Evaluating E-Cigarette Nicotine Form, Concentration, and Flavors Among Youth
Phase: NA
Conditions: E-cigarette Use
Sponsor: Ohio State University Comprehensive Cancer Center

IRB Protocol Number: 2020C0169 
IRB Approval Date: 11.21.2022 
Version: 6.0 
 
Evaluating E-Cigarette Nicotine Form, Concentration, and Flavors among Youth 
 
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Table of Contents 
Abstract ............................................................................................................................................... 2 
A. 
Specific Aims ................................................................................................................................ 3 
B. 
Significance .................................................................................................................................. 3 
C. 
Approach and Preliminary Studies ................................................................................................ 5 
D. 
Research Design and Methods ...................................................................................................... 5 
i. 
Design Overview ............................................................................................................................... 5 
ii. 
Study Procedures .............................................................................................................................. 7 
1. 
Recruitment Feasibility and Retention ......................................................................................... 7 
2. 
Detailed Study Procedures ............................................................................................................ 8 
3. 
Protocol Adherence and Quality Control .................................................................................... 11 
iii. 
Measures ......................................................................................................................................... 12 
E. 
Statistical Methods ..................................................................................................................... 15 
i. 
Power Analysis ................................................................................................................................ 15 
ii. 
Data Analytic Plan ........................................................................................................................... 15 
iii. 
Missing Data .................................................................................................................................... 15 
F. 
Gender/Minority/Pediatric Inclusion for Research ..................................................................... 15 
i. 
Inclusion of Women and Minorities ............................................................................................... 15 
ii. 
Inclusion of Children ....................................................................................................................... 16 
G. 
Human Participants .................................................................................................................... 16 
i. 
Recruitment and Informed Consent ............................................................................................... 16 
ii. 
Potential Risks and Protections against Risk ................................................................................... 16 
1. 
Risk of Using ECs: ........................................................................................................................ 16 
2. 
Loss of Confidentiality and Privacy: ............................................................................................ 17 
3. 
Venous Draws: ............................................................................................................................ 17 
iii. 
Potential Benefits of the Proposed Research ................................................................................. 18 
H. 
Data and Safety Monitoring Plan and Board ............................................................................... 18 
i. 
Plan ................................................................................................................................................. 18 
ii. 
Adverse Events ................................................................................................................................ 18 
I. 
Addendum ................................................................................................................................. 19 
i. 
COVID-19 Related Procedures ........................................................................................................ 19 
J. 
Literature Cited .......................................................................................................................... 20 
 

IRB Protocol Number: 2020C0169 
IRB Approval Date: 11.21.2022 
Version: 6.0 
 
Evaluating E-Cigarette Nicotine Form, Concentration, and Flavors among Youth 
 
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Abstract 
Electronic cigarette (e-cig) “vaping”, while being promoted as a safer alternative to conventional 
cigarettes, has disproportionally attracted adolescents and young adults (“youth”). E-cigs are now the 
most commonly used tobacco product among youth1, yet little research has examined youth e-cig use, 
addiction, health effects or strategies to help current users quit. Making matters worse, e-cigs and e-
liquids continue to evolve rapidly in a minimally regulated market, resulting in a product with increasing 
youth appeal and addictiveness, while at the same time exposing youth to cardiovascular and 
pulmonary toxicants during a sensitive and critical time of development. 
Over the last two years, there has been a significant surge in e-cig sales and use among youth. 
Regulatory and research efforts have largely focused on e-liquid flavors, that while important, do not 
appear to be the catalyst for the surge. Flavored e-cigs have been on the market since the late 2000s, 
but in a market saturated with these products, youth e-cig use declined by 29% during 2015-2016, 
where it remained through 20172. It was not until the proliferation of nicotine-salt based (NSB) e-cigs, of 
which the most well-known is JUUL, that youth e-cig use increased by 135% to its current record high 
(28%)1. Unlike previous e-cigs that relied on unprotonated, or “free-base” (FB) nicotine e-liquid, NSB 
devices use protonated forms (i.e., nicotine salts) by lowering the pH to protonate nicotine with an acid. 
Because this form of nicotine is not as harsh as the free-base form, inhaling high doses of protonated 
nicotine is much more palatable3. This allows “tobacco naïve” users to inhale high levels of nicotine, 
increasing their odds of becoming addicted to nicotine. The tobacco industry has utilized similar 
methodology to alter the pH of cigarette smoke to improve palatability and nicotine delivery4. Making 
conventional cigarettes easier to inhale was associated with more aggressive and frequent puffing and 
increased cardiovascular and pulmonary disease risk5. Whether this holds true for NSB devices is 
suspected but not determined. 
While the long-term health effects of e-cigarettes are still unclear, studies examining proximal 
biomarkers of health indicate that e-cig users are exposed to many cardiovascular and pulmonary 
toxicants, including carcinogens, such as carbonyls, furans, reactive oxygen species, and heavy metals6, 7. 
Early evidence indicates that e-cig users experience adverse health effects, including increased oxidative 
stress, respiratory and mucosal inflammation, arterial stiffness and altered hemodynamics and platelet 
activity8. Moreover, use of nicotine by youth can adversely affect attention, learning, and memory, as 
well as lead to increased impulsivity. Taken together these data suggest that sustained e-cig use will 
likely have notable adverse health effects9. Since their introduction in 2015, to our knowledge, no 
studies have examined the toxicological and physiological effects of NSB device use, nor the impact of 
nicotine form. Previous research has largely focused on free-base nicotine devices, with only a few 
focusing on pulmonary and cardiovascular effects. 
The youth vaping epidemic in the U.S. is drawing serious concern from parents, schools, health officials 
and regulators. There is now a wave of support and a need to create effective e-cig policies and 
regulations to prevent further proliferation of youth e-cig use. One of the most effective policies may be 
to create a product standard for nicotine to reduce the palatability and abuse liability of e-cigs for youth; 

IRB Protocol Number: 2020C0169 
IRB Approval Date: 11.21.2022 
Version: 6.0 
 
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however, strong scientific evidence is needed for the FDA to impose such regulations. The proposed 
project will begin to address this need.  
A. Specific Aims 
Utilizing a human laboratory design, we will examine the influence of nicotine form and concentration, 
and e-liquid flavor on youth vaping behavior, nicotine uptake, abuse liability, toxicant exposure, and acute 
cardiovascular and pulmonary effects.  H1a: Nicotine salt (vs. free-base) and menthol flavored e- liquids 
(vs. tobacco flavored) will result in puffs of longer duration and higher flow rate, and a greater total 
inhaled aerosol volume, and H1b: demonstrate greater nicotine uptake, abuse liability, and adverse 
cardiovascular and pulmonary effects.  H1c: High concentration, free-base nicotine (vs. salt nicotine) will 
result in puffs of shorter duration, lower flow rate, less volume, and lower abuse liability. 
B. Significance 
B.1. The Resurgence of E-cigarettes Among Youth and Adults  
The risk-benefit of e-cigs continues to be debated in the public health literature. E-cigs are now the most 
commonly used tobacco product in the U.S. among youth and young adults, and anticipated to exceed 
conventional cigarette use by 20201. The most recent estimates indicate that 10.8 million US adults 
(4.5%) have used an e-cig in the past 30 days10. Among high school students and young adults (18-24 
years), these rates are even higher, at 4.1 million (27.5%) and 2.8 million (9.2%), respectively1, 2. 
Moreover, e-cig prevalence rates have increased significantly over the last two years, nearly doubling for 
youth and young adults, with the emergence of nicotine salt-based (NSB) devices1. Indeed, several 
recent studies, including those conducted by our team11-13, suggest that NSB devices are not only seen as 
more appealing due to their small, sleek styling, and smooth delivery of high doses of nicotine, but that 
youths and adults who try NSB devices are far more likely to become regular users compared to those 
who try FB e-cigs, with approximately 40-60% of those who ever tried an NSB device, identifying as 
current users11-13. NSB devices have led to a resurgence in e-cig use among youth and adults alike. The 
combination of palatable, high doses of nicotine and small, light-weight, and reliable devices, has led to 
a product with high initiation and adoption potential across all age groups.  
B.2. The Possible Role of E-cigarette Liquid pH: What We Have Learned From Cigarettes  
In cigarette smoke, nicotine is present in protonated (i.e., less bioavailable) or unprotonated (i.e., free-
base, more bioavailable) forms14, 15. The proportion of protonated vs. unprotonated nicotine in smoke is 
pH dependent; when nicotine is at a higher pH (more alkaline or basic), a larger proportion of it is in its 
unprotonated form, which has much greater bioavailability, becoming more easily and rapidly absorbed 
across biological membranes15. An examination of tobacco industry documents, uncovers that tobacco 
manufacturers focused heavily on the pH of cigarette smoke, developing numerous techniques to 
systematically increase the pH and desired level of FB nicotine delivery16. Cigarette brands with the 
highest smoke pH, were consistently the top sellers16-18. Tobacco industry research reported that “as 
much as 50% of the variation in [cigarette] sales could be a consequence of smoke pH14.” Increasing the 

