Impact of Sugars on Tobacco Product Toxicity and Abuse Liability
Phase: NA
Conditions: Tobacco Use
Sponsor: Masonic Cancer Center, University of Minnesota

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Protocol Title 
Impact of sugars on tobacco product toxicity and abuse liability 
Principal 
Investigator/Faculty 
Advisor 
Name: Dorothy Hatsukami, Irina Stepanov 
Department:  Masonic Cancer Center Tobacco Research Programs 
Telephone Number:  612-626-2121/612-624-4998 
Email Address: hatsu001@umn.edu/ stepa011@umn.edu 
Student Investigator 
Name: NA 
Current Academic Status (Student, Fellow, Resident): 
  
Department: 
Telephone Number: 
Institutional Email Address: 
Scientific Assessment 
Nationally-based, federal funding organizations 
IND/IDE # (if 
applicable) 
P00116, IU0000703, IU0000711 
IND/IDE Holder 
Irina Stepanov & Dorothy Hatsukami 
Investigational Drug 
Services # (if 
applicable) 
NA 
Version 
Number/Date: 
Version 7|      01 DEC 2023 
 
PROTOCOL COVER PAGE 
 
 
 
 

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REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
1 
15 NOV 2021 
Revised screening process 
Y 
2 
19 JAN 2022 
Updated inclusion criteria, added 
additional MNWS survey 
N 
3 
26 JUL 2022 
Revised inclusion criteria (CPD)  
N 
4 
22 FEB 2023 
Revised exclusion criteria (Marijuana 
use), revised recruitment target (N 
from 30 to 25) 
N 
5 
01 DEC 2023 
Revised screened number and 
increased N to 30 account for data 
collection oversights with early 
completers.  Added language 
clarifying CTSI monitoring oversight 
and study cigarette storage 
temperatures. 
N 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
1.0 
Objectives 
5 
2.0 
Background 
5 
3.0 
Study Endpoints/Events/Outcomes 
7 
4.0 
Study Intervention(s)/Investigational Agent(s) 
7 
5.0 
Procedures Involved 
8 
6.0 
Data and Specimen Banking 
10 
7.0 
Sharing of Results with Participants 
11 
8.0 
Study Population 
11 
10.0 
Local Number of Participants 
13 
11.0 
Local Recruitment Methods 
13 
12.0 
Withdrawal of Participants 
13 
13.0 
Risks to Participants 
14 
14.0 
Potential Benefits to Participants 
15 
15.0 
Statistical Considerations 
16 
16.0 
Health Information and Privacy Compliance 
18 
17.0 
Confidentiality 
21 
18.0 
Provisions to Monitor the Data to Ensure the Safety of Participants 
22 
19.0 
Provisions to Protect the Privacy Interests of Participants 
24 
20.0 
Compensation for Research-Related Injury 
25 
21.0 
Consent Process 
25 
22.0 
Setting 
26 
23.0 
Multi-Site Research 
26 
24.0 
Coordinating Center Research 
27 
25.0 
Resources Available 
27 
26.0 
References 
27 
 

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ABBREVIATIONS/DEFINITIONS 
● AE: Adverse Event   
● CES-D: Centers for Epidemiological Studies 20-item scale 
● DAST: Drug Abuse Screening Test  
● FTND: Fagerstrom Test for Nicotine Dependence 
● HPHC: Harmful and Potentially Harmful Constituents 
● IUD: Intrauterine Device  
● IVRS/IVR: Interactive Voice Response System 
● MAST: Michigan Alcohol Screening Test (Short form)  
● SAE: Serious Adverse Event  
● UB: Usual Brand 
 
 

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1.0 
Objectives 
To investigate a comprehensive set of abuse liability and appeal measures, smoking intensity, 
as well as analyze the impact of sugar content on the formation of DNA adducts derived from 
aldehydes and oxidative stress in the oral cavity of smokers.  
 
2.0 
Background 
Chemical constituents of tobacco and cigarette smoke play crucial role in addictiveness, toxicity 
and carcinogenicity of tobacco products. The U.S. FDA established a list of 93 harmful and 
potentially harmful constituents (HPHC) in tobacco and cigarette smoke that cause or have 
potential to cause these and other harmful effects.1 Levels of many HPHCs in cigarette smoke 
can be substantially reduced by modifying cigarette manufacturing approaches.2 However, in 
the absence of regulation, smokers are being exposed to variable and often unnecessarily high 
levels of such constituents. According to the Family Smoking Prevention and Tobacco Control 
Act, the FDA can set standards for HPHCs.3 Such regulation is likely to serve as a powerful tool 
in efforts to protect public health. As an example, reduction of nicotine in cigarette tobacco can 
reduce abuse liability of cigarettes.4 In addition, prospective epidemiological studies have shown 
that the level of intake of some tobacco carcinogens is predictive of the risk of cancer 
development in smokers, suggesting that limiting smokers’ exposures to such constituents may 
be beneficial.5-7 Therefore, imposing standards for constituents that contribute to addictive and 
toxic properties of cigarette smoke can potentially help to reduce smoking prevalence and/or 
minimize harmful exposures in smokers who are unable or unwilling to quit. 
Soluble sugars such as sucrose, fructose, glucose are formed via enzymatic hydrolysis of starch 
in tobacco material during its processing, and are also added to tobacco blend during cigarette 
manufacturing.8 Tobacco manufacturers also use a variety of other sugar-containing ingredients 
such as brown sugar, honey, corn syrup, and molasses.8, 9 During cigarette combustion, 
processes such as Maillard reactions and sugar caramelization and pyrolysis can result in the 
formation of a variety of products (Figure 1), including aldehydes (e.g., formaldehyde, 
acetaldehyde, acrolein), furans (e.g., 2,5-dimethylfuran, furfural and 5-hydroxymethylfurfural), 
other volatile compounds (e.g., benzene, acrylamide, polycyclic aromatic hydrocarbons), 
ketones (e.g. diacetyl), and acids (e.g., formic and acetic acid). Therefore, sugars in tobacco filler 
are likely to have a profound impact on cigarette smoke properties. First, the majority of the 
products of sugar decomposition are important toxicants and carcinogens.10-18,21 In addition, 
some volatile products of caramelization and acids formed during sugar pyrolysis play an 
important role in palatability-related smoke  

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To summarize, as precursors to smoke constituents that play important roles in smoke toxicity, 
carcinogenicity, palatability, and addictiveness, sugars are likely the most versatile key 
constituents contributing to the smoking-associated morbidity and mortality. Manufacturer 
reporting of sugar levels in tobacco products could be required by the FDA if sugars are added 
to HPHC list, which would allow for a more accurate characterization of harmful potential of 
cigarettes and other combustible or heated tobacco products. Furthermore, reductions of sugar 
content in cigarette tobacco could potentially result in decreased palatability of cigarette smoke, 
make it harder to inhale due to increased harshness, and reduce levels of certain volatile 
toxicants and carcinogens.   
 
