PROJECT 4: CLINICAL TRIAL METHODS FOR ASSESSING A TOBACCO PRODUCT Part of "MODELS FOR TOBACCO PRODUCT EVALUATION
Phase: NA
Conditions: Smoker
Sponsor: University of Minnesota

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MODELS FOR TOBACCO PRODUCT EVALUATION 
 
PROJECT 4:  CLINICAL TRIAL METHODS FOR ASSESSING A TOBACCO PRODUCT 
 
 
Project Leader: 
 
 
Dorothy K Hatsukami, PhD 
Department of Psychiatry UMN 
University of Minnesota 
Tobacco Research Program 
717 Delaware St SE #260 
Minneapolis, MN 55414 
Phone 612-626-2121 
 
Site Leaders: 
 
Peter Shields, M.D.  
Ohio State University Comprehensive Cancer Center 
 
Richard O’Connor, Ph.D. 
Roswell Park Cancer Center 
 
 
UMN Investigators: 
 
Sharon Allen, MD 
Family Medicine and Community Health, Medical Director 
 
Chap Le, PhD 
Biostatistics, School of Public Health, Statistician 
 
 
Funding Sponsor: 
NIH / NCI   
 
 
Protocol  
Study 4 
 
 
IDS #:  
4226RO 
 
 
Final Version Date:  
4.7.2012 
Revised:  
 
 
1.15.2013 
8.22.2013 
10.15.2013 
10.17.2013 
 
 
 
 
 
 
 

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Revision History:    
 
 
Protocol 
Date 
Protocol Approval 
date 
Approved  
Consent Date 
Original Grant Protocol 
4/7/2012 
  7/13/2012 
Experimental Phase 
July 6, 2012  
Sampling Phase  
April 18, 2012  
Changes to design after funding 
(duration to 8 weeks and 
clarifications to protocol). 
 
1/15/2013 
  
 2/28/2013 
 
1/7/2013 
Additional biomarker collections, 
CoC, amend eligibility criteria, other 
clarifications/changes 
8/22/2013 
 
9/12/2013 
8/25/2013 
Correct compensation amounts; add 
usual brand urine; change 
advertisement; eligibility includes 5-
10 cig/day; NicAlert of 6 
10/15/2013 
1/9/2014 
10/15/2013 
Drop Sampling Phase criteria from 14 
to 7 snus 
10/17/2013 
11/18/2013 
NA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0  INTRODUCTION AND OVERVIEW 
 
A historic event for tobacco control in the United States was the passage of the Family 
Smoking Prevention and Tobacco Control Act (FSPTCA) that gave the Food and Drug 
Administration (FDA) jurisdiction over the regulation of tobacco products.  The FSPTCA allows 
the FDA to establish tobacco product performance standards (e.g., limits on yields of 
constituents in tobacco products including nicotine).  Also, the FDA will evaluate the evidence to 
support health claims for modified risk tobacco products (MRTPs), that is, “any tobacco product 
that is sold or distributed for use to reduce harm or the risk of tobacco-related disease 
associated with commercially marketed tobacco products”. Similar regulatory efforts are 
occurring worldwide.  For any decisions or actions in these areas, the FDA and others will need 
scientific data to promulgate regulations that result in improved public health.  The conduct of 
regulatory science presents a challenge because there are many gaps in our knowledge about 
the best methods for conducting human studies to determine how the products will be used and 
the resulting toxicant exposure and to evaluate the validity of health claims (3-7). The 
fundamental methodological issues that need to be addressed include methods for recruiting a 
sample representative tobacco users who are interested in using the tobacco product; the 
effects of the subject’s perception of the product on uptake and use; the effects of instructions 
for product use on the pattern of use and toxicant exposure; the change in responses to the 
tobacco product over time; and the identification of valid biomarkers of exposure and effect.    
Typically, these areas are investigated independently, yet it is the integration of findings that is 
necessary to accurately assess the impact of a tobacco product.  In this project, we will enroll 
690 subjects into a 8-week, 5-arm trial associated with varying instructions for use of an oral 
non-combustible tobacco product, Camel Snus, as a means to assess product substitution and 
dual use.   
 
2.0  SPECIFIC AIMS 
 
Primary Aims: 
1. To compare product use patterns and biomarkers of exposure and effect based on 
differing instructions for oral tobacco use: a) complete substitution vs. partial substitution 
for cigarettes; and b) specific instructions for use vs. no instructions (ad libitum use). 
2. To determine stabilization of product use by examining time effects for subjective (e.g., 
dependence), biological (e.g., biomarkers of exposure) and behavioral responses (e.g., 
smoking exposure and oral tobacco topography). 
3. To determine important moderators of use of a product and exposure (i.e., consumer 
perception of the product and consumer response to the product after sampling [Project 
3], nicotine metabolite ratio, nicotine dependence, gender, race and age). 
 
Secondary Aim: 
4. To develop and test cost-efficient and rapid measures to assess levels of exposure from 
oral tobacco products (determining exposure based on used oral tobacco products) and 
cigarettes (examining solanesol levels from cigarette filters). 
Hypotheses 
Primary Aims: 
1. Instructions for use will lead to significant differences in patterns of use, which will be 
related to biomarkers of exposure. 
2. Time in study will have an effect on outcome measures and will reach a plateau by at 
least 6 weeks. 
3. Moderators for exposure will include pattern and intensity of tobacco product use.  
Pattern and intensity of product use will be affected by subjective responses to products, 

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perception of safety of the product, gender, race, age, degree of dependence and 
nicotine metabolism phenotype.   
Secondary Aim: 
4. Biomarkers of exposure will be related to levels of chemical constituents extracted from 
used oral tobacco pouch products in the complete substitution condition, plus levels of 
solanesol in filters in the partial substitution condition. 
 
 
The outcome of this study will provide guidance on methods and measures that should be 
used in clinical trial assessments of tobacco products (e.g, MRTPs or new tobacco products). 
Furthermore, this study will novelly consider the interactions and effects of instructions of 
product use, perception and response to the product, and individual differences on product 
uptake and use and toxicant exposure. 
 
3.0  SIGNIFICANCE AND BACKGROUND 
We are experiencing an unprecedented time when we have a global convention for tobacco 
control (8) and in the U.S., federal governmental regulation over tobacco products (9). Two 
important components of both these tobacco control measures include: 1) governmental 
authority to mandate tobacco product performance standards, such as levels of chemical 
constituent yields and smoke emissions and toxicity; and 2) governmental requirement to 
evaluate exposure and health risk claims for tobacco products, including the so called modified 
risk tobacco products  (MRTPs) to assure that the claims are evidence-based and consumers 
are not misled (e.g., in the Articles 9-11 of the FCTC and Sections 907 and 910 of the FSPCA).  
Pivotal to the work of regulators is sound scientific evidence that is sufficient to make policy 
decisions with the goal of improving public health and/or minimizing public harm.  The FDA must 
also be able to defend their actions to the public, legislators and the courts.  This scientific 
evidence relies on the use of valid methods and measures to assess tobacco products.  The 
importance of having these assessment tools is clearly evident from the experiences that we 
have had with lower yield cigarettes in the 1970s and 1980s.  Because of the limited scientific 
knowledge and tools that we had possessed at the time, erroneous assumptions were made 
about “lights” and their assumed reduced toxicant exposure compared to regular yield 
cigarettes.  Only decades later did we learn that smokers do not smoke like machines, 
biomarkers that measure toxicant exposure are similar regardless of the yield of cigarettes, and 
cancer rates did not decrease with the decrease in tar yields of cigarettes (10).  With the influx 
of new MRTPs into the market intended by tobacco manufacturers to retain tobacco consumers, 
and the future possibility of tobacco product standards, the need for rigorous and valid methods 
to assess tobacco products has become imperative.  
An essential component of tobacco product assessment is human clinical trials (3, 11).  Only 
human studies provide sufficient evidence about human tobacco use and exposure.  The goals 
of these trials are to determine how the products are used, the extent of exposure to toxicants 
and the risk for disease with the use of these products.  As part of a National Cancer Institute 
contract (N01-PC-64402), we conducted an extensive review of the literature on clinical trial 
methods and measures for tobacco products, specifically MRTPs.  We also held a workshop on 
this topic with experts in the field of tobacco product evaluation, clinical trial methods, abuse 
liability and consumer perception testing, and subsequently published an article that provided 
recommendations for the conduct of these trials and that identified research gaps (4).  To date, 
human forced-switching studies have been one of the primary methods used to examine the 
toxicant exposure associated with the use of specific tobacco products including MRTPs.  
These studies typically involve randomization to one or more MRTPs and use of conventional 
cigarettes and/or no smoking with or without nicotine replacements as the control group(s) in a 
parallel arm design.  Despite these studies, we concluded that the best trial methods for 