IRB Protocol Number: 2020C0169 
IRB Approval Date: 11.21.2022 
Version: 6.0 
 
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pH of aerosolized nicotine, resulted in greater and more rapid nicotine delivery—both known to be 
critical in the development of addiction14, 19. Interestingly, tobacco industry documents also suggest that 
Phillip Morris in the race to increase levels of FB nicotine, had to course-correct and reduce the pH in a 
product that was too harsh and not acceptable to consumers 16. As such, industry studies suggest that 
there is a trade-off between the level of FB nicotine and the harshness of the smoke20, 21. The pH 
breakpoint where the smoke becomes noticeably harsh and undesirable to smokers was determined to 
be above 7.017. Consequently, tobacco manufacturers continued to refine cigarettes to balance nicotine 
delivery with a “smooth” smoking experience20. Today, cigarette smoke pH ranges from 6-7.822, 
indicating that 4.5%-29% of the total nicotine is in FB form15, 23.  
Early E-cig models relied on e-liquid with higher pH levels and consequently high levels of FB nicotine. In 
one study, greater than 50% of all nicotine-containing e-liquids had a pH >9.0 and only 2 samples tested 
had a pH of <7.024. To account for this high pH level, and the harshness of FB nicotine, manufacturers 
had to lower the concentration of nicotine in their e-liquids (typically, 1.2-2.4% nicotine). However, 
these products were typically perceived to be less satisfying and palatable to smokers compared to 
combustible cigarettes25. Moreover, as manufacturers began developing e-cig devices with significantly 
increased power (wattage) delivered to the heating coil (5- to 10-fold greater) in an effort to improve 
nicotine delivery26, users began to accommodate the increased wattage by decreasing the concentration 
of their high pH e-liquid (0.3-0.6%) to reduce harshness26. This strategy of high wattage and low nicotine 
concentration was successful in terms of improved nicotine delivery, but also had several unanticipated 
and negative effects26. Increased power led to increased user exposure to tobacco toxicants due to 
greater production of carcinogenic compounds in the e-cig aerosol, and compensatory puffing, as users 
needed to take larger puffs to achieve satisfactory levels of nicotine delivery26-30.  
By lowering the pH and protonating the nicotine in e-liquid, inhaling high concentrations (3-6%) of 
protonated nicotine (i.e., nicotine salts) is much more palatable, enabling low-powered e-cig devices 
(<10 watts) to provide nicotine delivery comparable to a cigarette31-33. This combination of high 
concentrations of protonated nicotine but low power may be beneficial in terms of reduced exposures 
to tobacco-related toxicants32, because lower coil temperatures reduce the amount of toxicants 
produced, and still give high levels of nicotine per puff32, reducing the number and size of puffs (smaller 
puff volume) needed to achieve satisfying nicotine levels34. On the other hand, with smaller, easily 
hidden devices (nicotine salt devices are often smaller since their low power requirement allows for 
smaller batteries), improved sensory experience, and higher concentrations of nicotine, use of nicotine 
salt e-liquid may result in: 1) more frequent dosing; 2) more intense puffing (faster flow rate, longer puff 
duration), with potential for greater deposition and absorption of nicotine deeper in the respiratory 
tract influencing lung cancer risk; and 3) greater nicotine delivery, abuse liability, and appeal34, 35. 
Indeed, support for the possibility of more frequent dosing and/or more intense puffing is the finding 
from a recent study demonstrating that adolescent users of nicotine salt devices exhibited higher mean 
urinary levels of the nicotine metabolite cotinine (244.8 ng/mL) than what is typically seen among 
adolescent smokers (155.2 ng/mL)36, 37.  

IRB Protocol Number: 2020C0169 
IRB Approval Date: 11.21.2022 
Version: 6.0 
 
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Lastly, the tobacco industry, especially in the manufacturing of smokeless tobacco products, 
manipulated pH to develop “starter products”—the industry’s term for products that are highly 
flavored, with a combination of low pH and low nicotine19. These products were developed to facilitate 
tobacco product initiation and to increase uptake and addiction19. Over time, as users developed 
tolerance to nicotine, they were able tolerate products with higher levels of biologically available 
nicotine19. While JUUL, the e-cig market leader with approximately 50% of unit sales and nearly 80% of 
the estimated market dollar share36, originally only contained e-liquid with a nicotine concentration of 
5%, the company now offers a lower nicotine concentration pod (3% nicotine), which is strangely higher 
than 20 mg/mL permitted for e-liquids sold in the European Union36. JUUL has provided no rationale for 
the lower nicotine concentration pod. Given that the 5% nicotine pod has demonstrated nicotine 
delivery and subjective effects that almost completely mimic a combustible cigarette36, the potential for 
compensation (i.e., greater consumption rate for the 3% nicotine pod) is high. Additionally, it is likely 
that with reduced nicotine concentration, these devices will be even more palatable, especially to 
nicotine naïve users. In summary, controlled studies examining the interaction between e-liquid pH and 
nicotine concentration are critical to help public health officials determine how manipulation of these 
levels influence users’ device power settings, subjective effects and puffing topography, as they are 
critical in the determination of abuse liability and exposure to harmful tobacco toxicants and disease 
risk.  
C. Approach and Preliminary Studies 
Our team has conducted five studies examining NSB e-cig devices11-13, including two recently completed 
human laboratory studies11, 12. Results of these studies demonstrated that NSB e-cigs can deliver 
cigarette-like levels of nicotine28, 38, have the potential for significant levels of addiction11-13, and that 
lower e-liquid pH was associated with reduced perceived harshness of the aerosol (p<.05), increased 
nicotine uptake (p<.05), and increased puffing flow rates and average puff volumes (ps<.05). 
D. Research Design and Methods 
i. 
Design Overview 
This study (Figures 1 and 3) will include Option A consisting of 9 lab visits each approximately 2 hours 
long, except visit 1, which will last up to 3 hours OR Option B consisting of 5 lab visits each containing 2 
vaping sessions separated by a 3-hour washout period and lasting approximately 6 hours.  Figure 2 
illustrates the study e-cig and e-liquid variations.  Figure 3 depicts the sequence of the proposed study.  
We will conduct an experimental study examining how the manipulation of nicotine form (nicotine salt 
(NSB) vs. free-base (FB)) influences vaping behavior, abuse liability, toxicant exposure and heart and 
lung health. 

