjects will be solicited to ask questions and will receive answers. The 
coordinator/research assistant will then ask several open-ended questions to assess 
comprehension of the study prior to signing the consent form (What is the purpose of this 
study? Can you please describe the types of things you will be doing at the visits? What are 
some of the risks and discomforts you may experience while participating in the study? What 
are some of the benefits of being in the study? If you are eligible to participate, how many 
weeks will the study last?)  After obtaining informed consent, collection of data can begin. The 
consenting process will be documented in the subject’s case report form progress notes:   
“Subject has read the consent form and the PowerPoint was presented for the study entitled 
“Impact of Very Low Nicotine Content Cigarettes in a Complex Marketplace.” The study was 
explained in full detail and subject was allowed to ask questions and receive answers. Subject 
agreed to participate and signed the consent form on:   _______________and received a copy 
of the consent form.” 
If any changes in risk are identified during the course of the subject’s participation, they will be 
informed of the issue and a new consent form will be presented and signed. The subject may 
choose to continue participation or withdraw from the study at that time. 
21.2. 
Wavier or Alteration of Consent Process 
None. 
21.3. 
Non-English speakers/readers 
Non-English speakers/readers are not eligible to participate. 
21.4. 
Participants Who Are Not Yet Adults 
Infants, children, and teenagers under 18/21 years of age (depending on site) are not eligible 
to participate. 
21.5. 
Cognitively impaired adults 
Cognitively impaired adults are not eligible to participate. 
21.6. 
Adults unable to consent  


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Adults unable to consent will not be eligible to participate 
22. 
Setting 
Recruitment and visits will be conducted by research staff at the sites respective clinics.  All 
original sites had an institutional IRB provide local approval of the study. For the new sites, 
Wake Forest University IRB will be the IRB of record and the original sites will seek reliance 
agreements to use this single site IRB  
• 
University of Minnesota: Tobacco Research Programs: Delaware Clinic Research Unit at 
717 Delaware St. SE, 200, Minneapolis, MN  
• 
Duke University:  Center for Addiction Science and Technology (CfAST) at 2608 Erwin 
Road, Suite 300, Durham, NC 27705 
• 
University of California:  UCSF Tobacco Research Center at 3130 20th Street 
Suite 308 San Francisco, CA 94110 
• 
Wake Forest University:  Tobacco Center of Excellence Biotech Place, 575 North Patterson 
Avenue, Suite 430, Winston-Salem, NC. 27101 
• 
University of Pennsylvania:  Center for Interdisciplinary Research on Nicotine Addiction 
(CIRNA), Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, 
Suite 4100, Philadelphia, PA 19104 
• 
Brown University: Center for Alcohol & Addiction Studies, Brown University School of 
Public Health, 121 South Main Street, Providence, RI 02903 
23. 
Multi-Site Research 
23.1. 
Study-wide Number of Subjects 
Approximately 400-450 randomized. 
23.2. 
Study-Wide Recruitment Methods 
Similar methods of recruitment will be used across sites as described in Section 12.   
23.3. 
Study-Wide Recruitment Materials 
Similar recruitment materials will be used across sites as described in Section 12.   
23.4. 
Communication Among Sites 
Initially, weekly conference calls will occur among the research coordinators at each of the 
sites to track progress and trouble shoot and to make sure that all protocol procedures are 
followed. Approximately on a once a month basis, the PI and co-investigators will participate in 
this conference call. During these conference calls, the number of subjects enrolled, the data 


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collection process, the results from data monitoring and other issues of concern will be 
discussed. Once the study has been initiated and is running smoothly with fewer day to day 
issues to discuss, the research coordinator calls will be held bi-weekly and then monthly, 
unless there is cause for more frequency.   
• 
As lead site, we will ensure that all sites have the current version of the protocol, consent 
form and HIPAA (if required) by providing these documents on our REDCap Administrative 
Projects site. 
• 
IRB initial approvals and continuing reviews will be uploaded into REDCap Administrative 
Project site. 
• 
Modifications to the protocol will be discussed on the Coordinator call. Submissions and 
approvals will be tracked on the REDCap website, which houses the site’s currently 
approved protocol and consent form. Only after IRB approval will the site have access to 
download the newly approved consent form. 
• 
All sites are academic institutions with the same rigorous requirements as the University of 
Minnesota’s security provisions. Data will be entered into REDCap whose server is housed 
by the University of Minnesota’s Academic Health Center. Identifiable HIPAA regulated 
information will not be shared between sites, all data entered is de-identified.  
• 
All study sites have Federalwide Assurance and therefore have met the standards to 
comply with federal regulation and local laws: 
o University of Minnesota:  FWA00000312 
o Duke University: FWA000009025  
o UCSF:  FWA00000068  
o Wake Forest University:  FWA00001732 
o University of Pennsylvania: FWA00004028 
o Brown University: FWA #00004460 
• 
Reporting of Non-compliance: 
Any site noncompliance with federal regulation or state laws information will be 
provided to the University of MN, the lead site, and the offending site’s IRB will be 
informed. UMN will provide this report to the UMN IRB. 
• 
Reportable Events: 
o Reportable events will be reviewed in the GCP training session at the study start-up 
meeting to ensure site personnel is aware of the requirements. Any reportable 
events will be sent to the local IRB and the lead site (UMN). These include: death of 
subjects, new or increased risk, adverse events or safety reports that require a 
change to the protocol or consent form, deviations that affect risk, audits or 
inspections, written reports from sponsor or FDA, allegation of non-compliance, 
unauthorized disclosure of confidential information, unresolved subject complaint, 
suspension or premature termination of the study, incarceration of subjects, medical 
board or hospital staff actions, or any other information deemed related to research 
and puts subjects or other at increased risk of harm. In addition, adverse events that 
are unanticipated, related to the study and involving increased risk will be reported. 
o Serious adverse events (SAEs) as defined in 21 CFR 312.32 (death, life-
threatening, hospitalization (initial or prolonged), disability or permanent damage, 


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congenital anomaly/birth defect, required intervention to prevent permanent 
impairment or damage (devices), other serious (important medical outcomes)) that 
are related or possibly related to study participation will be reported to the U54 
Administrative Core, all site IRBs, the NIDA Scientific Officer (Ann Anderson, MD), 
the NIDA Project Officer (Kevin Walton, PhD), FDA, and the Data Safety and 
Monitoring Board. All Site IRBs require that fatalities related to the study be reported 
within 24 hours, that all other unanticipated product related SAEs be reported within 
5 business days. Reports of all reportable SAEs will also be documented within 
FDA’s reporting system, within 72 hours.  
o Report of IRB actions:  Actions taken by the local IRBs in response to SAEs will be 
reported to the lead site who will report to the FDA and NIDA as will reports of 
changes or amendments to the protocol as a result of an SAE. In addition, NIDA will 
be informed of any change that is significant enough for IRB review and changes 
the protocol in substantive ways (e.g., changes to procedures, recruitment strategy, 
inclusions/exclusion criteria), before such changes are implemented (except an 
urgent safety measure). Recommendation for trial discontinuation, for significant 
changes or amendments to the protocol, or other significant findings as a result of 
an SAE will be reported immediately to the FDA and NIDA Scientific Officer (Ann 
Anderson, MD) and Project Officer (Kevin Walton, PhD) by the Principal 
Investigator. 
24. 
Resources Available 
24.1. 
Feasibility of recruitment 
A total of approximately 400-450 male and female subjects will be randomized in the clinical trial 
over the course of 4 years. Enrolling this number of subjects is not unreasonable.  In a recently 
completed study, each of the sites enrolled around 125 subjects within 2 years.  Four of the 
sites were also involved in successfully enrolling the required number of subjects for the Donny 
et. al. study.14  
24.2. 
Staff Effort 
Each site will have approximately 2 full time staff dedicated to this study, which will be sufficient 
for recruitment, conducting study visits and other procedures.  Principal Investigators at each 
site will be devoting ~10% effort to the project.  Each site has a Medical Director that is available 
for review of medical histories, adverse events or other issues involving medical oversight. 
24.3. 
Facilities 
University of Minnesota:  The study will be conducted at the University of Minnesota’s Tobacco 
Research Programs housed at the Delaware Clinical Research Unit at 717 Delaware St. SE 
Minneapolis, MN. Dr. Dorothy Hatsukami serves as the Director for this Program and Dr. 
Sharon Allen is the Medical Director. The shared space at the Delaware Clinical Research Units 


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includes waiting room with a receptionist, 7 physical exam rooms (two dedicated to the Tobacco 
Research Programs), 1 phlebotomy room, 5 interview rooms, 2 day-hospital rooms, an infusion 
room, 1 smoking laboratory with one way observation room, laboratory spaces for processing 
blood and urine, a locked medication supply room, locked protocol room for subject files, 
cubicles for data entry, management and analyses, locked supply storage and access to three 
conference rooms. Two restrooms are in the clinical space for urine collections. We have 
dedicated space, with key card access, containing ten -20 freezers. Equipment available 
includes vital sign and expired air CO and alcohol monitors. The study will also have access to 
all of the resources of the University of Minnesota for our use, as needed. 
 
Duke University: The project activities will take place in the Center for Addiction Science and 
Technology (CfAST) founded and directed by Dr. Joseph McClernon (PI) and located in the 
Lakeview Plaza building adjacent to the Duke University and VA Medical Centers in Durham, 
NC. The PI has over 1300 square feet of laboratory space that includes two interview rooms, 
two physical exam rooms, a control room, three cognitive testing rooms, a scanner simulator 
room  and a wet lab for conducting phlebotomy and biological specimen processing, and a 
dedicated sample storage room. In addition, the laboratory has two rooms equipped with a 
ventilation system that allows for indoor smoking. Finally, there is a secure room for medication 
storage and preparation. Equipment includes a computer system for electronic questionnaire 
administration (MediaLab), vital sign and expired air CO and alcohol monitors. 
University of California-San Francisco:  Research subjects are seen at the Tobacco Research 
Clinic located   in San Francisco in close proximity to San Francisco General Hospital. The 
Clinic has a reception area and three private exam rooms for subject interviewing and specimen 
collection. The exam rooms are equipped with supplies to measure height, weight, blood 
pressure, expired CO, and breath alcohol levels. Additionally, two of the exam rooms have 
computers for administration of electronic questionnaires. There is a private bathroom for 
collection of urine samples. There is a lab where the specimens are prepared and equipment is 
housed. There are four separate rooms/offices where the clinical research coordinators and 
project manager are located and supplies are kept. A total of 9 separate computer stations are 
available for clinical research coordinator use. Additionally, the site has 2 laptops available for 
staff use. This is an off-site leased space located at 3130 –20th Street, Suite 380. 
Wake Forest University: The study will be conducted at the Wake Forest Tobacco Control 
Center of Excellence housed at the Biotech Place in Winston-Salem, NC. Dr. Eric Donny serves 
as the Director for this Center. The space at the Wake Forest Tobacco Control Center of 
Excellence  includes a waiting room with a receptionist, 7 ventilated testing rooms for smoking 
studies with audio and visual system for observation, 1 phlebotomy room, locked protocol room 
for subject files, cubicles and offices for data entry, management and analyses, locked 
laboratory space for product storage including 2 product refrigerators, 1 large wet laboratory 
space containing 2 -80 freezers and space for biosample processing, a conference room, and 
men’s and women’s restrooms adjacent to the suite for biosample collection. Equipment 
available includes vital sign and expired air CO and alcohol monitors. The study will also have 
access to all of the resources of the Wake Forest School of Medicine for our use, as needed. 