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evaluating MRTPs are still uncertain.  For example, prior MRTP studies have varied in their 
instructions to subjects for product use (4, 7).  Studies have required complete or partial 
substitution of cigarettes with the assigned product and they have provided either instructions 
for specific amounts of product use or ad libitum use of the products (no required amounts of 
product use).  These varied instructional methods can answer different questions regarding the 
toxicant exposure associated with use of a MRTP.  Instructions for complete substitution may be 
more reflective of the toxicity associated with the product itself, whereas partial substitution may 
be more reflective of how consumers will tend to use the products in the “real world” setting.  
Most MRTP studies have employed complete substitution and only a few studies have used 
partial switching of MRTPs (4, 13), although there are several partial substitution studies that 
have been conducted with nicotine replacement products (14).  Partial substitution studies using 
nicotine replacements and using potential modified risk tobacco products show a reduction in 
cigarette consumption compared to baseline levels or continued smoking groups (13-16).  
Separately, studies employing ad libitum vs. specified amounts of use have been found to 
differentially affect biomarkers of exposure in a naturalistic setting (e.g., 17, 18), but not in a 
controlled residential setting (19).  These results suggest that the study setting, the instructions 
for how to use the product and amount of product use may influence outcomes measures.  To 
date, no study has directly compared the effects of these varied instructions on toxicant 
exposure.   
Another critical methodological issue that has not been addressed is the time to stabilization 
of product use and whether assessment of a product during the initial phase of use differs from 
assessments made after several weeks of use.  Examining the effects of duration of use on 
biological, behavioral and subjective outcome measures is important because MRTP study 
lengths have ranged from one day to one year (4), and if stabilization of use patterns have not 
occurred, then only incomplete information is being learned.  Recent studies conducted by 
tobacco industry scientists Roethig et al. (20) and Mendes et al. (21) suggest that stabilization 
may occur in the first few weeks of product switching, although no systematic study across 
different measures has been conducted.  If stabilization occurs within a few weeks, then clinical 
trials assessing product use and exposure only need to be this short duration, reducing cost and 
subject burden, and enhancing compliance. 
A third critical methodological question that has been inadequately addressed is the 
identification of individual factors that may moderate exposure.  Examining these factors is 
important in order to identify variables that significantly influence the uptake of a product, how 
the product is used and extent of toxicant exposure.  These data will help us to understand how 
a tobacco product might differentially affect subpopulations of smokers.  It will also help 
determine the essential recruitment criteria for subjects in future studies that are examining 
these outcome variables (4).  For example, if age is an important moderator variable, then future 
studies should have sampling strategies that account for age.  
In the proposed study, oral non-combusted tobacco, Camel Snus, has been chosen as the 
product to examine the above methodological issues associated with forced-switching studies.  
The proposed use of oral non-combusted tobacco products as a means of reducing harm in 
cigarette smokers has engendered a great deal of controversy.  Most public health officials 
agree that exclusive use of smokeless tobacco would be associated with less disease risk than 
smoking cigarettes and on an individual risk basis, is most likely to result in harm reduction 
compared to other modified combustible tobacco-containing products (22).  The risk of disease 
associated with smokeless tobacco use has been estimated to be 2% the mortality risk of 
cigarette smoking (23, 24).  If smokers completely switched to smokeless tobacco use, then the 
relative risk of disease would likely be dramatically reduced.  In Sweden, the increased uptake 
of smokeless tobacco or snus has been hypothesized to explain the decrease in cigarette 
smoking among men with a consequent decrease in lung cancer mortality (25).  Studies also 

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have shown that when smokers switch to oral tobacco products, a significant decrease in 
several biomarkers of exposure and effect are observed (2, 26), largely due to reduced delivery 
of toxicants that otherwise are produced by combustion when smoking. 
The urgency to examine oral tobacco products is driven by a number of important factors: 1) 
all the major cigarette companies have become important players in the smokeless tobacco 
market and are promoting these products as an alternative to smoking, or for use in situations 
where smoking is not permitted (e.g., workplaces, bars or restaurants); 2) some tobacco control 
advocates believe that the Swedish experience can be replicated in other countries and will lead 
to reduction in tobacco-related harm; 3) the extent of human toxicant and nicotine exposure 
from many smokeless tobacco products is unknown; and 4) patterns of use of these products 
are unknown, and smokers may engage in dual product use such that level of exposure to 
toxicants may in fact not reduce but increase (e.g., by maintaining or increasing nicotine 
dependence).  Because of these factors, oral tobacco products will serve as the vehicle to 
investigate the methodological issues.  
Because we are proposing to use an oral tobacco product, we will also be examining and 
testing measures of exposure.  For example, for oral tobacco products, determining the effects 
of oral tobacco topography and its relation to exposure biomarkers has been limited to a few 
studies (27, 28).  Novel methods, such as determining the amount of tobacco constituents 
extracted after use and relating these findings to biomarkers of exposure of these constituents, 
have never been explored, yet may prove to be cost-efficient compared to biomarker 
assessments.  Similarly, measuring the solanesol levels, a tobacco-specific compound in 
cigarette filters, as an indicator of exposure has shown promise and may be another cost-
efficient, rapid and simple measure of exposure, but requires further validation studies (29-31).  
Conceptual framework for tobacco product evaluation.  Clinical trials are a critical 
component of tobacco product evaluation (5, 32).   Figure 1 shows a framework for the 
evaluation of tobacco products.   
 
Figure 1.  Conceptual Framework for Tobacco Product Evaluation 
The primary goals 
of pre-clinical non-
human and pre-
market human 
product evaluation 
studies are to 
determine the 
toxicity of a product, its abuse liability (e.g., uptake and dependence producing potential), and 
consumer perception of the product that influences uptake and continued use (e.g., consumer 
reaction to promotion, packaging and price).  Another major goal is to determine the use of the 
product and consequent extent of exposure to toxicants and ensuing health risks.  The findings 
from these assessments will then be evaluated for potential individual and population risks and 
benefits should the product be released into the market or should a manufacturer make specific 
claims for reduced toxicant exposure of reduced health risks. Once introduced into the market 
with or without specific claims, then post-market analysis will be conducted to monitor and 
assess for public health harm (or even benefit).  While this Project will be conducting studies to 
examine methods for clinical trials, other Projects and Core B in this U19  will be conducting 
constituent analysis to assess levels of toxicants, studies examining animal and human models 
for assessing abuse liability and studies examining methods for assessing consumer perception 
and response.  The findings from these Projects will be integrated to determine the 
interrelationships of the findings and to identify strengths, limitations and gaps of the conceptual 
framework.  As described in Core A, the potential risks and benefits of the product on the 
Pre-clinical Studies
· Product design
· Constituent yield 
analysis
· Toxicological analysis
 (in vitro, in vivo)
Pre-market Human Studies
· Laboratory
- acute effects
- abuse liability
· Clinical trials
· Consumer perception 
Post-market Studies
· Clinical trials (ST and 
LT studies)
· Epidemiological
· Surveillance
· Consumer perception

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population as a whole will be assessed using modeling techniques that have been employed by 
Dr. David Levy, who is a member of our Scientific and Policy Advisory Committee.  Dr. David 
Levy has developed SimSmoke, which is a system based simulation model that can used to 
predict the potential impact of tobacco policies on smoking behavior and health outcomes (33)  
This model would be ideal to examine the population effects of introducing a modified risk 
tobacco product into the market.  The advantage of this model is that it takes into account other 
tobacco policies that would surround the introduction of a product onto the market, such as 
smoke-free air laws, the price of cigarettes, the price of snus product, marketing and labeling of 
tobacco products, mass media campaigns, youth access laws, and the availability, uptake and 
effectiveness of tobacco cessation services.  The model also takes into account long-term 
trends in smoking or smokeless tobacco use as well as population changes through birth and 
death. Undertaking this exercise will also help us to identify weaknesses and strengths in our 
conceptual framework for tobacco testing by identifying information gaps.  
In summary, this research project will provide researchers with fundamental data to design 
and conduct switching studies for tobacco products.  It will provide governmental agencies 
guidelines for evaluating research studies and their significance. This project will also provide 
insight into the extent of toxicant exposure and potential health effect from lower nitrosamine, 
oral tobacco products using novel modeling methods.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Overview of Experimental Design: 
This is a multi-center trial involving University of Minnesota, Ohio State University and 
Roswell Park Cancer Center. Subjects who are eligible will enter a Camel Snus sampling phase 
(N=793).  Smokers (estimated N=690) interested in continuing with the study after the sampling 
phase will undergo a 2 week baseline assessment phase and will then be randomized in the 
clinical trial phase to one of five experimental conditions for 8 weeks.  Tobacco use patterns, 
subjective responses to product, and nicotine and toxicant exposure will be assessed. 
 
