Telehealth Study Assessing the Removal of Filter Ventilation on Smoking Behavior and Biomarkers
Phase: NA
Conditions: Tobacco Use
Sponsor: Masonic Cancer Center, University of Minnesota

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 Consortium on Methods Evaluating Tobacco (COMET): Filter Ventilation and Product Standards 
COMET2:  PROJECT 1 – STUDY 2 
 
Telehealth study assessing the removal  
of cigarette filter ventilation on smoking behavior and biomarkers  
 
 
Project Leader: 
Dorothy K Hatsukami, PhD    
Department of Psychiatry UMN  
University of Minnesota 
Tobacco Research Program  
717 Delaware St SE #260 
Minneapolis, MN 55414 
E-mail: hatsu001@umn.edu 
Phone: 612-626-2121 
 
Co-Project and Site Leader: 
Peter Shields, M.D. 
Ohio State University Comprehensive Cancer Center 
460 W. 10th Avenue, 9th Floor, Suite D920 
Columbus, Ohio 43210-1240 
E-mail: peter.shields@osumc.edu  
Phone: 641-688-6563 
 
Statistician: 
Bruce Lindgren 
ACH CTSI Biostatistics 
lindg001@umn.edu 
 
Funding Sponsor:   National Cancer Institute 
 
UMN IRB #:  STUDY00012328 
OSU IRB #:  #2019C0003 
 
CPRC #:  2021LS034 
 
Version Date: 
V3: 12/08/2022  
 

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Revision History 
 
Revision Summary 
Protocol 
Version date 
Consent Form 
Version Date 
IRB 
Approval 
Date 
 
1 
Change from “roll you own” cigarettes to a 
manufactured cigarettes; brief in person or 
curbside visit 
 
5/11/21 
5/11/21 
6/23/21 
 
2 
Addition of buccal cell collection and 
inhalation measures on a subset of 
subjects; minor grammar corrections 
 
8/5/21 
8/5/21 
9/17/21 
 
3 
Changed number of randomized subjects to 
162; Increased cigarette per day eligibility 
criteria from 30 to 35 cigarettes; added 
Tobacco Policy Support Questionnaire; 
minor corrections  
 
12/08/22 
7/12/22 
 
 
 

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Table of Contents 
ABBREVIATIONS ............................................................................................................................................... 4 
STUDY SYNOPSIS .............................................................................................................................................. 6 
1 
STUDY OBJECTIVES AND HYPOTHESES .................................................................................................. 7 
2 
BACKGROUND ..................................................................................................................................... 7 
3 
SUMMARY ......................................................................................................................................... 10 
4 
SUBJECT SELECTION ........................................................................................................................... 10 
5 
EXPERIMENTAL DESIGN: ..................................................................................................................... 12 
1. 
STUDY PROCEDURES .......................................................................................................................... 14 
6 
DATA COLLECTION ............................................................................................................................. 27 
7 
RISKS TO SUBJECTS AND OTHERS ........................................................................................................ 32 
8 
POTENTIAL BENEFITS OF PARTICIPATION ............................................................................................ 34 
9 
ADVERSE EVENT REPORTING, SAFETY MONITORING AND WITHDRAWAL OF SUBJECTS ........................ 34 
10 
STATISTICAL CONSIDERATIONS ........................................................................................................... 38 
11 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................................. 42 
12 
CONDUCT OF THE STUDY .................................................................................................................... 45 
PROCEDURE TABLE ......................................................................................................................................... 47 
13 
REFERENCES ....................................................................................................................................... 50 
 
 
 

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Abbreviations 
AE: 
Adverse Events: is an undesired harmful effect resulting from a medication or other intervention 
/ study procedure. 
ANOVA: 
Analysis Of Variance: is a collection of statistical models used to analyze the differences between 
group means and their associated procedures 
BDI-II: 
Beck Depression Inventory, 2nd Edition: created by Aaron T. Beck, is a 21-question multiple-
choice self-report inventory, widely used instruments for measuring the severity of depression. 
BP: 
Blood Pressure: is the pressure exerted by circulating blood upon the walls of blood vessels and is 
one of the principal vital signs. 
COMET: 
Consortium on Models Evaluating Tobacco: the acronym selected for this program project grant. 
CES: 
Cigarette Evaluation Scale: a 12-item questionnaire that assesses the degree to which smokers 
experience the reinforcing effects of smoking. 
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. 
DVT/PE: 
Deep Vein Thrombosis / Pulmonary Embolism: 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. 
FDA: 
Food and Drug Administration: is a federal agency responsible for protecting and promoting 
public health through the regulation and supervision of tobacco products and other products. 
FSPTCA: 
Family Smoking Prevention and Tobacco Control Act: is a federal statute signed into law by 
President Barack Obama on June 22, 2009 that gives the Food and Drug Administration the power 
to regulate the tobacco industry. 
FTND: 
Fagerström 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. 
GAD: 
Generalized Anxiety Disorder-7 item questionnaire assessing severity of anxiety symptoms. 
hCG: 
Human Chorionic Gonadotropin: is a hormone produced by the placenta following implantation. 
The presence of hCG is detected in pregnancy tests. 
HIPAA: 
Health Insurance Portability and Accountability Act: A law designed to provide privacy standards 
to protect patients' medical records and other health information. 
HR: 
Heart Rate: a measure of the number of heart beats per minute (bpm) 
ITR: 
Interactive Text Response: Text messaging using Twilio, a service that invites participants via a 
web link unique to the participant for completion of a daily REDCap survey. REDCap stores all 
phone numbers and survey data. No data is ever saved by Twilio. 
MNWS: 
Minnesota Nicotine Withdrawal Scale: An 8 item scale assessing symptoms of tobacco 
withdrawal. 
NIAAA: 
National Institute on Alcohol Abuse and Alcoholism: part of the U.S. National Institutes of 
Health. 
NCI: 
National Cancer Institute: part of the U.S. National Institutes of Health. 
NIH: 
National Institute of Health: an agency of the United States Department of Health and Human 
Services. 
NMR: 
Nicotine Metabolite Ratio: is a urinary measure of the ratio of nicotine metabolites, which 
indicates speed of nicotine metabolism. 
NNAL: 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol: One of the tobacco specific nitrosamines, one of 
the most important groups of carcinogens in tobacco products, which are formed from nicotine 
during the curing and processing of tobacco. 

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OSU: 
Ohio State University 
PATH: 
Population Assessment of Tobacco and Health: a national, longitudinal study looking at tobacco 
use and health. 
PI: 
Principal Investigator: is the lead scientist for a particular well-defined research project, such as a 
laboratory study or clinical trial. 
PHQ (PrimeMD): Patient Health Questionnaire (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: a 10 item questionnaire to self-report smoking urges and 
cravings. 
REDCap: 
Research Electronic Data Capture (web based software): is a secure, HIPAA compliant, web-
based application for building and managing online surveys and databases. 
SAE: 
Serious Adverse Event: generally, any event which causes death, permanent damage, birth 
defects, or requires hospitalization is considered an SAE. 
SGR: 
Surgeon General’s Report 
SIDS: 
Sudden Infant Death Syndrome: is the sudden unexplained death of an infant. 
TLFB: 
Timeline Follow-back: 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 nicotine products 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. 
UMN: 
University of Minnesota 
WISDM: 
Wisconsin Inventory of Smoking Dependence Motives (Brief): a 37 item questionnaire to 
measure tobacco dependence by measuring a variety of smoking motives. 
 
 
 

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Study Synopsis 
Study Design: 
This single-blind, between-subject, randomized, multi-center study will assess 
the effect of cigarettes with unventilated vs. ventilated filters on smoking 
behavior and biomarkers of tobacco toxicant exposure. The study uses 
telehealth and brief in-clinic or curbside visits and will also examine the feasibility 
of remote collection of multiple biological samples. Subjective measures, 
alveolar carbon monoxide, blood pressure and cigarettes per day will be 
collected remotely. Biological samples collected at home will be dropped off at 
the clinic during a brief clinic or curbside visit where the study cigarettes will be 
dispensed. 
Primary Aim: 
To examine the effects of unventilated vs ventilated filter cigarettes on urinary 
biomarkers of toxicant exposure and smoking behavior (e.g., cigarettes per day, 
intensity of smoking). 
Secondary Aim 
To examine the effect of unventilated vs. ventilated filter cigarettes on cigarette 
dependence and subjective responses to cigarettes (e.g., perceptions of harm). 
Exploratory Aim 
To examine how the biomarkers analysis collected via different biological 
samples are concordant. 
Population: 
Cigarette smokers  
Study 
Procedures: 
Smokers using conventional cigarette brands with filter ventilation of about 16-
36% will enter a three phase study.  Phase 1 is a 1-week baseline period of 
smoking usual brand cigarettes; Phase 2 consists of 2 weeks of smoking  
ventilated study cigarettes; and Phase 3 where subjects are randomly assigned 
to one of two conditions: 1) ventilated cigarettes; or 2) unventilated cigarettes 
smoked for a 6 week period. Weekly telehealth visits are conducted to collect 
study measures and subjects attend a brief clinic or curbside visit to pick up 
study cigarettes and drop off biomarker samples. A follow-up telehealth visit will 
occur at one-month post intervention.    
Accrual Goal: 
162 (81 per group) enrolled 
Enrollment Period 
May 2021 – December 2022 

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1 Study Objectives and Hypotheses 
The goals of this project are to determine the effects of varying degrees of cigarette filter ventilation 
on biomarkers of toxicant exposure and smoking behavior and on subjective responses to the 
cigarette.  
1.1 Primary Objective 
The primary aim of this study is to examine the effects of ventilated vs. unventilated filter 
cigarettes on smoking behavior (cigs/day, smoking intensity) and biomarkers of toxicant 
exposure.  
1.2 Secondary Objectives 
The secondary objectives are to examine the effects of cigarette filter ventilation on subjective 
measures such as cigarette dependence and responses to study cigarettes.  As an exploratory 
analysis, the concordance for toxicant levels analyzed across multiple biosamples (urine, saliva, 
blood spots and hair) and subject acceptability of collecting these samples at home will be 
determined. 
 
We hypothesize that unventilated filter cigarettes will be associated with no higher number of 
cigarettes smoked, biomarkers of exposure or cigarette dependence and satisfaction compared to 
ventilated filter cigarettes; but smokers assigned to the ventilated filter cigarettes will smoke 
cigarettes more intensely and perceive them as less harmful than smokers assigned to the 
unventilated cigarettes.  We also hypothesize the level of toxicant exposure will be concordant across 
various methods of collecting biological samples.  
 
2 Background 
The Changing Cigarette.  Over 34 million people in the United States,1 and about 1.2 billion 
globally,2 smoke cigarettes. With about 500,000 deaths per year in the US1,3 and 6 million per year 
worldwide,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), signed into legislation 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 tobacco products, including alterations in the design of the product. A product standard that 
requires consideration is the use of ventilation in cigarette filters. Filter ventilation came onto the 
marketplace in the 1960s in response to consumer concerns about the negative health impact of 
cigarettes after a series of reports, including the 1964 U.S. Surgeon General’s Report4 (SGR), linked 
smoking to lung cancer and other diseases. Filter ventilation was a way for the tobacco industry to 
reduce machine-determined tar and nicotine yields in cigarettes, providing consumers with the 
perception that these cigarettes were “safer” to smoke. This perception, however, was false because 