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Brown University: Research participants are seen at the Addictive Behaviors Research 
Laboratory at Center for Alcohol and Addiction Studies (CAAS), a 4800 square feet in size and 
was renovated per our specifications for the purpose of conducting human laboratory studies. 
The CAAS lab space contains 18 observation rooms, a room equipped for conducting physical 
examinations, a workroom for the storage and analysis of biological samples and a bathroom for 
participants’ use. The CAAS lab is located in Brown University’s Public Health building in 
downtown Providence, RI.  
University of Pennsylvania:  Research participants are seen at the Center for Interdisciplinary 
Research on Nicotine Addiction (CIRNA) Perelman School of Medicine at the University of 
Pennsylvania. The laboratory includes five 10x10 rooms equipped with exhaust fans and 
viewing windows to observe participants. Comfortable chairs placed in each. Restroom facilities 
are available for urine collection and there is a lab area for processing samples. Necessary 
equipment includes CO monitors, vitals monitors, laptop and desktop computers, and two 
refrigerators dedicated to specimen storage and two refrigerators dedicated to study product. 
The laboratory is located in Philadelphia. 
24.4. 
Availability of Medical or Psychological Resources 
Each site has a Medical Director and other study designated medical professionals, including 
access to a licensed psychologists that can be contacted if needed.  Each site has specific 
Standard Operating Procedures that describe procedures to follow in case of emergency such 
as a suicidal participant.  The medical staff will be trained in the study protocol, inclusion-
exclusion criteria, and the conditions that may require temporary discontinuation of the study 
products or withdrawal from the study.   
25. 
Conduct of the Study 
25.1. 
Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory requirement(s).  
Essential clinical documents will be maintained to demonstrate the validity of the study and the 
integrity of the data collected.  Master files will be established at the beginning of the study, 
maintained for the duration of the study and retained according to the appropriate regulations.  
25.2. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki.  The IRB will review all appropriate study documentation in order to safeguard the 
rights, safety and well-being of the subjects. The study will only be conducted at sites where 
IRB approval has been obtained. The protocol, consent, written information given to the 
subjects, safety updates, annual progress reports, and any revisions to these documents will 
be provided to the IRB by the investigator.   
25.3. 
Record Retention 


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The investigator will retain study records including source data, copies of case report form, 
consent forms, HIPAA authorizations, and all study correspondence in a secured facility for at 7 
years after the study file is closed with the IRB and FDA.   
26. 
Subject Identifier 
The subject identifier is an alpha-numeric combination. Example: E-B001 would be University of 
Minnesota’s first subject. 
Project Identifier:    F= CENIC 2 Project 1 
Site Identifier: 
B = University of Minnesota 
C = Brown University 
E = University of Pennsylvania 
F = Duke University  
H = University of California – San Francisco 
M = Wake Forest University 
Subject ID:  
B001-300 
C001–300 
E001-300 
F001-300 
H001-300 
M001-300 
Data Collection Time Point Identification Numbers: 
94= Screening Visit 
93=Baseline Visit 1 
92=Baseline Visit 2 
91=Marketplace Visit 1 
00=Marketplace Visit 2 and Randomization 
01= Week 1 visit 
02= Week 2 visit 
03= Week 3 visit (discontinued in conversion to telehealth visits) 
04= Week 4 visit 
06= Week 6 visit 
08= Week 8 visit 


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10= Week 10 visit 
12= Week 12 End of Intervention visit 
16= 30 day follow-up visit 
Additional visit  (AV1, AV2, etc.)  
86 = Termination Visit  


27. 
Procedure Table 
Platform 
SCRN 
94 
BL 93 
BL 92 
MP 91 
MP 
00 
Week 
1-33 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Follow
-Up 16 
Early 
Term 
 
Phase 1 
Phase 2 
Phase 3 
  
Phone Recruitment Questionnaire 
REDCap 
X 
  
  
  
  
  
  
  
  
  
  
  
  
VISIT ASSESSMENTS   
Weight (Height at screen) 
Paper and REDCap 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test (if applicable) 
Paper and REDCap 
 
  
 X 
  
X 
  
X 
  
X 
  
X 
  
X 
Heart Rate & BP 
Paper and REDCap 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cotinine check, if needed 
Paper and REDCap 
X 
  
  
  
  
  
  
  
  
  
  
  
 
Breath Alcohol Test4 
Paper and REDCap 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine Toxicology4 
Paper and REDCap 
X 
  
  
  
  
  
  
  
  
  
X 
  
 
Concomitant Medications 
Paper and REDCap 
X 
X   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health Changes Questionnaire 
Paper and REDCap 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Assessment 
Paper and REDCap 
  
X   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Product Accountability Log 
Paper and REDCap 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Procedures & Compliance Review  
Paper 
  
  
X  
X  
X 
X 
X 
X 
X 
X 
X 
 
 
End of Visit Evaluation  
Paper and REDCap 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SCREENING QUESTIONNAIRES  
Tobacco Use History and  
Exposure & Cessation Methods 
Paper and REDCap  
X 
  
  
  
  
  
  
  
  
  
  
  
 
Identifying Information 
Paper and Access 
X 
  
  
  
  
  
  
  
  
  
  
  
 
Demographics for Registration 
Paper and REDCap 
 
  
  
  
X  
  
  
  
  
  
  
  
 
Demographics 
EDC  
X 
  
  
  
  
  
  
  
  
  
  
  
 
Brief Medical History 
Paper and REDCap 
X 
  
  
  
  
  
  
  
  
  
  
  
 
PHQ PrimeMD (Beck if applicable) 
Paper and REDCap 
X 
  
  
  
  
  
  
  
  
  
  
  
  
CES-D 
EDC 
X 
  
  
  
X 
  
X 
  
X 
  
X 
X   
X 
Beck Depression Inventory/GAD ( if 
+ PHQ or Elevated CES-D) 
Paper and REDCap 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 (MINI) Suicide Subscale 
On Paper only 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Drug Abuse Screening Test (DAST) 
EDC 
X 
  
  
  
  
  
  
  
  
  
  
  
     
Alcohol Use Questionnaire 12 mo  
EDC 
X 
  
  
  
  
  
 
  
 
  
 
  
  
Drug Use Questionnaire 12 mo  
Paper and REDCap 
 X  
  
  
  
  
  
  
  
   
  
  
  
  
Michigan Alcohol Screening (SMAST) 
EDC 
X 
  
  
  
  
  
  
  
  
  
 
  
 
Assessment Name 
Platform 
SCRN 
94 
BL 93 
BL 92 
MP 91 
MP 
00 
Week 
1-33 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
F-Up 
16 
Early 
Term 


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Assessment Name 
Platform 
SCRN 
94 
BL 93 
BL 92 
MP 91 
MP 
00 
Week 
1-33 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
F-Up 
16 
Early 
Term 
TOBACCO USE MEASURES 
  
Daily Call  (IVR-tobacco diary) 
IVR 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 X 
Timeline Follow-back  
Paper and REDCap  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
IVR Review 
Paper and REDCap  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ADVERSE CONSEQUENCES  
MNWS   
EDCs 
  
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
  
  
QSU-  Usual cigarettes 
EDC 
  
 X 
 X 
X 
X 
 
 
 
 
 
 
  
  
QSU -  Study cigarettes 
EDC 
  
  
  
 
 
X 
X 
X 
X 
X 
X 
  
  
Alcohol Use Questionnaire 1 mo.  
EDC 
  
X 
 
  
X 
  
X 
  
X 
  
X 
  
X 
Drug Use Questionnaire - 1 month 
Paper and REDCap 
  
X 
  
  
X 
  
X 
  
X 
  
X 
  
X 
Respiratory & Global Health Quest. 
EDC 
  
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DEPENDENCE MEASURES  
Cigarette Dependence Scale (FTND, 
PATH items, WISDM subscale) 
EDC 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vaping/Product Dependence Scale 
EDC 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Severson SLT  Dependence Scale 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Contemplation Ladder   
EDC 
 
  
X  
  
X 
  
 
  
 
  
 
 
 
ACCEPTABILITY MEASURES  
Cigarette Eval. Scale Usual brand 
EDC 
  
X 
X 
 X 
X 
  
  
  
  
  
  
X  
X 
Cigarette Eval. Scale Study cigs 
EDC 
  
  
 
 
 
 X 
X 
 X 
X 
 X 
X 
  
X 
Product Eval. Scale (all selected) 
EDC 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Perceived Health Risk Rating 
EDC 
  
  
X 
  
X 
  
  
  
  
  
X 
  
X 
Cigarette Purchase Task - Usual Cigs 
EDC 
  
  
X 
  
X 
  
  
  
  
  
X 
  
X 
Cigarette Purchase Task  - Study Cigs 
EDC 
  
  
  
  
  
  
  
  
  
  
X 
  
X 
Product Purchase Task - All products 
EDC 
  
  
 X  
  
X 
  
  
  
  
  
X 
  
X 
Assessment Name 
Platform 
SCRN 
94 
BL 93 
BL 92 
MP 91 
MP 
00 
Week 
1-33 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
F-Up 
16 
Early 
Term 