6.0  STUDY PROCEDURES 
 
6.2  Subject Selection:   
Cigarette smokers (n=793) will be recruited at multisite locations.   
 
Recruitment plan: 
Subjects will be recruited from advertisements through a variety of media outlets and the 
internet.  A variety of media will be used that will foster the recruitment across a spectrum of 
age, education and socioeconomic status, race/ethnicity, and light and heavy smoking. 
Cigarette smokers will contact the respective clinical trial centers and be screened for eligibility 
over the telephone.   
 
The advertisement would read as follows:  
Smokers who want to try a new oral tobacco product developed for smokers are needed for a 
research study that may reduce their exposure to harmful tobacco smoke.   
(The content of this advertisement was discussed amongst investigators and the NCI Contract 
Expert Consulting Committee and was considered informative and not misleading.) 
 
Eligibility Criteria 
Subjects must meet the following criteria for eligibility:  
The inclusion criteria are the following: 
a) Male or female subjects who are at least 18 years of age; 
b) Smoking history of >10 cigarettes daily and CO>10 ppm or if  CO <10 ppm a NicAlert   
equal to6 (over ~1000 ng/mL cotinine concentration in urine).  Subjects who smoke >5 to 
9 cigarettes per day will be eligible, but their NicAlert level must be equal to 6;  
c) Smoking daily for at least 1 year and no serious quit attempts in the last 3 months (to 
ensure stability of daily smoking, particularly for those randomized to the continued 
smoking group); 
d) No unstable and significant medical or psychiatric conditions as determined by medical 
history and Prime-MD (to ensure safety of the subject, to minimize the effects of poor 
health on biomarker measures and to maximize compliance to study procedures); 
e) Lack of stabilization of medications (determined by study MD); 
f) Subject has provided written informed consent to participate in the study (adolescents 
under the age of 18 will be excluded because this project involves continued use of 
tobacco products and new tobacco products); 
The exclusion criteria are the following: 
a) Immune system disorders, respiratory diseases, kidney or liver diseases or any other 
medical disorders that may affect biomarker data; 
b) Current or recent (<3 months) alcohol or drug abuse problems; 
c) Regular tobacco use (e.g., greater than weekly or 9 days in last 30 days) other than 
cigarettes; 

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d) Use of smokeless tobacco products within the last 3 months; 
e) Use of roll your own cigarettes that are unfiltered or not machine rolled; 
f) Currently using nicotine replacement or other tobacco cessation products (to minimize 
confounding effects of another product) or intention to quit in next three months; 
g) Pregnant or breastfeeding (due to toxic effects from tobacco products). 
h) Unable to read for comprehension or completion of study documents. 
i) Clinical Trial Additional Exclusion Criteria:  Regular substance use (other than alcohol) 
defined as use of a substance 15 of the last 30 days. This will be assessed via the Drug 
Use Questionniare-1month. 
 
If subjects meet the eligibility criteria for the study, they will be asked to attend an 
orientation meeting where the entire study will be explained in detail, informed consent will be 
obtained and the Screening Questionnaires will be completed (Appendix A, Scales and 
Subjective Measures). Pregnancy exclusion will be confirmed through a urine test. 
 
6.3  Randomization:  
Randomization will be stratified by site and number of cigarettes smoked per day (≤ 18/day vs. > 
18/day, the expected median number of cigarettes smoked per day) to assure balance across 
treatment groups. Treatment groups will be checked for balance on other factors post 
randomization and any imbalances will be accounted for in our analysis as described in the 
statistical analysis section.  
 
 
6.4  Study Procedures  
 
Sampling Phase:  
The purpose of this phase will be to gauge product acceptance, reduce dropouts in the 
clinical trial and recruit subjects in the clinical trial that may be more representative of those who 
might purchase and use the product.  Subjects will be provided the product for one week to 
determine palatability, sensory and consumer perception and initial pattern of product use.  
Subjects will return to the clinic after one week to determine their interest in continuing in the 
study.   
During the orientation visit of this sampling phase, we will collect data that may influence the 
subject’s perception of the product.  These measures include basic demographic data and 
smoking history, consistent with questions used in the Tobacco Use Supplement to the 2010 
Current Population Survey, and in the Population Assessment of Tobacco and Health (PATH) 
Survey allowing comparisons with a nationally representative sample of smokers.  Additionally, 
we will use the Fagerstrom Test for Nicotine Dependence (FTND), Wisconsin Inventory of 
Smoking Dependence Motives (WISDM), Cigarette Evaluation Scale, Stages of Change scale 
PrimeMD, CES-D, Short Michigan Alcohol Screening Test (SMAST) and Drug Abuse Screening 
Test (DAST) and Perceived Health Risk of cigarettes. At the orientation visit, subjects will be 
instructed on how to use the product and presented with the Winterchill and Robust flavor snus 
tins. They will be instructed to smell the product and choose a flavor to try during the visit.  After 
smelling the product, subjects will rate the sensory perception, taste and appeal of the product 
immediately after this initial exposure using the Odor/Haptic Scale (see Project 3). Afterward, 
the subject will place the snus pouch between their lip and gum for a 5 minute period and then 
expectorate the pouch.  Subjects will complete the Product Evaluation Scale (PES), Drug 
Effects/Liking Questionnaire, Tobacco Purchase Task and Perceived Health Risk after 
expectorating the snus. Participants will then be provided Camel Snus to use at home (4 tins @ 
15 pouches per tin) and told to “Use the product as you wish over the next week. If subjects 
want more, they can return to the clinic for a maximum of 14 tins/week.  Camel Snus was 

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chosen because it is now nationally marketed, and based on our pilot study, has levels of 
nicotine similar to a 4 mg nicotine lozenge and appears to be palatable to smokers.  Participants 
will complete a daily diary via IVR about the amount of snus, cigarette or any other nicotine-
containing product use.  .   
After 1 week when subjects return to the clinic, we will assess: 1) number of cigarettes, snus 
sachets, and other nicotine products used during the past 7 days; 2) responses to the Product 
Evaluation Scale, Drug Effects/Liking Questionnaire and the Perception of Health Risks; 3) 
consumer perception measures that examine risks, benefits and feelings associated with the 
product; 4) willingness/unwillingness to participate in the experimental phase of the study; 6) 
interest in switching from cigarettes to the Camel Snus if it were not for the study; 7) impact on 
interest in quitting tobacco use; and 8) interest in paying for the product and the amount the 
subject is willing to pay for the product to replace cigarette smoking (measures from Project 2).  
Compensation for Sample Phase:  Subjects will receive $5 for transportation, $5 for IVR 
completion, and $40 for trying the study product for 1 week for a total $50, whether they want to 
continue with the study or not.   
 
Clinical Trial Phase:  
At the end of the sampling phase, eligibility for the clinical trial phase will be determined. 
Eligible subjects will have used an average of at least 2 sachets of Camel Snus daily during the 
sampling phase or at least 7 snus sachets used over most days during the sampling period. 
Subjects must be willing to attend clinic visits weekly for 4 weeks and biweekly visits for 6 weeks 
and a follow-up visit at 12 weeks post study product use and agree to be called at 4 and 24 
weeks post-study.  Subjects who wish to continue in the study will undergo 2 weeks of baseline 
where they will resume smoking and then will be randomized to one of five experimental 
conditions.  
 
Baseline smoking period:  
Subjects will be required to attend baseline clinic visits during Week -2 (visit 91) and -1 (visit 
00) of the clinical trial phase, and they will record their cigarette or other tobacco intake on a 
daily basis using an interactive voice response system (IVR) (see Table 1).   
First baseline visit: This baseline visit will assess tobacco use status to determine if smoking 
has returned to levels prior to sampling phase.  Subjects will collect a first morning void urine 
sample and bring it in on the day of their clinic visit for study biomarkers.   
24 hours prior to second baseline visit:  Prior to the second baseline visit, subjects will 
collect all of their cigarette butts in a container provided for the entire day.  
Second baseline visit:  Subjects will collect a first morning void urine sample on the day of 
their clinic visit. The 24 hour cigarette butt collection and urine sample will be brought with them 
to their clinic visit.  Blood samples will be drawn for study biomarkers  Buccal cells will be 
collected 20 minutes after the subject brushes their teeth using a cytobrush rubbed against the 
buccal mucosa as per previous studies (34).  Oxygen saturation, CO, vitals and weight will be 
obtained. Subjective measures will include predictors for MRTPs use, factors that may influence 
the biomarker measures, and outcome measures (see Tables 1 and 2).  
 