IRB Protocol Number: 2020C0169 
IRB Approval Date: 11.21.2022 
Version: 6.0 
 
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Use own e-cig 
and e-liquid 
For eight subsequent sessions, use study e-cig held at a constant wattage, 
pre-filled with one of eight prepared e-liquids that differ by nicotine form, 
nicotine concentration, and flavor. 
Study Sequence 
Visit 1 
Visit 2 
Visit 3 
Vape Session 
1 
Vape 
Session 
2 
Vape 
Session 
3 
Vape 
Sessio
n 6 
Vape 
Session 
5 
Vape 
Session 
4 
Vape 
Session 
9 
Vape 
Session 
8 
Vape 
Session 
7 
Figure 3.  Study Sequence Option A and Option B 
Visit 4 
Visit 5 
Participants will be required to report at least 12 hours of abstinence from 
nicotine before each study visit. 
> 48 
Option 
A 
Option 
B 
Visit 1 
Visit 
2 
Visit 
3 
Visi
t 4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Figure 1. Vaping Session 

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ii. 
Study Procedures 
Utilizing a within-subjects, factorial design, 60 e-cig users (aged 21-25 years) will complete vaping 
sessions which will include a standardized, 5-minute, 10-puff vaping bout (30 seconds between each 
puff) followed by 30 minutes of ad libitum vaping.  Prior to session one, participants will be asked to 
bring their own e-cig device and a full tank/pod to the first visit.  In session one, participants will use 
their own e-cig and e-liquid. After visit 1, participants will take home a study e-cig device and 1 weighed 
pod pre-filled with study e-liquid (the participant was randomized to at the end of visit 1) to practice (20 
puffs per day with the study device and until the participant feels comfortable) using the device before 
visit 2. Practice use with the study e-cig device and pre-filled pod will be verified based on data 
downloaded (via eScribe) from the device during visit 2.  In the subsequent vape sessions, participants 
will use a study e-cig held at a constant wattage, and pre-filled with e-liquid of different nicotine form 
(free-base vs. nicotine salt), concentration (low-1% vs. high-5%), and flavoring (tobacco vs. menthol). 
There is no known commercial pair of nicotine liquids that differ only by nicotine form. For this study, 
we will prepare 8 e-liquids that differ by nicotine form, nicotine concentration, and flavor, simulating 
characteristics of popularly used nicotine liquids32, 39.  E-liquids will be prepared from pure (≥99%) S-(-)-
nicotine; protonation and dilution of nicotine will be done using USP grade benzoic acid, and glycerol 
and propylene glycol, respectively.  We will submit an Investigational Tobacco Product application to the 
U.S. FDA regarding the clinical use of the e-liquids.  All sessions will be completed over nine visits for 
schedule Option A and 5 visits for schedule Option B. Study Schedule A consist of 9 separate visits and 9 
separate vaping sessions. Study schedule B will consist of five separate visits (each visit will include up to 
2 vaping sessions) each separated by a 3-hour washout period to allow nicotine levels to return to 
baseline. Each visit will be at least 48 hours apart.  Participants will be required to report at least 12 
hours abstinent from nicotine before each study visit. Participants will be told that their abstinence will 
be confirmed at the time of visit via blood plasma nicotine analysis. This is a partial bogus pipeline40; 
3mL venous blood sample will be collected for later analysis.; those with plasma nicotine levels >3ng/mL 
at the time of their visit will be replaced post hoc with another participant.  We conservatively estimate 
replacing 10% of participants. Measures of topography, nicotine uptake, abuse liability, subjective 
effects, and cardiovascular and pulmonary effects will be collected (see Table 1).  Exposure to select 
toxicants, including nicotine and menthol in total particulate matter, and gas phase carbonyls and 
volatile organic compounds, will also be estimated post hoc using puff playback machine smoking. 
1. Recruitment Feasibility and Retention 
a) Recruitment 
We intend to recruit 130 e-cig users from the community over an 18-month period and have them 
complete nine study visits (Option A) or five study visits (Option B); therefore, we need 3-4 participants 
to be recruited and complete study procedures per month. 
We are confident our recruitment approach, laboratory facilities, and equipment redundancy will result 
in a sufficient participant processing rate, given our successful completion of other tobacco-related 
research of similar design41.  E-cig users will be recruited from advertisements through a variety of 
media outlets and the internet, including Study Search, as well as community events.  Participants from 

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IRB Approval Date: 11.21.2022 
Version: 6.0 
 
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other studies who have agreed to be contacted regarding other study opportunities will also be 
contacted.  Staff from those studies will prepare contact letters/emails and call participants on behalf of 
this study.  Interested participants will be referred to this study for screening.  Participants will access 
the screening questionnaire using a public survey link generated by REDCap.  Based on our team’s 
previous studies, we conservatively assume a 20% attrition rate.  Thus, we need to recruit 130 
participants to have 60 complete the study.   Participants who meet the following eligibility criteria will 
be asked to take part in the study. 
 
Inclusion criteria: 1) a current  e-cigarette user (≥1 vaping bout per day) for at least the past 3 months , 
2) 21-25 years old, 3) willing to abstain from all tobacco and nicotine for at least 12 hours prior to lab 
sessions, 4) willing to complete nine lab visits/vaping session lasting up to 2 hours each or five lab visits 
lasting up to 6 hours each (except Visit 1) , 5) able to read and speak English, 6) willing to provide 
informed consent 
Exclusion criteria: 1) self-reported diagnosis of lung disease including asthma, cystic fibrosis, or chronic 
obstructive pulmonary disease, 2) history of cardiac event or distress within the past 3 months, 3) 
currently pregnant (determined using urine pregnancy test), planning to become pregnant, or 
breastfeeding, 4) use of other tobacco products >10 days in the past month, 5) current marijuana use 
>10 times per month,  6) currently engaging in a vaping cessation attempt. 
Participants’ eligibility will be determined over the phone or via REDCap’s online screener. Those who 
are eligible and willing to participate will be invited to sign an informed consent and complete their 
baseline visit in a private participant room at the Ohio State University. All participants will be given 
adequate time to review the informed consent with a trained research staff to help answer any 
questions that may arise during the consent process. Additionally, a copy of the informed consent will 
be given to all participants. A pregnancy test will be completed at the initial visit as well as before 
starting all the in-lab visits to ensure that the participant is not pregnant. 
b) Retention and Compensation 
If participants choose Option A, they will receive $50, $50, $50, $50, $75, $75, $75, $75, and $100 for 
completing visit 1, 2, 3, 4, 5, 6, 7, 8, and 9, respectively, for a total of $600.  Participants who choose 
Option B will receive $50, $100, $125, $150, and $175 for completing visit 1, 2, 3, 4 and 5, respectively, 
for a total of $600.  Consistent with our previous studies, payments will be made using the Greenphire 
ClinCard to increase accountability and facilitate ease of payment.  We will facilitate visits by offering 
weekend appointments and using additional retention strategies (e.g., reminder calls/texts/emails).  
Participants will receive reminder calls in addition to email or text reminders.  Reminders will be sent by 
text or email based on a participant’s preferred method of contact. 
2. Detailed Study Procedures 
a) Study Sessions 
Prior to the start of the first laboratory visit, twelve-hour tobacco abstinence will be assessed via self-
report and confirmed with exhaled carbon monoxide testing (eCO< 10ppm). A research assistant will 

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explain the study to the participant and answer any questions they may have. The participant will give 
an exhaled breath sample into the handheld CO monitor to determine if they are eligible to participate 
in the laboratory vaping session. If the participant’s exhaled CO concentration <10 ppm, they are 
deemed eligible to participate further, and will be asked to read the informed consent form. Once all 
participant questions have been answered, the participant will be asked to sign their consent to 
participate in the study.  Pregnancy exclusion will also be confirmed with a urine test.  Participants will 
be asked to avoid eating (anything), drinking coffee, tea, sodas, juice, alcohol, and smoking (including 
any cigarette/nicotine replacements such as electronic cigarettes) at least 3 hours prior to their visit 
since that will affect the results of certain measures.  Participants will not be allowed to eat or drink 
(other than water) during the vaping sessions, but will be provided a light snack prior to IV placement 
and the start of vaping sessions. Participants will be allowed to eat and drink during the 3-hour washout 
periods for Option B visits 2-5.  
First, participants will complete background measures (Sociodemographic Measures, Tobacco Use 
History (including the Timeline Followback (TLFB) interview– week, month, lifetime and the Sensory E-
Cigarette Expectancies Scale (SEES)42), and the E-Cig Dependence (modified Cigarette Dependence 
Scale)43.  To measure nicotine uptake, a forearm venous catheter (placed by the research nurse) will be 
used to sample blood (~5 mL) as participants complete an initial 30-minute ad libitum vaping session 
using their own e-cig device and e-liquid. Blood will be collected at 4 time points (t=0, 5, 10, and 35 
minutes) during each vaping session. 
Markers of endothelial dependent and independent function will be measured by B-mode ultrasound44. 
Arterial stiffness, blood pressure, and heart rate will be measured at baseline. Arterial stiffness and 
vascular reactivity will be measured with pulse wave velocity (Vicorder or similar) and pulsewave-
analysis (AiX75, SphygmoCor, or similar)45. Inflammation will be measured by plasma levels of IFN- β, IL-
1β, IL-17, TNF-α as well as markers of oxidative stress, including OxLDL and Malondialdehyde46.  
Laboratory spirometry, airway inflammation, and airway reactivity47-49 will be measured.  Laboratory 
Spirometry will be conducted in a standing position and according to the recommendations of ATS 
Clinical Guidelines47. Forced expiratory volume (FEV1), forced vital capacity (FVC), and FEV1/FVC.  Airway 
Inflammation will be assessed using exhaled nitric oxide via the NIOX VERO. The current literature shows 
immediate changes in airway inflammation immediately follow e-cig use48. Airway Reactivity will be 
measured via TremoFlo, which is a well validated measurement of central obstruction, peripheral 
obstruction, and dynamic collapse49 and provides curves of Resistance (R) and Reactance (X) as well as 
parameters reflecting large and small airway function. The current literature show an increase in 
impedance, respiratory resistance and overall peripheral airway resistance following e-cig use48.     
In visit 1, which will last up to 3 hours, participants will use their own e-cig and e-liquid and participate in 
a single vaping session. After visit 1, participants will take home a study e-cig device and 1 weighed pod 
pre-filled with tobacco flavored e-liquid (the participant is randomized to at the end of visit 1) to 
practice (20 puffs per day with the study device and until the participant feels comfortable) using the 
device before visit 2. Practice use with the study e-cig device and pre-filled pod will be verified based on 
data downloaded (via eScribe) from the device during visit 2.  After visit 1, for the subsequent visits 