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Assessment Name 
Platform 
SCRN 
94 
BL 93 
BL 92 
MP 91 
MP 
00 
Week 
1-33 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Follow
-Up 16 
Early 
Term 
Biomarker Modifiers 
Dietary Intake 
EDC 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Environmental Tobacco Exposure 
EDC 
  
X 
 
  
X 
  
X 
  
X 
  
X 
  
X  
OTHER  
Social & Environmental Influences 
on Tobacco Use 
EDC 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Product Expectancy 
Questionnaires 
EDC 
  
  
X 
  
 
  
  
  
  
  
 
  
  
Expected Utility (ANDS) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
End of Study Questionnaire 
EDC 
  
  
  
  
  
  
  
  
  
  
  
X 
X  
EXPOSURE BIOMARKER AND RISK FACTORS  
Carbon Monoxide 
Paper and REDCap 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
Total Nicotine Equivalents  
(1st void urine) 
BMW Database 
&Excel* 
 
X 
(X*) 
  
X 
 
X 
 
X 
  
X 
X 
 X 
 Total NNAL (1st void urine) 
BMW Database 
&Excel* 
  
X 
 (X*) 
  
X 
  
X 
   
X 
  
X 
  
X 
Mercapturic acids of acrolein, 
benzene, crotonaldehyde, & 
acrylonitrile (1st void urine) 
BMW e Database 
&Excel* 
  
X 
(X*)  
  
X 
 
X 
 
X 
 
X 
  
X 
8-epi-PGF (1st void urine) 
BMW Database 
&Excel* 
  
X 
(X*)  
  
X 
   
X 
 
X 
   
X 
  
X 
Spot Urine or Saliva for compliance 
testing 
BMW Database 
&Excel* 
  
  
  
  
  
X 
X 
X 
X 
X 
X 
  
X 
Nicotine Metabolite Ratio (saliva) 
BMW Database 
&Excel* 
  
X  
 
  
  
  
  
  
  
  
  
  
  
Genotyping  (saliva) 
BMW Database 
&Excel* 
  
  
X 
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment Name 
Platform 
SCRN 
94 
BL 93 
BL 92 
MP 91 
MP 
00 
Week 
1-33 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Follow
-Up 16 
Early 
Term 
1 Administered if early termination is within visit window; 2 Samples may be used if subject was on study cigarettes at early termination visit; 3Visit 3 was discontinued in the COVID-
19 amended telehealth procedures; 4Procedure was discontinued in the COVID-19 amended telehealth procedures* Banked and analyzed if needed. 


28. 
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Statistical Analysis Plan 
CENIC 2, Project 1 
4/15/2017 
Modified 1/30/2018 
Modified 8/8/2019 
Modified 10/16/2019 
Modified 11/10/2021 
Modified 4/11/2022 
Modified 11/21/2022 
 


 
 
 
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Table of Contents 
1. 
Introduction .......................................................................................................................................... 2 
2. 
Trial Objectives ..................................................................................................................................... 2 
3. 
Trial Design ........................................................................................................................................... 2 
3.1. 
Randomization ............................................................................................................................. 2 
3.2. 
Sample Size ................................................................................................................................... 2 
4. 
Study Populations ................................................................................................................................ 4 
4.1. 
Intent-to-Treat .............................................................................................................................. 4 
4.2. 
Definition of Sub-Group Population in Different Analyses ......................................................... 4 
5. 
Trial Endpoints ...................................................................................................................................... 4 
5.1. 
Primary Endpoints ........................................................................................................................ 4 
5.2. 
Secondary Endpoints .................................................................................................................... 5 
5.3. 
Exploratory Endpoint ................................................................................................................... 5 
5.4. 
Safety Endpoints ........................................................................................................................... 5 
6. 
Statistical Analysis ................................................................................................................................ 5 
6.1. 
General Approach ......................................................................................................................... 5 
6.2. 
Describing the Study Population ................................................................................................. 5 
6.3. 
Primary Endpoint Analysis ........................................................................................................... 6 
6.3.1. 
Primary Analysis ................................................................................................................... 6 
6.3.2. 
Secondary Analysis ............................................................................................................... 6 
6.4. 
Secondary Endpoint Analysis ....................................................................................................... 6 
6.5. 
Exploratory Endpoint Analysis ..................................................................................................... 6 
6.6. 
Subgroup Analyses ....................................................................................................................... 7 
6.7. 
Safety ............................................................................................................................................ 8 
6.8. 
Missing Data ................................................................................................................................. 8 
6.9. 
Interim Analyses ........................................................................................................................... 8 
6.9.1. 
Interim Analysis for Sample Size Re-estimation (see above) ............................................. 8 
6.9.2. 
Interim Analysis Blinded to Investigators ............................................................................ 8 
References .................................................................................................................................................... 9 
 
 


 
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1. Introduction 
This document will serve as the Statistical Analysis Plan for CENIC 2 Project 1, entitled “Impact of Very Low Nicotine 
Content Cigarettes in a Complex Marketplace”. This document describes the planned statistical analysis for evaluating 
the impact of very low nicotine content cigarettes (VLNC) vs. normal nicotine content (NNC) in a complex marketplace. 
Details for the proposed analysis of the primary, secondary and other endpoints are provided. 
2. Trial Objectives 
The overall goal of this project is to determine pattern of product purchase and use when very low (0.4 mg/g) vs. normal 
nicotine (15.8 mg/g) content cigarettes are available in the marketplace. All participants will have access to non-
combustibles (e.g., conventional smokeless tobacco, snus, e-cigarettes, medicinal nicotine) in addition to the study 
cigarettes, but no access to other combustible, non-study products (e.g., little cigars, cigarillos). The primary aim is to 
examine the effects of cigarettes that vary in nicotine content on the number of cigarettes smoked and days abstinent 
from combustible tobacco products in the context of a marketplace with alternative nicotine-containing products. The 
secondary aims are to examine the characteristics of products alternative to cigarettes that are chosen and to better 
understand responses to these various products. 
3. Trial Design 
This is a randomized, multi-center, non-blind study design. 700 subjects will be recruited from 3 study cites and 
randomized to one of two conditions: 
1) very low nicotine content (VLNC) cigarettes with access to non-combusted tobacco/nicotine products; or 2) normal 
nicotine content (NNC) cigarettes with access to non-combusted tobacco/nicotine products.  The two conditions will be 
referred as the VLNC and NNC groups, respectively, hereinafter.  
Participants will undergo three experimental phases in the study: Phase 1: two weeks of baseline; Phase 2: two weeks of 
usual cigarette marketplace, where subjects will have access to their usual brand cigarettes and non-combusted 
tobacco/nicotine products; and Phase 3: 12 weeks’ study cigarette market place, where subjects will have access to 
study cigarettes along with non-combusted tobacco/nicotine products.  
3.1. Randomization 
Subjects will be randomized at the end of Phase 2 with a 1:1 ratio to the two studied conditions described above. 
Randomization will be stratified by site using a blocked randomization scheme with random block sizes of 2, 4, and 
6. We anticipate no or less than minimal block effects in our data based on previous studies with similar design.  
3.2. Sample Size 
Sample size was re-estimated for this project by Xianghua Luo, PhD on 8/21/2019.  After discussion with members of 
the CENIC External Advisory Board and representatives of the National Institute of Drug Abuse and Food and Drug 
Administration, we changed the sample size from 700 to 500.   
More power analysis was performed on 11/10/2021 for 2 smaller sample sizes (N = 450 and 400), with all the other 
parameters being the same as the power analysis performed on 8/21/2019. 
We will enroll at least 400 rather than the 700 subjects originally proposed (200 per group) to the study and assume 
a 20% attrition rate over the 12-week post randomization period. Power analysis was performed for two of the 
primary outcomes in the primary aim: CPD smoked at the end of Phase 3 and smoke-free days during Phase 3. 
3.2.1 Methods: See Section 6.9 for interim analysis and the methods for the sample size re-estimation.  


 
Page 3 of 9 
3.2.2 Parameters based on interim data analysis 
Table 1. Estimated Parameters Based on Interim Data 
 
Standard deviation 
(SD) of CPD of the 
pooled sample 
Rate of abstinence 
of the control 
group 
Overall 
9.62 
5.04% 
By Gender 
 
 
    Female (44.7%) 
8.84 
4.52% 
    Male (55.3%) 
10.41 
5.48% 
By Age (years) 
 
 
    18-24 (0.2%) 
Not estimable due 
to the small sample 
size 
No data 
    25-44 (53.4%) 
10.20 
2.85% 
    >=45 (44.7%) 
8.95 
8.04% 
 
3.2.3  Power re-estimation 
The power re-estimation is based on a total of 500, 450, and 400 enrolled subjects with a 20% attrition rate over the 
12-week post randomization period. Power analysis was performed for the two primary outcomes: CPD smoked at 
the end of Phase 3 and smoke-free days during Phase 3. The effect of the two primary outcomes was assumed to be 
the same as previously assumed: 7 and 15 mean CPD for the VLNC and NNC group; and a 11 day difference (we 
assumed 12 abstinence days vs. 1 abstinence day, out of 84 days, previously) in the smoke-free days for VLNC vs. 
NNC. The nuisance parameters were based on the interim analysis (see Section 6.9 and Table 1 above). 
The two-sided type-I error rate for each outcome (CPD and abstinence) was set at α=0.025 (=0.05/2 
outcomes by the Bonferroni method) for the overall sample as previously designed. The type I error rate for the 
gender subgroup analysis was set to be α divided by the number of subgroups (=2) as previously designed. The type I 
error rate for the age subgroup analysis was set to be α divided by 2, rather than 3 because based on the interim 
data, there were <1% of participants in the 18-24 age group, hence, this age group was dropped from the power 
analysis. The Subgroup Analysis section (Section 6.6) in the SAP was revised accordingly. 
The same statistical methods were used as previously designed. Specifically, t-test was used for the CPD 
outcome. For the smoke-free days outcome, we first calculated the rate of smoke-free days by dividing the number 
of smoke-free days by the total number of days in Phase 3 (84 days) and then used z-test for the Poisson rate 
difference. PASS 14 was used for power calculations. 
The estimated power for 500, 450, and 400 subjects is presented in Table 2.  
Table 2. Power Analysis for Total Enrolled N=500, 450, and 400 
Primary outcomes 
VLNC 
NNC 
Overall 
sample 
3Subgroup 
analysis by 
sex 
4Subgroup analysis 
by age 
F 
M 
18-
24 
25-
44 
45+ 