 
Experimental period:  
After the baseline assessment, subjects will be randomized to one of five experimental 
conditions: 1) smoking usual brand cigarette controls, who after 8-weeks will be offered Camel 
Snus and instructed for partial or complete substitution of cigarettes (subject’s choice); 2) 
complete substitution (i.e., no smoking) and ad libitum use of snus; 3) complete substitution 
(i.e., no smoking) and specific instructions for snus use based on the number of cigarettes 
smoked per day (if 10-20 cigarettes, use 8 pouches per day snus, and if >20 cigarettes then 12 

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pouches per day – these amounts were derived from a clinical trials conducted by us and by 
Eissenberg and associates [personal communication]).  4) partial substitution with ad libitum use 
of both snus and cigarettes; and  5) partial substitution with controlled use of snus (paralleling 
the instructions for complete substitution condition) and ad libitum smoking.  All subjects will be 
instructed to use the snus pouch for at least 5 minutes and optimally 30 minutes per occasion; 
Snus, but not cigarettes, will be provided to subjects at the clinic visits.   
Procedures for clinic visits:  Subjects will continue to complete daily diaries for tobacco and 
other nicotine product use.  At every clinic visit, vital signs, weight, oxygen saturation and 
expired air CO will be obtained.  At weeks 2, 4, and 8 of product use, blood, and first morning 
void urine collection samples will be collected.  At week 6, a first morning void urine sample will 
be provided.  Buccal cells will be collected at weeks 4 and 8.  Samples from weeks 4 and 8 will 
be analyzed for biomarkers as described below. Samples taken at week 2 will be aliquoted and 
stored for future analyses governed by results from the 4 and 8 week analyses or for other 
future studies.  Questionnaires that measure factors that may influence biomarker assessments 
will be administered at the time of biosample collection.  All other subjective measures will be 
collected thoughout the experimental phase. All cigarette butts, as appropriate for the study 
group, will be collected in a container 24 hours before the week 4 biomarker clinic visits. In 
addition, used and unused snus will be collected for 24 hours prior to week 4 to assess for 
amount of constituents that have been extracted. During this collection, time in and time out of 
snus products via a paper diary will be recorded to assess oral tobacco topography.  At the end 
of experimental phase, all subjects will be strongly encouraged to quit using all tobaco products 
and set a quit date.  A treatment manual (Clearing the Air) and treatment resources will be 
provided. 
Smoking Usual Brand Condition.  Subjects in this condition will undergo all the procedures 
as those subjects assigned to Camel Snus, except they will be told to smoke their usual brand 
of cigarettes and follow their normal patterns.  At the end of the 8-week period, they will be 
offered the product for up to 8 weeks, with a choice of how they want to use the product.  They 
will return to the clinic at 9, 10 and 12 weeks for assessment of use patterns (1, 2 and 4 weeks 
on the product).  During this period, subjects will keep daily diaries via Interactive Voice 
Response (IVR).  After 4 weeks of product use, they will come to the clinic whenever they want 
products for up to 8 weeks. At these clinic visits, their tobacco use patterns will be assessed via 
the Daily Use Summary and subjective forms.  At the end of the 8 weeks (Week 16) of snus 
use, subjects will bring in a first morning void urine sample for analysis of tobacco exposure 
measures.  Subjects will be paid $50 for the Week 16 visit.  Follow-up will occur as described 
below after the 8-week product access period (Weeks 20, 28 and 40).  If subjects in the Usual 
Brand Condition do not choose to use the Camel Snus, they will follow the Follow-up schedule 
for the snus arms. 
Follow-up.   Follow-up clinic visit will occur for all subjects at week 20 (12 weeks after the 
end of the trial period).  Tobacco use status (amount and type of tobacco product use) will be 
determined.  CO will be obtained and a first morning urine and blood sample.  These samples 
will be stored for cotinine assessment. Follow-up calls will occur at week 12 and 32 (4 and 24-
weeks post-study) and tobacco use will be assessed. Those continuing to smoke or use Camel 
Snus will be strongly advised to quit and treatment resources will be provided. 
Product Compliance Sessions.  At each visit, subjects will be asked and counseled about 
their use of Camel Snus. The procedures for inquiry and counseling will be standardized.  An 
intervention manual for each of the conditions will be developed.   
· 
Complete Substitution Condition:  Subjects will be asked about any concerns or 
obstacles associated with only using Camel Snus.  If difficulties are encountered, then 
subjects will be asked about why they think they are experiencing difficulties (e.g., taste, 

10/17/2013 
12 
 
lack of satisfaction, withdrawal symptoms) and will be asked to problem solve how to 
deal with these difficulties so that they can meet the requirements of the protocol.   
· 
Partial Substitution Condition: Subjects will be asked about their experience with using 
Camel Snus.  Subjects in the ad libitum condition will be encouraged to use as much or 
as litte as they want.  Subjects in the other condition will be encouraged to follow specific 
instructions for use.  
 
Product compliance. The importance of honest reporting will be stressed to the subjects.  
Compliance to the instructions for product use will be determined by: a) daily diary records; b) 
tobacco product logs where the amount of products dispensed will be recorded and unused 
products collected and recorded; and c) use of biomarkers to confirm if subjects were abstinent 
from combustible products (e.g., CO < 6ppm, using biomarkers for volatile constituents) in the 
complete substitution groups. If a subject in the complete substitution group has a CO >6, a 
spot urine will be collected. The sample may be used to look at toxicants related to tobacco 
combustion which could confirm asbstinence from cigarettes. 
.     
Compensation for Clinical Trial Phase. Subjects will receive a nominal payment ($5) per 
clinic visit to cover transportation costs for the 7 Clinical Trial Phase visits ($40). In order to 
maximize abstinence in the complete substitution group, subjects will be paid for protocol 
compliance including staying abstinent (with biochemical confirmation) from smoking. We will 
use an escalating amount of money for each week of protocol compliance for all subjects (e.g., 
starting at $10 and for each week of compliance, payment will increase in $10 increment; if non-
compliant with the protocol requirements, then the amount is reset to $10). Subjects will be told 
that compensation is contingent on compliance and this will be monitored via their daily diaries, 
product accountability, completion of forms, CO levels and potentially biomarker sample levels.  
If CO is elevated (CO > 6 ppm) in the complete substitution condition, a spot urine sample will 
be collected for analysis of biomarkers of cigarette use (e.g. thiocyanate or anabasine).  
Compensation for IVR completion will start at $5 per week for week 1 of the Clinical Trial Phase 
and then increase $5 per week for completion of calls, if compliant.  If days are missed, the 
payment reverts back to the $5 level. Subjects will receive $40 for the follow-up visit and $10 
each for two follow-up phone calls.  Total payment will be up to $585. This procedure using 
contingency management has been successfully used in prior biomarker studies that required 
total abstinence from cigarettes (see Premiminary Studies).  Subjects in the partial substitution 
group will undergo the same payment schedule and are paid for protocol compliance (attending 
visits, completing forms, submitting biosamples).  The use of payment contingences for 
compliance with specific instructions for use of the snus was ruled out because of the greater 
likelihood of false reporting and honesty of product use is critically important. Subjects will 
receive free Camel Snus while participating in the study. 
 
 
Measures 
Subjective measures (Table 1):  
The following measures comprise the TobPRAC Screening Questionnaire (developed as part of 
an NCI contract; N01-PC-64402):  
1) Tobacco Use History and Exposure, derived from the Tobacco Use Supplement to the 
2010 Current Population Survey and Population Assessment of Tobacco and Health 
(PATH)  Survey, measures variables such as smoking amount, cigarette brand, age of 
initiation of smoking, number of quit attempts, duration of quit attempts, duration of 
smoking;  
2) Demographic History inquires about age and gender, race, ethnicity, current occupation 
and usual occupation, and income;  

10/17/2013 
13 
 
3) Medical History and Current Health Status lists current diagnoses, symptoms and past 
health problems;  
4) Concomitant Medications Questionnaire lists medications that are currently being taken; 
5) Prime MD is a brief questionnaire developed for evaluation of mental disorders by 
primary care physicians (35);  
6) Centers for Epidemiological Studies 20-item scale (CES-D) assesses current symptoms 
of depression (36);  
7) Short Michigan Alcohol Screening Test (SMAST) Short form assesses any negative 
consequences from alcohol use by self report (37); and  
8) Drug Abuse Screening Test (DAST) assesses negative consequences from using drugs 
of abuse (38). 
  