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smokers enhanced their puff topography (increased velocity, duration of puffs, puff volume, inhalation 
depth and reduced inter-puff intervals) and/or smoked more cigarettes per day to compensate for 
lower nicotine yields.1,5,6  That is, filter ventilation made the cigarette more “elastic,” allowing the 
smoker to manipulate the cigarette in ways to maintain the desired systemic level of nicotine. 
Research has shown that regardless of the extent of cigarette ventilation, among the range of 
ventilated cigarettes on the market, the amount of nicotine and other toxicant intake is similar when 
measured in the blood and urine, with the possible exception of the most highly ventilated 
cigarettes.1,5-7  Furthermore, ventilated cigarettes provide the perception of smoothness that added to 
the consumers’ false beliefs that these cigarettes are potentially healthier.8,9 This misperception of 
less harm associated with smoking ventilated cigarettes, or what was marketed as “light” or 
“ultralight” cigarettes, led to the majority of smokers switching to or initiating smoking with ventilated 
cigarettes by the 1980s.10 Unfortunately, not only did this cigarette design potentially reduce the 
number of people who would have otherwise quit smoking, but also it may have led to a higher 
incidence of adenocarcinoma lung cancer. 
Filter ventilation and increased risk of adenocarcinoma. With decreasing smoking rates, the 
overall incidence of lung cancer in men declined over the last half century. However, while squamous 
cell cancers decreased, there was a paradoxical increase in the proportion of lung adenocarcinomas, 
counter to the expectations that all lung cancers would proportionately decrease. The risk for lung 
adenocarcinoma grew dramatically since the introduction of filter ventilation. Other methods were 
also used to reduce tar and nicotine yields (e.g., cut size of the reconstituted tobacco sheet, density 
of the tobacco in the rod, the composition and design of the filter material, the porosity of the 
cigarette paper, etc.), but they do not allow for elasticity of the cigarette. After reviewing these and 
other data, the 2014 SGR1 concluded that, “adenocarcinoma has been increasing in the U.S. as a 
fraction of all lung cancers and becoming the most common histological type of lung cancer. Despite 
decreases in prevalence of smoking and smoking caused squamous cell carcinoma, the incidence of 
adenocarcinoma in smokers has increased since the 1950s when changes occurred in cigarette 
design and composition (p. 177).” 
The 2014 SGR1 further concluded that, “the evidence is not sufficient to specify which design 
changes are responsible for the increased risk of adenocarcinoma, but there is suggestive evidence 
that ventilated filters and increased level of tobacco specific nitrosamines have played a role (p. 
186).” Since the SGR, after reviewing the scientific literature and tobacco industry documents, we 
have proposed in a weight of evidence review and causation analysis that there are several 
pathways and reasons by which ventilated cigarettes could increase adenocarcinoma lung cancer.7 
Ventilated cigarettes are associated with slower and lower temperature burn time leading to a longer 
time for the coal to smolder and less airflow, which results in the formation of more toxic combusted 
and incomplete combusted constituents and mutagens (e.g., 4-(methylnitrosamino)-1- (3-pyridyl)-1-
butanone [NNK], polycyclic aromatic hydrocarbons and volatile organic compounds) per mg of tar. 
Additionally, the slower burn time and increased resistance of the smoke allows for the particle to 
absorb more water and constituent gases. As greater volumes of smoke that contain higher amounts 
of harmful constituents are puffed and inhaled more deeply (due to compensatory smoking), they are 
more able to reach the distal regions of the lung where adenocarcinoma more commonly occurs. 
Furthermore, studies have shown that the peripheral parts of the lung contain greater amounts of 
cells that may be more sensitive to NNK and the development of adenocarcinomas.  

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It should be noted that filter ventilation is not considered to be the sole causative factor for higher 
incidence of adenocarcinoma lung cancer. An increase in levels of tobacco specific nitrosamines 
(TSNAs), such a NNK and N’-nitrosonornicotine (NNN), also occurred over the last half-century and 
so may be another important contributing factor.  However, whether or not increasing NNK also 
contributed to the increasing adenocarcinoma does not preclude the FDA from regulating filter 
ventilation. It also should be noted that while the evidence for filter ventilation causing the 
adenocarcinomas is highly suggestive, there are reasons independent of this concern that would 
support regulating filter ventilation. These reasons include the misperceptions of relative health risks 
among smokers.  
In our efforts to explore the effects of filter ventilation, our research group has recently conducted a 
cross-sectional analysis of a national survey showing that smokers of more highly ventilated cigarette 
demonstrated similar rather than higher levels of toxicant exposure as smokers of lower unventilated 
cigarettes; however smokers of more highly ventilated cigarettes reported lower levels of perceived 
harm of their cigarettes11 which might contribute to the maintenance of smoking.  To date, no study 
has systematically examined the effects of switching from ventilated to unventilated cigarettes on 
toxicity and appeal.  
Developing the science to determine if filter ventilation should be banned. The 2014 SGR 
stated that, “if the risk of lung cancer has increased with changes in the design and composition of 
the cigarettes, then the potential exists to reverse the risk through changes in design and 
composition (p. 186).” The report went on to say that “even a modest reduction in the large burden of 
mortality from lung cancer would result in saving a substantial number of lives over time (p. 186).”  
This study will use a systematic and comprehensive effort to examine one type of design feature, 
based on extensive review of the literature that may have led to the increase in lung cancer deaths, 
in particular adenocarcinoma lung cancer. Independent of the effects of ventilated cigarettes on lung 
adenocarcinoma, removing filter ventilation has the potential to reduce misperceptions regarding the 
relative harm of these cigarettes. We begin with the premise that ventilated cigarettes should be 
regulated, and herein we study its complete removal. This proposed study complements other 
studies conducted by our research team examining the effects of cigarette ventilation levels on 
biomarkers from lung bronchoscopies and particle distribution in the lungs.  The aim of this study will 
be to examine the impact of ventilated vs. unventilated cigarettes on several biomarkers of specific 
exposures and effects (assessed via urine, saliva, oral cells and potentially hair and blood and 
inhalation measures), and examining smoking topography via spent filter analysis while holding 
levels of TSNAs constant.  The overarching goal is to make sure that a proposal to ban filter 
ventilation does not lead to greater toxicant exposure, dependence and thereby potential harm, 
complementing other program project studies that examine misperceptions of ventilated cigarettes 
and potentially greater harm by examining the effects of these cigarettes in the lung. 
Note: The original NIH funded study design involved in person contact with the participants. This 
study was approved by the IRB (STUDY 00003531). Since the COVID-19 pandemic, we have limited 
our in-person contact  while conducting human clinical trials that do not have a direct therapeutic 
benefit to the participant. Because it is unknown when we will be able to conduct the originally 
designed trial again and the uncertainty regarding the course of the pandemic, we have adapted this 
original study to be conducted primarily remotely, with a brief clinic or curbside component to drop off 
biosamples and pick up study cigarettes. The recent improvements in controlling the COVID-19 virus 

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has allowed us to conduct some of our measures face-to-face. As the situation continues to improve, 
we propose to resume the inhalation measures on a subset of study participants. 
3 Summary  
The primary aim of this study is to examine the effects of unventilated vs. ventilated filter cigarettes 
on an exposure biomarker of a potent lung carcinogen and smoking behaviors (e.g., cigarettes per 
day, filter analysis).    
A secondary aim includes determining the effects of unventilated vs. ventilated filter cigarettes on 
cigarette dependence and subjective response to cigarettes. 
Study Design 
This is a randomized, single-blind, multi-site study where subjects (N=162;  81 in each group) are 
randomly assigned to one of two cigarettes with different filter designs: 1) Ventilated cigarettes; or 2) 
Unventilated cigarettes.  
4 Subject Selection 
4.1 Recruitment 
Subjects will be recruited through various media (internet, television, newspaper, radio) or 
from a waitlist kept for those interested in potential studies. An example of the advertisement 
would read as follows:  
Smokers are wanted for a [University of XX] study that provides cigarettes with different filters. 
It’s free to participate and you may earn up to $855 
4.2 Inclusion/Exclusion Criteria 
Inclusion Criteria 
a) Male or females at least 21 years of age.  
b) Self-report of daily smoking of at least 5+ cigarettes and no more than 35 cigarettes for >3 
months.  
c) Biochemically confirmed regular smoking status (CO >8 ppm; if CO < 8 ppm, then nicotine 
level indicating regular smoking). 
d) Smoking a current brand (or if smoking roll-your-own cigarettes, indicates a preferred 
manufactured brand) of 16-36% ventilation. This range of ventilation was chosen based 
on our pilot data (unpublished). A list will be provided with eligible brands that corresponds 
to the predominant type of cigarettes currently used by smokers, i.e., previously marked 
as “lights” and approximates the assigned ventilated study cigarettes.  
e) Has regular access to a smartphone or tablet for use with CO device and smartphone, 
tablet or computer with functioning camera and internet access for telehealth visits and 
surveys.  

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Exclusion Criteria 
a) Unstable health conditions (any significant serious, unstable medical condition including, 
but not limited to cardiovascular disease, liver or kidney disease, COPD, bronchitis within 
the past 3 months, seizure disorder and cancer (cancer-free <5 years except some skin 
cancers can be within 5 years), or as determined by the licensed medical professional at 
each site, a COVID-19 positive test or COVID-19 symptoms in the last 30 days). 
b) Unstable mental health (to be determined by medical history, Patient Health 
Questionnaire (Prime-MD) after review by the licensed medical professional at each site. 
c) Excessive drinking or problems with drinking or drugs-including marijuana (assessed by PI or 
licensed medical professional). 
d) Use of other tobacco or nicotine products more than 9 days out of the last 30 days. 
e) Currently pregnant, breastfeeding or intending to become pregnant for the duration of the 
study or unwilling to agree to use adequate protection to avoid pregnancy. 
f) Taking exclusionary medications, unstable dosing of medications, or unstable control of 
symptoms for ongoing medical conditions (medications or conditions that would impact 
biomarkers or patient safety to be determined by the licensed medical professional at each 
site). 
g) Vital signs outside of the following range: 
i. Systolic BP greater than or equal to 160 
ii. Diastolic BP greater than or equal to 100 
iii. Systolic BP below 90 and symptomatic (dizziness, extreme fatigue, difficulty thinking, 
inability to stand or walk, feeling faint) 
iv. Diastolic BP below 50 and symptomatic (dizziness, extreme fatigue, difficulty thinking, 
inability to stand or walk, feeling faint) 
v. Heart rate greater than or equal to 105 bpm 
Heart rate lower than 45 bpm and symptomatic (dizziness, extreme fatigue, difficulty 
thinking, inability to stand or walk, feeling faint). Participants failing for heart rate or 
blood pressure will be allowed to re-screen once). 
h) Expired air carbon monoxide (CO) level greater than 80 ppm. 
i) Household member enrolled in the study concurrently. 
j) Participated in a prior research study during the past three months that would impact 
baseline smoking or response to study products. 
k) Inability to independently read and comprehend the consent form and follow other written 
study instructions, materials or measures.  Participants are required to complete parts of 
the protocol at home independently and must show ability to comply with directions. 
l) Unstable living environment that would compromise the ability to sequester study products 
or complete study procedures. 
Justification for Inclusion/Exclusion Criteria: 
Individuals under age 21 are excluded because they cannot legally buy cigarettes. 
Requirement of 5+ cigarettes daily for the past three months ensures smoking stability. Those 
subjects considered to have unstable medical or medication conditions will be determined by 
site’s medical professional and are excluded if these symptoms pose a safety issue or are 
believed to render the subject unable to fully participate in the study. Examples include but 

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are not limited to the following: angina, stroke, heart attack which occurred recently, blood 
clots in the arms or legs for which the individual is undergoing active medical treatment, 
cancer requiring active chemotherapy or radiation therapy, fractured limbs, severe arthritis, or 
other debilitating conditions of mobility, 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, COVID-19 or its 
symptoms, 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 cigarette 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. Unstable living situations, such as homelessness, could compromise 
the subject’s ability to control access to the study cigarettes and any medical or psychiatric 
conditions (to be determined by medical history and PHQ) that would be deemed to pose a 
safety issue to the subject. 
4.3 Participant Registration 
Study registration will occur after the informed consent process is completed, consent form is 
signed and screening eligibility is confirmed. No study procedures will be conducted until after 
the consent form is signed, either electronically or a paper copy mailed or faxed to the clinic. 
To be enrolled in this study following screening, the participant must meet each criterion listed 
on the eligibility checklist based on the eligibility assessment documented in the case report 
record. Upon completion of the screening evaluation, and confirmation of eligibility, the study 
coordinator or designee will enroll the subject into REDCap. 
5 Experimental Design: 
Smokers will undergo a screening and then a three phase, 9 week experimental trial (Figure 1) 
with a one month follow-up at Week 10: 
1) Phase 1 – Usual Brand Baseline: 1 week baseline assessment period of usual brand 
cigarette smoking; 
2) Phase 2 – Study Cigarette Adaptation & Baseline Period: 2 week period allows the subject 
to adjust to the ventilated study cigarettes and obtain baseline data prior to randomization; 
3) Phase 3 – Intervention: Randomization to either ventilated or unventilated study cigarettes 
for 6 weeks. 
Figure 1: 
Design 
Subjects will be randomized at the end of Phase 2 (Visit 00) to one of the two experimental 
conditions (ventilated vs. unventilated cigarettes) for the 6-week intervention. An intervention 
 
 
 
 
Phase 1: Baseline  
Usual Brand  
(1 week) 
Phase 2: 
Adaptation & 
Baseline 
Ventilated  
Study Cigarettes 
(2 weeks) 
Phase 3:  
Intervention: 
Ventilated vs 
Unventilated Study 
Cigarettes  
(6 weeks) 
 

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and is widely used for focusing on respiratory disease. The spent cigarette filter (cigarette butt) 
from the session will be collected. 
Study Procedures 
5.3 Telehealth Visit Scheduling Requirements: 
Scheduling window for Phase 1 usual brand baseline screening (93) to baseline (92) visit is 7 
days (+ 7 days). If the subject is unable to schedule within 30 days, they will be re-consented, 
but will maintain the original assigned Subject Identifier.  
Scheduling window for Phase 2 weekly adaptation visits (92) to randomization (00) visits is 7 
days (+4) days. 
 