 
Page 4 of 9 
N enrolled = 500  
1Cigarettes (study or non-study) per 
day smoked at the end of Phase 3 
(calculated as mean CPD based on 7 
days’ IVR data before the week 12 
visit) 
7 
15 
>.99 
>.99 
>.99 
- 
>.99 
>.99 
2Number of smoke-free days during 
Phase 3 (12 weeks or 84 days) 
11 days 
difference 
.94 
.55 
.61 
- 
.72 
.41 
N enrolled = 450  
1Cigarettes (study or non-study) per 
day smoked at the end of Phase 3 
(calculated as mean CPD based on 7 
days’ IVR data before the week 12 
visit) 
Same as 
above 
>.99 
>.99 
>.99 
- 
>.99 
>.99 
2Number of smoke-free days during 
Phase 3 (12 weeks or 84 days) 
.92 
.49 
.56 
- 
.67 
.37 
N enrolled = 400 
1Cigarettes (study or non-study) per 
day smoked at the end of Phase 3 
(calculated as mean CPD based on 7 
days’ IVR data before the week 12 
visit) 
Same as 
above 
>.99 
>.99 
>.99 
- 
>.99 
>.99 
2Number of smoke-free days during 
Phase 3 (12 weeks or 84 days) 
.88 
.43 
.50 
- 
.61 
.32 
1We assumed an equal SD for the two treatment arms. See Table 1 (left panel) for SD for the overall group, by gender, and by age. 
2The NNC arm’s rate of abstinence was based on the interim analysis result (see Table 1, right panel). 
344.7% female and 55.3% male, based on the interim data (see Table 1). 
40.2%, 53.4%, and 44.7% for 18-24, 25-44, and >= 45 years old, respectively, based on the interim data (see Table 1). 
 
4. Study Populations 
4.1. Intent-to-Treat  
The primary analysis of all endpoints will adhere to the intent-to-treat principle. Under this principle, all randomized 
subjects will be included in the analysis in the group to which they were randomized regardless of protocol 
violations and compliance to treatment assignment.  
4.2. Definition of Sub-Group Population in Different Analyses 
We intend to complete pre-planned subgroup analyses by sex, age groups (18-44, and 45+), and whether the 
participant was recruited pre- or post-COVID. Subgroup analysis will allow us to evaluate the consistency of the 
effect of VLNC vs. NNC across important subgroups. 
5. Trial Endpoints 
5.1. Primary Endpoints 


 
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• 
Cigarettes per day (CPD): the mean cigarettes (study and non-study cigarettes) smoked per day based on 7 days’ 
Daily Interactive Voice Response (IVR)-Revised (corrected with participant for errors) data before the week 12 
visit. 
• 
Smoke-free days during Phase 3: the number of days not smoking any combustible products based on IVR-
Revised. 
 
5.2. Secondary Endpoints 
• 
Biomarker: percent change in biomarker, CEMA, at the weeks 4, 8 and 12 visits during Phase 3 as compared to 
the last visit in Phase 2. 
• 
Study cigarettes per day (CPD): the mean of study cigarettes smoked per day based on 7 days’ Daily IVR-Revised 
data before the week 12 visit. 
• 
Seven-day abstinence: if total CPD=0 for all 7 days before the week 12 visit and CO ≤ 6ppm at week 12. 
 
5.3. Exploratory Endpoint 
• 
Non-combusted tobacco/nicotine products use: the number of days using any non-combusted tobacco/nicotine 
products in Phase 3. 
• 
Characteristics’ of products chosen (type, flavor, nicotine strength).  
• 
Biomarkers: percent change in biomarkers (Total Nicotine Equivalents, total NNAL, mercapturic acids at the 
weeks 4, 8 and 12 visits during Phase 3 as compared to the last visit in Phase 2. 
• 
Product satisfaction (Product Evaluation Scale if they used the product since the last visit; Cigarette Evaluation 
Scale if they smoked cigarettes since the last visit). 
• 
Perceived health risk (Phase 1, Phase 2 and end of week 12 of Phase 3: all products for all subjects). 
• 
Measures of discomfort/dysfunction: MNWS-R, QSU, CESD (NNC vs VLNC cigarettes irrespective of use of 
products). 
• 
Dependence (FTND, WISDM, PATH items; monthly for study cigarettes). 
 
5.4. Safety Endpoints 
• 
Potential adverse consequences: Change in mental (CESD) or physical health (heart rate, blood 
pressure, weight).  
• 
 Increased TNE (corrected by creatinine), calculated as change from Phase 1 baseline. 
• 
Adverse events and Serious Adverse events. 
 
6. Statistical Analysis 
6.1. General Approach 
All statistical analyses will be performed using SAS or R. All statistical tests will be two-tailed. A Bonferroni multiple-
comparisons adjustment will be used to account for multiple comparisons for each of the two primary endpoints (α 
= 0.025). Analyses of the secondary and exploratory endpoints will not be adjusted for multiple comparisons (α = 
0.05). All analyses will be completed using the intent-to-treat principle unless otherwise noted. Methods for 
handling missing data will be specified below.   
6.2. Describing the Study Population 
Descriptive statistics will be performed for data collected at different visits. Daily Interactive Voice Response (IVR) 
data will be summarized by phase and by visit (according to the actual visit dates or scheduled visit dates if a visit is 
missed). Baseline data will be compared between the two studied conditions with t test or Wilcoxon rank sum test 


 
Page 6 of 9 
for continuous variables and chi-square test or Fisher’s exact test for categorical variables, which include sex, age, 
race, education, menthol status, dependence (FTND), CPD, nicotine metabolite ratio (NMR), and TNE. Baseline CPD 
and TNE are based on Phase 2. 
6.3. Primary Endpoint Analysis 
The primary endpoints are (1) the mean cigarettes (study and non-study cigarettes) smoked per day based on 7 
days’ Daily Interactive Voice Response (IVR)-Revised data before the week 12 visit; and (2) the number of smoke-
free days out of the total number of days in Phase 3. 
6.3.1. Primary Analysis 
We expect the two groups to, on average, be balanced for important baseline characteristics due to 
randomization, so the primary analyses will be regressions for the difference in CPD and the number of smoke-
free days between two conditions, adjusting for only the baseline value (the mean CPD and the percent of 
smoke-free days during Phase 2, respectively).  Specifically, for the CPD outcome at week 12, we will use linear 
regression; for the number of smoke-free days, we will use Poisson regression or negative binomial regression 
when there is over-dispersion in the count data. 
6.3.2. Secondary Analysis 
For the Week 12 CPD and total number of smoke-free days, we will perform an adjusted analysis, adjusting for 
baseline value, study site (the randomization stratification factor), whether the Week 12 visit is pre-COVID or 
not, and any baseline characteristics (listed in Section 6.2) which are different at p<0.20, in multivariable 
regressions to improve efficiency.  
For the CPD outcome measured repeatedly, we will use linear mixed effects models (Verbeke and Molenberghs, 
2000). Fixed effects in the model will include: treatment group, visit, treatment group by visit interaction, 
baseline CPD, study site, whether the visit time is pre-COVID or not (as a time-dependent covariate), and any 
baseline characteristics (listed in Section 6.2) which are different at p<0.20. A random intercept for each subject 
will also be included in the model to account for within subject correlation. 
6.4. Secondary Endpoint Analysis 
The secondary endpoints will first be summarized by treatment group using mean and standard deviation. We will 
use similar adjusted regression methods for the secondary endpoints as for the primary endpoints described in 
Section 6.3.2. Details are described as follows. 
• 
For the percent change (relative to the measure at the end of Phase 2) of the biomarker measured repeatedly 
(weeks 4, 8, 12), we will use linear mixed effects models (Verbeke and Molenberghs, 2000). Fixed effects in the 
model will include: treatment group, visit, treatment group by visit interaction, study site, whether the visit time 
is pre-COVID or not (as a time-dependent covariate), and any baseline characteristics (listed in Section 6.2) 
which are different at p<0.20.  A random intercept for each subject will also be included in the model to account 
for within subject correlation. 
• 
For study cigarette smoked, similar analyses to total cigarettes per day will be performed.  
• 
For the abstinence outcome, we will use logistic regression. 
6.5. Exploratory Endpoint Analysis 


 
Page 7 of 9 
• 
For the number of days of non-combusted tobacco/nicotine products use, we will use Poisson or negative 
binomial regression, adjusting for baseline value, study site, whether the visit is pre-COVID or not, and any 
baseline characteristics which are different at p<0.20. 
• 
We will descriptively examine the characteristics of the various products that are chosen (type, nicotine 
strength, flavor).  
• 
For other biomarkers, similar analyses to Secondary Endpoint will be performed.  
• 
Product satisfaction (Product Evaluation Scale, Cigarette Evaluation Scale) at the first time a participant tried a 
product will be summarized using mean and standard deviation and compared between two treatment arms 
using linear regression.  
• 
Repeated measures of perceived health risk will be analyzed using the mixed effects model as described in 
Section 6.3.2. 
• 
Discomfort as assessed by MNWS-R, QSU, CESD will be compared between the VLNC vs. NNC cigarette 
conditions. The methods for comparing discomfort measures between VLNC and NNC cigarettes will be the 
same as for those described for the primary endpoints in Section 6.3.  
• 
Repeated measures of dependence of study cigarettes will be analyzed using mixed effects model described in 
Section 6.3.2. 
• 
We will examine the cross-sectional associations of non-combusted products use with cigarettes smoked and 
biomarkers at different visits using marginal generalized estimating equations (GEE) model (Diggle et al, 2002, 
Chapter 12) with the non-combusted product use as the independent variable. 
• 
We will explore baseline predictors of responses. We will use multivariable regressions to determine predictors 
of product use patterns, e.g., non-combusted product use, combusted product use, and smoke-free days.  
Predictor variables (depending on the responses measured) will include baseline CPD, total nicotine equivalents, 
FTND, age, sex, racial ethnic group, SES, perceived risk of products, product expectancy, product utility, social 
and environmental influences, contemplation ladder,  menthol cigarette use, and nicotine metabolite ratio 
(NMR, reflecting rate of nicotine metabolism).  Similar regression models as described in Sections 6.3 and 6.4 
will be used. 
6.6. Subgroup Analyses 
Subgroup analyses will play an important role in understanding the effect of nicotine reduction for different 
subpopulations. We will explore the effect of VLNC vs. NNC within subgroups defined by age (18-44 and 45+) or sex. 
We will also conduct subgroup analysis by the time of the participant being recruited, pre- or post-COVID. Subgroup 
analysis will follow the same approach described above as for the overall sample, but significance will be assessed by 
a Bonferroni-adjusted type-I rate (α/2 for a sex group or an age group, where α is the type-I error pre-specified for a 
specific outcome variable for the overall sample; See Section 6.1 for the values of α).  
Formal testing of the interaction between subgroup and treatment effect is not the primary concern of our 
subgroup analyses. Instead, subgroup analyses will provide information about the consistency of the treatment 
effect across subgroups, which will provide supplementary information for full understanding of the relationship 
between the studied interventions and the study endpoints. 