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participants will use a study e-cig held at a constant wattage, and pre-filled with e-liquid of different 
nicotine form (free-base vs. nicotine salt), concentration (low-1% vs. high-5%), and flavoring (tobacco vs. 
menthol). There is no known commercial pair of nicotine liquids that differ only by nicotine form. For 
this study, we will prepare 8 e-liquids that differ by nicotine form, nicotine concentration, and flavor, 
simulating characteristics of popularly used nicotine liquids32, 39. Prior to each visit, e-liquids will be 
prepared from pure (≥99%) S-(-)-nicotine; protonation and dilution of nicotine will be done using USP 
grade benzoic acid, and glycerol and propylene glycol, respectively. 
E-cig abuse liability will be measured across several domains during and after the vaping session. During 
the vaping session, e-cig puff topography will be measured to produce measures of puff count, puff 
duration, inter-puff-interval, puff flow rate, average puff volume, and total puff volume50. Post vaping 
session, subjective effects including the Drug Effects/Liking Questionnaire and modified Cigarette 
Evaluation Questionnaire (mCEQ)51, 52 will be conducted. 
Next, behavioral economic demand will be assessed using the E-Cigarette Purchase Task53 and E-Cig 
craving/suppression of craving and withdrawal will be assessed using the Tiffany-Drobes Questionnaire 
of Smoking Urges: Brief Form54, and the Minnesota Nicotine Withdrawal Scale55.. 
E-liquid consumption will be determined by weighing (mg) the participant e-liquid pod before and after 
the vaping session.  To estimate toxicant exposure, the e-cig device, e-liquid, and participants’ average 
puffing topography data for that e-liquid (across all participants) will be used to control a vaping 
machine. The e-cig aerosol produced will be collected on filters or in impingers for later analysis using 
high performance liquid chromatography, gas chromatography/mass spectrometry or similar methods 
of instrumental analysis. 
E-cig device characteristics, including device voltage, coil resistance, and pressure drop; and e-liquid 
characteristics including pH, nicotine concentration, and PG/VG ratio will be determined. Since 
participants will primarily use the study e-cig and e-liquid for this study, to determine exposures 
associated with the least and most intense puffing behaviors, topographies in the upper tertile will be 
averaged to produce a single topography, and likewise for the lowest tertile. Machine vaping will be 
conducted for each e-liquid type, using the associated human-derived puffing regimens, to estimate the 
range of tobacco toxicant exposure. 
For the 8-test e-liquids, these measures will be repeated during each of the visits.  Study schedule A 
consists of 9 separate visits and 9 separate vaping sessions. Study schedule B consists of 5 visits. The first 
lasting about 2 hours and the subsequent visits 2-5 lasting about 6 hours each, 2 vaping sessions each 
visit, and each session separated by a 3-hour washout period to allow nicotine levels to return to 
baseline.   
After each visit has been completed, participants will sign to confirm they have received $50, $50, $50, 
$50, $75, $75, $75, $75, and $100 for completing visit 1, 2, 3, 4, 5, 6, 7, 8, and 9, respectively, for a total 
of $600 if they chose Option A or received $50, $100, $125, $150, and $175 for completing visit 1, 2, 3, 4 

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and 5, respectively, if they chose Option B. Participant compensation will be loaded on a Greenphire 
ClinCard. 
b) Study Products 
For the first study session, participants will vape using their own e-cig and e-liquid.  After visit 1, 
participants will take home a study e-cig device and 1 weighed pod pre-filled with study e-liquid (the 
participant was randomized to at the end of visit 1) to practice (20 puffs per day with the study device 
and until the participant feels comfortable) using the device before visit 2. Practice use with the study e-
cig device and pre-filled pod will be verified based on data downloaded (via eScribe) from the device 
during visit 2.  In the subsequent sessions, participants will use a study e-cig held at a constant wattage, 
and pre-filled with e-liquid of different nicotine form (free-base vs. nicotine salt), concentration (low-1% 
vs. high-5%), and flavoring (tobacco vs. menthol). There is no known commercial pair of nicotine liquids 
that differ only by nicotine form. We will prepare 8 e-liquids that differ by nicotine form, nicotine 
concentration, and flavor, simulating characteristics of popularly used nicotine liquids53, 54. E-liquids will 
be prepared from pure (> 99%) S-(-)-nicotine; protonation and dilution of nicotine will be done using 
USP grade benzoic acid, and glycerol and propylene glycol, respectively.  
c) Authentication of Key Biologicals and/or Chemical Resources 
 
E-liquids 
E-liquids are prepared using USP-grade ingredients, when available, in an onsite clean room at Flagship 
Vapor Company, or similar clean-room facility. We will conduct independent chemical analysis and 
testing of these liquids via proton nuclear magnetic resonance spectroscopy (HNMR) to confirm 
appropriate quantities of nicotine, propylene glycol, glycerol, benzoic acid and menthol. We will submit 
an Investigational Tobacco Product application to the U.S. FDA for the e-liquids. Both MPIs Wagener and 
Shields and Co-I Brinkman have submitted ITP applications to FDA resulting in an FDA letter of no further 
concerns regarding their use in clinical trials (U01DA045537; U01DA045530; R01CA209961; 
R01CA229306). 
Chemicals and other molecular reagents 
All reagents necessary for the completion of chemical and molecular assays in the proposed study will 
be procured and stored by shared resources at OSU (NPASR and PhASR) and VCU Bioanalytic Corp under 
established standards and protocols. Certificates of analysis will be maintained, and reagents will be 
stored as specified, and used prior to expiration. 
 