Scheduling window for Phase 3 weekly visits for Week 1-6 is 7 days (-3/+4) days. 
Follow-up (Week 10) scheduling window is 70 days from Week 00 visit (-3/+21). 
5.4 Orientation and Screening Phase – Visit 93 and 93a 
Cigarette smokers will be screened for eligibility with a brief telephone screener. Eligibility 
criteria will be aimed towards being inclusionary to ensure generalizability of results to a 
broader population of smokers. If subjects meet the initial telephone screening eligibility 
criteria for the study, they will be asked to participate in a more thorough screening via a 
virtual remote visit using telehealth technology.  
Orientation: The purpose of the orientation is to inform the subjects about the study protocol. 
The Researcher will review the study via telehealth technology with a PowerPoint detailing 
the study purpose, procedures and risks. The subject is provided a copy of the consent form 
and HIPPA for review. After the subject has been able to ask questions and receive answers 
and show comprehension, the consent form and HIPPA will be electronically signed or paper 
copies mailed back to the Researcher. Signed copies will be provided to the subject at their 
first brief clinic or curbside visit. 
Screening:  After obtaining informed consent, basic information and screening 
questionnaires will be completed to further screen for eligibility.  
93. Screening Procedures (see Table of Procedures page 45): 
A. Physiological Measures: 
1) Measures will be taken during the brief in-person visit 93a (see below). 
B. Surveys – link sent to participant to complete REDCap based survey: 
Screening forms 
1) Demographics (including items needed for Masonic Cancer Center registration). 

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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. 
a. Concomitant Medication:  Current use and use within the prior 30 days. 
b. Date of last menstrual period and length of cycle will be acquired to assess 
pregnancy status.  
3) Patient Health Questionnaire (PHQ/Prime-MD) will be used to assess current 
symptoms of depression and anxiety. BDI-II and or GAD7 will be administered for 
clinician to review if positive for depression or anxiety. 
4) Contemplation Ladder to assess readiness of smoking cessation. 
5) NIAAA Alcohol Use Questionnaire (12 month version) 
6) Nicotine Dependence Questionnaire  
7) Drug Use Questionnaire (1 month version) 
C. Interviews - Research Assistant interviews participant and enters directly into REDCap 
(except Identification Form): 
1) Tobacco Use History and Nicotine Exposure Questionnaire 
2) Brief Medical History Follow-up form (completed as needed by study staff to further 
assess current diagnoses, symptoms or past health problems). 
3) Tobacco Use 7 Day Followback Form for cigarettes per day, alcohol and marijuana 
4) COVID-19 Related Questions 
5) An 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 other study 
investigators. 
6) End of Visit Evaluation 
After the telehealth visit, medical review will be conducted by the licensed medical 
professional and eligibility criteria will be confirmed. If eligibility criteria appear to be met, the 
participant will be enrolled in the Daily Interactive Text Response (ITR) for data collection via 
REDCap (described below). If the subject shows compliance with providing the daily ITR data 
for 5 days, they will attend a brief, in-person visit to complete the screening. 
 
93a In-Person Screen 
 
Physiological Measures:  
Prior to the appointment, the COVID Assessment will be completed via phone call. The vitals 
and carbon monoxide (CO) measures will be taken during the in-person screening visit (93a) 
using the monitors that will be provided for home use. The subject will receive training on use 
of the devices and staff will observe the procedure to verify accurate technique and assess 
competence. 
1) Height and weight  
2) Carbon monoxide will be collected using iCO Smokerlyzer, a portable carbon 
monoxide monitor that can be used at home with a smartphone. 
3) Blood pressure and heart rate is assessed with the at home monitor provided. 

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4) A spot urine sample will be collected for a pregnancy test [hCG detection] for female 
participants of childbearing potential to confirm eligibility. 
5) Participants may be asked to provide 3 of their usual brand cigarettes for ventilation 
testing. 
If the carbon monoxide level, blood pressure and heart rate are within the guidelines, the 
participant will be considered eligible to enroll. If the CO is below 8ppm, a nicotine check strip 
may be used to verify regular smoking status.  
In addition, biological sample collection supplies and handouts will be provided.  
Daily Interactive Text Response (ITR) System and Data Management 
At the Screening visit (93), eligible subjects will be trained to use the Daily Text (ITR) system. 
The ITR system uses a stand-alone REDCap project, in conjunction with Twilio (REDCap 
approved service provider) to send automatic survey invitations to the participant’s phone via 
a text message. Participants will receive a text message each day throughout the study with a 
unique link to the REDCap survey. The survey will ask for the previous day’s number of 
cigarettes (both study and non-study cigarettes), use of any other tobacco or nicotine 
products, marijuana and alcoholic drinks.  
To be enrolled in the recording system, research staff must enter subject initials, telephone 
number, subject identifier and start dates into the HIPAA compliant REDCap project. 
Identifying information (initials and telephone numbers) will be marked as identifiers and not 
allowed to be extracted with the data by the Bioinformatics group. 
Any missing data due to incomplete or entry errors (e.g., subject entered 88 study cigarettes 
rather than 8 study cigarettes) will be reviewed at the next visit via the Timeline Follow-back 
method and compiled in the ITR Review Form. This data will be integrated into the ITR as 
revised data. The original subject entered data will also be retained in the ITR database. 
 
5.5 Phase 1:  Baseline Smoking Usual Brand 
During Phase 1, (Screening Visit 93a through Visit 92), eligible subjects will purchase their 
own cigarettes and smoke their preferred brand as usual. Data will be collected during a 
telehealth visit and biological sample for biomarker analysis will be collected at the brief clinic 
or curbside visit (see below).  
Procedures for Baseline 1 Telehealth Visit (92)  
A. Physiological Measures and Biomarker Samples 
1) Vital signs (blood pressure, heart rate) will be obtained while conducting the 
telehealth visit 
2) Carbon monoxide level will be obtained while conducting the telehealth visit. 

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3) Biological sample collection to assess for nicotine and carcinogen metabolites. A 
first void urine sample will be collected the morning of the visit and saliva will be 
collected during the telehealth visit. Samples will be dropped off at the brief clinic 
or curbside visit. 
 
B. Surveys – link sent to participant to complete REDCap based survey: 
 
Biomarker Modifier Questionnaires: 
1) Environmental Tobacco Smoke Questionnaire 
Subjective Outcome Measures: 
1) Minnesota Nicotine Withdrawal Scale(MNWS) 
2) Questionnaire of Smoking Urges-Brief Scale – Usual Brand (QSU) 
3) Respiratory and Global Health Questionnaire 
4) Modified Cigarette Evaluation Scale – Usual Brand 
5) Perceived Health Risk  
6) Cigarette Purchase Task – Usual Brand 
7) Duke Sensory Questionnaire – Usual Brand 
8) BDI-II and or GAD7 will be administered for clinician to review if monitored for 
depression or anxiety. 
9) Tobacco Policy Support Questionnaire 
C. Interviews - Research Assistant interviews participant and enters directly into REDCap: 
1) COVID-19 Assessment 
2) Health Changes and Menstrual Cycle Questionnaire 
3) Adverse Events 
4) Concomitant Medications 
5) Daily ITR Review form (follow-up on missing and unusual reports) 
6) Timeline Follow-back Questionnaire (since last visit) 
7) Intention to Quit 
8) Drug accountability: Complete Dispensing Logs for study cigarettes to be dispensed at 
brief clinic or curbside visit 
9) Study Compliance Review  
10) End of Visit Evaluation 
Dispensing Study Product: 
At the brief in-person clinic or curbside visit, the participant will be provided the ventilated 
study cigarettes. The subject will receive instruction on how to track the use of their study 
cigarettes for the Daily ITR. The subject will be allocated 150% of their baseline usual brand 
cigarettes per day. Allocating an additional 50% will allow for compensatory smoking behavior 
and provide a cushion for possible late visits. A nominal amount of money for each unused 
pack of cigarettes that are returned will be provided in order to disincentivize wasteful use of 
cigarettes (sharing with friends, hoarding cigarettes). Subjects who return unopened packs of 
their study cigarettes will receive a $2 credit per pack that will be paid out at the follow-up 
visit, with a max credit up to $30. 

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5.6 Phase 2:  Adaptation to Ventilated Study Cigarette 
During Phase 2 (baseline 92 to randomization visit 00), eligible subjects will be provided study 
ventilated cigarettes. Subjects will be instructed to continue to report on daily intake of 
tobacco and nicotine products, alcohol and marijuana in the ITR. Data will be collected during 
telehealth visits and biological samples for biomarker analysis collected at the brief clinic or 
curbside visit.   
Procedures for Visit Telehealth Visit (Visit 91)  
A. Physiological Measures: 
 
1) CO level will be measured while conducting the telehealth visit. 
2) Vitals signs (blood pressure, heart rate) will be obtained while conducting the 
telehealth visit. 
B. Surveys – link sent to participant to complete REDCap based survey: 
Subjective Outcome Measures: 
1) Minnesota Nicotine Withdrawal Scale(MNWS) 
2) Questionnaire of Smoking Urges-brief scale  - Study Cigarette (QSU) 
3) Modified Cigarette Evaluation Scale – Study Cigarettes 
4) Respiratory Symptoms and Global Health Questionnaire  
5) Duke Sensory Questionnaire – Study Cigarettes 
6) BDI-II and or GAD7 will be administered for clinician to review if monitored for 
depression or anxiety. 
     C. Interviews - Research Assistant interviews participant and enters directly into REDCap: 
 
1) COVID-19 Assessment 
2) Health Changes and Menstrual Cycle Questionnaire 
3) Adverse Events 
4) Concomitant Medications 
5) Daily IVR Call Review (follow-up on missing and unusual reports) 
6) Timeline Follow Back Questionnaire 
7) Intention to Quit 
8) Drug accountability: Complete Dispensing Logs 
9) Compliance Review  
10) End of Visit Evaluation. 
 
Supplies, sample collection containers and handouts will be provided to the participant at the 
Baseline 91 brief clinic or curbside visit for collection of cigarette butts, urine, saliva and blood 
spots for the Week 0 baseline sample collection.  Participants will be asked to collect cigarette 
butts 24 hours prior to Visit 00. 
 
 

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Procedures for Visit 2 Telehealth Visit (Visit 00)  
At the second Baseline visit (00), subjects will be informed that they have been randomized to 
either ventilated or unventilated study cigarettes. Subjects will complete several measures 
and provide biological samples for biomarker analysis as described below.  
A. Physiological Measures and Biomarker Samples: 
1) Vitals signs (blood pressure, heart rate) will be obtained while conducting the 
telehealth visit. 
2) Carbon monoxide level will be obtained while conducting the telehealth visit. 
3) Biological sample collection for analysis of nicotine and carcinogen metabolites will 
be collected prior to (first void urine sample) or at the telehealth visit (saliva and 
possibly blood spots) and then dropped off at the brief clinic or curbside visit. Oral 
cells will be collected during the telehealth, in-person curbside or clinic visit. 
Subjects will be instructed to brush teeth prior to the collection.   
4) Review Cigarette Butt Collection: The 24-hour collection of cigarette butts prior to this 
visit will be reviewed and dropped off at brief clinic or curbside visit. These spent filters 
will be analyzed for cigarette butt staining to inform intensity of smoking behavior. 
 
B. Surveys – link sent to participant to complete REDCap based survey: 
 
Biomarker Modifier Questionnaires: 
1) Environmental Tobacco Smoke Questionnaire 
Subjective Outcome Measures: 
1) Minnesota Nicotine Withdrawal Scale(MWSC) 
2) Questionnaire of Smoking Urges-Brief Scale – Study Cigarette (QSU) 
3) Respiratory Symptoms and Global Health Questionnaire  
4) Modified Cigarette Evaluation Scale – Study Cigarette  
5) Perceived Health Risk 
6) Cigarette Purchase Task – Study Cigarette 
7) Nicotine Dependence Questionnaire  
8) Duke Sensory Questionnaire – Study Cigarette 
9) BDI-II and or GAD7 will be administered for clinician to review if monitored for 
depression or anxiety. 
 