3.0 
Study Endpoints/Events/Outcomes 
3.1 
Primary Endpoint/Event/Outcome  
To evaluate the impact of sugar content on smoking intensity (nicotine levels in spent filters), 
subjective responses to cigarettes (e.g., reinforcing and sensory effects) and behavioral 
measures (multiple choice procedure, cigarette purchase task). We hypothesize that the 
collected measures will indicate lower abuse liability for cigarettes with lowest sugar content. 
3.2 
Secondary Endpoint(s)/Event(s)/Outcome(s)  
To conduct an exploratory analysis of the relationship between sugar content in study 
cigarettes and levels of aldehyde- DNA adducts in oral cells of study participants after smoking 
these cigarettes.  Aldehydes are known to cause respiratory tumors in laboratory animals and 
DNA adducts in the human lung10,11,14 
 
4.0 
Study Intervention(s)/Investigational Agent(s) 
4.1 
Description of study cigarettes 
Winston brand cigarettes will be modified by adding a mixture of sucrose      to each cigarette 
at 2 levels so that the amount of total (originally present and added) sugar content in these 
cigarettes matches median and highest levels found in popular brands analyzed in Aim 2.      
For example, median and highest levels of the sum of sucrose, glucose, and fructose in the CDC 
publication were 5.7% and 8.9% (w/w), respectively, across the 20 unidentified brands.50 The 
brand #19 in that study has the lowest sum of these sugars at 3.3% w/w. This allows for 
addition of      sucrose to this brand at 2.4% and 5.6% w/w to achieve median and highest 
levels in that study. We will use similar calculations to determine the amount of sugars to be 
added to study cigarettes in this laboratory study.  
 
Medicinal-grade ultrapure      sucrose manufactured under GMP standards will be used for the 
modification of Winston cigarettes. The prepared cigarettes will be conditioned at 25 °C and 
60% relative humidity for 2 days, and then stored at 4 °C until their use in study procedures. 
We used this approach in our previous studies in which we added NNK to cigarettes that were 
smoked by study participants under the FDA Center for Tobacco Products Protocol Number 
P00006. 

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4.2 
 Handling of Study Cigarettes 
The finished study cigarette product will be packaged by the Stepanov laboratory in sterilized 
tins containing 3 (1 extra) cigarettes with a label that encodes the level of sugar content, which 
will remain blind to the study investigators.  The tins will be transported to the research 
clinic.  The number of cigarettes transported from the laboratory to the clinic will be recorded 
at the lab and then at the clinic upon receipt.  At the clinic, the cigarettes will be refrigerated 
until their use at 4 degrees Celsius. Any temperature variations over +/- 3 degrees C will be 
discussed with PI to determine if the product freshness has been impacted.  Upon participant 
randomization, the appropriate tin with a specified label will be pulled from the 
refrigerator.  The label on the tin will be put in the participant's case report book and recorded 
on the product distribution log.  All unused cigarettes will be destroyed and disposed of. 
 
4.3 
Biosafety: NA  
4.4 
Stem Cells: NA 
4.5 
Fetal Tissue: NA 
 
5.0 
Procedures Involved 
5.1 
Study Design 
Overview: Participants (N=30 completers) will complete a baseline visit where they will smoke 
their usual brand cigarette. In the next three sessions, they will receive one of three study 
cigarettes with varying sugar content (low, medium and high) in a double-blind manner and 
counterbalanced order across participants.  In each session, participants will first smoke either 
their usual brand cigarettes (at baseline) or their assigned study cigarette (subsequent 
sessions) in a regimented manner: 10 puffs total, 30 seconds between puffs. There will be a 
one-hour interval since the time of cigarette extinction before smoking the next cigarette. 
After this interval, participants will smoke their assigned cigarette ad libitum within a 10 
minute time period. Safety and subjective measures will take place during this session as 
described below.  
Anticipating a 60-65% attrition rate based on current experiences, we will recruit up to 75 
participants.  
Study Procedures:  Smokers who smoke at least 5 cigarettes/day will attend 4 laboratory 
sessions during which they will be asked to smoke their usual brand (UB) cigarettes and then 
one of three study cigarettes with low, medium and high levels of sugar in separate sessions 
using a within-subject design with conditions counterbalanced determined by a Latin square. 
In each session, smokers will be asked to smoke a cigarette in a standardized manner (10 puffs, 
30 second interval between puffs) and 1 hour later, ad libitum.  Each of the sessions will be 
separated by at least 48 hours but not more than 5 days. The proposed study design has been 
used to assess the abuse liability of electronic cigarettes compared to other tobacco/nicotine 
products,99-101 that vary in flavors and modified risk claims,102 and that vary in menthol 

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The first session for all participants will involve smoking their UB cigarettes. Participants will 
be asked to refrain from smoking for at least 12 hours prior to each session and must have 
alveolar CO ≤     10           ppm to qualify for the session. Subsequently, the IVR records will 
be examined and vitals (blood pressure and heart rate) will be assessed through an 
automated cuff to ensure that eligibility criteria are still met. After a 30-minute rest period, 
participants will complete the MNWS, submit an alveolar CO sample, and will smoke their UB 
cigarettes in a regimented manner (10 puffs total, 30 seconds between puffs).  Five minutes 
after extinguishing the cigarette, another CO measurement will be taken and participants will 
be asked to complete the mCEQ, Drug Effects/Liking Questionnaire, MNWS, QSU and Sensory 
Effects of Smoking Questionnaire, in a specified order via REDCap. The spent cigarette filter 
will be collected for nicotine analysis. There will be a one- hour interval since the time of 
cigarette extinction before smoking the next cigarette. During the intervening times between 
cigarettes, smokers will be allowed to read magazines, listen to neutral podcasts, or watch 
neutral videos. After this interval, participants will submit another CO, complete the MNWS 
and smoke their UB cigarettes ad libitum within a 10-minute timeframe and the same testing 
procedures will be followed. Twenty minutes after the second cigarette, the Perceived Health 
Risk Questionnaire will be administered and then at 30 minutes the Cigarette Purchase Task 
and Multiple Choice Procedures for the UB cigarettes will be administered. At 50 minutes (2 
hours after smoking the first cigarette), participants will be asked to rinse their mouths and 
oral cells will be collected. At the very end of the session, the Willingness to Switch 
questionnaire will be administered. Once the Willingness to Switch questionnaire has been 
completed a number will randomly be selected from the Multiple Choice Procedures task. 
This will be done by pulling a number 1- 16 out of a jar. The participants will receive either an 
additional cigarette or the money associated with that number, depending on which choice 
was made for that number. The participant may choose to smoke the cigarette or not.  
In the next three sessions, participants will then  be asked to smoke one of three study 
cigarettes with varying sugar content in a double-blind and counterbalanced order across 
participant     s. Each study cigarette type will be labeled with a symbol (diamond, square or       
star to minimize ranking bias). Blinding of the cigarettes      will occur in Dr. Irina Stepanov’s 
laboratory, where staff do not have contact with participants. The same procedures as 
implemented with UB      cigarettes will be followed.  
5.2 
Study Duration 
Potential participants must be willing to participate in a study that involves four, 5-hour 
sessions over the course of 2-3 weeks.  
We anticipate being able to enroll three participants per month and complete all study 
procedures, including data analysis within 18 months.  
5.3 
Use of radiation: NA 
5.4 
Use of Center for Magnetic Resonance Research: NA 
 