3. Protocol Adherence and Quality Control 
Data Management 
All data collection will follow HIPAA guidelines. Data will be collected directly from the participant by a 
research assistant and/or research nurse. Data will include participant responses to computer-based 
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liquid characteristics, e-cig device characteristics, physiological (pulmonary) effects, cardiovascular 
measures, markers of endothelial dependent and independent function, and puff topography. 
Quality Assurance 
All research staff will have completed Human Subjects and HIPAA training. Standard operating 
procedures (SOP) will be developed, and all staff will be trained to ensure adherence to the SOP. As is 
standard practice for our team’s current studies, each visit will have its own checklist of specific 
measures to be completed and the order in which they are to be administered. To reduce data entry 
errors, participants will enter data into secured computer-based questionnaires. All specimens collected 
for biomarker analysis will be given individualized bar codes. All key on-site personnel will meet face-to-
face weekly throughout the entire study. During these meetings, recruitment, enrollment, data 
collection, data monitoring results, and any concerns/issues will be discussed. 
iii. 
Measures 
All measures (see Table 1) are validated and have been used previously by our team. Sociodemographic 
measures and tobacco use history (including the Timeline Followback (TLFB) interview– week, month, 
lifetime and the Sensory E-Cigarette Expectancies Scale (SEES)42) will be collected in addition to e-cig 
dependence using the modified Cigarette Dependence Scale43. E-cig Abuse liability will be measured 
across several domains, including 1) E-cig puff topography to produce measures of puff count, puff 
duration, inter-puff-interval, puff flow rate, average puff volume, and total puff volume50, 2) Subjective 
effects, including the Drug Effects/Liking Questionnaire and modified Cigarette Evaluation Questionnaire 
(mCEQ)51, 52, 3) Behavioral economic demand using the E-Cigarette Purchase Task53, and 4) E-cig 
craving/suppression of craving and withdrawal using the Tiffany-Drobes Questionnaire of Smoking 
Urges: Brief Form54 and Minnesota Nicotine Withdrawal Scale55. Nicotine uptake: a forearm venous 
catheter will be used to sample blood (~5 mL). Blood will be collected at 4 time points (t=0, 5, 10, 35 
min) during each vaping session. E-liquid consumption: e-liquid containers for pods will be weighed (mg) 
before and after each vaping session. Toxicant exposure: to estimate toxicant exposure, the e-cig device, 
e-liquid, and participants’ average puffing topography data for that e-liquid (across all participants) will 
be used to control a vaping machine. The e-cig aerosol produced will be collected on filters or in 
impingers for later analysis using high performance liquid chromatography, gas chromatography/mass 
spectrometry or similar methods of instrumental analysis. E-cig device characteristics, including device 
voltage, coil resistance, and pressure drop; and e-liquid characteristics including pH, nicotine 
concentration, and PG/VG ratio will be determined. Since participants will primarily use the study e-cig 
and e-liquid to determine exposures associated with the least and most intense puffing behaviors, 
topographies in the upper tertile will be averaged to produce a single topography, and likewise for the 
lowest tertile. Machine vaping will be conducted for each e-liquid type, using the associated human-
derived puffing regimens, to estimate the range of tobacco toxicant exposure. Laboratory spirometry, 
airway inflammation, and airway reactivity47-49 will be measured. Laboratory spirometry will be 
conducted in a standing position and according to the recommendations of ATS Clinical Guidelines47. 
Forced expiratory volume (FEV1), forced vital capacity (FVC), and FEV1/FVC. Airway inflammation will be 
assessed using exhaled nitric oxide via the NIOX VERO. The current literature shows immediate changes 

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in airway inflammation immediately follow e-cig use48. Airway reactivity will be measured via TremoFlo, 
which is a well validated measurement of central obstruction, peripheral obstruction, and dynamic 
collapse49 and provides curves of Resistance (R) and Reactance (X) as well as parameters reflecting large 
and small airway function. The current literature shows an increase in impedance, respiratory resistance 
and overall peripheral airway resistance following e-cig use48. Markers of endothelial dependent and 
independent function will be measured by B-mode ultrasound44. Arterial stiffness, blood pressure, and 
heart rate will be measured at baseline. Arterial stiffness and vascular reactivity will be measured with 
pulse wave velocity (Vicorder or similar) and pulsewave-analysis (AiX75, SphygmoCor or similar)45. 
Inflammation will be measured by plasma levels of IFN- β, IL-1β, IL-17, TNF-α as well as markers of 
oxidative stress, including OxLDL and Malondialdehyde46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 1: Project 3 Sub-study 2 Study Measures 
 
Project/Study 
P3S2 
Visit 
1 
2-9 (Option A) or 
 2-5 (Option B) 
Background Measures 
 
 
Sociodemographic Measures 
X 
 
Tobacco Use History & Sensory E-Cigarette Expectancies 
Scale (SEES) 
X 
 
E-Cig Dependence (modified Cigarette Dependence Scale) 
X 
 
Timeline Followback (week, month, lifetime) 
X 
 
E-cig Abuse Liability 
 
 
EC Puff Topography (puff count, puff duration, inter-puff 
interval, puff flow rate, average puff volume, total puff 
volume) 
X 
X 
Subjective Effects 
 
 
Drug Effects/Liking Questionnaire 
X 
X 
modified Cigarette Evaluation Questionnaire (mCEQ)  
X 
X 
Sensory E-Cigarette Expectancies Scale 
X 
X 
Behavioral Economic Demand 
 
 
E-Cigarette Purchase Task 
X 
X 
E-cig Craving/Suppression of Craving and Withdrawal 
 
 
Tiffany-Drobes Questionnaire of Smoking Urges: Brief Form 
X 
X 
Minnesota Nicotine Withdrawal Scale Self-Report 
X 
X 
Nicotine Uptake 
 
 
Forearm Venous Catheter 
X 
X 
E-liquid Consumption 
 
 
e-liquid containers for pods will be weighed 
X 
X 
Toxicant Exposure 
 
 
Average topography “puff playback,” and e-cig aerosol 
produced and collected on filters 
X 
X 
Liquid and Gas Chromatography/Mass Spectrometry 
X 
X 
E-cig Device Characteristics 
 
 
Device voltage, coil resistance, pressure drop 
X 
X 
E-liquid Characteristics 
 
 
pH, nicotine concentration, and PG/VG ratio 
X 
X 
Physiological Effects (Pulmonary) 
 
 
Laboratory Spirometry (SpiroLab) 
X 
X 
Airway Inflammation (NIOX VERO) 
X 
X 
Airway Reactivity (TremoFlo) 
X 
X 
Cardiovascular Measures 
 
 
Vascular Reactivity (Vicorder or similar) 
X 
X 
Blood Pressure 
X 
X 
Heart Rate 
X 
X 
Markers of endothelial dependent and independent function 
 
 
B-mode ultrasound (Vicorder or similar) 
X 
X 
Arterial stiffness 
 
 
Pulse wave velocity and analysis (Vicorder or similar) 
X 
X 

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E. Statistical Methods 
Generalized linear mixed models will be employed to identify associations of nicotine form, nicotine 
concentration, and flavoring with various outcome measures (e.g., plasma nicotine, spirometry, flow-
mediated dilation). Models will include relevant covariates (e.g., gender), a random effect for 
participant, main effects for nicotine form and concentration, and the interaction between nicotine 
form and concentration and nicotine form and flavor. Because of multiple measurements tested, we will 
assume a significance threshold corresponding to one expected false discovery per 100 tests (p=0.01). 
i. 
Power Analysis 
This study, for each of the main effects and alpha = 0.01, achieves 80% power to detect an effect size of 
0.5 standard deviations of the paired differences. For interaction effects, we will estimate 80% power 
(effect size 0.5 SD) to distinguish between any two of the interaction groups (e.g., free base/low nic, free 
base/high nic), while correcting for the pairwise tests (p=0.01/6=0.0017). Carryover and period effects 
will also be examined. 
ii. 
Data Analytic Plan 
Because product sampling will be randomized using a Latin Square, a fixed effect for session and a 
random effect for sequence will be included in all analyses. 
iii. 
Missing Data 
While we will make every effort to minimize the missing data for this study, missing data can arise due 
to various reasons. Violation of missing complete at random (MCAR) will be checked by evaluating 
whether any covariates are associated with missing data. If so, these covariates will be subsequently 
included and controlled for in the GLMM model. Our primary analysis will use mixed models which 
assumes Missing At Random (MAR) to deal with the missing data problem. In addition, sensitivity 
analyses will also be conducted using results from multiple imputation and complete cases strategies. 
F. Gender/Minority/Pediatric Inclusion for Research 
i. 
Inclusion of Women and Minorities 
Inclusion of Women and Minorities: According to U.S. Census Data, 51.3% of Columbus, OH residents 
are female. In our previous studies with smokers, 55-62% of participants were female. According to U.S. 
Census data, the racial composition of individuals living in Columbus is 61% White, 28% Black or African 
American, 5% Asian, 0.2% American Indian/Alaska Native, 0% Native Hawaiian/Other Pacific Islander, 
and 4% two or more races. The ethnic composition of individuals living in Columbus is 6% 
Hispanic/Latino. We expect that our distributions will be similar to these but we may potentially have a 
larger distribution of ethnic and racial minorities, based on our previous studies. However, we will 
continuously monitor enrollment in order to ensure that we are meeting recruitment goals to avoid 
under-recruiting minorities. If the targeted enrollment for minorities is not met because they do not 