C. Interviews - Research Assistant interviews participant and enters directly into REDCap: 
1) COVID-19 Assessment 
2) Health Changes and Menstrual Cycle Questionnaire 
3) Adverse Events 
4) Concomitant Medications 
5) Daily ITR Review (follow-up on missing and unusual reports) 
6) Timeline Follow-back Questionnaire (since last visit) 

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7) Randomization to either ventilated or unventilated cigarettes - Read appropriate 
script 
8) Intention to Quit 
9) Product Accountability Log 
10) Compliance Review 
11) End of Visit Evaluation 
Dispensing Study Product: 
At the brief clinic or curbside visit, the participant will be provided their randomized study 
cigarettes (ventilated or unventilated). The subject will continue to be allocated 150% of their 
baseline cigarettes per day and receive a $2 credit per pack for each unused pack of 
cigarettes that are returned in order to disincentivize wasteful use of cigarettes (sharing with 
friends, hoarding cigarettes; max credit up to $30). 
 
5.7 Phase 3:  Assigned Study Cigarette Phase:  
Subjects will be smoking the assigned ventilated or unventilated study cigarettes. Subjects 
will be instructed to continue to report on daily intake of tobacco and nicotine products, 
alcohol and marijuana in the ITR. In addition, measures as described in the Table of 
Procedures will be collected. At the Week 3 and 6 visits, biological samples will be collected. 
Study cigarettes, supplies, collection containers and handouts are dispensed prior to the 
respective collection weeks during brief clinic or curbside visits. Additionally, cigarette butts 
will be collected 24 hours prior to Week 3 and 6 visits. 
Procedures for Telehealth Weeks 1, 2, 4 and 5 
 
A. Physiological Measures:  
1) Vital signs (blood pressure, heart rate) will be obtained while conducting the 
telehealth visit. 
2) Carbon monoxide level will be obtained while conducting the telehealth visit. 
B. Surveys – link sent to participant to complete REDCap based survey: 
Subjective Outcome Measures: 
1) Minnesota Nicotine Withdrawal Scale (MNWS) 
2) Questionnaire of Smoking Urges-Brief Scale – Study Cigarette (QSU) 
3) Respiratory Symptoms and Global Health Questionnaire 
4) Modified Cigarette Evaluation Scale (Week 1 only) – Study Cigarette 
5) Perceived Health Risk (Week 1 only)  
6) Duke Sensory Questionnaire (Week 1 only) – Study Cigarette 
7) BDI-II and or GAD7 will be administered for clinician to review if monitored for 
depression or anxiety. 
C. Interviews - Research Assistant interviews participant and enters directly into REDCap: 
1) COVID-19 Assessment 

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2) Health Changes and Menstrual Cycle Questionnaire 
3) Adverse Events 
4) Concomitant Medications 
5) Daily ITR Review (follow-up on missing and unusual reports) 
6) Timeline Follow-back Questionnaire (since last visit) 
7) Intention to Quit  
8) Product Accountability Log 
9) Compliance Review 
10) End of Visit Evaluation 
Procedures for Telehealth Week 3  
A. Physiological Measures and Biomarker Samples:  
1) Vital signs (blood pressure, heart rate) will be obtained while conducting the 
telehealth visit. 
2) Carbon monoxide level will be obtained while conducting the video/phone visit. 
3) Biological sample collection for analysis of nicotine and carcinogen metabolites 
collected at the prior to (first void urine) or at the telehealth visit (saliva) to be 
dropped off at the brief clinic or curbside visit. 
4) Review cigarette butts collection from 24 hours prior to the visit. These spent filters will 
be dropped off at their brief clinic or curbside visit and analyzed for cigarette butt 
staining to inform intensity of smoking behavior. 
B. Surveys – link sent to participant to complete REDCap based survey: 
Biomarker Modifier Questionnaires: 
1)  Environmental Tobacco Smoke Questionnaire 
Subjective Outcome Measures: 
1) Minnesota Nicotine Withdrawal Scale (MNWS) 
2) Questionnaire of Smoking Urges Brief Scale – Study Cigarette (QSU) 
3) Respiratory Symptoms and Global Health Questionnaire 
4) Modified Cigarette Evaluation Scale- Study Cigarette 
5) Perceived Health Risk 
6) Duke Sensory Questionnaire – Study Cigarette 
7) BDI-II and or GAD7 will be administered for clinician to review if monitored for 
depression or anxiety. 
C. Interviews - Research Assistant interviews participant and enters directly into REDCap: 
1) COVID-19 Assessment 
2) Health Changes and Menstrual Cycle Questionnaire 
3) Adverse Events 
4) Concomitant Medications 
5) Daily ITR Review (follow-up on missing and unusual reports) 
6) Timeline Follow-back Questionnaire (since last visit) 
7) Intention to Quit  
8) Product Accountability Log 
9) Compliance Review 

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10) End of Visit Evaluation 
 
Dispensing study product for Weeks 1-5 
The participant will be provided their study cigarettes at the brief clinic or curbside visit. The 
subject will be allocated 150% of their baseline cigarettes per day. Allocating an additional 
50% will provide cushion for possible late visits and/or compensatory smoking behavior. 
Subjects who return unopened packs of their study cigarette will continue to receive a $2 
credit per pack that will be paid out at the follow-up visit. 
 
Procedures for Telehealth Week 6: 
A. Physiological Measures and Biomarker Samples:  
1) Self-reported weight 
2) Vital signs (blood pressure, heart rate) will be obtained while conducting the 
telehealth visit. 
3) Carbon monoxide level will be obtained while conducting the telehealth visit. 
4) Biological samples will be collected prior to (first void urine) or at (saliva and 
optional collection of hair and blood spots) the telehealth visit to be dropped off at 
the brief clinic or curbside visit. Oral cells will be collected during the telehealth, in-
person curbside or clinic visit.. Subjects will be instructed to brush teeth prior to 
collection.   
a) Urine pregnancy tests [hCG detection] will be performed for female 
participants of childbearing potential to confirm eligibility. 
5) Review cigarette butts collection from 24 hours prior to the visit. These spent filters will 
be dropped off at their brief clinic or curbside visit and analyzed for cigarette butt 
staining to inform intensity of smoking behavior. 
B. Surveys – link sent to participant to complete REDCap based survey: 
Biomarker Modifier Questionnaires: 
1)  Environmental Tobacco Smoke Questionnaire 
Subjective Outcome Measures: 
1) Minnesota Nicotine Withdrawal Scale (MNWS) 
2) Questionnaire of Smoking Urges-Brief Scale – Study Cigarette (QSU)  
3) Respiratory Symptoms and Global Health Questionnaire 
4) Perceived Health Risks  
5) Modified Cigarette Evaluation Scale – Study Cigarette  
6) Cigarette Purchase Task – Study Cigarette 
7) Nicotine Dependence Questionnaire 
8) Duke Sensory Questionnaire – Study Cigarette 
9) BDI-II and or GAD7 will be administered for clinician to review if monitored for 
depression or anxiety 
10) Contemplation Ladder 

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11) Tobacco Policy Support Questionnaire 
12) End of Study and Feasibility Questionnaire  
C. Interviews - Research Assistant interviews participant and enters directly into REDCap: 
1) COVID-19 Assessment 
2) Health Changes and Menstrual Cycle Questionnaire 
3) Adverse Events 
4) Concomitant Medications 
5) Daily ITR Review (follow-up on missing and unusual reports) 
6) Timeline Follow-back Questionnaire (since last visit) 
7) Intention to Quit   
8) Product Accountability Log 
9) Compliance Review 
10) Smoking Cessation Counseling 
11) End of Visit Evaluation 
Dispensing study product 
None  
Cessation Materials at End of Intervention  
At the end of the 6 week experimental period, subjects will be strongly encouraged to stop 
smoking and set a quit date and if possible, stop using all tobacco products. A treatment 
manual for cessation will be provided and subjects will be encouraged to call the state 
telephone quit line. Nicotine replacement products (1 box of choice of nicotine gum, lozenge 
or patches) will be provided to those setting a quit date.   
5.8 Brief In-Person Clinic or Curbside Visits 
A brief in-person visit will be scheduled following each of the telehealth visits. Depending on the 
circumstances, participants may have a brief in-person clinic or a curbside visit. If clinic visits are 
not optimal (due to COVID-19 prevalence/restrictions, use of public transportation or if a 
participant is not interested in being seen in the clinic) curbside contact will be arranged.  The 
visits should be scheduled to occur as soon as possible after the telehealth visit. If the visit cannot 
be scheduled within 24 hours, a partial telehealth visit will occur to update the record. For the 
brief clinic or curbside pick-up, participants will be required to have a mask of either their own, 
sent by staff or provided one and told to wear it during the visit. Staff will wear PPE as required 
(optional if vaccinated. Any sample collection supplies, containers and other handouts will be 
provided at this time. 
 
During the brief clinic or curbside visit, subjects will drop off the appropriate biosamples, cigarette 
butts and collect the week’s supply of study cigarettes and return empty packs. If there have been 
device issues with the vitals or CO monitors, they can troubleshoot at this visit. 
 
Biosamples to be returned at this visit: 

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1) First morning void urine collection (Weeks 92, 00, 3, 6, Early Terminating (ET) if 
applicable) 
2) Saliva sample obtained for nicotine metabolite ratio-NMR (Week 92) 
3) Saliva sample for TNEs (Weeks 92, 00, 3, 6, ET if applicable). 
4) Blood spot (Weeks 00, 6); this collection is optional. 
5) Hair sample (Week 6); this collection is optional. 
6) Cigarette butt collection (Weeks 00, 3, 6)  
Procedures to be conducted at this visit: 
1) Oral cells will be collected during the telehealth, in-person curbside or clinic visit. Subjects 
will be instructed to brush teeth prior to arrival at the visit.   
2) Inhalation measures (Weeks 00 and 6) will be conducted on a subset of subjects. 
5.9 Follow-up 
Procedures for Follow-up Telehealth Visit Week 10 
Follow-up will occur 4 weeks after the end of the experimental period. Tobacco use status 
(amount and type of tobacco product use) will be determined. Quitting smoking or staying quit 
will continue to be strongly encouraged. The following procedures will only involve checking 
records of product use, vital signs and questionnaires. There is no in-person visit at Week 10. 
A. Physiological Measures: 
1) Vital signs (blood pressure, heart rate) will be obtained while conducting the telehealth 
visit. 
2) Carbon monoxide will be obtained while conducting the telehealth visit. 
B. Surveys – link sent to participant to complete REDCap based survey (optional – RA enter 
direct into REDCap): 
Subjective Outcome Measures: 
1) Respiratory Symptoms and Global Health Questionnaire 
2) Nicotine Dependence Questionnaire 
C. Interviews - Research Assistant interviews participant and enters directly into REDCap: 
1) COVID-19 Assessment 
2) Health Changes and Menstrual Cycle Questionnaire 
3) Adverse Events (close out any open events) 
4) Concomitant Medications 
5) Tobacco Use 7 Day Followback Form   
6) Smoking Cessation Counseling 
7) End of Visit Evaluation 
5.10 Early Termination 

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Procedures for Early Termination Telehealth Visits 
If a subject decides to withdraw from the study prior to completion or if they are withdrawn by 
the Project Leader due to safety concerns, they will be scheduled for an early termination 
visit. If the participant is contacted 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, 4 or 
5, additional safety measures will be obtained since these measures are not scheduled at 
those visits. If the subject is seen outside the regularly scheduled visit window, safety 
measures will be obtained. 
A. Physiological Measures: 
1) Vital signs (blood pressure & heart rate) will be obtained while conducting the 
telehealth visit. 
2) Carbon monoxide level will be obtained while conducting the telehealth visit. 
3) Biomarker collection (first void or spot urine and saliva) collected prior to or at the 
telehealth visit and then dropped off at the brief clinic or curbside visit. 
B. Surveys – link sent to participant to complete REDCap based survey: 
The following additional assessments will be completed at early termination via REDCap, 
if not part of the usual measures scheduled for the regularly scheduled visit: 
Subjective Outcome Measures: 
1) Respiratory Symptoms and Global Health Questionnaire 
2) Perceived Health Risk  
3) Modified Cigarette Evaluation Scale – Study cigarette 
4) Cigarette Purchase Task – Study Cigarette 
5) Nicotine Dependence Questionnaire 
6) Duke Sensory Questionnaire - Study Cigarette 
7) Tobacco Policy Support Questionnaire 
8) End of Study and Feasibility Questionnaire 
C. Interviews - Research Assistant interviews participant and enters directly into REDCap: 
1) COVID-19 Assessment 
2) Health Changes and Menstrual Cycle Questionnaire 
3) Adverse Event 
4) Concomitant Medications 
5) Daily ITR Review (follow-up on missing and unusual reports) 
6) Timeline Follow-back Questionnaire 
7) Intention to Quit 
8) Product Accountability Log 
9) Smoking Cessation Counseling 
10) End of Visit Evaluation  
 
 
 