6.0 
Data and Specimen Banking 

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6.1 
Storage and Access 
Cigarette butts and biomarker specimens will be collected and stored at the study site 
(University of Minnesota - Tobacco Research Programs, 717 Delaware St. SE) until delivery to 
the Masonic Cancer Center’s Dr. Irina Stepanov laboratory for storage and analysis. Samples 
that are not used for the primary analysis of study biomarkers will be banked for future use. 
The banked samples will be stored until analyses and destroyed if it is determined they are no 
longer needed. The samples, which may also include DNA or RNA, may be stored 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 
consent and HIPAA documents. If this occurs, any remaining identifiable research sample(s) 
will be destroyed.   
6.2 
Data 
Data will be stored in a secure database (RedCap) and on University of Minnesota 
servers. Only study personnel directly involved with the study will have access to the 
linked records.  The samples that will be transferred to the laboratory or stored for 
future analyses will be de-identified.  We will not be transferring data that has any 
identifying information over the internet.     
Biomarker samples (buccal cells) that are banked after the completion of the primary 
analyses will be stored at the Masonic Cancer Center Stepanov laboratory located at 
the Cancer and Cardiovascular Research Building for future use. 
 
6.3 
Release/Sharing 
No identifying information will be shared with outside investigators. If used in any 
collaborative efforts beyond the scope of this study, any shared data will be de-identified. 
However, records for the study may be reviewed by departments at the University with 
appropriate regulatory oversight.  The records may also be reviewed by a representative of the 
funding agency, National Institutes of Health, and the Food and Drug Administration. 
 
7.0 
Sharing of Results with Participants 
7.1 
Sharing of genetic testing  
Information will not be shared with participants. 
 
8.0 
Study Population 
8.1 
Inclusion Criteria: 
a) Male or female age 21 years or older; 
b) Must smoke at least 5 cigarettes/day for at least 1 year (confirmed by CO 
>10 ppm or NicCheck test of 6 or greater); 

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c) Smoking cigarettes that have been evaluated to have medium levels of 
sugar content; 
d) No quit attempts in the past month nor intentions to quit smoking in the 
next month; 
e) Participants  are in good physical health (no unstable medical conditions) 
as determined by the licensed medical professional; 
f) Participants  are in stable, good mental health (e.g. not currently, within 
the past 6 months, experiencing unstable or untreated psychiatric 
diagnosis) as determined by the licensed medical professional; 
g) Stable vitals sign measurements (systolic BP ≤ 160 and >90 mmHg, 
diastolic BP ≤ 100 and >50 mmHg and heart rate ≤105 and > 45 bpm) as 
determined by the licensed medical professional 
a. Participants failing for vital signs will be allowed to re-screen once; 
h) Participants must be able to read for comprehension or completion of 
study documents (confirmed during informed consent process); 
i) Participants have provided written informed consent to participate in the 
study. 
8.2 
Exclusion Criteria:  
a) Significant immune system disorders, respiratory diseases, kidney or liver 
diseases or any other medical disorders that may affect biomarker data as 
determined by the licensed medical professional; 
b) Current or recent alcohol or drug abuse problems or use of substances of 
abuse (other than marijuana) in the past month; 
c) Tobacco use other than cigarettes or marijuana for > 9 days per month 
d) Current use (within past 2 weeks) of nicotine replacement or other 
tobacco cessation products; 
e) Women who are pregnant or nursing or planning to become pregnant. 
f)  Frequent marijuana use. Quantified as >9 days of marijuana use in the 
last 30 days 
 
8.3 
Screening 
Participants who agree to go through the pre-     screening process will be assigned a screening 
number and taken through a screening questionnaire.  Participants  who meet the eligibility 
criteria described in section 8.1 and 8.2 will be      asked to complete a more thorough 
screening visit, where the entire study will be explained in detail, informed consent will be 
obtained and the screening measures will be completed. The format for this visit will either be 
done in-person in the clinic or remotely via a secured-video conferencing link. In either 
scenario, participants will sign an e-consent. 
 
9.0 
Vulnerable Populations 

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9.1 
Vulnerable Populations 
No vulnerable populations will be used in the study.  
 
10.0 Local Number of Participants 
10.1 
Local Number of Participants to be Consented 
Up to 75 smokers will be consented in order to get 30 completers.  
 
11.0 Local Recruitment Methods 
11.1 
Recruitment Process 
We will recruit  up to 75 adult smokers (30 completers) from the Minneapolis-St. Paul metro 
area who smoke at least 5 cigarettes per day. Smokers will be recruited through the University 
of Minnesota Tobacco Research Programs. A variety of media will be used that will foster the 
recruitment across a spectrum of age, education and socioeconomic status, and race/ethnicity. 
11.2 
Identification of Potential Participants 
Participants will be recruited through various media (internet, television, newspaper, radio). 
Smokers will contact our clinic and be screened for eligibility over the telephone.  During this 
screening, we will maximize retention of the participants between the screening and clinic 
visits by covering transportation costs and compensating them for their time.  We will provide 
a respectful environment for the subject and train personnel on methods for minimizing 
subject dropouts. 
11.3 
Recruitment Materials 
Participants will be recruited through printed flyers and advertisements through a variety of 
media outlets and the internet, including but not limited to, Facebook, newspapers, radio, and 
television ads.  
11.4 
Payment 
Payment will be made using the Greenphire Clincard. Participants will be paid $25 for the 
screening visit and $25 for the baseline visit ($10 for transportation reimbursement, $15 for 
the study visit). Eligible participants will be paid $75 for each of the clinic visits ($10 for 
transportation reimbursement, $65 for the study visit x 4 visits = $300). Additionally, 
participants may earn up to an additional $5 each study visit based on the MCP questionnaire.      
At the end of the study, participants will be paid a $75 bonus for completing all sessions. The 
maximum total amount a participant will be paid is $445.  
 
12.0 Withdrawal of Participants 
12.1 
Withdrawal Circumstances 

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A study participant may be discontinued from the study if investigators determine that this is 
the best decision in order to protect his/her safety. In the event that a participant either 
withdraws from the study or the investigators decide to discontinue a participant due to an 
adverse event (AE) or serious adverse event (SAE), the participant will have appropriate follow-
up assessments and if necessary, referrals will be made for medical care. The participant 
experiencing an AE/SAE will be followed until the problem resolves, stabilizes, or is clearly 
unrelated to the study product. Any AE that remains open will be reviewed and closed at the 
last study visit. 
12.2 
Withdrawal Procedures 
Subject will be informed about the withdrawal at the visit and data collection will stop. 
12.3 
Termination Procedures 
No additional procedures will be conducted if participants are withdrawn. 
 