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respond to the advertisements, we will make special efforts to solicit their participation by advertising in 
community newspapers, local church organizations, and community centers. 
ii. 
Inclusion of Children 
This study will be restricted to individuals 21 years of age and older, which is the legal age to purchase 
tobacco products.  
G. Human Participants 
i. 
Recruitment and Informed Consent 
At first contact, all participants will be screened according to the study’s inclusion/exclusion criteria.  
Those who are eligible will be given a brief verbal overview of the study and invited to participate.  
Informed consent (including a description of the nature, purpose, risks, and benefits of the study) of the 
participant will take place through both oral and written explanation of the study. The voluntary nature 
of the study and the participant’s right to withdraw at any time will be stressed during the consent 
process. A copy of the informed consent will be provided to the participant in written form at the time 
of consent for them to keep. Informed consent will be collected by IRB approved study personnel.  
Recruitment script and materials, consent forms, and all study procedures will be approved by the OSU 
Institutional Review Board. All participants will provide written consent before any study data is 
collected. 
ii. 
Potential Risks and Protections against Risk 
There are minimal risks associated with this protocol. The protocol requires e-cig users 21 to 25 years of 
age to undergo 12 hours of tobacco/nicotine abstinence on nine occasions. These e-cig users will 
complete 9 vaping sessions – one session in which participants will use their own e-cig and e-liquid and  
subsequent sessions in which participants will use a study e-cig held at a constant wattage, and pre-
filled with e-liquid of different nicotine form (free-base vs. nicotine salt), concentration (low-1% vs. high-
5%), and flavoring (tobacco vs. menthol).  
The participants are already using e-cigarettes and will only be asked to use or switch to what will be a 
fully characterized e-cigarette device and ITPs that have been fully described to FDA Center for tobacco 
products. Questionnaires, exhaled breath, and urine collection procedures are all non-invasive and 
involve minimal risk to study participants. Potential risks are as follows: a) risk of using e-cigarettes, b) 
loss of confidentiality or privacy, and c) risk of infection from blood draws. 
1. Risk of Using ECs: 
 
Risks 
The risk of side effects and adverse events are very low. The commercial device we are using is sold 
online, and at e-cigarette specialty stores and convenience stores nationwide, without a prescription. 
 
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Nevertheless, all participants will be screened for general medical precautions (pregnancy, 
cardiovascular disease) and monitored for adverse events during the study period. Study personnel will 
assess for adverse events via self-report at all follow-up visits. Any serious adverse events will be 
reported to the study’s DSMB, and then to the OSU IRB and to the NIH. We will withdraw participants 
who have a serious adverse event, or become pregnant, begin to breastfeed, or have a cardiovascular or 
pulmonary event during the study. The most likely adverse (potential for nicotine overdose) event is 
anticipated to be rare (<5% in our team’s previous studies) and mild (nausea, headache, disrupted 
sleep), and will be handled quickly (i.e., advice to participant to reduce or stop e-cig use). Lab studies of 
toxin exposure suggest that e-cigs incur no greater risk to health than do conventional cigarettes. 
Indeed, e-cigarettes generally show lower levels of harmful and potentially harmful constituents. To 
date, e-cigarette studies discussing adverse events report mild and tolerable side effects that generally 
resolved completely over time with continued use; the most predominant of which were mouth/throat 
irritation, cough, and headache. In four randomized clinical trials, no serious adverse events were 
reported, and the e-cigarette group and the nicotine patch group had comparable levels of adverse 
events in two studies. The most common were mouth irritation, throat irritation, dry cough and 
headache. Following the completion of the study, we will encourage all participants to quit their use of 
e-cigarettes. 
 
2.  Loss of Confidentiality and Privacy: 
Risks 
There is a risk of breach of confidentiality or a loss of privacy associated with taking part in the study. 
Protections 
Protection against loss of confidentiality and privacy will be maintained by numerically coding all data, 
disguising identifying information, and keeping data locked in file drawers or in a secure, password-
protected database. Only study research assistants and the PI will have the information that connects 
participant’s name and ID number. All electronic data will be numerically coded and stored in a password 
protected database, on a password protected computer in a secure research space. Participant 
information will be accessible only to research staff, who are pledged to confidentiality and complete 
training in the ethical conduct of research (i.e., both HIPAA and CITI trainings). Identifying information 
will not be reported in any publication. 
3. Venous Draws:  
Risks 
The risks involved in drawing blood from a vein may include, but are not limited to, momentary 
discomfort at the site of the blood draw, possible bruising, redness, and swelling around the site, 
bleeding at the site, feeling of dizziness or lightheadedness when the blood is drawn, nausea, and rarely, 
an infection at the site of the blood draw. 
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Blood will be drawn by trained research staff/research nurse. IVs will be placed by an RN or LPN. Sterile 
instruments will be used, and for blood draws, the participant’s skin will be cleaned with an alcohol wipe 
at the site of the needle stick. 
 
iii. 
Potential Benefits of the Proposed Research 
Whereas no assurance can be made to an individual participant that s/he will personally benefit from 
this research, the experience should be beneficial. The immediate benefits of this research are scientific 
in nature, which in the long-term should benefit society as a whole. The study will also benefit e-cig 
users, as a group, by providing information as to the abuse liability of other e-cig/e-liquid products; and 
serve as evidence to inform regulatory action that improves public health. Overall, it is expected that the 
potential benefits to participants in the proposed study outweigh the potential risks. 
 
H.   Data and Safety Monitoring Plan and Board 
i. 
Plan 
Data will be analyzed initially after 20 participants are accrued, to ensure electronic data capture 
systems employed (i.e., REDCap) are accurately capturing data and to ensure the format and 
completeness of all data collected. 
 
ii. 
Data and Safety Monitoring Board 
The data and safety monitoring plan will involve the continuous evaluation of safety, data quality and 
data timeliness. Investigators will conduct continuous review of data and patient safety at their regular 
Disease Group meetings (at least monthly). The PI of the trial will review toxicities and responses of the 
trial where applicable at these disease center meetings and determine if the risk/benefit ratio of the trial 
changes. Frequency and severity of adverse events will be reviewed by the PI and compared to what is 
known about the agent/device from other sources; including published literature, scientific meetings 
and discussions with the sponsors, to determine if the trial should be terminated before completion. 
Serious adverse events and responses will also be reviewed by the OSUCCC Data and Safety Monitoring 
Committee (DSMC). The PI will also submit a progress report (biannually for Phase II and quarterly for 
Phase I) that will be reviewed by the committee per the IRB of record as per the policies of the IRB. All 
Serious Adverse Events are to be submitted to the DSMC for their review. Submissions are made via 
OnCore. 
 
 Adverse Events 
Adverse events will be assessed by study staff at each visit via participant self-report and managed 
immediately. All adverse events will be reported to the OSU IRB. We will monitor for risk of 
smoking/vaping by screening participants for general medical precautions (pregnancy, cardiovascular 
disease). Any adverse events, breaks of confidentiality, or any other data or safety issues that arise will 
be discussed immediately between study personnel and Dr. Wagener. Dr. Wagener will be responsible 
for completing an Adverse Events Form should an event occur. Dr. Wagener will report Serious Adverse 

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Events to the OSU IRB within 24 hours of having received notice of the event. Dr. Wagener will gather 
any information needed to investigate the event and to determine subsequent action. Any subsequent 
action will be documented and reported to the OSU IRB and the Program Officer at NIH. Adverse event 
reports will be reviewed annually with the OSU IRB to ensure participant safety. 
 