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5.11 Study Completion: 
Any adverse events that remain open from the last study session will be discussed and 
closed. Once a participant has completed all study procedures and all open events have been 
closed or designated as ongoing at end of trial, the Site Leader will review the participant’s 
binder and sign a form indicating study completion for that participant. If any of the measures 
raise concern, the Site Leader will determine if the subject should be followed further.  
5.12 Product and Procedures Compliance Review Sessions 
At each visit, subjects will be counseled about use of only cigarettes obtained through the 
study. Participants will be asked about any concerns or obstacles associated with use of the 
study cigarettes. The importance of honest reporting will be stressed. Participants will be told 
that it is crucial for them to report any use of products obtained from outside the study, even 
though it is discouraged. If difficulties are encountered, participants will be asked why they 
think they are experiencing difficulties (e.g., taste, withdrawal symptoms) and to problem-
solve how to deal with these difficulties in order to meet the protocol requirements. 
Additionally, participants will be counseled about their Daily ITR text completion, telehealth 
visit attendance and product accountability. These review sessions should be about 5-10 
minutes in length. 
5.13 Quit Attempts During the Study Protocol: 
At each session, we will ask the participant if he/she is currently abstaining from smoking 
and/or has the intention of quitting or planning to quit smoking prior to his/her next scheduled 
visit. If the answer is yes, they will be provided with information on local quit lines to assist 
them in their quit attempt and a cessation manual provided. If the subject chooses to quit 
during the study, they will be encouraged to do so and will be offered their choice of 1 box of 
nicotine replacement products (gum, lozenge or patch) to aid in their quit attempt. 
If Currently Abstinent from Smoking:  
• 
Encourage continued abstinence from smoking.  
• 
Provide the cessation manual and local smoking cessation resources.  
• 
Follow visit schedule and procedures. 
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. 
• 
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 6-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 

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line. A box of nicotine replacement (e.g., gum, lozenge or patch) will be provided to those who 
have a quit date or have quit smoking.  
5.14 Compensation for Clinical Trial 
Participants will be compensated $30 for the initial telehealth screening visit and $10 for their brief 
in-person screening follow-up visit (CO/vital measurements and devices pick-up).They will 
receive $30 for the shorter visits (91, 1, 2, 4, 5 and Follow-up) and $40 for the longer visits (92, 0, 
3 and 6) for a total of $380. In addition to the visit compensation, subjects will receive a $10 
reimbursement for travel for each clinic or curbside visit ($100). Required biomarker samples 
(urine and saliva: visits 92, 0, 3, 6; buccal cells: visits 0, 6) and optional biomarker samples (hair: 
visit 6 and blood spots: visits 0, 6) will be compensated at $10 per sample; and cigarette butt 
collection at $25/collection (visit 0, 3 and 6 for maximum of $185). Payment for ITR completion 
will be a weekly bonus of $10 for not missing any texts ($90 maximum). A $100 bonus will be 
given for completion of the study. The maximum earned will be $855. In addition, money for 
unopened returned packs ($2/pack) will be added at the follow-up visit for a maximum of $30. A 
subset of participants who have been asked to participate in the addendum inhalation study will 
receive an additional $25 per session. 
5.15 Product Compliance and Data Consistency 
The importance of honest reporting by subjects will be stressed. Consistency across data 
collection will be examined by comparing: a) daily text records; b) Timeline Follow-back; and 
c) Product Accountability Logs where the amount of products dispensed will be recorded and 
number of unsmoked cigarettes are recorded via photos sent to us or shown during the 
telehealth visit. Participants will be provided feedback regarding the consistencies across the 
data and encouraged to be more accurate if the data are inconsistent. In the event that 
subjects uses non-study cigarettes (e.g., purchased or provided by a friend), they will be 
asked to report the type and amount of product to us. Also, self-reported abstinence will be 
biochemically confirmed by tobacco nicotine equivalents (TNE) for abstinence from all 
nicotine-containing products. No biochemical verification methods exist to determine if 
smokers used their usual brand cigarettes in addition to the research cigarettes. Therefore, 
we will encourage accurate reporting of any cigarettes or nicotine products. 
6 Data Collection 
Subject information including name and date of birth, race/ethnicity, and information about 
participation in this study will be entered into a secured database at the time of registration. 
The primary source of study data will be the protocol specific electronic case report forms. 
Research related results will not be placed in the participant’s medical record.  Data related to 
study participation will be collected and retained in REDCap and through the ITR Daily Text 
system. Subjects will directly enter their responses to surveys into REDCap’s HIPAA secured 
website. In the event that REDCap is not functioning, the assessments will be completed as 
soon as REDCap is available. Other source documents will be kept in the participant’s 
electronic binder and the interviewer will save the data in Box or upload as pdf to REDCap.  
Biosamples will be tracked via Biomarker Management Website on REDCap.  Databases will 
be maintained indefinitely.  

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6.1 Questionnaires and Other Measures 
The following measures will be obtained. Some forms are administered only at baseline to 
assess history and eligibility criteria and others are repeated measures: 
Questionnaires:   
1) Tobacco Use History and Exposure, derived from the Population Assessment of Tobacco 
and Health (PATH) assesses the generalizability of our study subjects 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 inquiries about age, gender, race, ethnicity, current occupation and usual 
occupation, and income. 
3) Brief Medical History includes current health status for current 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) Patient Health Questionnaire-PHQ (Prime-MD) assesses depression and anxiety 
symptoms, a brief questionnaire developed for evaluation of mental disorders by primary 
care physicians.14   
5) Beck Depression Inventory 2nd Edition15 (BDI-II) is a severity measure assessing 
symptoms of depression and will be administered if the PHQ is positive for any diagnoses 
or if monitoring for depression. 
6) Generalized Anxiety Disorder GAD-7 is used for rapid screening for the presence of a 
clinically significant anxiety disorder (GAD, PD, SP & PTSD), especially in outpatient 
settings.16 
7) Concomitant Medications Questionnaire will assess prescription, over-the-counter 
medications and supplements used 30 days before the screening and throughout the 
clinical trial. 
8) COVID-19 Assessment will assess current symptoms or potential exposure to a person 
who has tested positive for COVID-19.  
9) End of Visit Questionnaire asks about any issues encountered during the visit or concerns 
about the participants compliance with the protocol. 
Biomarker Modifier Questionnaires 
1) Environmental Tobacco Smoke Exposure Questionnaire consists of 1 question related to 
tobacco smoke exposure at home, work and socially.  
Subjective Outcome Measures 
The following measures will be obtained according to Table of Procedures. 
Subjective Outcome measures: 
1) Interactive Text Response (ITR) record the amount of cigarettes and other tobacco 
and nicotine containing products on a daily basis. Also recorded is use of marijuana 
and alcohol. 

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2) Timeline Follow-back17 will be used at each visit to assess tobacco and nicotine intake 
not assessed on the ITR  and alcohol and marijuana use. Cigarettes (study and non-
study) per day missing from ITR texts (or errors needing correction) will be collected in 
ITR Review form.  
3) ITR Review Form assesses study and non-study use of cigarettes missing from the 
ITR texts, correct errors in ITR entries or clarify any discrepancies or unusual ITR 
reports.  
4) Nicotine Dependence Questionnaire for usual brand or study cigarettes includes 
questions from the Fagerström Test for Nicotine Dependence (FTND);18 Brief 
Wisconsin Inventory of Smoking Motives (WISDM) Primary Dependence Motives 
subscale;19  and several PATH dependence items. 
5) Minnesota Nicotine Withdrawal Scale (MNWS) is an 8 item assessing symptoms of 
tobacco withdrawal.20 
6) Questionnaire of Smoking Urges is a 10 item scale measuring urge to smoke.21 
7) Contemplation Ladder evaluates readiness to quit.22 
8) Adverse Events Scale assesses the nature, severity, duration, action taken, and 
outcome of adverse events related to tobacco product use 
9) Respiratory Symptoms and Global Health Questionnaire rates cough, phlegm 
production, shortness of breath and other respiratory symptoms along with a rating of 
current overall health. 
10) NIAAA Alcohol Use Questionnaire (12 month) assesses frequency and quantity of 
alcohol use.23 
11) Drug Use Questionnaire (1 month) assesses amount, frequency in past year, past 
month and date of last use of drugs.   
12) Perceived Health Risk assesses perceived health risks of no tobacco use, usual brand 
of cigarettes.24 
13) Modified Cigarette Evaluation Scale (mCES) measures different dimensions of 
responses to cigarettes (e.g. psychological reward, satisfaction, aversiveness, and 
additional oral and respiratory sensation items.25-27 The modified scale has 7 additional 
questions. 
14) Cigarette  Purchase Task for behavioral economics measures purchase tendency for 
cigarettes based on price.28 
15) Duke Sensory Questionnaire a questionnaire rating it for liking, satisfaction, and 
estimated nicotine delivery. Subjects also rated the strength of each puff in different 
regions of the respiratory tract comprising the nose, tongue, back of the mouth and 
throat, windpipe, and chest. Ratings were made using a 7-point scale ranging from not 
at all (0) to extremely.29  
16) Intent to Quit Questionnaire assesses whether a quit date has occurred or a quit date 
is planned before the next visit. 
17) End of Study and Feasibility Questionnaire an open-ended questions administered at 
the Week 6 or Early Termination visit which enquires about the subject’s knowledge, 
attitudes and beliefs about the study cigarettes, reactions to a policy that bans 
ventilation, ideas about how this policy should be conveyed to the public and what 
needs to be in place to reduce any negative effects. Subject response will be coded 
for consistency in themes and categorized and evaluated in an exploratory way. The 
feasibility portion is a questionnaire that asks the subject to rate the degree of difficulty 

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or ease with completing the subjective measures, collecting carbon monoxide and 
blood pressure and collecting of biological samples. 
18) Tobacco Policy Support Questionnaire assesses subject’s opinion on potential 
tobacco control policies. 
 
6.2 Biological Specimens  
Biological samples will be collected and brought to the clinic or curbside visits for biomarkers 
analysis. Subjects will be asked to collect urine and saliva sample at weeks 92, 00, 3 and 6 
visits for biomarker assessments. Buccal cells will be collected during the telehealth, in-
person clinic visit or curbside at weeks 0 and 6. Blood spots (optional) will be collected at 
weeks 00 and 6. Hair collection will be optional and collected at week 6. These optional 
samples will be used to determine the feasibility of collection and analytic capabilities and 
concordance of results across biosample type. Participants who have experienced extensive 
hair loss will be exempt from the hair sample collection. The optional biosamples collected 
over the duration of the study will be at the discretion of the lead PI’s. This would occur if it is 
determined that one type of biomarker has a negative impact on recruitment (e.g., few people 
willing to collect hair sample) or we find the sample(s) collected do not yield sufficient 
biomarker levels. Cigarette butts (24-hour collection) will be collected at visits 00, 3 and 6 and 
the butts from the inhalation measures. 
Samples will be stored in a -20 or -80°C freezer. Specimens will be collected, stored at sites 
and shipped to the Masonic Cancer Center at intervals upon request from the lead site. 
The samples may be stored until they are used up or no longer needed up to a maximum of 
10 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 HIPAA 
document. If this occurs any remaining identifiable research sample(s) will be destroyed.  
Rationale for choice of biomarkers:  
The biomarkers for this project have been selected to represent exposures to carcinogens. 
We have chosen 2 types of biomarkers found in saliva, blood spots or hair. The first is related 
to nicotine intake, namely total nicotine equivalents (TNE). Knowing that smokers adjust their 
smoking behavior to maintain nicotine exposure, it is important to understand if this occurs 
when smoking an unventilated cigarette (e.g., complete or partial compensation). Also, 
because tobacco carcinogens are increased with filter ventilation, the consideration of intake 
of these carcinogens are important to understand in the context of the nicotine intake. Thus, 
the other validated biomarker, NNAL, was selected to represent exposure to carcinogenic 
tobacco specific nitrosamines because this is a known lung carcinogen. DNA adducts N6-
hydroxymethyl-deoxyadenosine and N2-ethylidene-deoxyguanosine derived from 
formaldehyde and acetaldehyde, respectively. DNA adducts will be analyzed in buccal cells. 
Buccal cells (cells gently scraped from the inside of the cheek with a cytobrush) can serve as 
a minimally invasive tool to measure the responses to tobacco and can be leveraged to 
determine the biological effects associated with tobacco- and nicotine-related toxicant 
exposure. 

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Biomarker Analysis: 
The following biomarkers has been selected to represent exposures to nicotine and 
carcinogen, NNK:  
1) Nicotine: Total nicotine equivalents – TNE (molar sum of nicotine and its metabolites) in 
urine will be used primarily to assess overall cigarette exposure. For subjects who state 
they are no longer smoking, we will confirm cigarette-free days and abstinence from all 
tobacco products with TNE. TNE was selected because it accounts for 73-96% of the 
nicotine dose and is a useful measure of daily nicotine exposure. Nicotine metabolite 
ratios can also provide other important information, such as differences in nicotine 
metabolism rate. Cotinine and 3-hydroxycotinine will be measured in saliva and blood 
spots for comparison across the different assays.  
 