 
Page 8 of 9 
6.7. Safety 
The distinction between the primary/secondary outcomes and safety outcomes is not as clear in this trial as it would 
be in a typical clinical trial of a novel therapeutic agent. Many outcomes that would typically be considered potential 
adverse consequences or safety outcomes will be analyzed similarly as the secondary outcomes. For example, the 
other tobacco product use will be analyzed using similar statistical methods as for the other continuous 
primary/secondary endpoints.  
AEs and SAEs will be recorded as described in the Adverse Event SOP. AEs and SAEs will be tabulated and compared 
across treatment groups.  Count of AEs will be analyzed using Poisson regression or negative binomial regression as 
described in Section 6.4. 
6.8. Missing Data 
Every effort will be made to limit the amount of missing data in this trial. Study participants will be incentivized to 
attend study sessions and complete the daily IVR as detailed in the study protocol (Participate Compensation 
subsection). However, some level of missing data is inevitable in a study of this kind. We will compare subjects who 
do and do not complete the study in order to identify baseline covariates associated with study completion.  
We will use multiple imputation with the Markov Chain Monte Carlo (MCMC) method (Schafer, 1997; Little and 
Rubin, 2002), carried out in PROC MI in SAS. If the treatment group is associated with missing values, we will 
conduct multiple imputation for each treatment group separately (Molenberghs and Kenward, 2007). At least 10 
imputed data will be generated, with the treatment effect being assessed in each imputed data set. A final single 
assessment of treatment arm difference will be obtained from combining the results across the imputed datasets 
using PROC MIANALYZE in SAS. 
We will then conduct sensitivity analyses of primary and secondary endpoints by baseline imputation and the last 
observation carried forward (LOCF) method. Specifically, for the baseline imputation method, for a day with missing 
IVR data, the Phase 2 mean CPD will be imputed and non-abstinence will be assumed. For the outcome of 
biomarkers, missing data will be replaced by baseline values (i.e., no change in biomarkers). This will serve as a 
“worse-case scenario” as treatment group will be, on average, balanced at baseline. The results of these analyses 
will be compared to the primary analysis to evaluate the robustness of our conclusions.  
6.9. Interim Analyses 
6.9.1. Interim Analysis for Sample Size Re-estimation (see above) 
One interim analysis was conducted for sample size re-estimation. Nuisance parameters were estimated based 
on non-comparative data, whereas the significance level, the desired power, and the assumed targeted 
difference in outcome due to treatment assignment were not changed. In general, sample size re-estimations 
based on non-comparative data are expected to have a negligible effect on the Type I error (USDHHS, FDA, 
CDER, and CBER, 2018). 
First, we calculated the distribution of gender and age (18-24, 25-44, and ≥45 years old). For the outcome of 
CPD, we calculated the variance for the pooled sample. For the outcome of cigarette abstinence, we evaluated 
the control (NNC) group’s average rate of abstinence, which is calculated as the total number of smoke-free 
days observed among randomized participants divided by the total number of IVR days during Phase 3 (12 
weeks).  
6.9.2. Interim Analysis Blinded to Investigators 


 
Page 9 of 9 
The purpose of this interim analysis is to provide the FDA with preliminary results from this study, if the FDA 
issues a Proposed Rulemaking for reducing nicotine in cigarettes to non-addictive or minimally addictive levels.  
This analysis will be conducted:  (1) when the proposed rulemaking is issued; (2) by a statistician at Wake Forest 
who is independent of this project; (3) on the primary endpoints only.  The results will be reviewed and 
submitted by a researcher who is independent of the project.  Because this interim analysis will not be shared 
with the sponsor or investigators associated with the study, no changes will be made to the protocol as a result 
of this analysis.  
 
References 
 
Diggle P. J., Heagerty P. J., Liang K.-Y., Zeger S. L. (2002). Analysis of Longitudinal Data, 2nd edn. Oxford: Oxford 
University Press. 
 
Donny, E.C., Denlinger, R.L., Tidey, J.W., Koopmeiners, J.S., Benowitz, N.L., Vandrey, R.G., al’Absi, M., Carmella, S.G., 
Cinciripini, P.M., Dermody, S.S., Drobes, D.J., Hecht, S.S., Jensen, J., Lane, T., Le, C.T., McClernon, F.J., Montoya, I.D., 
Murphy, S.E., Robinson, J.D., Stitzer, M.L., Strasser, A.A., Tindle, H., Hatsukami, D.K. (2015). Randomized trial of reduced-
nicotine standards for cigarettes. New England Journal of Medicine, 373(14):1340-1349. 
 
Hatsukami, D.K., Luo, X., Dick, L., Kangkum, M., Allen, S.S., Murphy, S.E., Hecht, S.S., Shields, P., al’Absi, M. (2017). 
Reduced nicotine content cigarettes and use of alternative nicotine products:  Exploratory trial. Addiction, 112(1): 156-
167. 
 
Little, R.J.A., Rubin, D.B. (2002). Statistical Analysis with Missing Data, Second Edition, John Wiley & Sons, Inc., Hoboken, 
New Jersey. 
 
Molenberghs, G. and Kenward M. (2007). Missing Data in Clinical Studies. Wiley. 
 
Schafer, J.L. (1997). Analysis of Incomplete Multivariate Data. New York: Chapman and Hall. 
 
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research 
(CDER), and Center for Biologics Evaluation and Research (CBER). Adaptive Designs for Clinical Trials of Drugs and 
Biologics Guidance for Industry Draft Guidance. September 2018. 
 
Verbeke, G., Molenberghs, G., (2000). Linear Mixed Models for Longitudinal Data, Springer, New York, NY. 
 

ICF_001.pdf: 
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Impact of Very Low Nicotine ContentCigarettes in a Complex 
Marketplace Telehealth Visits plus 
Curbside Contact or In-Person Clinic Visits
Researcher Team Contact Information:  Dorothy Hatsukami, Ph.D.
For questions about research appointments, the research study, research results, or other 
concerns, call the study team at: 
Researcher Name:  Dorothy Hatsukami, Ph.D.
Researcher Affiliation: University of Minnesota
Phone Number: 612-626-2121
Email Address: hatsu001@umn.edu
Study Coordinator:  Andy Egbert 
University of Minnesota
Phone Number:  612-626-5107
Email Address: egber014@umn.edu
Supported By:  This research is supported by National Institute on Drug Abuse.
Financial Interest Disclosure:  The study team has no financial interest in the outcome of this 
study.
Why am I being asked to take part in this research study?
We are asking you to take part in this research study because you are a cigarette smoker who 
may or may not be interested in quitting smoking, but you are willing to participate in a study 
that involves study cigarettes and other tobacco or nicotine products.
What should I know about a research study?

Someone will explain this research study to you.

Whether or not you take part is up to you.

You can choose not to take part.

You can agree to take part and later change your mind.

Your decision will not be held against you.

You can ask all the questions you want before you decide.
Why is this research being done?
The purpose of this study is to understand how smoking a very low nicotine content (VLNC) 
cigarette compared to smoking a cigarette with nicotine levels about the same as your usual 
brand may affect your tobacco use pattern and measures of health. This study looks at whether 
you choose to use nicotine products, like nicotine gum or patch, e-cigarettes and other vaping 
devices or other tobacco products while you are assigned to the study cigarettes. The health 
measures that we examine include exposure to tobacco toxins and related cancer-causing 
agents, nicotine levels and risk factors for heart disease. The study will also evaluate how using 
the study cigarettes and use of these other nicotine and tobacco products affects withdrawal 
symptoms, mood and responses to the products, such as tobacco satisfaction.  


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The Food and Drug Administration (FDA) regulates tobacco products. One of the ideas for 
reducing the use of cigarettes is to reduce nicotine in cigarettes to levels below the point that 
they lead to addiction. This would mean that smoking a cigarette is truly a choice and not 
because you are addicted to the nicotine. If the FDA were to reduce these nicotine levels, 
cigarette smokers may use other less harmful products that contain nicotine. This study looks at 
whether smokers would choose to use other products and what products they would use.
The cigarettes used in this study are investigational and have been obtained through the 
National Institute on Drug Abuse. The FDA has not approved these cigarettes for marketing but 
has given us permission to use these cigarettes after review of our study protocol and the 
potential effects of the study cigarettes.  
How long will the research last?
We expect that you will be in this research study for about 20 weeks after screening. During this 
time, you will attend 13 telehealth visits that last 1-2½ hours and come in for either an in-
person clinic visit or a curbside visit for drop off or pick up of study supplies and drop-off of 
biological samples at the Delaware Clinic Research Unit. Telehealth visits will require you to 
have a computer, tablet, iPad or smart phone. You will attend weekly visits for 6 weeks and 
then every other week for 10 weeks. Finally, you will attend a follow-up visit 4 weeks after you 
stop the study products. 
How many people will be studied?
We expect about 100 or more people will be in this research study at the University of 
Minnesota. This study will also be done at Duke University, Wake Forest University, University 
of Pennsylvania, Brown University and the University of California-San Francisco and a total of 
500 people will be studied.
What happens if I say “Yes, I want to be in this research”?
Screening Procedures
If you agree to be in this study, we will find out if you are eligible to participate. To see if you 
are eligible, we will follow these screening steps. 

You will be asked questions about any symptoms of COVID-19 or any exposure to 
someone who is positive for the virus in the last two weeks.

You will be interviewed or asked to complete forms through a website link on the 
computer that asks personal questions about medical and emotional history, tobacco 
use history and dependence, smoking habits, motivation to quit, use of alcohol and 
other recreational drugs.  

We will ask your weight.


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
If you are a woman, we will ask about your use of birth control. 