Collection of Adverse Events 
 
The collection of adverse events will be on a self-report basis and logged within an electronic data 
capture system (REDCap) or collected using standardized paper forms and will only be identified with 
the study ID of the participant. 
I. Addendum 
i. COVID-19 Related Procedures 
Due to the COVID-19 pandemic, processes and procedures have been implemented to help protect 
participants and research staff. These processes and procedures are to be followed as long as social 
distancing requirements are necessary for conducting study visits.  
Only one study participant per study coordinator will attend study visits at the CTR at any given time. All 
study participants will be provided with a face mask upon entry. Only one coordinator will meet the 
participant at their car for a temperature check, direct the participant into the building, and the two of 
them will ride the elevator to the 4th floor physically distanced at least 6 feet apart, both wearing masks.  
No more than 2 persons may ride the elevator at any given time. The participant will be immediately 
escorted to a private exam/draw room. Therefore, there will be no waiting in open lobby/waiting areas. 
 
When in the exam room, the study coordinator will stand at least 6 feet away from the study participant 
to give instructions.  Afterwards, the study coordinator will leave the exam room to allow the study 
participant to conduct the instructed procedures. The study coordinator and study participant will be at 
least 6 feet away from one another and wearing protective masks at all times during each visit.   
 
Each study coordinator will have a designated exam/draw room and smoking room in which to conduct 
their designated research study. Each smoking room is separated from the staff control station in the 
hallway by its own door and contains a large window for the study coordinator to be able to see in and 
monitor study participant activity within the room. There is also a speaker and microphone system 
within each smoking room along with the Genetec software system on the outside of each room at the 
smoking room computer stations. Therefore, the study coordinator and study participant can 
communicate without being in the room together.   
 
For study measures which cannot be physically distanced, appropriate PPE will be worn at all times by 
research staff during these procedures including goggles, face masks, gloves, and isolation gowns or lab 
coats.  
After each participant visit is complete, there will be at least a 45-minute period for cleaning and air 
exchanges in the negative pressure rooms and for cleaning exam rooms and equipment before the next 

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participant visit. All smoking rooms are under negative pressure with a ventilation rate of 36.8 – 44.1 air 
changes per hour (ACH). 
J. Literature Cited 
1. 
Wang T, Gentzke A, Sharapova S, Cullen K, Ambrose B, Jamal A. Tobacco product use 
among middle and high school students—United States, 2011-2017. MMWR Morb Mortal 
Wkly Rep. 2018;67(22):629- 633. 
2. 
AS Gentzke et al., MMWR Morb Mortal Wkly Rep 68 (6), 157 (2019). 
3. 
Brunnemann K, Hoffmann D. The pH of tobacco smoke. Food and Cosmetics Toxicology. 
1974;12(1):115-124. 
4. 
KD Brunnemann and D Hoffmann, Food Cosmet Toxicol 12 (1), 115 (1974). 
5. 
NC Institute, Monograph 13 (2001). 
6. 
S Gottlieb, Press Release (2018). 
7. 
NAo Sciences, National Academies Press (2018). 
8. 
ND Buchanan et al., Cardiovasc Res 116 (1), 40 (2020). 
9. 
G St Helen and DL Eaton, JAMA Intern Med 178 (7), 984 (2018). 
10. 
Mirbolouk M, Charkhchi P, Kianoush S, et al. Prevalence and distribution of e-cigarette use 
among US adults: behavioral risk factor surveillance system, 2016. Annals of internal 
medicine 2018;169:429-38. 
11. 
ELS Leavens et al., Addict Behav 95, 178 (2019). 
12. 
ELS Leavens et al., Addict Behav 99, 106047 (2019). 
13. 
EI Brett et al., Drug Alcohol Depend 194, 358 (2019). 
14. 
Ashley DL, Pankow JF, Tavakoli AD, Watson CH. Approaches, challenges, and experience in 
assessing free nicotine. Handb Exp Pharmacol 2009:437-56. 
15. 
Benowitz NL, Hukkanen J, Jacob P, 3rd. Nicotine chemistry, metabolism, kinetics and 
biomarkers. Handb Exp Pharmacol 2009:29-60. 
16. 
Historical trends in tar, nicotine and smoke Ph of Winston and Marlboro. 1977. (Accessed 
October 1, 2019, 2019, at http://tobaccodocuments.org/rjr/509308839‐8849.html.) 
17. 
Implications and activities arising from correlation of smoke Ph with nicotine impact, other 
smoke qualities, and cigarette sales. TDO website, 1973. (Accessed October 1, 2019, 2019, 
at http://tobaccodocuments.org/product_design/344.html.) 
18. 
Jr CF. Correlation of pH with share performance. 1973. 
19. 
Henningfield JE, Keenan RM. Nicotine delivery kinetics and abuse liability. J Consult Clin 
Psychol 1993;61:743-50. 
20. 
L.O. M. Effects of varying smoke pH on Kool KS/244. 1984. 
21. 
L C. pH of smoke: a review. 1976. 
22. 
Pankow JF, Tavakoli AD, Luo W, Isabelle LM. Percent free base nicotine in the tobacco 
smoke particulate matter of selected commercial and reference cigarettes. Chem Res 
Toxicol 2003;16:1014-8. 
23. 
Watson CH, Trommel JS, Ashley DL. Solid-phase microextraction-based approach to 
determine free-base nicotine in trapped mainstream cigarette smoke total particulate 
matter. J Agric Food Chem 2004;52:7240-5. 
24. 
Stepanov I, Fujioka N. Bringing attention to e-cigarette pH as an important element for 

IRB Protocol Number: 2020C0169 
IRB Approval Date: 11.21.2022 
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Evaluating E-Cigarette Nicotine Form, Concentration, and Flavors among Youth 
 
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research and regulation. Tob Control 2015;24:413-4. 
25. 
Wagener TL, Meier E, Hale JJ, et al. Pilot investigation of changes in readiness and 
confidence to quit smoking after E-cigarette experimentation and 1 week of use. Nicotine 
Tob Res 2014;16:108-14. 
26. 
Wagener TL, Floyd EL, Stepanov I, et al. Have combustible cigarettes met their match? The 
nicotine delivery profiles and harmful constituent exposures of second-generation and 
third-generation electronic cigarette users. Tobacco control 2017;26:e23-e8. 
27. 
Tackett AP, Lechner WV, Meier E, et al. Biochemically verified smoking cessation and vaping 
beliefs among vape store customers. Addiction 2015;110:868-74. 
28. 
Leavens ELS, Mehta T, Hale JJ, Shihadeh A, Halquist MS, Wagener TL. Nicotine delivery and 
abuse liability of pod-mod electronic cigarettes compared to combustible cigarettes. 
Submitted abstract. 
29. 
Cox S, Kosmider L, McRobbie H, et al. E-cigarette puffing patterns associated with high and 
low nicotine e-liquid strength: effects on toxicant and carcinogen exposure. BMC Public 
Health 2016;16:999. 
30. 
Brinkman M, Keller-Hamilton B, Carney-Knisely G, et al. Effect of pH of the nicotine liquid 
on JUUL puffing behavior and nicotine uptake. Submitted abstract. 
31. 
Ramamurthi D, Chau C, Jackler RK. JUUL and other stealth vaporisers: hiding the habit from 
parents and teachers. Tobacco control 2018:tobaccocontrol-2018-054455. 
32. 
Talih S, Salman R, El-Hage R, et al. Characteristics and toxicant emissions of JUUL electronic 
cigarettes. Tobacco control 2019:tobaccocontrol-2018-054616. 
33. 
Cohen  G MP, Carbonara  C, Wynne  C. Acute use of nicotine salt-based ends and 
combusted cigarettes. .  24th Annual Society for Research on Nicotine and Tobacco. 
Baltimore, MD2018. 
34. 
Wagener TL. Will the Debate Over e-Cigarettes Start Cooling Down? JAMA network open 
2018;1:e185945-e. 
35. 
Leventhal AM, Strong DR, Kirkpatrick MG, et al. Association of electronic cigarette use with 
initiation of combustible tobacco product smoking in early adolescence. Jama 
2015;314:700-7. 
36. 
Goniewicz ML, Boykan R, Messina CR, Eliscu A, Tolentino J. High exposure to nicotine 
among adolescents who use Juul and other vape pod systems ('pods'). Tob Control 2018. 
37. 
Benowitz NL, Nardone N, Jain S, et al. Comparison of Urine 4-(Methylnitrosamino)-1-
(3)Pyridyl-1-Butanol and Cotinine for Assessment of Active and Passive Smoke Exposure in 
Urban Adolescents. Cancer epidemiology, biomarkers & prevention : a publication of the 
American Association for Cancer Research, cosponsored by the American Society of 
Preventive Oncology 2018;27:254-61. 
38. 
Brinkman M, Keller-Hamilton B, Carney-Knisely G, et al., Presentation at the Annual Society 
for Research on Nicotine and Tobacco Conference (2020). 
39. 
B Herzok and KP Nielsen, Wells Fargo Equity Research Reports (2018). 
40. 
Roese NJ, & Jamieson, D. W. Twenty Years of Bogus Pipeline Research: A Critical Review 
and MetaAnalysis. Psychological Bulletin. 1993;114(2):363-375. 
41. 
WV Lechner et al., Addiction 110 (5), 862 (2015). 
42. 
Morean ME, Krishnan-Sarin S, Sussman S, Foulds J, Fishbein H, Grana R, Halpern-Felsher B, 
Kim H, Weaver SR, O’Malley SS. Development and psychometric validation of a novel 