2) Biomarkers of Carcinogen Exposure 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.30,31   
 
a. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its N- and O-glucuronides 
(exposure to tobacco-specific lung carcinogen NNK) in urine and possibly hair or blood 
spots.   
b. Tobacco specific oral and esophageal carcinogen N′-nitrosonornicotine (NNN) and its N-
glucuronide in urine.  
c. Phenanthrene tetraol and 3-hydroxy phenanthrene (exposure to and metabolism of the 
representative polycyclic aromatic hydrocarbon phenanthrene) in urine. 
d. Mercapturic acids (exposure to acrylonitrite (CEMA), acrolein (3-HPMA) and 
crotonaldehyde (HMPMA) in urine.  
e. DNA adducts N6-hydroxymethyl-deoxyadenosine and N2-ethylidene-deoxyguanosine 
derived from formaldehyde and acetaldehyde, respectively. DNA adducts will be 
analyzed in buccal cells  
3) Inflammatory and Oxidative Stress Biomarkers 
PGE-M and 8-iso-PGF2α in urine will be measured to assess inflammation and oxidative 
stress. 
 
4) Other biomarkers 
a. Untargeted metabolomics also will be measured in the urine by gas chromatography and 
mass spectroscopy. This is an emerging technology that provides a broad screen for 
exposures and cellular responses that represent biomarkers of exposure and potential 
harm. They will be employed for the analysis of urine to identify novel biomarker profiles 
distinguishing exposures from ventilated and non-ventilated cigarettes for totality of cigarette 
smoke-derived exposures and enodgenous cellular responses.32,33 
b. Exhaled carbon monoxide (CO) collected at every clinic visit.  
c. In addition, other tobacco-related validated biomarkers for assessment in urine, saliva, 
buccal cells, hair or blood spots may be developed over time and these additional 

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assays will be completed as appropriate using samples stored in the Biobank. Also, in 
the future, samples may be analyzed for metabolism of tobacco toxicants or nicotine 
and tobacco-related exposures or harm.  
5) Spent Filter Analysis:   
Filters will be collected at Week 00, Week 3 and after 6 weeks on study cigarettes. They 
will be analyzed for constituent yield and filter ventilation blocking and may also be used 
for filter staining analysis. For extraction of spent cigarette filters, one-cm portions will be 
removed from the mouth end of the spent cigarette filters, stripped of the wrapping 
paper and transferred into clean vials for constituent extraction. Filters will be analyzed 
for nicotine, TSNA, and PAH. Cigarette butts will be collected the day before visit 00, 3 
and 6. 
Biomarker Specimen Tracking: 
The Biomarker Management Website will be using REDCap for tracking biomarker samples. 
All samples will be scanned into the website at the study site thereby tracking initial collection 
and then scanned into Excel and uploaded to REDCap, prior to shipment of samples. 
Samples will be scanned into Excel and uploaded to REDCap, upon receipt at the UMN 
Masonic Cancer Center Tobacco Labs. 
7 Risks to Subjects and Others 
Potential risks of participation include the following: 
1) 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 
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, lower bone density in postmenopausal women, hip fracture in 
women, male sexual dysfunction; age-related macular degeneration, blindness and 
cataracts. 
2) Smoking assigned study cigarettes: Cigarettes similar or identical to research cigarettes 
are currently on the market, therefore, the major side effects associated with research 
cigarettes are similar to usual brand cigarettes. In addition to the above medical problems, 
participants may experience some minor adverse health effects such as headaches, 
dizziness, nausea, sore irritated throat, or increase in cough using the unventilated 
cigarettes. Due to free study cigarettes, there could be an increase in the number of 
cigarettes smoked per day. This rate of smoking may persist after completing the study. 

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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. Should an increase in smoking 
behavior occur, guidelines have been developed for terminating subjects from the study to 
avoid a marked increase in cigarettes smoked. 
3) Medicinal Nicotine (nicotine polacrilex and transdermal patch) if requested for use while 
quitting smoking:  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.  
4) 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. 
5) 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. 
6) 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.   
1) 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 baseline visit 91 and week 6 or early termination. They will be asked about their 
pregnancy status and date of last period to confirm status at all other visits. 
7) Smoking and medications: Quitting smoking can greatly benefit participants’ health. 
However, changes in smoking can lead to changes in metabolism of some medications. 
Subjects should disclose all medications they are taking. We also recommend that 
participants discuss any planned or actual changes in how much they smoke with their 
physician, especially if they are taking any medications for psychiatric, cardiovascular, or 
other serious diseases. 
8) Survey Questionnaires: The questionnaires will include medical history, drug and alcohol 
use, and questionnaires about mood. Answering these personal questions could make the 
subject feel uncomfortable. 

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9) Obtaining blood pressure: Researchers may find out the participant has abnormal blood 
pressure and refer the subject to their primary care physician. In addition, the blood 
pressure cuff may cause minimal discomfort. 
10) Breach of Confidentiality: There is a slight risk of loss of privacy if other people find out the 
results of the individual subject’s interview or other tests. 
11) Other: Risk of exposure to COVID-19 if using public transportation for an in-person visit. 
Risks to Others 
Tobacco products in the home can be toxic to children and pets. Smoking can lead to 
secondhand exposure that can increase risk for disease. All participants will be informed to keep 
products inaccessible to children and pets and informed about the harms of secondhand smoke 
and vapor exposures in the home or in cars.   
8 Potential Benefits of Participation 
There are no immediate benefits from participating in the study. Whereas no assurance can be 
made to an individual subject that he/she will personally benefit from such research, the 
experience should be beneficial by providing a better understanding of their smoking behavior. 
The risks compared to potential benefits are minimal to the individual research subject and 
virtually nonexistent to other or society in general.  
Importance of knowledge gained: 
The information obtained from this type of study may ultimately help the Food and Drug 
Administration decide how best to regulate tobacco products with the goal of improving public 
health. The benefit to society may be potentially significant if the end result from this study is to 
determine the potential feasibility and impact of banning ventilated cigarettes as a public policy 
measure.  
9 Adverse Event Reporting, Safety Monitoring and Withdrawal of Subjects 
9.1 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. Medical events will 
typically be identified during the administration of the Health Changes Questionnaire and 
Respiratory Health Questionnaire. Other events may be identified from physiological study 
measures or by spontaneous reports during assessments. 
Questionnaire items that will be reviewed to assess the occurrence of an Adverse 
Event: 
Health Changes Questionnaire: If the participant answers ‘YES’ to Questions 1, 2, 3b or 3c , 
the interviewer should assess for adverse events. 

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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 Health Questionnaire: If the participant indicates ‘YES’ to regarding having a cold 
or flu the interviewer should assess for adverse events. 
Vital signs will be reviewed: 
Blood Pressure: 
• 
The ‘Adverse Event Log’ and ‘Blood Pressure and Heart Rate Symptom Checklist’ 
should be completed if an automatic and second automatic blood pressure 
measurement during the same visit is at or above 160 systolic or 100 diastolic. 
• 
The ‘Adverse Event Log’ and ‘Blood Pressure and Heart Rate Symptom Checklist’ 
should be completed if an automatic and second automatic blood pressure 
measurement during the same visit is below 90 systolic or 50 diastolic and the 
participant is experiencing symptoms listed on the ‘Blood Pressure and Heart Rate 
Symptom Checklist.’ 
Heart Rate: 
• 
The ‘Adverse Event Log’ and ‘Blood Pressure and Heart Rate Symptom Checklist’ 
should be completed if an automatic and second automatic heart rate measurement 
during the same visit is at or above 105 bpm. 
• 
The ‘Adverse Event Log’ and ‘Blood Pressure and Heart Rate Symptom Checklist’ 
should be completed if an automatic and second automated heart rate measurement 
during the same visit is below 45 bpm and the participant is experiencing 
symptoms listed on the ‘Blood Pressure and Heart Rate Symptom Checklist.’ 
Attribution of Adverse Events:  
• 
Unrelated: The AE is clearly NOT related to the intervention 
• 
Remotely (Unlikely) likely: The AE is doubtfully related to the intervention 
• 
Possibly related: There is a reasonable possibility the AE may be related to the 
intervention 
• 
Definitely Related: The AE is clearly related to the intervention 
• 
Unknown: The AE is not easily associated with the intervention, concomitant 
medications, health states or personal norms. The cause is uncertain. 
9.2 Withdrawal or Monitoring of Participants 
For the participant’s protection, participants will be withdrawn immediately from the 
study if any of the following occur: 

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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 participant will be withdrawn if he/she attempts suicide at any time 
during participation in the study. 
4) Psychiatric Hospitalization: A participant will be withdrawn if he/she is hospitalized for 
psychiatric reasons at any time during participation in the study. 
5) Pregnancy: If a participant becomes pregnant during the study she will be withdrawn from 
the study if using tobacco products.  A pregnancy will trigger an ‘Adverse Event’ to be 
documented and this event will remain open until delivery. If the participants agrees, 
approximately 30 days after being withdrawn or reporting 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 and will update the open Adverse Event.  
6) Diagnosis of severe COVID-19: If a participant reports a positive test or symptoms 
consistent with the diagnosis and experienced significant illness (e.g. hospitalization) they 
will be withdrawn from the study. 
The following will be monitored and can lead to the participant being withdrawn by the 
PI or Licensed Medical Professional: 
1) Blood pressure (BP) or heart rate (HR) changes: If any of the following occur post-
enrollment: 1) BP is at or above 160 systolic or 100 diastolic, 2) BP is below 90 systolic or 
50 diastolic 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) Medication changes: If a participant begins taking any of the exclusionary medications or 
other medications that could potentially have a smoking-drug interaction post-enrollment, 
the medical professional 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. 
3) Any hospitalization or debilitation in which participation in the study could be detrimental to 
the recovery process. This will be self-reported by the participant and will be reviewed by 
the site PI and medical professional to determine whether continued participation in the 
study is appropriate.  
4) If a participant 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.  

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5) If there is reason to believe the participant is sharing large quantities of the study 
cigarettes with other people. 
Withdrawal Procedures 
If the decision to withdraw a subject occurs at a study visit, regular procedures will be conducted 
as well as the additional early termination procedures described in 6.7. 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 telehealth visit to 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, product accountability be 
completed. We will also stress the importance of being able to assess safety measures for the 
subject’s safety.  
9.3 Management of SAEs and Other Study Risks 
Subjects will be screened for any potentially compromising medical condition and will be 
monitored throughout the study. Subjects who experience any adverse side effects of concern 
will be reviewed by the study’s licensed medical professionals, sent to the emergency clinic or 
referred to their physician, depending on the nature and severity of the adverse event. 
Subjects will be encouraged to quit smoking and optimally all tobacco use at the end of study 
and we will conduct a 4 week follow-up to assess tobacco use status. If necessary, we will 
continue follow-up to make sure that no greater harm is experienced by the subject and to 
continue to encourage quit attempts. If biomarker analysis determined significantly greater 
exposure to toxicants than prior to the study, the subject will be contacted to discuss the 
results and cessation of all tobacco products will be strongly recommended.  
The site 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. 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 have appropriate follow-up medical monitoring. The participant experiencing an 
AE/SAE will be followed 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.  
9.4 Reporting of SAEs to the IRB, FDA, and NCI 
Serious or unexpected adverse events (SAE or SUSAR) as defined in 21 CFR 312.32 (death, 
life-threatening, hospitalization (initial or prolonged), disability or permanent damage, 
congenital anomaly/birth defect, required intervention to prevent permanent impairment or 
damage (devices), other serious events (important medical outcomes) that are related or 
possibly related to study participation will be reported to the Administrative Core, all site IRBs 
(annually unless a Reportable Event), the NCI Project Officer, FDA, and the Data Safety and 
Monitoring Board. Site IRBs require that fatalities related to the study be reported promptly.  