13.0 Risks to Participants 
13.1 
Foreseeable Risks 
The potential risks for participants recruited for this study are minimal. Potential risks for all 
participants include: emotional discomfort, breach of confidentiality, risks associated with 
smoking, risks to fetuses, and changes in blood pressure/heart rate. 
Survey Questionnaires. The interviews will include questions about medical history, drug and 
alcohol use, and questionnaires about mood. Answering these personal questions could make 
the subject feel uncomfortable. 
Risk of breach of confidentiality. There is always a small risk of breach of confidentiality. All 
subject samples and case report forms will be labeled with a unique numerical identifier in place 
of direct identifiers. The link between a participant and this unique identifier, and any other 
computer files containing direct identifiers will be kept in a password-protected file on a locked 
computer. Only the PI, study staff, and possibly approved regulatory officials (as required by the 
policies of the University of Minnesota and federal agencies such as the NIH, NCI, or FDA) will 
have access to direct identifiers. Case report forms with direct identifiers, demographic 
information and medical history will be kept separately and securely at all times. 
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  

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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 
Study Cigarettes. The levels of sugar that will be added to study cigarettes will be no higher 
than those found in most popular cigarette brands. There is no additional risk to participants 
by using the study cigarettes.  
At the end of the trial, participants will be strongly encouraged to stop use of all tobacco 
products and to set a quit date, and if requested, we will provide treatment resources and 
referral to different treatments including the state quit line. 
Participants will be under medical supervision throughout their study participation and 
adverse symptoms will be recorded and monitored by the project PI, Dr. Hatsukami along with 
the study licensed medical professional.  
13.2 
Reproduction Risks 
Pregnant women will not be recruited.  If participants choose to be sexually active, they should 
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 the female should be using prescribed “birth control” pills, injections, or implants. 
Female participants with child-bearing potential will be tested for pregnancy at the screening 
visit. If a participant becomes pregnant during the study, she will be withdrawn from the 
study. Approximately 30 days after being withdrawn or having a positive pregnancy test, the 
research staff will call the participant to confirm her due date. The licensed medical 
professional will follow-up with the participant after delivery to ask questions about the baby’s 
health. A separate consent form will be signed in order to obtain data from pregnant 
participants. 
13.3 
Risks to Others  
NA 
 
14.0 Potential Benefits to Participants 
14.1 
Potential Benefits 
Whereas no assurance can be made to an individual subject that he/she will personally benefit 
from such research, the experience should not impose any significant risk. Participants will 
have the opportunity to learn about factors that may be associated with tobacco use.  Quitting 
tobacco will be strongly recommended to our participants and cessation materials will be 
provided if requested.  Referrals to community resources can also be made. 
 

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15.0 Statistical Considerations 
15.1 
Data Analysis Plan 
Trial design 
The aim of this study is investigate the impact of sugar content in cigarette tobacco on cigarette 
abuse liability and appeal. The hypothesis is that the collected measures will indicate lower 
abuse liability for cigarettes with lowest sugar content. 
This is a within-subject crossover study design with multiple periods and multiple treatments. 
The orders of the 3 sugar levels are counterbalanced using a Latin square, which will be created 
in advance by an independent statistician. 
Trial endpoints 
Outcome measures include subjective responses to cigarettes, behavioral measures, and 
mouth-level nicotine exposure. 
Two primary outcome measures, which were used for power/sample size determination, 
include (1) the satisfaction of the Modified Cigarette Evaluation Questionnaire (mCEQ) and (2) 
the crossover point from the Multiple Choice Procedure task. 
The other subjective and behavioral outcomes and mouth-level nicotine exposure will be 
secondary.   
 
15.2 
Power Analysis 
A total of 30 completed participants will achieves >80% power, for each of the two primary 
outcomes (satisfaction and crossover point), to detect two sugar conditions (high vs. low)’ 
difference of a moderate effect size (d = 0.6, the target scenario) at a 0.025 (= 0.05/2 primary 
outcomes) significance level, assuming a moderate correlation between sessions (r = 0.50) based 
on a T2 test using PASS14 (NLSS, 2015). A total of up to 75 eligible smokers  will be enrolled..  
We note that because of the uncertainty of the effects of sugars and the range of effect sizes, 
we chose an effect size that is more conservative but near the range of the effect sizes (based 
on the endpoint of crossover point from the Multiple Choice Procedure task) used in most 
studies. The powers of the target scenario and other scenarios by changing the within-subject 
correlation and effect size, with the fixed sample size (n = 30) and type I error (α = 0.025), are 
presented in the table below.  We note that the actual power for the factor of sugar level could 
be larger since 3 sugar levels will be studied.  
Scenario 
Power 
Effect size 
(d) 
Within-
subject 
correlation (r) 
Target 
scenario 
0.81 
0.6 
0.5 
 
 
0.89 
0.6 
0.6 
0.64 
0.5 
0.5 

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Other 
scenarios 
0.75 
0.5 
0.6 
0.92 
0.7 
0.5 
0.96 
0.7 
0.6 
 
15.3 
Statistical Analysis 
General Approach 
All statistical analyses will be performed using SAS or R. All statistical tests will be two-tailed. A 
Bonferonni adjustment will be used to account for 2 primary endpoints (p < 0.025 considered 
significant). Analyses of the secondary endpoints will not be adjusted (p < 0.05 considered 
significant). Proper transformation such as the logarithm transformation will be used to 
approximate normality for the outcome variables. 
Describing the Study Population 
Baseline characteristics of the participants will be summarized using mean and standard 
deviation (SD) for continuous variables and frequency and percentage for categorical variables.  
Primary Analysis 
The primary data analysis method will be linear mixed models including the two within-subject 
factors, sugar condition (2 dummy variables for the medium and high sugar levels) and time (2 
dummies for the 3rd and 4th sessions), adjusted for the nicotine levels in spent filters of the first 
study cigarette used in each of the laboratory sessions (under the fixed puffing pattern). The 
potential carry-over effect will be tested by including the previous session’s condition, i.e., 2 
dummies for the previous session being medium and high sugar level (Diggle et al., 2002, p150-
153). Note that the usual brand’s measure (collected at the 1st session) and other participant-
level factors are naturally adjusted across different sugar conditions because of the within-
subject design, and hence are not included in the model. However, participant-level factors will 
be examined for any potential moderating effect (i.e., interaction) as an exploratory analysis. 
Subgroup Analysis 
Subgroup analyses will be performed for female and male smokers. The analyses will follow the 
same approach described for the overall group. Note that this study is not powered for detecting 
the potential interaction of gender and sugar level, however, we will report the size and 
significance of the interaction together with the subgroup analysis results to provide 
information for understanding of the role of gender. 
Missing data 
Every effort will be made to limit the amount of missing data in this trial, and study 
participants will be incentivized to attend study sessions. We anticipate a high retention rate 
(>80%) because of the short period of time of this laboratory study.   
We will compare subjects who do and do not complete the study sessions in terms of their 
baseline characteristics. All observed data will be utilized in the analyses, with missing data 
being assumed to be missing at random, by using the mixed effects models. 