You will be enrolled in a daily phone call system where you will track your cigarettes 
smoked per day (more information below).
If it appears you meet the study criteria thus far:

You will be asked to attend either a brief in-person visit at our clinic or, if you are not 
comfortable attending an in-person visit, we can arrange for a curbside pick up, or we 
will mail you the study materials. 

We will provide a monitor to take your vital signs and another device that you will use to 
take your carbon monoxide (CO) level at home. CO will tell us whether you have been 
smoking recently. We will provide instructions and watch you complete the test and you 
will show us the results. We may also check your urine sample that you drop off at the 
in-person or curbside visit to see if you are smoking enough to be in this study. If you 
attend an in-person or curbside visit, we may be able to provide both monitors in the 
same visit and make assessments in the clinic or in your home, respectively.  If the 
materials are mailed to you, we may send both devices to you or we may need to 
arrange two separate mailings and telehealth visits.

If you prefer the devices can be mailed out to you, you will contact us after you have 
received the monitors to set up another telehealth visit and we will show you how to 
use the monitors and check if your readings are acceptable. 
After you complete all of these measures, our medical staff will review the information to see if 
you meet study eligibility. If you are eligible, you will be enrolled in the study and begin the 
study procedures.
Study Procedures
There will be three phases in this study. 
Phase 1: During this Phase you will attend weekly telehealth and curbside or in-person clinic 
visits for two weeks. Our study research assistants will gather “baseline” information while you 
are still smoking your regular cigarette at your normal amount.  
Phase 2: In this Phase, you will attend weekly telehealth and curbside or in-person clinic visits 
for two weeks. We will show you our web-based marketplace on your computer, tablet, iPad or 
smart phone. This marketplace will have your usual brand cigarettes and other tobacco and 
nicotine products. These other products include snuff, snus, nicotine pouches, electronic 
cigarettes (e-cigs or vaping devices) and nicotine patch, gum and lozenge. You will be provided 
vouchers with points that can be exchanged for any of these products in our marketplace 
during the study. If you don’t use all of your points during the study, they can be traded for cash 
at the very end of the study. All tobacco or nicotine products that you use during the study 
should only be from our web-based market. You will come by our clinic for  pick-up of the study 
products you have chosen and drop off your first morning urine sample.


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Phase 3:  Phase 3 is the experimental phase. During this phase, you will attend 7 telehealth and 
curbside or in-person clinic visits over 12 weeks. For the first 2 weeks, you attend telehealth 
visits once every week. For the remaining 10 weeks, you will attend once every other week.  
You will be randomly assigned (like the flip of a coin) to a reduced nicotine content study 
cigarette or a study cigarette with levels of nicotine about the same as your usual brand of 
cigarettes. You will be told which of the study cigarettes you will receive. These cigarettes will 
be provided in the web-based marketplace along with the other tobacco and nicotine products. 
You will also be able to get other products (snuff, snus, nicotine pouches, electronic cigarettes 
(e-cigs or vaping devices) and nicotine patch, gum and lozenge) during Phase 3. You will 
continue to be provided a voucher with points at each visit that can be exchanged for your 
assigned study cigarette and/or any of the other products from our marketplace.
If you need more tobacco products, you can contact the clinic at any time during normal clinic 
hours to arrange to pick up products as long as you have enough saved points to trade. You 
may need to take your carbon monoxide level, vital signs or other safety measures on a 
telehealth visit prior to the pick-up of products. 
At the end of Phase 3, we will stop providing the study cigarettes and we will talk to you about 
the benefits of becoming smoke-free and provide you with information about quitting smoking.  
However, you can quit smoking at any time throughout the study and still remain in the study.
Follow-up: You will attend a telehealth and curbside or in-person clinic follow-up visit 1 month 
after the end of Phase 3, when you stop using the study cigarettes or our study products. At 
that final visit, you will return any Marketplace products except for nicotine replacement. We 
will also ask about your tobacco use and health since your last visit and complete other 
questionnaires.  
Curbside or In-Person Clinic Visits:  You will have an option of either picking up study product 
and dropping off your samples, empty cigarettes packs and used products either curbside or in 
our clinic for a brief visit. This option depends on your preference and the whether your clinic 
staff is able to see participants in person in the clinic due to clinic policies. 
Study Visit Procedures: 
At most of the telehealth visits, the following procedures will be carried out:

Answer questions about any symptoms of COVID-19 or any exposure to someone who is 
positive for the virus in the last two weeks. We will also have you take your temperature 
and provide us with the reading.  If you do not show any indications that you might have 
or at risk for COVID-19, we will conduct a telehealth visit and ask you can come to the 
clinic for a visit. 


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
Collect breath carbon monoxide (CO) level to measure your amount of smoking.  

Complete several online forms asking about tobacco use, withdrawal symptoms, urges 
to smoke, mood, reaction to the products, and current medication use and health 
symptoms.  A website link will be sent to you.  

Collect blood pressure and pulse. 

Provide your weight.

Provide you with supportive counseling to help you follow the study instructions. 

Review the amount of study cigarettes that you have decided to get with your points. 

Review your study cigarette packs (full, empty or partial packs) and how many you have 
smoked since last visit.  These cigarettes are owned by the government and we are 
required to keep careful track of them. You will need to keep track of all of the study 
cigarettes we give to you. 

For Phase 2 and 3, select study products using the Marketplace App (link will be 
provided to you).  Review the amount of other tobacco or nicotine products that you 
decided to get with your points.
After you have completed these measures, we will set up a time for you to come to the clinic’s 
curbside location or be seen in-person in the clinic. You will be provided a mask that you will be 
required to wear while interacting with the researcher who will also be wearing personal 
protection to keep you safe. 
At the curbside or in-person visit, you will:

Return your study tobacco or nicotine products containers (full, empty or partially used) 
and review how much you have used.

Receive the study products you have chosen using the Marketplace app.

Provide a saliva sample you had collected on the telehealth call. A few of the samples 
will be randomly picked to check for accurate reporting of the products that you are 
using.
At several visits, the following added measures will take 30-45 minutes more to complete:  

A urine sample from the first time you urinate in the morning after waking up will be 
collected and brought to the curbside or in-person clinic visit. This urine sample will be 
tested for nicotine, cancer-causing agents and other chemicals that are in tobacco and 
their breakdown products. This sample will be collected six times. 

Additional questionnaires that you will complete through telehealth that look at things 
that might affect the results from your urine samples. These questionnaires are related 
to your diet, contact with smoke at home or work, and alcohol or recreational drug use.

If you are a woman who could get pregnant, we will also test your urine sample for 
pregnancy at some visits using your first void urine sample. If your visit is over 8 hours 
from the time of collection, we will ask you to collect a spot urine right before your visit. 
If you become pregnant while you are smoking the study cigarettes or using any tobacco 
products, you will not be eligible to continue in the study. 


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You will provide a saliva sample at the Phase 1 visits. The sample may be used for 
looking at genes related to how your body breaks down nicotine and other toxins 
related to tobacco and nicotine or your health risks related to tobacco and nicotine use.
Daily Phone Call
Every day throughout the study, you will report the number of cigarettes you smoke and any 
other tobacco or nicotine products you use to an automated message system. You will make 
this report using your home phone or a cell phone. We will give you instructions on how to 
complete the daily calls. You will complete the daily telephone calls every morning for 17 weeks 
while you are in the study. These phone calls will take less than 3 minutes. To be enrolled in this 
telephone system, we will be providing the vendor’s website with some identifiable information 
(your telephone number only). This information will be used for website enrollment only; the 
data analysis group will not have access to identifying information nor will it be shared with 
anyone outside of this study.
Randomization to Study Cigarettes
The study cigarettes you will receive are chosen by chance, like flipping a coin. Neither you nor 
the study staff will choose what treatment you get. You will have an equal chance of being 
given either the Very Low Nicotine Content (VLNC) cigarette or the Normal Nicotine Content 
(NNC) cigarette. Both you and the researchers will know which type of cigarette you receive. 
You will be able to choose to receive menthol or non-menthol cigarettes.
What are my responsibilities if I take part in this research?
If you take part in this research, you will be responsible for completing the procedures 
described above including attending visits, keeping track of tobacco and nicotine use through 
daily calls, keeping track of the study products you receive and providing the biological samples. 
In addition, you will be asked to avoid smoking any non-study substances including marijuana 
use, for 48 hours before each appointment as the exposure to smoke will interfere with our 
tests.
What happens if I do not want to be in this research?
This is a research study and you can choose whether or not you want to participate. 
What happens if I say “Yes”, but I change my mind later?
You can leave the research study at any time. Leaving will not be held against you. If you decide 
to leave the research study, contact the study staff so that we can schedule an exit visit and you 
can bring back any study cigarettes. 
Choosing not to be in this study or to stop being in this study will not result in any penalty to 
you or loss of benefit to which you are entitled. Meaning, your choice not to be in this study will 


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not negatively affect your right to any present or future medical treatment, your academic 
standing as a student, or your present or future employment. 
If you stop being in the research, already collected information about you will not be removed 
from the study database.
What are the risks of being in this study?  Is there any way being in this study could be 
bad for me?
This research may hurt you in the following ways and you should be aware of these before 
deciding to be part of the study:
Smoking Any Cigarettes
Cigarette smoking is the leading cause of preventable death in the United States and kills half of 
all long-term users. On average, smokers die 10 years earlier than nonsmokers.  
Smoking any cigarette is harmful to a person's health and can lead to the following medical 
problems:
a) Heart and blood vessel disease: Heart disease, heart attack, stroke, peripheral vascular 
disease (PVD), reduced blood circulation, abdominal aortic aneurysm;
b) Lung disease: Emphysema, asthma, bronchitis, tuberculosis and chronic airway 
obstruction (COPD); 
c) Cancer: Lung, bladder, liver, colon, cervical, esophageal, kidney, larynx, mouth, 
pancreatic, throat, stomach cancers and acute myeloid leukemia;
d) Diabetes; 
e) Changes in immune function, rheumatoid arthritis;
f)
Other health risks: 
o
Infertility
o
Tubal pregnancy
o
Miscarriage 
o
Sudden infant death 
syndrome (SIDS)
o
Birth defects
o
Lower bone density in 
postmenopausal women 
and increased risk for hip 
fracture in women 
o
Male sexual dysfunction
o
Vision problems 
o
Age-related macular 
degeneration
g) Smoking and nicotine can affect your heart and blood vessels which may result in 
changes in blood pressure and/or heart rate; 
h) Addiction to nicotine.
 