TABLE 1 - SUBJECTIVE MEASURES 
 
Screen Sample 
Baseline 
Intervention 
F 
-up 
Phone 
f-ups 
WEEKS 
 
-93 
-92 
-91 
 
-00 
 
1 
2 
3 
4 
6 
8 
20 
12 & 
32 
TobPRAC Screening Questionnaire 
 
Tobacco Use History and 
Exposure; Smoking Cessation 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History & Current Health 
Status  
X 
 
 
 
 
 
 
 
 
 
 
 
CES-D 
X 
 
 
 
 
 
 
 
 
X 
 
 
Prime MD  
X 
 
 
 
 
 
 
 
 
X 
 
 
MAST  
X 
 
 
 
 
 
 
 
 
 
 
 
DAST 
X 
 
 
 
 
 
 
 
 
 
 
 
Biomarker Modifier Questionnaires 
 
Environmental & Social 
Influences Questionnaire  
 
 
 
 X 
 
 
 
 
 
 
 
X    
 
 
 
X 
 
 
NIAAA Alcohol Use 
Questionnaire  
 
 
  
X 
 
 
 
 
X    
   
X 
 
 
Drug Use Questionnaire 
 
 
X 
 
 
 
 
X   
  
X 
 
 
Perceived Stress Questionnaire  
 
 
X 
 
 
X 
 
X 
 
X 
 
 
Health Changes Questionnaire 
 
X 
X  
X 
X 
X 
 
X 
X 
X 
X  
X 
Respiratory symptoms 
Questionnaire  
 
 
 
  
 
X 
 
  
 
X 
 
 
X 
 
 X 
 
X 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Other Subjective Measures 
 
Adverse Events  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tobacco Daily Diary  (IVR) 
 
X 
X  
X 
X 
X 
X 
X 
X 
X 
 
 
Daily Use Summary 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X  
Fagerstrom (FTND) Test for 
Nicotine Dependence  
X 
  
 
 
X 
X 
 
X 
 
X 
X 
  
Wis. Index of Smoking 
Dependence Motives WISDM 
X 
  
 
 
X 
X 
 
X 
 
X 
 
 
Stages of Change 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Cigarette Evaluation Scale 
X 
X  
X 
X 
X 
X 
 
X 
X 
X 
X  
 
Product Evaluation Scale 
X 
 X  
  
  
X 
X 
 
X 
X 
X 
X  
 
Drug Effects/Liking  
X 
X  
 
 
X 
X 
 
X 
X 
X 
 
 
Perceived Health Risk 
X 
X 
 
 
X 
X 
 
X 
  
X 
 
 
Odor and Haptics 
X 
X 
 
 
 
  
 
X 
  
 
 
 
Tobacco Purchase Task 
X 
X 
 
 
 
X 
 
X 
  
X 
 
 
PANAS 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
MN Withdrawal Scale 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Questionnaire of Smoking/Snus 
Urges 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
 

10/17/2013 
14 
 
 
Biomarker Modifier Questionnaires  
The following measures comprise Biomarker Modifier Questionnaires (measures of factors that 
may moderate biomarkers of exposure and effect):  
1) Environmental and Social Influences Questionnaire consists of questions related to 
tobacco smoke exposure at home, work and socially (40);  
2) NIAAA Alcohol Use Questionnaire examines rate of alcohol use, current (last month) and 
lifetime. This questionnaire has been adapted to include lifetime maximum use patterns 
(41);  
3) Recreational Drug Use History assesses amount, frequency and date of last use of 
recreational drugs;  
4) Perceived Stress Questionnaire is a 14-item form measuring the degree to which life 
situations are appraised as stressful (43);  
5) Health Changes Questionnaire assesses any new health problems since their last clinic  
visit; 
6) Respiratory Symptoms Questionnaire is used to rate cough, phlegm production, 
shortness of breath and other respiratory symptoms on a scale ranging from 0 = none up 
to 10 = severe with a total respiratory score determined by adding the scores of each of 
these items. 
Subjective outcome measures:  
1) Interactive Voice Response system will be used on a daily basis to record amount of 
product use, cigarette and other nicotine containing products and tobacco use status will 
be reviewed and recorded at each clinic visit;  
2) Fagerstrom Test for Nicotine Dependence (FTND) (44);  
3) Wisconsin Index of Smoking Dependence Motives is a multidimensional measure of 
dependence based on theoretically grounded motives for drug use and intended to reflect 
mechanisms underlying dependence and has been found to be related to smoking 
heaviness, DSM-IV symptoms of depression and relapse (45);  
4) Minnesota Nicotine Withdrawal Scale (46);  
5) Questionnaire of Smoking Urges, a 32-item questionnaire on smoking urges, assesses a 
multidimensional conceptualization of craving to smoke (47);  
6) Adverse Events Scale assesses the nature, severity, duration, action taken, and outcome 
of adverse events related to tobacco product use;  
7) Perceived Health Risks Assessment asks subjects to rate their perception of their usual 
tobacco product against the study product to which they were randomly assigned;  
8) Product Evaluation Scale is a 7-point Likert-type scale that is modified from the Cigarette 
Evaluation Scale (48). In addition, items from a scale that was used to evaluate various 
medicinal nicotine products is incorporated in the Product Evaluation Scale (49). This 
scale has been used in a number of our studies. Cigarette Evaluation Scale will be used 
at baseline;  
9) Drug Effects/Liking Questionnaire (50);  
10) Stages of Change (51);  
11) Consumer Product Perception. This measure will be developed by Project 3 of this U19 
and include cognitive and affective measures and Odor/Haptics; and  
12) Tobacco Purchase Task. Participants will be asked “How much would you be willing to pay 
for one tin of Camel Snus?” As a reference point, participants are also asked to report how 
Interest in Switching/Quitting 
 
X  
 
 
 
 
 
 
 
X  
X  
 
WEEKS 
-93 
-92 
-91 
-00 
1 
2 
3 
4 
6 
8 
20 
 
Abbreviations: CESD= Centers for Epidemiological Studies-Depression, MAST=Michigan Alcohol Screening 
Test, DAST=Drug Abuse Screening Test; 1Consumer Perception Measures from Project 3 including Oral/Haptic 
Scale.  
 

10/17/2013 
15 
 
much they usually pay for one pack of cigarettes. The ratio of these prices can give an 
indication of the relative value of Camel Snus, and would allow comparison across the study 
sites, where cigarette prices vary. Subjects will also be provided the Tobacco Purchase 
Task developed, which will be used to generate demand curves by asking participants to 
report the number of units of a tobacco product that they would consume in a day if the units 
cost various amounts of money. This procedure has been used to study demand for 
cigarettes (52-53). 
13) Interest in Switching or Quitting assesses interest in switching from cigarettes to the Camel 
Snus if it were not for the study; impact on interest in quitting tobacco use; and interest in 
paying for the product. 
A panel of biomarkers has been selected to represent exposures to different toxicants and 
different disease risk factors. Samples will be analyzed for some or all of the following 
biomarkers and will be sent to a Biobank with de-identified information. Please see Table 2 for 
list of biomarkers. 
1. Carcinogen biomarkers of exposure and effect and cardiovascular risk indicators were 
chosen because they have shown reasonable laboratory reproducibility, have clear 
differences in levels between smokers and nonsmokers and/or decrease upon tobacco 
cessation (33-34).  
2. Cardiovascular biomarkers were selected because they are associated with different 
pathogenesis for disease and have also shown reasonable laboratory reproducibility.  
3. Nicotine exposure and metabolite ratio (NMR) and the total nicotine equivalents will be 
determined. The latter accounts for 73-96% of the nicotine dose and are a useful 
measure of daily nicotine exposure. The NMR is an indicator of CYP2A6 enzyme activity 
and is the ratio between two nicotine metabolites, cotinine and trans-3’-hydroxycontinine 
(3-HC).  
 
 
TABLE 2 - BIOMARKER MEASURES 
1Biomarkers for Carcinogen Exposure 
 
Screen 
Sample 
Baseline 
Intervention 
 
20  
F-up4 
WEEKS 
-93 
-92 
-91 
-0 
1 
2 
3 
4 
6 
8 
20 
Total  NNAL  
 
 
X 
X 
 
X 
 
X 
 
X 
 
Total  NNN  
 
 
X 
X 
 
X 
 
X 
 
X 
 
Phenanthrene Tetroal 
 
 
X 
X 
 
X 
 
X 
 
X 
 
Mercapturic acids of acrolein, 
benzene, 1,3-butadiene, 
crotonaldehyde, and 
ethylene oxide 
 
 
 X 
X 
 
X 
 
X 
 
X 
 
PGEM 
 
 
 X 
X 
 
X 
 
X 
 
X 
 
8-epi-PGF2 
 
 
X 
X 
 
X 
 
X 
 
X 
 
1Nicotine Exposure and Metabolite Ratio 
Total nicotine equivalents 
(Serum/Urine) 
 
 
X 
X 
 
 
 
X 
 
X 
X 
Nicotine metabolite ratio 
(serum) 
 
 
 
X 
 
 
 
 
 
 
 
C-Reactive protein* 
 
 
 
X 
 
 
 
X 
 
X 
 
Hematology  
 
 
 