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15.4 
Data Integrity 
A variety of measures will be taken to ensure data accuracy and completeness. The regular 
research team meetings will include discussions of proper methods for data collection, 
transmission, and storage, limiting data collection to those in protocol required to answer a 
research question, de-identifying data, and encryption methods. 
A comprehensive data dictionary will be created to specify definitions and value codes for all 
variables that will be entered into REDCap and other study databases. Electronic forms for the 
collection of subjective measures via REDCap will include programming features to ensure 
valid data (i.e., input masks, validation criteria, skipout logic) and will be stored on the 
University of Minnesota, HIPAA compliant, computing system.  Double entry will be used for 
all other de-identified data entered into REDCap.  Spent cigarette filters and biological 
specimens (oral cells) will be labeled with barcode labels that incorporate the participant ID. 
The secured biospecimen website will identify the location of each sample at the clinic (prior 
to submission to the laboratory) and in the Stepanov laboratory.   
Oversight of the study cigarette distribution will be conducted by the Project Manager in 
collaboration with the co-Principal Investigators. The order of study cigarette use (sugar levels) 
will be generated by an independent statistician. The schedules and the link between the study 
cigarette code and order assignment will be maintained securely by the Project Manager.  A 
Product Tracking database will be created to track study cigarette inventory and assignment of 
order to participants based on the randomization schedule. 
Quality control procedures will be conducted for all data collected, including analysis of 
missing data, and logic checks for out of range and other anomalous values. Queries will be 
made regarding such data issues, with documentation of any changes made in the data. 
 
16.0 Health Information and Privacy Compliance 
16.1 
Select which of the following is applicable to your research: 
☐ My research does not require access to individual health information and 
therefore assert HIPAA does not apply.   
 
☒ I am requesting that all research participants sign a HIPCO approved HIPAA 
Disclosure Authorization to participate in the research (either the standalone 
form or the combined consent and HIPAA Authorization). 
☐ I am requesting the IRB to approve a Waiver or an alteration of research 
participant authorization to participate in the research. 
☐ An external IRB (e.g. Advarra) is reviewing and we are requesting use of the 
authorization language embedded in the template consent form in lieu of the 
U of M stand-alone HIPAA Authorization.  Note: External IRB must be serving 
as the privacy board for this option. 

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16.2 
Identify the source of Private Health Information you will be using for your research 
(Check all that apply)   
☐ I will use the Informatics Consulting Services (ICS) available through CTSI 
(also referred to as the University's Information Exchange (IE) or data 
shelter) to pull records for me 
☒ I will collect information directly from research participants. 
☐ I will use University services to access and retrieve records from the Bone 
Marrow Transplant (BMPT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) database. 
☐ I will pull records directly from EPIC. 
☐ I will retrieve record directly from axiUm / MiPACS 
☐ I will receive data from the Center for Medicare/Medicaid Services  
☐ I will receive a limited data set from another institution  
☐ Other.  Describe: 
16.3 
Explain how you will ensure that only records of patients who have agreed to have 
their information used for research will be reviewed. 
Participants who are interested in the study will contact the Tobacco Research Programs. All 
PHI will be self-reported by the participant.  
16.4 
Approximate number of records required for review 
 NA 
16.5 
Please describe how you will communicate with research participants during the 
course of this research.  Check all applicable boxes 
☐ This research involves record review only. There will be no communication 
with research participants. 
☐ Communication with research participants will take place in the course of 
treatment, through MyChart, or other similar forms of communication used 
with patients receiving treatment.  
☒ Communication with research participants will take place outside of 
treatment settings. If this box is selected, please describe the type of 
communication and how it will be received by participants.  
We will communicate with participants via phone, email and text messages. We will ask each 
participant for his or her preferred method of communication.  

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16.6 
Explain how the research team has legitimate access to patients/potential 
participants: 
All investigators and staff associated with this project have been trained, and new hires will be 
trained, on human research ethics and Good Clinical Practice in accordance with the 
requirements of the University of Minnesota. 
16.7 
Location(s) of storage, sharing and analysis of research data, including any links to 
research data (check all that apply).   
☐ In the data shelter of the Information Exchange (IE)  
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In the Bone Marrow Transplant (BMT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) Database  
 ☐ Store 
☐ Analyze 
☐ Share 
☒ In REDCap (recap.ahc.umn.edu)  
 ☒ Store 
☐ Analyze 
☒ Share 
☐ In Qualtrics (qualtrics.umn.edu) 
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In OnCore (oncore.umn.edu)  
 ☐ Store 
☐ Analyze 
☐ Share 
☒ In the University’s Box Secure Storage (box.umn.edu) 
 ☒ Store 
☒ Analyze 
☒ Share 
☒ In an AHC-IS supported server. Provide folder path, location of server and IT 
Support Contact: 
\\tobacco.ahc.umn.edu\tobacco\TobaccoResearch\SugarsProject 
 ☒ Store 
☒ Analyze 
☒ Share 
☒ In an AHC-IS supported desktop or laptop.  
Provide UMN device numbers of all devices:  
Device #1: 20180114  
 ☒ Store 
☒ Analyze 
☒ Share 
☐ Other. Describe:  

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Indicate if  data will be collected, downloaded, accessed, shared or stored using a 
server, desktop, laptop, external drive or mobile device (including a tablet 
computer such as an iPad or a smartform (iPhone or Android devices) that you 
have not already identified in the preceding questions 
☐I will use a server not previously listed to collect/download research data 
☐I will use a desktop or laptop not previously listed 
☐I will use an external hard drive or USB drive (“flash” or “thumb” drives) not 
previously listed  
☐I will use a mobile device such as an tablet or smartphone not previously listed 
 
16.8 
Consultants. Vendors. Third Parties 
NA 
16.9 
Links to identifiable data 
NA 
16.10 Sharing of Data with Research Team Members 
Data files will be stored in a UMN Box folder or on the Tobacco Research Programs shared 
server.  
16.11 Storage and Disposal of Paper Documents 
Paper files will be kept in subject binders in a locked file cabinet stored in a locked office. 
Original signed consent forms and other identifiable information will be kept separate from 
the research information. Paper files will be kept for the longest applicable standard as 
required by this study.  
 
17.0 Confidentiality 
17.1 
Data Security  
All investigators and staff associated with this project have been trained, and new hires will be 
trained, on human research ethics and Good Clinical Practice in accordance with the 
requirements of the University of Minnesota. 
Only the immediate study team (Project Manager, Study Coordinator and Principal 
Investigators) will have access to individually identifiable private information about 
participants.  Coded ID’s will be used throughout the study by all the researchers involved.  
Because this study uses an investigational product and we are required to obtain 
Investigational Tobacco Product approval through the Food and Drug Administration, the 
records may potentially be monitored by this governmental agency. This information will be 
provided to the IRB and will be included in the human consent form. Original signed consent 

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forms and other identifiable information will be kept separate from the research information 
in a secure and locked space/database. 
 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
18.1 
Data Integrity Monitoring 
Oversight for quality control and adherence to protocol procedures will be conducted by the 
Project Manager in collaboration with the co-Principal Investigators. A start-up meeting with 
the whole research team will take place prior to participant enrollment. During this meeting, 
there will be training on the study protocol, standard operating procedures, equipment and 
data collection platforms.  Independent monitoring of the study will be conducted by the 
University of Minnesota’s Clinical and Translational Science Institute (CTSI) clinical trial 
monitoring service. The CTSI monitors will confirm that study activities are in compliance with 
the approved protocol and applicable regulatory authorities. The investigator will give the 
study monitors direct access to source documentation, study data, and relevant regulatory 
documentation. 
Standard operating procedures will be developed for consistent implementation of the 
protocol. The Study Coordinator will be administering all measures during clinic visits and 
entering the information about each subject into a database. Each visit will have a checklist of 
all measures that need to be obtained and the order by which they will be administered. The 
Project Manager will be directly supervising the Study Coordinator and will periodically review 
protocol compliance and implementation, and adherence to good clinical practice procedures. 
The Study Coordinator will go over the questionnaire instructions and will be available to the 
participant to answer any questions he/she may have.  Questionnaires will be reviewed for 
completeness while the participant is present.  Several biochemical measures (expired breath 
CO and urine pregnancy) will be analyzed immediately, while the participant is present.  If 
necessary (e.g., if the sample volume is insufficient for analysis), the Study Coordinator can 
gather another sample immediately and re-analyze. 
Once a participant has completed all study procedures and all open events have been closed, 
the PI will review the participant’s binder and sign a form indicating study completion for that 
participant. 
 