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Reports of all unexpected product related SAEs will also be documented within FDA’s SAE 
data monitoring system, within 72 hours 
Reporting of IRB Actions to NCI 
Actions taken by the local IRBs in response to SAEs will be reported to NCI in the annual 
noncompetitive continuation application, as will reports of changes or amendments to the 
protocol as a result of an SAE.  Recommendation for trial discontinuation, significant changes 
or amendments to the protocol, or other significant findings as a result of an SAE will be 
reported immediately to the NCI Project Officer by the Project PI. 
Reporting Changes or Amendments to the Protocol 
Any changes or amendments to the protocol made in response to adverse events/SAEs will be 
reviewed by PIs and then requested in writing to the IRB, which will then grant or deny permission 
to make the requested change in protocol. The DSMB, FDA and NCI will be notified about any 
significant changes to the protocol. NCI will be informed of any approved changes in protocol by 
documentation in the noncompetitive continuation application. Changes that significantly alter the 
scope of the research or the ability of the research to achieve its specific aims will be submitted to 
the DSMB, FDA, and NCI for approval prior to implementation.   
10 Statistical Considerations 
10.1 Trial Endpoints 
Primary Endpoint:   
• 
The change in total NNAL from visit 00 to week 6 visit. 
• 
The mean CPD based on 7-day IVR data between week 00 and Week 6 visit 
Secondary Endpoint:   
• 
Change in TNE, CEMA, and PheT from visit 00 to week 6 visit 
• 
Change in intensity of smoking measured by filter analysis collected at 00, Week 3 and Week 
6. 
• 
Change in parameters of inhalation depth measured at 00 and Week 6.   
• 
Change in subjective measures (dependence as measured by the FTND, mCES, and 
Perceived Health Risk) from visit 00 to Week 6 visit.   
 
 
Exploratory Endpoints: 
• 
Change in biomarkers of other volatile organic compounds (e.g.,3-HPMA, HMPMA) from visit 
00 to Week 6 visit. 
• 
Determine concordance in biomarkers of exposure across different sample collection 
methods. 
Secondary Endpoint 
Safety Endpoints: 
• 
Adverse Events (AEs) 

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• 
Serious adverse events (SAEs) 
Randomization 
Subjects will be randomly assigned using a stratified (by site), block randomization scheme into 
the following groups: (1) ventilated filter cigarettes; or (2) unventilated filter cigarettes. 
 
Sample size and power considerations  
To determine the sample size for a test of non-inferiority for unventilated filter cigarettes 
compared to ventilated filter cigarettes (control group), we used pilot data from our original 
ventilated/unventilated study 1 (Hatsukami, personal communication).  For the purposes of 
sample size considerations, we will focus on total NNAL as one of the primary outcomes. Seventy 
subjects had a baseline NNAL value while smoking their usual brand and 19 and 16 subjects had 
an end of study NNAL value for the ventilated and unventilated groups, respectively. The 
endpoint of interest is the change in NNAL from baseline.  To normalize the distribution of NNAL, 
the calculations were performed in the log scale.  The non-inferiority margin (NIM) was set at a 
15% change between groups.  This criterion was chosen because it is close to, but not greater 
than the upper limit of the 95% confidence interval (CI) for the geometric mean of the change in 
NNAL. Therefore, 73 subjects per group will achieve 80% power to detect non-inferiority for the 
mean change in NNAL using a one-sided, two sample t-test with a significance level of 0.05.  
Furthermore, with these sample sizes, a one-sided, two-sample t-test for the mean difference in 
cigarettes per day (CPD) from baseline will have 90% power to determine non-inferiority with a 
significance level of 0.05 if the NIM is 2 cigarettes.  A mean difference between ventilation groups 
of less than 2 cigarettes is considered to be in the range of equivalence.  To accommodate a 10% 
loss-to-follow-up rate, we plan to enroll 81 subjects per group for a total of 162. 
 
Study Populations 
Intent-to-treat  
 
The first analysis of all primary and secondary endpoints will adhere to the intent-to-treat 
principle. Under this principle, all subjects randomized to one of the two study arms will be 
included in the analysis in the group to which they were randomized regardless of protocol 
violations and compliance to treatment assignment.  
 
Per-Protocol 
A second per-protocol analysis will include only participants who complete the 6 week visit 
without protocol violations or non-compliance. 
10.2 Statistical analysis plan  
The primary objective of the statistical analysis is to compare the effects of cigarette 
ventilation between two study groups: ventilated filter cigarettes and unventilated filter 
cigarettes.  All statistical analyses will be performed using SAS version 9.4 (SAS Institute Inc., 
Cary NC) and a p-value less than 0.05 will be considered significant.   

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Describing the Study Population 
Descriptive statistics will be performed for data collected on demographic characteristics, 
subjective measures and biomarkers at different phases and visits.  Baseline data will be 
compared between the two ventilation groups with the two-sample t-test or the non-parametric 
Wilcoxon rank sum test for continuous or ordinal variables and chi-square tests for categorical 
variables.  Biomarker data may be log transformed if necessary. 
Primary Endpoint Analysis 
The primary endpoints are (1) the total NNAL at the 6-week visit adjusted for NNAL at end of 
Phase 2 (visit 00); and (2) the mean CPD based on 7 days ITR data before week 6 visit adjusted 
for the mean CPD during Phase 2 (visit 00).  The analysis of these two endpoints will evaluate 
non-inferiority of the unventilated group compared to the ventilated group. 
Primary Analysis 
The primary analysis will be a one-sided, two-sample t-test for non-inferiority.  The null hypothesis 
for total NNAL (analyzed in the log scale) is that the increase from end of Phase 2 (visit 00) is 
15% greater in the unventilated group compared to the ventilated group.  The NNAL alternative 
hypothesis is that the increase from baseline (visit 00) is no higher than 15% in unventilated over 
ventilated groups.  If the null hypothesis is rejected in favor of the alternative hypothesis, we will 
conclude that the unventilated filters are no more harmful in terms of NNAL exposure than the 
ventilated filter and may actually be less harmful.  Similarly for the CPD, the non-inferiority t-test 
will have a null hypothesis that the 6 week mean increase in CPD from end of Phase 2 (visit 00) 
for the unventilated group is greater than 2.0 cigarettes compared to the ventilated group.  The 
alternative hypothesis is that the CPD increase in the unventilated group is no more than a mean 
of 2.0 cigarettes verses the CPD increase in the ventilated group and the unventilated group may 
even smoke fewer cigarettes.   
Secondary Analysis 
The above methods will be supplemented with multiple linear regression analysis to include the 
baseline (visit 00) value for NNAL or CPD and the stratification variable (site), plus any other 
subject specific characteristics which might not be balanced between the study groups (p-
value<0.2).   
 
Finally, NNAL and CPD will be analyzed for all visits, starting at visit 00, using a linear mixed 
effects model (SAS PROC MIXED). . The fixed effects are ventilation group indicator, plus other 
potential predictors.  To model the variation within subjects, several candidate variance-
covariance structures will be compared using both graphical and information criteria.  Variance 
parameters will be estimated using restricted maximum likelihood method with the Satterthwaite 
approximation.  This analysis will provide useful information about the change in toxicant 
exposure and the change in the number of cigarettes smoked per day over time. 
 
Both linear regression models and repeated measures analysis can be modified for the 
equivalence and non-inferiority testing situations.34 
Secondary Endpoint Analysis 

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The secondary analyses include the other biomarkers (as listed above).  The analysis for these 
potential toxicants will be the same as that outlined above for NNAL with measurements at end of 
Phase 2 (visit 00) and at the 6 week visit.  A non-inferiority margin has not been established for 
many of these biochemical measures.  Instead, group differences or ratios (if in the log scale) will 
be estimated with their 95% CI and examined as to whether or not they contain 0 for differences or 
1 for ratios.  Inhalation measures and smoking intensity (solanesol levels in the filter butts) will be 
analyzed with similar methods as the change in biomarker and CPD with regression models 
incorporating covariates for baseline variables that may be different between groups (p-value<0.2). 
The FTND as a measure of dependency is a composite score that ranges from 0 to 10.  With the 
expectation of non-inferiority for the unventilated group, a linear regression model for FTND at 6 
weeks will include the FTND at baseline (visit 00) and the ventilation group indicator, plus any other 
important subject characteristic.  The 95% CI for the estimated coefficient for the group indicator 
will be calculated to verify that it contains the value zero, indicating no difference in dependency 
between ventilation groups.  The mCES and PHR questionnaires produce a series of subscales.  
To identify differences between ventilated and unventilated groups, non-parametric methods will 
be utilized, first with the Wilcoxon signed rank test to check for changes from end of Phase 2 to 6 
weeks within each ventilation group and then with the Wilcoxon rank sum test for differences 
between groups.  
Exploratory Analysis 
The exploratory analysis for the other volatile organic biomarkers (listed in section 6.2) will be the 
same as that outlined above for NNAL and the other secondary biomarkers. 
 
Correlation procedures (Pearson and Spearman) will measure the degree of association for the 
same biomarkers assayed from two or more biosamples. 
Safety Endpoints 
AEs and SAEs will be recorded as described in the Adverse Event SOP. AEs and SAEs will be 
tabulated separately for the two groups. We expect study product-related AEs and SAEs to be 
rare in this trial and, therefore, no formal statistical comparison of the rate of AEs and SAEs 
across treatment groups is planned for this trial. 
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. That said, 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 sessions in 
order to identify baseline covariates associated with study completion.  
Our primary approach to handling missing data will be a sensitivity analysis using multiple 
imputation with the Markov Chain Monte Carlo (MCMC) method35 carried out in PROC MI in SAS, 
where missing values are imputed using regression models developed from baseline covariates. 
Values can be imputed for both continuous and categorical variables. If the ventilation groups are 
associated with missing data, we will conduct multiple imputation for each ventilation group 
separately. Following imputation, standard statistical methods can be applied. A final single 

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assessment of ventilation group difference will be obtained from combining the results across the 
imputed datasets using PROC MIANALYZE in SAS.   
Interim Analyses  
No interim analysis is planned. 
11 Supporting Documentation and Operational Considerations 
Informed Consent Procedure and Documentation  
Potential subjects will be told the nature of the research over the phone during screening and 
then at a virtual orientation meeting where the study is described in detail. All potential study 
participants will be provided a copy of the IRB-approved consent form to review prior to 
signing. They will be told they may discontinue participation at any time and will not be 
discriminated against if they choose to do so. 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 be made known. The investigator or designee 
will explain all aspects of the study in lay language and answer all questions regarding the 
study. Subjects will be required to demonstrate an understanding of the study purpose and 
procedures prior to signing the consent form. If the participant decides to participate in the 
study, he/she will be asked to sign and date the consent document and will receive a copy for 
their records. Consent form must be signed before the research is started. 
Confidentiality of Data 
Participation in the project will be strictly confidential, any identifying information will be available 
to the project investigators and institutional or federal regulatory groups only, and no identifying 
information concerning the data and results will otherwise be made known. All raw data will be 
coded with numbers and any form with identifying information (e.g. consent forms) will be kept 
electronically in a password protected database. Subjects will have written assurance that while 
de-identified individual subject data may be available to other researchers for research purposes, 
only a summary of the results will ever be published or otherwise publicly released. Identifying 
information (initials and telephone numbers) entered in the Daily Text system will not be shared 
nor extracted with the data by the Biostatistics and Data Management Core. 
All data will be de-identified and posted on a secure, password-protected website that is only 
available to research investigators (both inside and outside the institutions affiliated with the 
Program Project Grant) due to data sharing requirements; subjects will be informed of this 
during the informed consent process.  
The data from these studies will not be used to direct patient care. Therefore, participation in 
this study will have no influence on the care the subject receives nor will it influence treatment 
decisions. If subjects would like their information on vitals or other findings released to 
another party, they will be asked to sign a release of information form.  

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To help protect the participant’s privacy, a Certificate of Confidentiality from the National Institutes 
of Health is 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. 
Data Security 
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. All 
identifying information will be kept separate from the data in a locked, 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 placed in subject’s medical records. 
Data Management 
Data for this study will be entered into a REDCap database, which uses a MySQL database 
via a secure web interface with data checks used during data entry to ensure data quality. 
REDCap includes a complete suite of features to support HIPAA compliance, including a full 
audit trail, user-based privileges, and integration with the institutional LDAP server. The 
MySQL database and the web server will both be housed on secure servers operated by the 
University of Minnesota Academic Health Center’s Information Systems group (AHC-IS). The 
servers are in a physically secure location on campus and are backed up nightly, with the 
backups stored in accordance with the AHC-IS retention schedule of daily, weekly, and 
monthly backups retained for 1 month, 3 months, and 6 months, respectively. Weekly backup 
tapes are stored offsite. The AHC-IS servers provide a stable, secure, well-maintained, and 
high-capacity data storage environment, and both REDCap and MySQL are widely-used, 
powerful, reliable, well-supported systems. Access to the study's data in REDCap will be 
restricted to the members of the study team by username and password. 