X 
 
 
 
X  
 
X 
 
Other Biomarkers 
Alveolar carbon monoxide 
(CO) 2 
X 
X  
X  
X 
X 
 
X 
X 
X 
X 
X 
 
Oxygen saturation  
X 
 X 
X 
X 
 
X 
X 
X 
X 
X 
 

10/17/2013 
16 
 
Expectorated SLT 
samples/Cig Butts and 
Filters 
 
 
 
 
2X 
 
 
 
 
 
X 
 
   
 
 
 
Vital signs and weight 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Buccal cells 
 
 
 
X 
 
 
 
X 
 
X 
 
Urine pregnancy screen 
X 
 
 
 
 
 
 
 
 
 
 
3Biobank Samples 
Urine 
 
 
X 
X 
  
3X 
 
3X 
X  
X 
X 
Spot urine (if appropriate) 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Blood 
 
 
 
X 
 
X 
 
X  
 
X 
X  
Genetic analysis5 
 
 
 
 
 
 
 
 
 
 
WEEKS 
-93 
-92 
-91 
-0 
1 
2 
3 
4 
6 
8 
20 
1Justification for Biomarkers in Core B and Hatsukami et al., (2005); 2Cigarette butts only 
 3Samples collected at weeks 2 and 4 will be stored for potential analyses in the future as needed or funded.  
4Only week 20 at follow-up will be a clinic visit, week 12 and 32 are telephone; 5Samples will be stored for future funding 
for analysis for genetic predisposition for tobacco toxicant metabolism, behavior and harm. Abbreviations: Total NNAL: 4-
(Methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides; Total NNN: N'-Nitrosonornicotine and its glucuronides; 
PheT: r-1,t-2,3,c-4-Tetrahydroxy-1,2,3,4-tetrahydrophenanthrene; Mercapturic acids: S-Phenylmercapturic acid; 
Monohydroxybutylmercapturic acid; 3-Hydroxypropylmercapturic acid; 4-Hydroxybut-2-ylmercapturic acid; 2-
Hydroxyethylmercapturic acid; PGE-M: 11-α-Hydroxy-9,15-dioxo-2,3,4,5-tetranorprostane-1,20-dioic acid; 8-epi-
PGF2α:9,11,15-Trihydroxyprosta-5,13-dien-1-oic acid. NOTE:  Minor tobacco alkaloids (nornicotine, anabasine, 
anatabine, myosamine and cotinine) will be analyzed in 50 complete substitution subjects for the analysis proposed by 
Project 1.     
 
 
Other biomarkers will include: 
1. Exhaled carbon monoxide (CO) and oxygen saturation as indicators of the extent to 
which red blood cells may be carrying their usual load of oxygen.  
2. Biobank:  Other tobacco-related biomarkers for assessment in blood, urine, or buccal 
cells may be determined to be necessary or may be developed over time and these 
additional assays will be completed as appropriate. Also, in the future, samples may be 
analyzed for genetic predisposition for tobacco toxicant metabolism, behavior and harm. 
 
Product constituent testing:   
Pouches of used smokeless tobacco product will be obtained for chemical constituent 
analysis.  Prior to the clinic visit at week 4 subjects will be asked to collect all used samples 
during the 24 hours before the visit.  These samples will be placed in a small cooler and brought 
to the clinic visit.  In addition, five unused oral tobacco pouches from their tin will be collected.  
Both these samples will be frozen.  These samples will be shipped on dry ice to the CDC when 
samples from all the visits have been collected.  At the CDC, the levels of selected chemical 
constituents in the unused and used pouch will be analyzed.  These chemical constituents 
include nicotine, tobacco specific nitrosamine (NNK, NNN), BaP and catechols.  Solanesol in 
cigarette filters will also be tested by CDC, which is a measure of tobacco smoke exposure (see 
30, 31 for description of analysis conducted at CDC).   
 
 
Product intervention dose: 
The dose of unprotonated nicotine for Camel Snus Frost is 3.58, Camel Snus Mellow is 3.36, 
Camel snus Robust is 5.09 and Camel Snus Winterchill is 4.59 and our prior PK study 
(unpublished) showed that these doses led to levels that were about equivalent to or slightly 
higher than 4 mg medicinal nicotine lozenge.  We will initiate use with the highest dose and if 
side effects are experienced, then we will assign the product with the lower dose.  In our current 
study, the majority of smokers are able to tolerate the higher doses (95%; 21 out of 22 smokers) 

10/17/2013 
17 
 
and choose Winterchill (82%, 18 out of 22 smokers).  The levels of exposure to toxicants (e.g., 
carcinogens) are lower than observed from cigarettes (2).  
 
 
6.5  Potential Risks of Study Participation:  
The potential risks for subjects are minimal. Subjects’ medical history will be reviewed at 
orientation prior to entry into the study. Subjects will be under medical supervision throughout 
their participation in the study and adverse symptoms will be recorded at each clinic visit and 
monitored by the PIs and study medical personnel. We will also be available 24 hours a day for 
emergency calls. 
The major side effects associated with Camel Snus are nausea, dizziness and 
lightheadedness, mouth sores, gastrointestinal distress, headache, hiccups, dry mouth and sore 
throat. Nicotine is toxic to the fetus and pregnant women are excluded from participation. 
The oral tobacco product administered to subjects is currently marketed and sold over-
the-counter. All subjects are current regular smokers and thereby exposed to nicotine and 
tobacco toxicants. Oral tobacco products may be linked with an increased risk for oral and 
pancreatic cancer, although compared to cigarettes, the risk is dramatically less. The reduction 
in risk is largely due to delivery of lower number and sometimes levels of tobacco toxicants from 
smokeless tobacco to the user simply because the tobacco is not burned, which yields 
thousands of combustion products. However, as this study will examine, some users may 
maintain their baseline smoking rate while using oral tobacco thereby may increase their 
exposure to nicotine and perhaps some tobacco related toxicants.  We will minimize this risk by 
seeing the subjects on a weekly and then bi-weekly basis to assess increased tobacco use.  In 
addition, all subjects will be strongly advised to quit all tobacco use at the end of the study and 
will be provided cessation materials.    
There is also the chance of continued use of the products after the study has ended; 
however, cessation of all tobacco products will be recommended to the subjects.  If at any time 
the subject wants to quit smoking or use of all tobacco products, this decision will be 
encouraged and supported. Subjects will be provided with a treatment manual and referral to 
different treatments. 
Other risks include blood draws and a trained laboratory technician or a registered nurse 
will obtain blood samples. Otherwise, the physiological and subjective measures will be 
noninvasive and should present no psychological or medical risk to the subject. 
Some questionnaires may be of a sensitive nature assessing subjects’ drug and alcohol 
use or psychiatric symptoms.  Subjects will be told that they may refuse to answer, however, 
refusal may effect continued participation in the study.   
 
7.0  Statistical Analysis 
This study has three primary aims: to determine the effect of instructions for use and the 
amount of substitution on biomarkers of exposure and patterns of oral tobacco use (primary 
endpoint at 4 weeks, but also assessed at 8 weeks), to determine when stabilization of product 
use occurs by examining the time effects for subjective, biological, topographic and behavioral 
responses (analysis for 2, 4, 6 and 8 weeks) and to determine important moderators for product 
use and exposure. Secondary aims include developing innovative measures to assess levels of 
exposure from smokeless tobacco and cigarettes. 
 
Demographic and smoking history variables of those who entered the sampling phase 
and the trial phase will be summarized and compared to national survey data for the general 
population of smokers and smokers most interested in using oral tobacco products (e.g., 1).  
Baseline covariates will be summarized by treatment group to check that groups are balanced 
after randomization. Continuous measures will be summarized by mean (SD), median (range) 

10/17/2013 
18 
 
or other summary measures. Categorical covariates will be summarized by contingency tables. 
Numerical variables measured more than once at the baseline assessments will be assessed 
for reproducibility using the intra-class correlation coefficient and the average will be used for 
the baseline variable if adequate reproducibility is observed. 
 
The primary outcome measures (tobacco use, biomarkers, subjective measures) will be 
assessed up to five times for each individual. The analysis of our primary aims will use linear 
mixed models to account for potential intra-subject correlation due to repeated measurements 
from a single individual. Linear mixed models are sensitive to miss-specification of the within-
subject correlation structure. We will use exploratory graphical methods to identify the 
appropriate within-subject correlation structure. Residual plots and other diagnostic methods will 
be used to check other model assumptions. 
 