18.2 
Data Safety Monitoring 
This is a minimal risk, non-therapeutic study. While participating in the trial, AEs and 
concomitant medications will be assessed at every study visit and vital signs will be 
obtained. The Principal Investigator Dorothy Hatsukami and Co-Investigator Irina 
Stepanov will meet weekly with the study staff to review recruitment progress and 
any adverse events.  Entrance criteria will be reviewed following screening.  Study 
participants will be under medical supervision while in the study and our research 

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staff will make appropriate referrals to the physician should any adverse events 
occur.   
AEs will typically be identified during the administration of the Health Changes Questionnaire. 
Other events may be identified from physiological study measures or by spontaneous reports 
during assessments. 
If any questions arise regarding the health status of the participant before, during or after the 
laboratory session, either Drs. Hatsukami or Sharon Allen (medical director) will be available 
for consultation. 
The study’s Data and Safety Monitoring Plan will be in compliance with the University of 
Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan (DSMP), which can be 
accessed at https://z.umn.edu/dsmp. For the purposes of data and safety monitoring, this 
study is classified as moderate risk. Therefore the following requirements will be fulfilled: The 
Masonic Cancer Center Data and Safety Monitoring Council (DSMC) will review the trial’s 
progress twice yearly. 
Assessment of Questionnaire Items  
● Health Changes Questionnaire: If the participant answers ‘YES’ to Questions 1, 2, or 3, 
the interviewer will assess for an ‘Adverse Event.’  
1) Have you had any negative changes in your health since your last visit?  
2) Have you had any changes in medication since your last visit? 
3) Since your last visit, have you received any form of medical care? 
 
Adverse Events Communicated by Participants 
The occurrence of AEs will be sought by non-directive questioning of the participant at each 
visit during the study. AEs also may be detected when the participant volunteers them during 
or between visits or through physical examination, laboratory test, or other assessments. 
Review and Reporting of Adverse Events and Serious Adverse Events 
Co-Principal Investigators with oversight from Sharon Allen, M.D. (Medical Monitor) will 
review all AEs and assess whether they are related to the study product. 
An AE is defined as the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study procedures even if the event is not considered to 
be related to the study product. Medical conditions/diseases present before starting the study 
are only considered adverse events if they worsen after starting the study product. Abnormal 
laboratory values or test results constitute adverse events only if they induce clinical signs or 
symptoms, are considered clinically significant, or require therapy; there are no plans for 
active monitoring of laboratory tests as part of this project.   
To the extent possible, each adverse event will be evaluated to determine: 
1. the severity grade (mild, moderate, severe) 
2. its relationship to the study product used (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 

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4. outcome (resolved/improved/unchanged/worsened; study product temporarily 
interrupted or permanently discontinued due to this adverse event; 
concomitant medication taken; non-drug therapy administered) 
5. whether it constitutes a SAE 
Information about all SAEs will be collected and recorded on the project’s Serious Adverse 
Event Report Form. A SAE is defined an undesirable sign, symptom or medical condition which: 
1. is fatal or life-threatening; 
2. requires or prolongs hospitalization; 
3. results in persistent or significant disability/incapacity; 
4. constitutes a congenital anomaly or a birth defect; 
5. is medically significant, in that it may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
Events not considered to be SAEs are hospitalizations that are: 
1. elective or pre-planned, for a pre-existing condition that is unrelated to the 
products under study and did not worsen; 
2. for general care, and/or overnight observation; 
3. treatment on an emergency, outpatient basis for an event not fulfilling any of 
the definitions of serious given above and not resulting in hospital admission. 
 
Safety evaluation will be performed on all accrued participants for whom study products were 
dispensed. The assessment of safety will be based on the frequency of AEs and severity grade 
of AEs. Other safety data (e.g.  vital signs) will be considered as appropriate. 
Any SAE occurring after the participant has signed the consent form and until the last 
encounter with the participant will be reported. All AEs will be summarized by presenting, for 
each treatment group, the number and percentage of participants who experienced any AE, 
the number reporting AEs in each body system and the number of AEs by type. Any other 
information collected (e.g., severity or relatedness to study product) will be listed as 
appropriate. A summary of clinically relevant toxic events, such as AEs leading to death or 
rated as SAEs, those with a suspected relationship to study product, or AEs requiring further 
medication or non-drug therapies will be provided. Reports will be reviewed regularly by the 
study investigators. 
19.0 Provisions to Protect the Privacy Interests of Participants 
19.1 
Protecting Privacy 
It will be made clear to participants that all information obtained during assessments is 
confidential and that no information will be shared with the participants’ clinicians unless the 
participant requests this in writing.  
While all the samples and information will be collected specifically to achieve the goals of this 
proposal, de-identified individual subject data and back-up samples may be made available to 
other researchers for research purposes after our study is complete.  We will obtain 
permission from participants through the main consent process and form to allow de-

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identified biosamples to be stored in a biorepository for future analyses of biomarkers or 
genotyping. 
19.2 
Access to Participants 
There will be no access to medical records or any other sources of private information about 
the participating participants 
20.0 Compensation for Research-Related Injury 
20.1 
Compensation for Research-Related Injury 
The study poses minimal risk to participants. In the event of a research related injury, 
treatment will be provided. Such care will be billed to the participant or their insurance 
company in the ordinary manner.  
20.2 
Contract Language 
NA 
21.0 Consent Process 
21.1 
Consent Process (when consent will be obtained) 
The consenting process will take place virtually via a secured video-conferencing 
meeting invitation or in-person at the Tobacco Research Programs (717 Delaware St 
SE). Potential participants will be told the nature of the research during pre-screening 
and then at the screening visit. They will be told they may discontinue participation at 
any time and will not be discriminated against if they choose to do so. Interested 
subjects will be provided considerable time to review the consent form, consider 
whether or not to participate, and have any questions answered by the coordinator. 
Participants will be required to demonstrate an understanding of the study purpose and 
procedures prior to signing the consent form. Assessment of the subject’s understanding 
will be completed via questions by a slideshow presentation. The consent form must be 
signed before the research is started. Immediately after signing, the participant will 
receive an email with a signed copy of the consent form.  
The electronic consent forms will be stored in a REDCap database with restricted access 
for essential study personnel only. The electronic informed consent (eIC) will be built 
using the ‘UMN e-Consent HRP-592-TEMPLATE-Biomedical’. The template will be 
customized to match the written informed consent form exactly. The electronic 
signatures obtain in the outline above are intended to be the equivalent of handwritten 
signatures. Therefore, the electronic signatures will occur in accordance with the 
predicated rule (e.g. approved, reviewed and verified) as outlined in the Food and Drug 
Administration’s CFR part 11. 
      