Smoking Study Cigarettes
The study cigarettes are made in the same way as your usual cigarettes. But in order for the 
study cigarettes to be lower in nicotine, they are made from genetically modified tobacco 
plants (GMO). As with other tobacco products made by tobacco companies, this tobacco has 
not been tested for safety.  Long-term effects of inhaling the study cigarettes are unknown. 
Smoking the study cigarette is not any less risky than your usual brand of cigarette and could 
pose increased health risks. 


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There is a potential for a change in your use of cigarettes due to the lower nicotine levels 
including how you inhale the smoke or smoking more cigarettes per day. This increased rate of 
smoking may continue after completing the study. You may experience an increase in exposure 
to carbon monoxide, a gas from smoke, due to altered smoking habits. 
Nicotine Withdrawal or Too Much Nicotine
You may experience symptoms of nicotine withdrawal if you are assigned to the very low nicotine 
content cigarettes. These symptoms may include: craving tobacco, irritability, frustration or anger, 
anxiety, nervousness, impatience, restlessness, sleep problems, trouble with concentration, 
depressed or sad mood, constipation, dizziness, coughing, nausea, sore throat and increased 
appetite or weight gain. These feelings can be uncomfortable, but are of low risk.
The use of the nicotine replacement products (gum, lozenges or patch) and use of other tobacco or 
nicotine products in addition to smoking cigarettes may cause some symptoms of too much nicotine. 
Symptoms of too much nicotine may include headache, dizziness, shakiness, nausea, vomiting or 
diarrhea, weakness and fast heartbeat. You will be monitored for any of these side effects to make 
sure you are you safe. If serious side effects occur, we may stop the use of the nicotine replacement 
or study products. Use of both cigarettes and other tobaccos may result in an increase in your 
nicotine and tobacco related toxin levels.
Worsening of Mental Health Symptoms
Smoking cigarettes and nicotine can affect a person’s mood and emotions and are associated with 
mental health problems including major depressive disorder, general anxiety disorder, bipolar 
disorder and eating disorders. Any changes in nicotine or tobacco consumption could have a negative 
effect on mental health conditions.
Interaction of Study Cigarettes with Medications
Quitting smoking can greatly benefit your health. However, changes in your smoking can lead to 
changes in the levels of your medications. Please make sure to tell us about all the medications you 
take. We also recommend you discuss any planned or actual changes in how much you are smoking 
with your doctor, especially if you are taking medications for mental health, heart or blood vessel 
problems, or other serious diseases.
Nicotine Replacement (Medicinal Nicotine) or Nicotine Pouches
Side effects of the nicotine replacement (nicotine lozenge, gum, or patch) or nicotine pouches may 
occur. Side effects from the nicotine gum or lozenge or nicotine pouches include mouth and throat 
irritation, mouth sores, hiccups or belching, dizzy or lightheaded, upset stomach, vomiting, 
heartburn, diarrhea and high blood pressure. Using the nicotine gum may aggravate the jaw joint or 
dental work. You should not use the gum if you have dentures. Side effects of the nicotine patch 
primarily include redness, itching or swelling at patch site and sleep problems.
Smokeless Tobacco/Snus


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If you use smokeless tobacco products, you could experience an increased risk for mouth sores, gum 
disease and tooth loss, nausea or upset stomach, vomiting, or high blood pressure. These risks also 
include nicotine addiction. Smokeless tobacco products may increase the risk of cancer, particularly 
oral and pancreatic cancer. However, these risks are less than the health risks you are exposed to as 
a cigarette smoker.
E-cigarettes (e-cigs, vaping devices)
Do not let anyone else use your study e-cigarette or vaping device.  
Side effects of the electronic cigarette or vaping devices are not known since little research has 
been done on this product.  There is a notice from the FDA regarding the safety of this product 
that says they do not know whether e-cigarettes or vaping devices are safe for their intended 
use, how much nicotine or other potentially harmful chemicals are being inhaled during use, or 
if there are any benefits associated with using these products. Some of the samples tested have 
low but detectable levels of toxic chemicals. Side effects may be similar to the use of the 
nicotine inhaler, such as sore throat or burning in the throat, stomachache, nausea, or pain, 
belching, coughing, or stuffy nose. They may also include changes in taste, mouth sores, dry 
mouth, headache, dizziness, increased heart rate or palpitations, tremors, vomiting or diarrhea. 
The FDA has recently acknowledged reports of seizures following the use of an e-cigarette 
between 2010 and 2019. They are carefully monitoring e-cigarette adverse event reports to 
determine if e-cigarette use is linked to seizures.  If you experience loss of consciousness, 
memory lapse, change in mental status, confusion, tremor, shaking, or seizure discontinue the 
use of the device and contact study staff immediately.
CDC and FDA are investigating recent reports of serious lung disease associated with use of 
vaping devices. Many of the incidences are related to vaping cannabis (THC) oil.  FDA has 
advised consumers to avoid buying vaping products on the street and refrain from using THC oil 
or modifying or adding any substance to products purchased at stores. If you experience any 
symptoms such as cough, shortness of breath or chest pain, nausea, vomiting or diarrhea seek 
prompt medical attention. 
In addition, there have been rare occasions where the batteries in e-cigarettes and vaping 
devices have exploded and injured users.  You should not store a device where the power 
button can be repeatedly turned on accidently (like in a pocket) as it may overheat and cause 
burns.  Some people may have an allergic reaction to the compounds in the e-liquid such as 
propylene glycol, glycerin or flavor additives.  Defective cartridges, tanks or devices may leak e-
liquid. If this should happen, wash the exposed area to remove the e-liquid immediately. The e-
liquid does contain nicotine, an addictive chemical that could lead to long-term use.  In 
addition, nicotine may contribute to diseases associated with smoking.  While not harmless, e-
cigarettes and vaping devices generally contain fewer toxins than smoked tobacco products.  


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The liquid used in e-cigarettes and vaping devices (often called e-liquid or e-juice) can contain 
nicotine that can cause harm and possible death if the e-liquid or the refill cartridges 
containing e-liquid are swallowed. 
Keep all e-liquid and cartridges away from pets and children.
If you or someone else drinks the liquid, call the Poison Control Center (1-800-222-1222) immediately 
and contact study staff.  For skin exposure: wash well with soap and water for 10-15 minutes.      
Continued use of dual tobacco products
There is a risk you may continue to use other tobacco products along with smoking after the study is 
completed. We will look at your use at your one-month follow-up visit and will look at your nicotine 
levels to see whether you are exposed to more nicotine than when you started the study. We will 
encourage you to quit tobacco use and we will provide referral information for you if you are using 
any tobacco products. You are encouraged to call us at the number listed at the beginning of this 
document if you have any questions or concerns. 
Survey Questions 
You will be asked questions about your medical history, drug and alcohol use and mood.  Answering 
these kinds of questions may make some people feel uncomfortable.
Abnormal Vital Signs or Other Health Findings
You will have your vital signs (heart rate and blood pressure) taken every visit.  You may find out that 
your blood pressure or heart rate is out of the normal range. You may tell us about health problems 
during the study (things like chest pain, numbness or shortness of breath) that our medical staff feels 
should be examined more closely. If this should happen, we will ask you to follow up with your 
primary care doctor and may require you to do so to stay in the study.
Breach of Confidentiality
There is a risk of loss of privacy if other people find out about your participation. This would include 
the alcohol and drug testing results. All efforts are made to keep your information confidential, but 
confidentiality cannot be guaranteed.
Other
If you are using public transportation to get to your appointment, you may put yourself at 
increased risk for exposure to the COVID-19 virus. We advise you to wear a mask and practice 
social distancing when possible while using public transportation.
In addition to these risks, this research may hurt you in ways that are unknown.  These risks 
may be a minor inconvenience or may be so severe as to cause death.  At each visit, we will ask 
you how you feel, and if we think that being in this study is putting your health at risk, we will 
stop your participation. 


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If any of these side effects mentioned above occur, please notify the research staff (612-624-
5178 or 763-242-5119 after hours).  If these side effects are serious, discontinue the use of the 
study products.
What do I need to know about reproductive health and/or sexual activity if I am in this 
study?  
Risk of Smoking While Pregnant 
Smoking any cigarette is a risk for pre-mature birth, stillbirth, and low birth weight. To avoid 
these risks, it is important that you are not pregnant during this study or while using any tobacco 
products. Avoiding sexual activity is the only certain method to prevent pregnancy unless you are 
at an age where your periods have stopped for more than 2 years or you have had a 
hysterectomy. However, if you are sexually active and able to become pregnant, you should use 
an appropriate “double barrier” method of birth control (such as using a diaphragm, intrauterine 
device (IUD), or contraceptive sponge, in addition to your partner’s use of a condom). You should 
be aware, pregnancy could still result even with the use of these birth control methods. While 
use of prescribed “birth control” pills, injections, or implants is an acceptable method of birth 
control to be in this study, you should be aware that use of this type of birth control is not 
recommended for women who smoke. Smoking greatly increases the chance of serious heart or 
blood vessel side effects from oral contraceptive (birth control pills) use. The risk increases with 
age and with heavy smoking (about 15 or more cigarettes per day) especially in women over 35 
years of age. It is unclear whether smoking while using birth control injections or implants 
increases the risks of heart attack and stroke, so it is recommended that women who use 
injections or implants do not smoke.
You should not be or become pregnant or breastfeed while participating in this research study. 
Pregnancy tests will be done at the beginning (baseline) and every month while you are 
smoking study cigarettes. If you become pregnant while participating in this research study, it is 
important that you tell the study doctor or other research team member immediately. You may 
be required to stop participation in this study.  We will ask to follow up with you after you have 
had your baby to follow pregnancy outcomes in the event of a pregnancy.
Will it cost me anything to participate in this research study?
Taking part in this research study will not lead to any costs to you. 
Will being in this study help me in any way?
There is no direct benefit for you from taking part in this study. However, this information will 
help inform the FDA about what happens when nicotine levels in cigarettes are reduced. 