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All the data servers are managed by the Academic Health Center – Information Systems 
(AHC-IS) virtual servers which utilize clustered infrastructure to provide real-time failover of 
virtual servers. This real-time clustering is physically limited to the UMN data center. All 
relevant AHC IS procedures related for PHI compliant servers (as required by the Center of 
Excellence for HIPAA Data). 
The integrated data will be stored in PHI compliant servers managed by AHC IS with access 
given to those authorized users in the Clinical and Translation Science Institute Informatics 
team (CTSI BPIC and MCC CISS). The data will be integrated and extracted to researchers 
through the CTSI Informatics team and will be delivered through secure and compliant 
mechanisms (e.g. AHC IE data shelter, BOX, SFTP, etc.). If data de-identification is needed, 
then compliant AHC IE data de-identification tools will be used. The informatics team will 
grant the IRB approved study team members access to data. Key study personnel are trained 
on the use of these platforms and will comply with protocol specific instructions. 
Data Integrity: Adherence to Protocol Procedures and Training  
Standard Operating Procedures will include overall study procedures and visit procedures will 
be provided. Extensive training for research personnel will occur at a remote site initiation visit 
prior to the study start, where the protocol and procedures will be carefully described. Case 
Report Forms will be electronic to maximize parallel recording of data across studies and allow 
for remote access. Each visit will have a checklist of all the measures that need to be 
administered and the order by which these measures are administered. All subjective forms will 
be provided on web-based REDCap including the telephone screening. Additionally, conference 
calls will be held regularly with lead site, PIs and coordinators to review project status, accruals, 
and procedures. The project manager from UMN will monitor the study remotely and possibly 
monitor in–person at OSU once COVID travel restrictions are lifted to review study procedures, 
audit the documents and observe study visits. Data on REDCap will be monitored by UMN for 
missing data or any unusual value through data quality checks.  
11.1 Data and Safety Monitoring Plan (DSMP) 
See the full Data and Safety Monitoring Plan document for complete information. 
At each of the sites, the site PI and licensed medical professional will conduct regular 
conference calls or virtual meetings 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 medical professional for 
any contraindications for the use of the study cigarettes and out of range vital signs checked 
at each visit. Subjects will be under medical supervision while in the study and contacted on 
an ongoing basis by our research staff who will assess adverse events and make appropriate 
referrals to the medical staff. The study coordinator (with direction from the medical 
professional) at each of the sites will be responsible for the daily oversight of subject safety. 
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. 

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The DSMB for this center will review the protocol and establish 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, recruitment, study 
retention, and examine other factors that may affect study outcome. They will also review the 
participants’ 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. 
The University of Minnesota and The Ohio State University 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 at least a yearly basis. 
All product-related adverse events of a non-serious nature will be reported to the IRB at the 
time of renewal. Reportable serious and related adverse events will be reported by telephone 
or email to the IRB within the 5 days of our receipt of information regarding the event and 
written reports will be submitted within 10 days. The DSMB will review all serious or 
unexpected adverse events and provide recommendations. 
NCI will be informed of any significant action taken as a result of the DSMB’s findings. 
Subjects will be informed of any changes in risk. 
Record Retention 
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 
least 6 years after the study file is closed with the IRB and FDA.  
12 Conduct of the Study 
Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory requirements.  
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. 
Ethical Considerations 

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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 patients. The study will only be conducted at sites where 
IRB approval has been obtained. The protocol, consent, written information given to the 
patients, safety updates, annual progress reports, and any revisions to these documents will 
be provided to the IRB by the investigator.  
Duration of Study Participation 
A subjects’ direct study involvement is approximately 13 weeks: 
Phase 1: Baseline ~1 week; 
Phase 2: Ventilated Study Cigarette - 2 weeks 
Phase 3: Intervention: Unventilated or Ventilated Study Cigarette - 6 weeks  
Follow-up: One visit 4 weeks post intervention. 
Study sites 
The sites will be University of Minnesota-Twin Cities (PI: Dorothy Hatsukami) and The Ohio State 
University (PI: Peter Shields) 
Subject Identifier 
Project and Site Identifier: 
8 = University of Minnesota 
9 = Ohio State University 
 
Subject ID:   
UMN:   8001 – 8350 
OSU:   9001 – 9350 
 
Data Collection Time Points Identification Numbers: 
93 = Screening 
92 = Phase 1: Baseline  
91 = Phase 2: Ventilated study cigarettes  
00 = Phase 3: Randomization to ventilated or unventilated 
01 = Week 1 visit 
02 = Week 2 visit 
03 = Week 3 visit 
04 = Week 4 visit 
05 = Week 5 visit 
06 = Week 6 visit - End of Intervention visit 
10 = Week 10 Follow-up visit 
86 = Early Termination Visit 
98 = Additional Visit 

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Procedure Table  
Platform 
SCRN 
93  
 
BL-92 
BL-91 
BL-00 
Week  
1 
Week 
2 
Week  
3  
Week 
4 
Week 
5 
Week  
6 
Follow-
Up 10 
Early 
Term 
 
UB 
Phase 2  
Phase 3   INTERVENTION 
  
Phone Recruitment Questionnaire 
REDCap/Interview 
X 
 
 
 
 
 
 
 
 
 
 
 
VISIT ASSESSMENTS 
Weight & height (92 only) 
REDCap/Interview 
X 
 
 
 
 
 
 
 
 
 
 
 
Vitals (blood pressure & heart rate)1 
REDCap/Interview 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Carbon Monoxide1 
REDCap/Interview 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Screen [hCG detection] 
REDCap 
X 
 
 
 
 
 
 
 
 
X 
 
 
Compliance Review 
Progress Note  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Intention to Quit 
REDCap/Survey 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Smoking Cessation Counseling2 
Progress Note 
 
 
 
 
 
 
 
 
 
X  
X 
X 
VISIT FORMS 
Concomitant Medications 
REDCap/Survey 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
Health Changes Questionnaire 
REDCap/Interview 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Assessment 
REDCap/Interview 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
REDCap/RA 
 
 
 
X 
 
 
 
 
 
 
 
 
Product Accountability Log 
REDCap/RA 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
End of Visit Evaluation  
REDCap/RA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SCREENING QUESTIONNAIRES  
Tobacco Use  and Exposure History 
REDCap/Interview 
X 
 
 
 
 
 
 
 
 
 
 
 
Identifying Information 
REDCap/Survey 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics for MCC Registration 
REDCap/Survey 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
REDCap/Survey 
X 
 
 
 
 
 
 
 
 
 
 
 
Brief Medical History 
REDCap/Survey 
X 
 
 
 
 
 
 
 
 
 
 
 
PHQ (PrimeMD)3 
REDCap/Survey 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Use Questionnaire 12 mo.  
REDCap/Survey 
X 
 
 
 
 
 
 
 
 
 
 
 
Drug Use Questionnaire 1 mo.  
REDCap/Survey 
X 
 
 
 
 
 
 
 
 
 
 
 
BIOMARKER MODIFER QUESTIONNAIRE 
Environmental Exposure Question 
REDCap/Survey 
 
X 
 
X 
 
 
X 
 
 
X 
 
  
TOBACCO USE MEASURES 
ITR Daily Text   
ITR (RC/Twilio)  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 X 
ITR Review 
ITR (RC/Twilio) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 X 
Timeline Follow-back 
REDCap/Interview 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 X 

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Procedure Table  
Platform 
SCRN 
93  
 
BL-92 
BL-91 
BL-00 
Week  
1 
Week 
2 
Week  
3  
Week 
4 
Week 
5 
Week  
6 
Follow-
Up 10 
Early 
Term 
 
UB 
Phase 2  
Phase 3   INTERVENTION 
  
Tobacco Use 7 Day Followback Form 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
ADVERSE CONSEQUENCES 
MNWS  
REDCap/Survey 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
QSU - Usual cigarettes 
REDCap/Survey 
 
X 
 
 
 
 
 
 
 
 
 
 
QSU -  Study cigarettes 
REDCap/Survey 
 
 
X-V 
X-V 
X 
X 
X 
X 
X 
X 
 
 
Respiratory Symptom Questionnaire 
REDCap/Survey 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OTHER MEASURES 
Nicotine Dependence Questionnaire  
REDCap/Survey 
X-UB 
 
 
X-V 
 
 
 
 
 
X-SC 
X-UB 
X-SC 
Contemplation Ladder   
REDCap/Survey 
X 
 
 
 
 
 
 
 
 
X 
 
 
Covid-19 Symptom  Questionnaire 
REDCap/Interview 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
End of Study Questionnaire 
REDCap/Survey 
 
 
 
 
 
 
 
 
 
X 
 
X 
ACCEPTABILITY MEASURES 
Cigarette Eval. Scale Usual brand 
REDCap/Survey 
 
X 
  
  
 
 
 
 
 
 
 
 
Cigarette Eval. Scale Study cigs 
REDCap/Survey 
 
 
X-V 
X-V 
X 
  
X  
  
  
X 
 
X 
Perceived Health Risk   
REDCap/Survey 
 
X 
  
X-V 
X 
 
     X  
  
 
X 
 
X 
Cigarette Purchase Task-Usual Cigs 
REDCap/Survey 
 
X 
  
  
 
 
 
 
 
 
 
X 
Cigarette Purchase Task-Study Cigs 
REDCap/Survey 
 
  
  
X-V 
 
 
 
 
 
X 
 
X 
Duke Sensory Questionnaire  
REDCap/Survey 
 
X 
X-V 
X-V 
X 
 
X 
 
 
X 
 
X 
Tobacco Policy Support Questionnaire 
REDCap/Survey 
 
X 
 
 
 
 
 
 
 
X 
 
X 
OTHER 
Cigarette Butt Collection 
REDCap/RA 
 
 
 
X 
 
 
X 
  
 
X 
 
 
Inhalation Measures 
REDCap/RA 
 
 
 
X 
 
 
 
 
 
X 
 
 
BIOMARKERS4 
Total Nicotine Equivalents  
BMW (REDCap) 
 
X 
 
X5 
 
 
X 
 
 
X 
  
X  
Total NNAL    
BMW (REDCap) 
 
X 
 
X5 
 
 
X 
 
 
X 
 
X  
N HOCH-dAdo and N ethylidene-dGuo  
BMW (REDCap) 
 
X 
 
X5 
 
 
X 
 
 
X 
  
X  
Phet & 3-PheOH  
BMW (REDCap) 
 
X 
 
X5 
 
 
X 
 
 
X 
 
X  
Mercapturic acids6 
BMW (REDCap) 
 
X 
 
X5 
 
 
X 
 
 
X 
  
X  
8-iso-PGF and PGE-M  
BMW (REDCap) 
 
X 
 
X5 
 
 
X 
 
 
X 
 
X  

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Procedure Table  
Platform 
SCRN 
93  
 
BL-92 
BL-91 
BL-00 
Week  
1 
Week 
2 
Week  
3  
Week 
4 
Week 
5 
Week  
6 
Follow-
Up 10 
Early 
Term 
 
UB 
Phase 2  
Phase 3   INTERVENTION 
  
Metabolomics  
BMW (REDCap) 
 
X 
 
X5 
 
 
X 
 
 
X 
 
X  
2 (4.5ml) Biorepository  
BMW (REDCap) 
 
X 
 
X5 
 
 
X 
  
 
X 
 
X  
BIOSAMPLES 
 
Saliva NMR 
BMW (REDCap) 
 
X 
 
  
 
 
 
 
 
 
 
 
Urine 
BMW (REDCap) 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
Saliva 
BMW (REDCap) 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
Buccal cells 
BMW (REDCap) 
 
 
 
X 
 
 
 
 
 
X 
 
 
Blood Spot 
BMW (REDCap) 
 
 
 
X 
 
 
 
 
 
X 
 
 
Hair Sample 
BMW (REDCap) 
 
 
 
 
 
 
 
 
 
X 
 
 
1CO and vital signs will be measured by participant at home with devices provided by the study; CO and vitals for eligibility is collected at 93a In-Person Screen. 2If quit date prior to Week 6, self-help 
materials & NRR will be offered; 3If PrimeMD or CES-D positive, Beck or GAD administered; 4Urine & Saliva at Week 92, 00, 3, 6; Buccal Cells at Week 00 and 6; Optional: Blood Spots at Week 00 and 6; 
Hair at Week 6 only. Specific types of biosamples collected over the duration of the study will be at Lead PI discretion; 5 Week 00 is collected as a back-up baseline sample. 6Mercapturic acids of acrolein 
(3-HPMA), benzene, crotonaldehyde (HMPMA), & acrolonitrile 
 

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13 
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2.  Eriksen MP, Mackay J, Schluger N, Gomeshtapeh FI, Drope J. The Tobacco Atlas. Fifth ed. Atlanta, GA: 
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3.  Carter BD, Abnet CC, Feskanich D, et al. Smoking and mortality--beyond established causes. N Engl J 
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4.  Advisory Committee to the Surgeon General of the Public Health Service. Smoking and Health. Vol 
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12.  Hatsukami DK, Kotlyar M, Hertsgaard LA, et al. Reduced nicotine content cigarettes: effects on toxicant 
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13.  Mendes P, Kapur S, Wang J, Feng S, Roethig H. A randomized, controlled exposure study in adult 
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