21.2 
Waiver or Alteration of Consent Process (when consent will not be obtained) 
NA 

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21.3 
Waiver of Written/Signed Documentation of Consent (when written/signed consent 
will not be obtained) 
Participants will be screened over the phone or via a REDCap survey for initial eligibility using a 
recruitment script. All elements of consent are addressed in said script. Consent will be 
obtained prior to asking research related questions. 
21.4 
Non-English Speaking Participants 
NA 
21.5 
Participants Who Are Not Yet Adults (infants, children, teenagers under 18 years of 
age) 
NA 
21.6 
Cognitively Impaired Adults, or adults with fluctuating or diminished capacity to 
consent 
NA 
21.7 
Adults Unable to Consent 
NA 
22.0 Setting 
22.1 
Research Sites 
The study will be conducted at the University of Minnesota, Twin Cities 
● Subject recruitment and sample collection will take place at Tobacco Research 
Programs (717 Delaware St. SE, Minneapolis, MN 55414). 
● Biochemical analysis will be carried out in the Masonic Cancer Center (2231 6th St. SE, 
Minneapolis, MN 55455). 
22.2 
International Research 
NA 
23.0 Multi-Site Research 
NA 
23.1 
Study-Wide Number of Participants 
NA 
23.2 
Study-Wide Recruitment Methods 
NA 
23.3 
Study-Wide Recruitment Materials 
NA 
23.4 
Communication Among Sites 

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NA 
23.5 
Communication to Sites 
NA 
24.0 Coordinating Center Research 
NA 
24.1 Role:  
24.2 Responsibilities:  
24.3 Oversight:  
24.4 Collection and Management of Data:  
25.0 Resources Available 
25.1 
Resources Available 
The study will be conducted at the University of Minnesota’s Tobacco Research Programs 
housed at the Delaware Clinical Research Unit at 717 Delaware St. SE Minneapolis, MN. Dr. 
Dorothy Hatsukami serves as the Director for this Program. We have a Research Project 
Manager       who oversees all research and is responsible for logistics of implementing the 
protocols and standard operating procedures. She is also responsible for the quality control of 
the projects by ensuring that all studies follow ethical scientific standards and that procedures 
meet GCP standards, that all regulatory forms are completed including Institutional Review 
Board applications, and that the DSMB process is in place.       She has been working in this 
capacity for over 10 years. We also have an Administrator who ensures the smooth operation 
of the daily activities of the Program.  In addition, the Program has a registered nurse 
practitioner and many research project coordinators. The shared space at the Delaware 
Clinical Research Units includes a shared waiting room with a receptionist, 7 physical exam 
rooms (two dedicated to the Tobacco Research Programs), 1 phlebotomy room, 5 interview 
rooms, 2 day hospital rooms, an infusion room, 1 smoking laboratory with one way 
observation room, laboratory space for processing blood, urine processing laboratory, a locked 
medication supply room, locked protocol room for subject files, cubicles for data entry, 
management and analyses, locked supply storage and access to three conference rooms. Two 
restrooms are in the clinical space for urine collections. We have dedicated space for our 
biorepository with key card access containing ten -20 freezers. We also have access to all of 
the resources of the University of Minnesota for our use, as needed. 
 
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Federal Register A, 2012. Harmful and potentially harmful constituents in tobacco 
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Hoffmann D, Hoffmann I, El Bayoumy K. The less harmful cigarette: a controversial 
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Family Smoking Prevention and Tobacco Control Act. 2009. 

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4. 
Hatsukami DK, Luo X, Jensen JA, et al. Effect of Immediate vs Gradual Reduction in 
Nicotine Content of Cigarettes on Biomarkers of Smoke Exposure: A Randomized 
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Yuan JM, Koh WP, Murphy SE, et al. Urinary levels of tobacco-specific nitrosamine 
metabolites in relation to lung cancer development in two prospective cohorts of 
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6. 
Hecht SS, Murphy SE, Stepanov I, Nelson HH, Yuan JM. Tobacco smoke biomarkers and 
cancer risk among male smokers in the Shanghai Cohort Study. Cancer Letters. 
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7. 
Stepanov I, Sebero E, Wang R, Gao YT, Hecht SS, Yuan JM. Tobacco-specific N-
nitrosamine exposures and cancer risk in the Shanghai cohort study: Remarkable 
coherence with rat tumor sites. International Journal of Cancer. 2013;134:2278-2283. 
8. 
Talhout R, Opperhuizen A, van Amsterdam JG. Sugars as tobacco ingredient: Effects on 
mainstream smoke composition. Food Chem Toxicol. 2006;44(11):1789-1798. 
9. 
Roemer E, Schorp MK, Piade JJ, Seeman JI, Leyden DE, Haussmann HJ. Scientific 
assessment of the use of sugars as cigarette tobacco ingredients: a review of published 
and other publicly available studies. Crit Rev Toxicol. 2012;42(3):244-278. 
10. 
International Agency for Research on Cancer. Re-evaluation of Some Organic 
Chemicals, Hydrazine and Hydrogen Peroxide. IARC Monographs on the Evaluation of 
the Carcinogenic Risk of Chemicals to Humans. Vol 71. Lyon, FR: IARC; 1999. 
11. 
International Agency for Research on Cancer. A Review of Human Carcinogens: 
Chemical Agents and Related Occupations. IARC Monographs on the Evaluation of 
Carcinogenic Risks to Humans, Vol. 100F. Lyon, France2012. 
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International Agency for Research on Cancer. Dry Cleaning, Some Chlorinated Solvents 
and Other Industrial Chemicals. IARC Monographs on the Evaluation of Carcinogenic 
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Feng Z, Hu W, Hu Y, Tang M-S. Acrolein is a major cigarette-related lung cancer agent. 
Preferential binding at p53 mutational hotspots and inhibition of DNA repair. Proc Natl 
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14. 
Zhang S, Villalta PW, Wang M, Hecht SS. Analysis of crotonaldehyde- and acetaldehyde-
derived 1,N2-propanodeoxyguanosine adducts in DNA from human tissues using liquid 
chromatography-electrsopray ionization-tandem mass spectrometry. Chem Res Toxicol. 
2006;19:1386-1392. 
15. 
International Agency for Research on Cancer. Dry Cleaning, Some Chlorinated Solvents 
and Other Industrial Chemicals. IARC Monographs on the Evaluation of Carcinogenic 
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International Agency for Research on Cancer. Some Industrial Chemicals. IARC 
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Ding YS, Ashley DL, Watson CH. Determination of 10 carcinogenic polycyclic aromatic 
hydrocarbons in mainstream cigarette smoke. Journal of Agricultural and Food 
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18. 
International Agency for Research on Cancer. Some Non-Heterocyclic Polycyclic 
Aromatic Hydrocarbons and Some Related Exposures. IARC Monographs on the 
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19. 
Hecht SS. Tobacco carcinogens, their biomarkers, and tobacco-induced cancer. Nature 
Rev Cancer. 2003;3:733-744. 
20. 
Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P. Tobacco 
smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. 
Oncogene. 2002;21:7435-7451. 
21. 
Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst. 
1999;91:1194-1210. 
22. 
Fisher P. Manufacture, in Tobacco: Production, Chemistry and Technology. Oxford: 
Blackwell Science; 1999. 
23. 
Shelar GR, Bernasek PF, Furin OP. Sugar/Nicotine Study. Truth Tobacco Industry 
Documents. . Bates No 510697389-510697410 1992;Available at: 
https://www.industrydocumentslibrary.ucsf.edu/tobacco/docs/#id=fxbl0037. 
24. 
Rodgman A. Some Studies of the Effects of Additives on Cigarette Mainstream Smoke 
Properties. II. Casing Materials and Humectants. Beiträge zur Tabakforschung 
International/Contributions to Tobacco Research. 2002;20(4):279-299. 
25. 
Foddai M, Dosia G, Spiga S, Diana M. Acetaldehyde increases dopaminergic neuronal 
activity in the VTA. Neuropsychopharmacology. 2004;29(3):530-536. 
26. 
Belluzzi JD, Wang R, Leslie FM. Acetaldehyde enhances acquisition of nicotine self-
administration in adolescent rats. Neuropsychopharmacology. 2005;30(4):705-712. 
27. 
Leffingwell JC. Chemistry: baisc chemical constituents of tobacco leaf and differences 
among tobacco types. In Tobacco: Production, Chemistry and Technology. Oxford: 
Blackwell Science; 1999. 
28. 
Baker RR, Coburn S, Liu C, Tetteh J. Pyrolysis of saccharide tobacco ingredients: a TGA-
FTIR investigation. J Anal Appl Pyrol. 2005;74(1-2):171-180. 
29. 
Sanders EB, Goldsmith AI, Seeman JI. A model that distinguishes the pyrolysis of D-
glucose, D-fructose, and sucrose from that of cellulose. Application to the 
understanding of cigarette smoke formation. J Anal Appl Pyrol. 2003;66(1-2):29-50. 
30. 
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ANCILLARY REVIEWS 
DO NOT DELETE.  Submit the completed checklist below with your protocol. 
Which ancillary reviews do I need and when do I need them? 
Refer to HRP-309 for more information about these ancillary reviews. 
Select yes or 
no 
Does your study… 
If yes… 
Impact on 
IRB Review 
☐ Yes 
☒ No 
 