Hypothesis 1 will be analyzed by fitting a linear mixed model for each of the outcome 
measures (using week 6 as the primary endpoint):  total NNAL, NNN, phenanthrene tetarol, 
mercapturic acids, PGEM, 8-epi-PGF2α, Total nicotine equivalents; and cardiovascular risk 
factors.. The mean model will include an effect for time, group and a time by group interaction. 
Specific hypotheses will be tested by testing the significance of the appropriate contrast.   A 
secondary analysis will be completed adjusting for important factors such as environmental 
toxicant exposures, nutrition, stress and health to determine the effect their inclusion has on the 
association between group and the outcomes. Finally, we will complete an exploratory analysis 
that includes a site by group interaction to determine if the group effect changes by location. 
 
Hypothesis 2 will be analyzed by fitting separate linear mixed models for each group 
using biomarkers, snus topography, cigarettes and other subjective responses as the outcome. 
We will test for significant time effects and present plots of the outcomes to visually represent 
the time effects.  Stabilization will be considered to have occurred when the variance between 
time-points does not exceed the coefficient of variation of the measures as assessed in the 
usual brand smoking group. 
 
Hypothesis 3 will be analyzed using a linear mixed effects models with a mean model 
that includes time, group and potential moderators (e.g., use patterns, age, sex, dependence, 
subjective responses, etc.).  Interactions between group and the potential moderators will be 
included in the model and tested to determine if the potential moderator modifies the effect of 
group on the outcome (total nicotine equivalents, total NNAL). 
 
Hypothesis 4 will be evaluated using scatter plots and other visual methods. 
Associations will be summarized by Pearson’s or Spearman’s correlation coefficient, as 
appropriate, and formal inference will be completed using linear regression. 
 
 Compliance to the assigned treatment is a concern in this study. Our primary analysis 
will follow the intent-to-treat principle, where subjects are analyzed in the group they were 
randomized to regardless of compliance, to preserve the integrity of a randomized study. In 
addition, we will summarize compliance by treatment group and evaluate the correlation 
between compliance and baseline covariates to identify potential predictors of treatment 
compliance. Finally, we will complete a secondary analysis that accounts for non-compliance. A 
standard analysis adjusting for compliance in a regression setting is known to be susceptible to 
selection bias and, therefore, our secondary analysis will be completed using a principle 
stratification framework (56). 
 
Other Analyses of Interest 
 
Hypothesis: Those subjects who rate the products positively on the Product Evaluation 
Scale, Drug Effects/Liking Questionnaire and Perceived Health Risks during the sampling phase 
and extent of willingness to pay for the product are more likely to use more products during 
sampling, remain in the study and use products during the clinical trial phase.    

10/17/2013 
19 
 
 
Hypothesis:  Most subjects (controls) will choose the ad libitum partial substitution 
method for tobacco use the most and very few smokers will choose the complete substitution 
condition.  The rate at which subjects choose the various methods for use will be summarized 
by the sample proportion and confidence intervals.  
Interaction of components tested across all projects will be conducted under Core A 
 
 
Sample-size determination.   
A sample of size 138 per group (690 in the five groups) would be required to assure an 
80% chance of demonstrating that complete substitution leads to higher reduction in NNAL 
levels compared to the partial substitution after controlling for baseline NNAL levels (assuming a 
correlation of 0.6 between baseline and follow-up NNAL scores, and an effect size of low to 
medium) and accounting for drop-out rates and an abstinence rate of 40 to 50%. See Human 
Subjects section for details. 
 
Randomization:  Stratified randomization will be generated by the Biostatistics and Informatics 
Core of this grant.   
 
8.0 ADMINISTRATIVE CONSIDERATIONS 
 
8.1 Conduct of the Trial 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP), the Declaration of Helsinki, and the appropriate 
regulatory requirement(s).   
The University Of Minnesota 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/EC or Campus Administrator approval has been obtained.  The protocol, 
informed consent, written information given to the patients, annual progress reports, and any 
revisions to these documents will be provided to the IRB by the investigator.   
Essential clinical documents will be maintained to demonstrate the validity of the study and the 
integrity of the data collected.  Master files should be established at the beginning of the study, 
maintained for the duration of the study and retained according to the appropriate regulations.   
 
8.2 Data Management 
 
Quality control and adherence to protocol procedures: 
Standard operating procedures will ensure that all study sites are following the same 
procedures.  Face-to face training for research personnel will occur prior to the study, where the 
protocol and procedures will be carefully described. Case report books will be provided for the 
different sites to maximize parallel data recording. Each visit will have a checklist of all the 
measures that need to be taken and the order by which these measures are administered. As 
another measure to ensure data collection integrity, an experienced study monitor will make a 
visit to clinical sites after they have enrolled their first several subjects to make sure that the 
protocol is being followed carefully and all the data are being collected properly. Another onsite 
visit will occur after the initiation of the study. Regular telephone conference calls will occur 
among the research coordinators to provide updates on study progress, trouble shoot problems 
and to make sure that all protocol procedures are followed. On a once a month basis, the 
investigators will participate in this conference call. During these conference calls, the number of 
subjects enrolled, the data collection process, the results from data monitoring and other issues 
of concern will be discussed. 

10/17/2013 
20 
 
Urine and blood biosamples and pre- and post-use smokeless tobacco (ST) collections 
will be given individualized bar codes for each subject (See Biomarker Labeling SOP). Each site 
will receive barcoded labels which have been packaged at the research coordinating site 
(University of Minnesota). Most of the subjective measures will be administered via Qualtrics, a 
secured website for the subject to enter the date in electronic forms. Forms will include 
programming features to ensure valid data (i.e., input masks, validation criteria, skipout logic) 
and will be exported to files that are de-identified of any personal health identifiers.  
All other data not captured directly in Qualtrics at the other sites (e.g., pencil-and-paper 
forms) will be sent to the coordinating site (with photocopies of originals maintained at the other 
sites). A data monitor will be available at the research coordinating site and irregularities (e.g., 
wrong date on the forms, inconsistent data) or missing data will be flagged by the monitor and 
sent to the site for comment or correction to ensure the integrity of the data. 
All de-identified biosamples will be sent to the University of Minnesota on a quarterly 
basis. Lists of subject number and biosamples sent will be recorded by each site and when the 
samples are received, the researcher at the coordinating site will note each subject number and 
biosample that was received. The samples-received list will be posted on a secure website so 
that each site can check it against their own lists. 
 
Data Identification: 
Human subject consent forms will indicate corresponding subject ID and will not be 
stored with the data.  Paper and pencil subjective forms, and other Case Report Forms (CRF) 
will be identified with subject number and initials, and visit number and date will be entered onto 
appropriate forms.  Data entered into the database will be de-identified, with only subject 
number as a link.  Biomarker samples will be labeled with a scanner barcode indicating study 
site, subject number, visit number, specimen type (e.g., urine, serum, saliva) and intended 
assay or biobank samples. 
All records will be confidential.  All shared date will be de-identified.  A Certificate of 
Confidentiality from NIH will be obtained to protect subject data from subpoena.  A study 
monitor from the University of Minnesota will review each site’s records to ensure all the study 
records are accurate and that all consents have been signed, thereby having access to names 
of individuals at different sites.  However, no record of this identifying information will leave the 
premises.  All data from the subjects at the different sites will be on a secure web-site or sent to 
the University of Minnesota, and all information will be de-identified. All biosamples sent to the 
University of Minnesota will also be de-identified. 
 
Randomization Procedures: 
 
Randomization will be stratified by location and number of cigarettes smoked per day (≤ 
18/day vs. > 18/day, the expected median number of cigarettes smoked per day) to assure 
balance across treatment groups. Treatment groups will be checked for balance on other factors 
post randomization and any imbalances will be accounted for in our analysis as described in the 
statistical analysis section.  
Subjects who have completed the Sampling Phase and are interested and eligible (use 
of >14 sachets and used most days) will be entered into the clinical trial and randomized to one 
of 5 arms.  Subjects will be randomly assigned to the groups in an unblended fashion using a 
blocked random assignment list generated by the Biostatistics and Informatics Core.  Each 
study site will receive a copy of the Randomization List for their study site.  Subjects will be 
assigned sequentially to the product associated with the next open randomization number.  This 
randomization number will be entered into the CRF.   
  
Study Tobacco Product and Accountability:  

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The dose of Camel Snus (Winterchill and Robust) is about 2.82 mg of free-nicotine per 
portion and our prior PK study (unpublished) showed that the dose is likely to lead to levels that 
were no higher than 4 mg medicinal nicotine lozenge. If these doses are too high, subjects will 
be switched to lower nicotine level Camel Snus products (Frost and Mellow).  In the 
experimental condition that involves specific amounts of use, we based the dosing schedule on 
prior study results that showed that smokers who smoke 20 cigarettes a day on average use 7-8 
pouches of Camel Snus and a study conducted by Dr. Thomas Eissenberg who found that 
those who smoke >20 cigarettes a day use about 12 packets per day. The levels of exposure to 
toxicants (e.g., carcinogens) are lower than observed from cigarettes (Kotlyar et al.).   
 