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This is not a quit smoking treatment program. If you decide to quit smoking during the study, you 
may continue in the study. You will not be required to smoke the study cigarettes if you choose to 
quit smoking.  
What happens to the information collected for the research?
Efforts will be made to limit the use and disclosure of your personal information to people who 
have a need to review this information. We cannot promise complete privacy. Organizations 
that may inspect and copy your information include the Institutional Review Board (IRB - 
oversees subject safety for all studies) and other representatives of this institution, including 
those that have responsibilities for monitoring or ensuring compliance. 
Certificate of Confidentiality 
In this study, you will be asked about illegal activities or highly personal behavior. We have 
obtained a Certificate of Confidentiality from the federal government. This means in most cases 
the information you share is protected and will not be released to authorities upon request. 
However, we may still be required under certain circumstances to release your information. 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States federal or state government agency sponsoring the project and that will be used for 
auditing or program evaluation of agency funded projects or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA). 
You should understand that a Certificate of Confidentiality does not prevent you or a member 
of your family from voluntarily releasing information about yourself or your involvement in this 
research. If you provide your written consent to receive research information, then the 
researchers will not use the Certificate to withhold that information. The Certificate of 
Confidentiality will not be used to prevent disclosure of certain information to state or local 
authorities.  If we learn about current or ongoing child or elder abuse or neglect, we may be 
required by law or policy to report this information to authorities. In addition, if we learn that 
you intend to harm yourself or others, we may be required to report this information.  
Some of the urine and saliva collected will be kept for future research along with information on 
age, race, health and tobacco use history and your response to study products. Although the 
exact tests that will be done are not known at this time, researchers may study: 1) how diet, 
lifestyle, environment, race/ethnicity, age and other factors are related to the development of 
cancer or other diseases or affect use of products; 2) how differences in genes affects one’s 
ability to process substances that cause diseases; 3) how damage to one’s chromosomes is 
related to risk of cancer and other diseases. Any studies using these stored samples for other 
purposes will be done in accordance with the guidelines of the Committee on Human Studies 
and with federal regulations for the protection of human subjects. The specimens will be kept at 
the Masonic Cancer Center Biobank and they will be kept until they are used up or no longer 


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needed. These samples may be shared with other investigators associated with this Center. 
These samples will only be identified by your study number. 
Information on your participation in this study will be shared, as needed, with the other 
researchers in the Tobacco Research Programs. This includes information about the type and 
duration of study, your health information and tobacco use status. The information is shared to 
make sure you are only in one study at a time, meet the eligibility criteria to participate and to 
maintain your safety.
A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. This law generally will protect you in the 
following ways:

Health insurance companies and group health plans may not request your genetic 
information that we get from this research.

Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums.

Employers with 15 or more employees may not use your genetic information that we 
get from this research when making a decision to hire, promote, or fire you or when 
setting the terms of your employment.
Be aware that this federal law does not protect you against genetic discrimination by 
companies that sell life insurance, disability insurance, or long-term care insurance.
The sponsor, monitors, auditors, the IRB, the University of Minnesota Research Compliance 
Office and other University compliance units, the US Office of Research Integrity (ORI), the US 
Office for the Protection of Human Research Protections (OHRP), National Institute on Drug 
Abuse, and the US Food and Drug Administration (FDA) may be granted direct access to your 
study records to oversee the research. By signing this document, you are authorizing this 
access. 
We may publish the results of this research. However, we will keep your name and other 
identifying information confidential.
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Website will not include information that can identify you. At most, the 
Website will include a summary of the results. You can search this Website at any time.
Who do I contact if I have questions, concerns or feedback about my experience?
This research has been reviewed and approved by an Institutional Review Board (IRB) within 
the Human Research Protections Program (HRPP). To share feedback privately with the HRPP 


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about your research experience, call the Research Participants’ Advocate Line at 612-625-1650 
(Toll-free: 1-888-224-8636) or go to z.umn.edu/participants.  You are encouraged to contact the 
HRPP if: 

Your questions, concerns, or complaints are not being answered by the research team.

You cannot reach the research team.

You want to talk to someone besides the research team.

You have questions about your rights as a research participant.

You want to get information or provide input about this research.
Will I have a chance to provide feedback after the study is over? 
After the study, you might be asked to complete a survey about your experience as a research 
participant. You do not have to complete the survey if you do not want to. If you do choose to 
complete the survey, your responses will be anonymous.  
If you are not asked to complete a survey, but you would like to share feedback, please contact 
the study team or the HRPP. See the “Investigator Contact Information” of this form for study 
team contact information” and “Whom do I contact if I have questions, concerns or feedback 
about my experience?” of this form for HRPP contact information.
Can I be removed from the research without my OK?
The study doctor or Principal Investigator may stop your participation without your approval. Some 
examples of why this could happen is if you develop medical problems, experience serious side 
effects to the study cigarette, or do not comply with the study requirements or your appointment 
schedule.
We will tell you about any new information that may affect your health, welfare, or choice to 
stay in the research.
What else do I need to know?
In the event that this research activity results in an injury, treatment will be available, including 
first aid, emergency treatment and follow-up care as needed. Care for such injuries will be 
billed in the ordinary manner to you or your insurance company. If you think that you have 
suffered a research related injury, let the study physicians know right away.
 
Will I be compensated for my participation? 
If you agree to take part in this research study, we will give you up to $770 for your time and 
effort. You will receive $10 for transportation for curbside or in-person clinic visits and $40 for 
your time at each visit in the form of a Greenphire Clincard described below. You will receive an 
additional $15 for the longer visits where we collect samples and you complete additional 
forms. 


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In addition, at the end of the study you will receive $10 for each week that you completed all of the 
daily calls. If you have completed all other study procedures, you will receive a $300 bonus. To be 
eligible for the bonus you must attend the study visits, provide the urine and saliva samples, keep 
track of study products, complete your daily phone calls and avoid the use of non-study products you 
have obtained from outside our Marketplace. If you have a slip and use a non-study product and 
accurately report this information to us, you will receive $100 for the bonus.  In addition, at follow-up 
you can trade in your unspent points. If you choose not to use the points and have not bought 
products outside of the study marketplace, the remaining points can be traded for dollars that will be 
added to your final payment at the end of the study (1 point = $1).  Both the bonus and the 
exchange of voucher points for money will be provided only if you complete the study, and your 
biological sample results show you have avoided non-study products or accurately reported a slip. 
If you are withdrawn from the study by the Principal Investigator for safety reasons, you will receive 
the amount you have earned prior to exiting the study.
The bonus and point exchange amount will be available to you when we have received the results of 
the lab tests form your spot urine samples (at or after the follow up visit). If the lab tests show that 
you have avoided non-study products, you will receive the bonus and the point exchange amount.  
You will be paid for all aspects of the study that you do complete and not paid for study tasks that 
you missed. 
The schedule below shows the amount you receive if you complete all study activities.
Visit
Transportation 
Compensation
(Cash or gift card)
Study visits 
Compensation
(Gift card)
Biological Samples
(Gift card)
Screening visit
$10 (in-person only)
$40
-
Phase 1 visit 1
$10
$40
$15
Phase 1, visit 2
$10
$40
$15
Phase 2, visit 3
$10
$40
-
Phase 2, visit 4
$10
$40
$15
Phase 3, visit 5
$10
$40
-
Phase 3, visit 7
$10
$40
-
Phase 3, visit 8
$10
$40
$15
Phase 3, visit 9
$10
$40
-
Phase 3, visit 10
$10
$40
$15
Phase 3, visit 11
$10
$40
$15
Phase 3, visit 12
$10
$40
$15
Follow-up, visit 13
$10
$40
$15
Total for visits:  $770
$130
$520
$120
After completing the follow-up visit, you would receive the additional amount you have earned for 
bonus, telephone calls and voucher points:
Diary Calls ($10 per week when all calls are completed)
Maximum $170
Bonus for completing all study requirements
Up to $300


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Tobacco/nicotine product points 
(amount of voucher points that you have left)
Amount will vary but the 
maximum is $200
Payment will be made using a pre-paid debit card called Greenphire ClinCard. It works like a 
bank debit card. We will give you a debit card and each time you receive a payment for 
participation in this study, the money will be added to the card after each completed visit.
You may use this card at any store that accepts MasterCard or you can use a bank machine to 
remove cash. However, there may be fees drawn against the balance of the card for cash 
withdrawals (ATM use) and inactivity (no use for 3 months). We will give you the ClinCard 
Frequently Asked Questions information sheet that answers common questions about the debit 
card. You will also receive letters with additional information on how you can use this card and 
who to call if you have any questions. Be sure to read these letters, including the cardholder 
agreement, for details about fees. 
The debit card system is administered by an outside company. The company, Greenphire, will 
be given your name, address, phone number, and social security number. They will use this 
information only as part of the payment system. Your information will not be used for any 
other purposes and will not be given or sold to any other company. Greenphire will not receive 
any information about your health status or the study in which you are participating.
You should be aware that the income you receive from being in the study may be considered taxable 
income and need to be reported to the IRS on your income tax return. You will be required to 
complete a W-9 Request for Taxpayer Identification Number (TIN) to provide the University of 
Minnesota with the information needed to give you the study payments and report income paid to 
you. If you receive more than $600 in a calendar year from the University of Minnesota, the income 
will be reported to the IRS, as required by law, and an IRS Form 1099 (Miscellaneous Income) will be 
sent to you. It is up to you to understand how this payment may affect your tax or public benefit 
status.
Study Results 
After the study is fully completed, the data has been analyzed and the results written up, you 
will receive a letter informing you of the results.
Optional Elements:
The following research activities are optional, meaning that you do not have to agree to them in 
order to participate in the research study. Please indicate your willingness to participate in 
these optional activities by placing your initials next to each activity.


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I agree
I disagree
I agree to provide a saliva sample that will be stored for possible future 
gene analysis
The researcher may contact me in the future to see whether I am 
interested in participating in other research studies by the Principal 
Investigator of this study or other investigators working with Tobacco 
Research Programs at the University of Minnesota. 
The researcher may keep any leftover urine or saliva samples taken 
during the study. These samples may be used for other research not 
related to this study. These samples will be retained in non-identifiable 
form, meaning that there will be no information associated with the urine 
or saliva samples that will allow anyone to readily know my identity. The 
samples may be shared with other investigators in the study Center or 
working with the Tobacco Research Programs. 
Your signature below documents your permission to take part in this research.  You will be 
provided a copy of this signed document.
_______________________________________________      __________________
Signature of Participant                                                                   Date
_______________________________________________
Printed Name of Participant
______________________________________________           __________________
Signature of Staff Obtaining Consent                                               Date
______________________________________________
Printed Name of Staff Obtaining Consent