Include Gillette resources, staff 
or locations 
Gillette Scientific review and Gillette 
Research Administration approval is 
required.  Contact: 
research@gillettechildrens.com   
Required 
prior to IRB 
submission 
☐ Yes 
☒ No 
 
Involve Epic, or Fairview 
patients, staff, locations, or 
resources? 
The Fairview ancillary review will be 
assigned to your study by IRB staff 
Contact: ancillaryreview@Fairview.org 
Approval 
must be 
received 
prior to IRB 
committee/ 
designated 
review.   
 
Consider 
seeking 
approval 
prior to IRB 
submission. 
☒ Yes 
☐ No 
 
Include evaluation of drugs, 
devices, biologics, tobacco, or 
dietary supplements or data 
subject to FDA inspection? 
The regulatory ancillary review will be 
assigned to your study by IRB staff 
Contact: medreg@umn.edu  
 
See: 
https://policy.umn.edu/research/indide  
☐ Yes 
☒ No 
 
Require Scientific Review? Not 
sure? See guidance in the 
Investigator Manual (HRP-
103). 
 
Documentation of scientific merit must 
be provided.   
Contact: hrpp@umn.edu  
☒ Yes 
☐ No 
 
Relate to cancer patients, 
cancer treatments, cancer 
screening/prevention, or 
tobacco? 
Complete the CPRC application process.  
Contact: ccprc@umn.edu  
☐ Yes 
☒ No 
 
Include the use of radiation? 
(x-ray imaging, 
radiopharmaceuticals, external 
beam or brachytherapy) 
Complete the AURPC Human Use 
Application and follow instructions on 
the form for submission to the AURPC 
committee. 
Contact: barmstro@umn.edu  
Approval 
from these 
committees 
must be 
received 
prior to IRB 
approval;  
 
These 
groups 
☐ Yes 
☒ No 
 
 
Use the Center for Magnetic 
Resonance Research (CMRR) 
or MR at Masonic Institute for 
the Developing Brain (MIDB) as 
a study location? 
Complete the CMRR pre-IRB ancillary 
review  
Contact: ande2445@umn.edu  

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☐ Yes 
☒ No 
 
Include the use of recombinant 
or synthetic nucleic acids, 
toxins, or infectious agents? 
Complete the IBC application via 
eprotocol.umn.edu 
each have 
their own 
application 
process.  
☐ Yes 
☒ No 
 
Include the use of human fetal 
tissue, human embryos, or 
embryonic stem cells? 
Contact OBAO for submission 
instructions and guidance 
☐ Yes 
☒ No 
 
Include PHI or are you 
requesting a HIPAA waiver? 
If yes, HIPCO will conduct a review of 
this protocol. 
Contact: privacy@umn.edu  
☐ Yes 
☒ No 
Include the use of a controlled 
substance?  
If yes, University Health and Safety 
Compliance for controlled substances 
will review the protocol. 
Contact: cshelp@umn.edu 
  
Approval 
must be 
received 
prior to IRB 
approval. 
 
These 
groups do 
not have a 
separate 
application 
process but 
additional 
information 
from the 
study team 
may be 
required. 
 
☒ Yes 
☐ No 
 
Plan to use CTSI Monitoring 
services, and/or have an IND, 
IDE, or designated NSR-IDE by 
the UMN IRB? 
The CTSI monitoring ancillary review 
will be assigned to your study by IRB 
staff. 
Please note eligibility criteria here. 
Contact: fencl003@umn.edu 
☐ Yes 
☒ No 
 
Use data from CTSI Best 
Practices Integrated 
Informatics Core (BPIC)  
Formerly the AHC Information 
Exchange (IE)? 
The Information Exchange ancillary 
review will be assigned to your study by 
IRB staff 
Contact: bpic@umn.edu  
☐ Yes 
☒ No 
 
Use the Biorepository and 
Laboratory Services to collect 
tissue for research? 
The BLS ancillary review will be 
assigned to your study by IRB staff. 
Contact: Jenny Pham 
Pham0435@umn.edu 
☐ Yes 
☒ No 
 
Have a PI or study team 
member with a conflict of 
interest? 
The CoI ancillary review will be 
assigned to your study by IRB staff 
Contact: becca002@umn.edu  
☒ Yes 
☐ No 
 
Need to be registered on 
clinicaltrials.gov? 
If you select “No” in ETHOS, the 
clinicaltrials.gov ancillary review will be 
assigned to your study by IRB staff 
Contact: fencl003@umn.edu  
☒ Yes 
☐ No 
 
Require registration in 
OnCore? 
If you select “No” or “I Don’t Know” in 
ETHOS, the OnCore ancillary review will 
be assigned to your study by IRB staff 
Contact: oncore@umn.edu  
Does not 
affect IRB 
approval. 
 
 
 

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