Record of study product purchased will be available at the study site showing number of 
tins purchased, purchase site, and purchase price.  Study product accountability will be also 
documented in the CRF under the “Product Accountability” form denoting the lot number for the 
tin, the number of tins of Camel Snus dispensed, number of unused tins returned, and any 
discrepancy between dispensed, and reportedly used product on the daily diary.   
 
Biobank: 
A separate consent form will be used to obtain permission from subjects to allow de-
identified biosamples to be stored in a biobank for future analyses of biomarkers or genotyping. 
Investigators at each site will only have access to identifying subject information of their 
subjects. This information will be kept locked in a secure area. Neither the other sites nor the 
main coordinating site will have access to this information. All biobank samples will be in the PL 
control and collaborating researchers will submit an application to be reviewed and assessed by 
PL prior to sample sharing.  
 
 
8.3  Data and Safety Monitoring Plan 
The study coordinator and the research nurse will be responsible for the daily oversight of 
subject safety.  At the University of Minnesota site, Drs. Dorothy Hatsukami and the Medical 
Director, Dr. Sharon Allen, will meet weekly 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 for any contraindications for 
the treatment products and vital signs checked on a weekly basis. Patients will be under 
medical supervision while in the study and seen on an ongoing basis by our research staff who 
will assess adverse events and make appropriate referrals to the physician.  Similar procedures 
will be instituted at the other institutions.   Any adverse symptoms will be discussed over the 
telephone on the weekly calls across the sites.  Urgent issues can be dealt with more 
immediately.   
Drs. Hatsukami and Shields will conduct internal monitoring of subject safety across all sites.  
Any medical issues that occur at the three other sites will be conveyed to them.   These issues 
will be recorded and tracked. In addition, a Data and Safety Monitoring Board, which will be 
comprised of experts in the areas of smoking tobacco products, tobacco addiction and clinical 
trials, will be convened.  The Board will include Patrick Nan-Sinkam MD, Associate Professor of 
Internal Medicine and Co-Director Research Programs in the Division of Pulmonary Allergy, 
Critical Care and Sleep Medicine at Ohio State University; Michael Kotlyar, PharmD, Associate 
Professor of Experimental and Clinical Pharmacology at the University of Minnesota; Scott 
Leischow, PhD, Professor in the UA College of Medicine; and Haitao Chu, PhD, Associate 
Professor, Division of Biostatistics, School of Public Health. 
The Data and Safety Monitoring Board will begin by reviewing the protocol and establishing 
guidelines for data and safety monitoring.  This will include developing standard procedures for 
day-to-day monitoring by the internal monitors, investigators and study staff.  This Board will 

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22 
 
meet at regular intervals (at least once a year) to evaluate the progress of the trial, review data 
quality, patient recruitment, study retention, and examine other factors that may affect study 
outcome.  They will also review the participant’s ability to achieve the study requirements and 
the rates of adverse events to determine whether there has been any change in participant risk.  
Their review will ensure that subject risk does not outweigh the study benefits.  A brief report will 
be generated from each of these meetings for the study record and forwarded to the each of the 
study site’s 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 patient 
experiences.  They will make appropriate recommendations for changes in protocol, if needed. 
 
The University of Minnesota NCI designated Cancer Center also has a Cancer Protocol 
Review Committee that meets on a monthly basis to review all cancer-related protocols.  This 
study will also be subjected to review by this committee.  Reports to this committee are 
submitted on a yearly basis, and for some projects, on a quarterly basis. Reports from all sites 
will be submitted.  
 
All drug related adverse events of a non-serious nature will be reported each institution’s 
IRB on at the time of renewal.  Serious adverse events related to the study product or 
procedures will be reported by telephone to the IRB within the 3 days of our receipt of 
information regarding the event and written reports will be submitted within 10 days.  The Data 
and Safety Monitoring Board will review all serious or unexpected adverse events and provide 
recommendations.  
We will inform NIH of any significant action taken as a result of the Data and Monitoring 
Board’s findings. We will inform the subjects of any changes in risk.  
 
8.4  Event Reporting to IRB and Cancer Center’s Data and Safety Monitoring Council 
(DSMC) 
 
Safety concerns for this project are expected to be minimal and include breach of confidentiality; 
issues related to coercion; effects of nicotine withdrawal; effects of returning to regular smoking; 
and effects associated with Camel Snus.  The expected safety concerns will be addressed at 
IRB annual review unless it is appropriate to file a UPIRTSO immediately.    
Any events meeting an unexpected, serious adverse event defined as reportable (such as 
hospitalization) on the IRB’s website at http://www.research.umn.edu/irb/ae/.   The DSMC will 
be copied on all reports to the IRB. 
In addition, to be in compliance with local and federal regulations the following events/problems 
will be reported to the IRB and DSMC within the 10 working day time frame: 
· 
Any serious event (including on-site and off-site adverse events, injuries, side effects, 
deaths or other problems) which in the opinion of the local researcher was unanticipated, 
involved risk to subjects or others, and was possibly related to the research procedures 
· 
Any serious accidental or unintentional change to the IRB-approved protocol that 
involves risk or has the potential to recur;  
· 
Any deviation from the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research subject; 
· 
Any publication in the literature, safety monitoring report (including Data and Safety 
Monitoring Reports), interim result or other finding that indicates an unexpected change 
to the risk/benefit ratio of the research; 
· 
Any breach in confidentiality that may involve risk to the subject or others; 

10/17/2013 
23 
 
· 
Any complaint of a subject that indicates an unanticipated risk or that cannot be resolved 
by the research staff.  
 
Adverse Events 
An Adverse Event (AE) is any untoward occurrence in a subject administered a study product 
and it may or may not have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (including a clinically significant abnormal laboratory 
finding) and symptom or disease temporally associated with the use of an oral tobacco product, 
whether or not considered related to the product.  AEs include any illness, sign, symptom, or 
clinically significant laboratory test abnormality that has appeared or worsened during the 
course of the clinical trial, regardless of causal relationship to the product(s) under study. Each 
AE will be evaluated to determine severity (mild, moderate, severe); duration; relationship to 
study product; action taken, if any; and whether it meets criteria to be considered a Serious 
Adverse Event.  
Adverse events will be assessed at each visit and compared to baseline rates of 
occurrence.  All adverse events of a severe or serious nature will be presented to the PI and 
medical oversight at the study site and the coordinating site will be informed of the event.   
 
Serious Adverse Events 
Serious Adverse Event (SAE) is an adverse event occurring at any dose that results in either:  
1) Death; 2) “Life-threatening” event; 3) Persistent or significant disability/incapacity; 4) Requires 
or prolongs hospitalization; 5) Congenital anomaly or birth defect; 6) Cancer; 7) An important 
medical event which may jeopardize the patient and may require intervention to prevent a 
serious outcome; or 8)  A medically significant/important event based on the Investigator’s 
assessment.  All Pertinent information for completing serious adverse events CRF will be 
obtained including: Subject Number, demographics, diagnosis (if known) or symptom, date of 
onset, maximum intensity, outcome, date of resolution or death, action taken with study drug, 
withdrawal from study, relationship to study drug, possible cause of serious event other than 
study drug, relevant medical conditions or risk factors, current medications or other relevant 
details or assessments such as laboratory data and/or test results. Details of all study product 
taken until the onset of SAE should be provided. The association or relationship of the study 
product with a Serious Adverse Event will be determined by the clinical investigator. 
 
Reporting Requirements 
 
A serious event (SAE) must  reported to the coordinating site (UMN) if it is both 
unexpected and associated with the use of the study product within 24 hours of acquiring the 
information.  The coordinating site will notify the FDA, IRB and all investigators of the event, in 
writing, within 10 working days after initial receipt of the information.  Since this study is not 
conducted under an IND, telephone reports within 24 hours will not be required.  
Any SAE occurring after the patient has signed the informed consent and until 4 weeks 
after the patient has stopped study participation must be reported. SAEs occurring more than 4 
weeks after study discontinuation need only be reported if a relationship to ST use is suspected. 
 
 
COLLABORATING SITES:   
 
The sites include University of Minnesota (Dorothy Hatsukami), Ohio State University (Peter 
Shields) and Roswell Park Cancer Institute in Buffalo, NY (Richard O’Connor).  Dorothy 
Hatsukami will lead and oversee the project.  Each site will have a Project Leader and Co-leader, 
Project Coordinator and study assistant.  All sites will obtain IRB approval from their institutions 
with reference to the main institution (University of Minnesota), which will be collecting all data 

10/17/2013 
24 
 
and receiving biosamples.  All personnel will be trained on study procedures, human protection 
issues and regulatory requirements. 
 
 
 
 
 
 
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