IRB Protocol Number: 2020C0169 
IRB Approval Date: 11.21.2022 
Version: 6.0 
 
Evaluating E-Cigarette Nicotine Form, Concentration, and Flavors among Youth 
 
Page 22 of 22 
 
measure of sensory expectancies associated with E-cigarette use. Addictive behaviors. 2019 
Apr 1;91:208-15. 
43. 
JF Etter et al., Neuropsychopharmacology 28 (2), 359 (2003). 
44. 
RA Harris et al., Hypertension 55 (5), 1075 (2010). 
45. 
M Butlin and A Qasem, Pulse (Basel) 4 (4), 180 (2017). 
46. 
E Ho et al., Redox Biol 1, 483 (2013). 
47. 
JS Wanger and BH Culver, (American Thoracic Society, 2016). 
48. 
CI Vardavas et al., Chest 141 (6), 1400 (2012). 
49. 
OS Usmani et al., Respiratory medicine 116, 19 (2016). 
50. 
EM Lee et al., Nicotine Tob Res 5 (5), 673 (2003). 
51. 
JC Cappelleri et al., Addict Behav 32 (5), 912 (2007). 
52. 
JP Zacny et al., J Pharmacol Exp Ther 280 (3), 1159 (1997). 
53. 
J MacKillop et al., Exp Clin Psychopharmacol 16 (1), 57 (2008). 
54. 
LS Cox et al., Nicotine Tob Res 3 (1), 7 (2001). 
55. 
JR Hughes and D Hatsukami, Arch Gen Psychiatry 43 (3), 289 (1986). 
 

CONSENT & 
AUTHORIZATION 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2020C0169 
IRB Approval date:  12.04.2020 
Version:  5.0 
 
 
Page 1 of 11 
3Form date: 
05/17/2019  
 
The Ohio State University Combined Consent to Participate in 
1 
Research and HIPAA Research Authorization 
2 
 
3 
Study Title: 
Evaluating E-Cigarette Nicotine Form, 
Concentration, and Flavors among Youth 
Principal Investigator: 
Theodore L. Wagener, PhD 
Sponsor:  
American Heart Association (AHA) 
 
4 
• This is a consent form for research participation.  It contains important information 
5 
about this study and what to expect if you decide to participate.  Please consider the 
6 
information carefully. Feel free to discuss the study with your friends and family and 
7 
to ask questions before making your decision whether or not to participate. 
8 
• Your participation is voluntary.  You may refuse to participate in this study.  If you 
9 
decide to take part in the study, you may leave the study at any time.  No matter what 
10 
decision you make, there will be no penalty to you and you will not lose any of your 
11 
usual benefits.  Your decision will not affect your future relationship with The Ohio 
12 
State University.  If you are a student or employee at Ohio State, your decision will 
13 
not affect your grades or employment status. 
14 
• You may or may not benefit as a result of participating in this study.  Also, as 
15 
explained below, your participation may result in unintended or harmful effects for 
16 
you that may be minor or may be serious depending on the nature of the research. 
17 
• You will be provided with any new information that develops during the study 
18 
that may affect your decision whether or not to continue to participate.  If you 
19 
decide to participate, you will be asked to sign this form and will receive a copy of the 
20 
form.  You are being asked to consider participating in this study for the reasons 
21 
explained below.  
22 
 
23 
Key Information About This Study 
24 
The following is a short summary to help you decide whether or not to be a part of this study. 
25 
More detailed information is listed later in this form.  
26 
 
27 
You are being asked to participate in this research study to examine and learn more about 
28 
the influence of nicotine on youth vaping behavior as well as the heart and lung effects 
29 
associated with this behavior. If you choose to participate, you can do 5 or 9 visits, which 
30 
involve vaping sessions, the details of each schedule option will be discussed below. You 
31 
will be asked to complete regular surveys, heart and lung measures, and blood and urine 
32 
samples will be collected. There is no direct benefit to you by participating; however, 
33 
using this research, we hope the information learned will help us understand how e-
34 
cigarettes affect smoking behavior and health as well as assist in creating effective e-cig 
35 

CONSENT & 
AUTHORIZATION 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2020C0169 
IRB Approval date:  12.04.2020 
Version:  5.0 
 
 
Page 2 of 11 
3Form date: 
05/17/2019  
 
policies and regulations to prevent further increase of youth e-cig use. The risks of this 
36 
study include discomfort in answering questions asked of you, risks of nicotine to 
37 
pregnant or breastfeeding females, and the risks of e-cigarette exposure. More information 
38 
about these risks can be found below. You will be compensated for your time and effort in 
39 
this study.  
40 
 
41 
1.   Why is this study being done? 
42 
 
43 
The purpose of this study is to examine the influence of nicotine form, concentration, and 
44 
e-liquid flavor on youth vaping behavior.  It is also to examine nicotine uptake (the dose), 
45 
abuse liability (the tendency of use), toxicant exposure (the harmful tobacco-related 
46 
substances a user may be exposed to), and the heart and lung effects of vaping behavior. 
47 
 
48 
2.   How many people will take part in this study? 
49 
 
50 
Up to 130 people will take part in this study. 
51 
 
52 
3.   What will happen if I take part in this study? 
53 
 
54 
The following provides a summary of what will take place at each visit. 
55 
 
56 
Option A: Over the course of 9 study visits, there would be 9 vaping sessions. There is 
57 
one vaping session during today’s visit and 8 subsequent vaping sessions during the 
58 
subsequent visits.  
59 
 
60 
Option B: Over the course of 5 study visits, there will be 9 vaping sessions. There is one 
61 
vaping session during today’s visit and 2 vaping sessions separated by 3 hours of 
62 
downtime during each of the 4 remaining visits. 
63 
 
64 
After initially choosing Option A or B for your scheduled visits, you will be required to 
65 
stay in that option’s visit structure for the entirety of the study. So, please take time to 
66 
consider the best option for you. 
67 
 
68 
At each visit, you will complete regular surveys and physical measures such as blood 
69 
pressure, weight, and breath tests. If you are female, we will perform a pregnancy test to 
70 
ensure you are not pregnant at the beginning of each visit. During each visit, we will 
71 
perform a lung function test and collect biosamples including blood (a venous catheter 
72 
will be placed to repeatedly collect samples at different time periods during the vaping 
73 
sessions) and urine. 
74 
 
75 
The lung function test consists of breathing hard into a machine several times. It is 
76 
painless and only takes a few minutes to complete. The blood sample is approximately 
77 

CONSENT & 
AUTHORIZATION 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2020C0169 
IRB Approval date:  12.04.2020 
Version:  5.0 
 
 
Page 3 of 11 
3Form date: 
05/17/2019  
 
15mL or one tablespoon of blood. The blood will be used to look at the different amounts 
78 
of nicotine-related chemicals present in the blood. 
79 
 
80 
You will be required to be nicotine-free (abstinent) at least 12 hours before each study 
81 
visit. We will confirm you are nicotine-free at the beginning of each visit via blood 
82 
plasma nicotine analysis. During the first visit, you will use your own e-cig and e-liquid. 
83 
After visit 1, you will take home a study e-cig device and 1 pod with pre-filled tobacco 
84 
flavored e-liquid to practice (20 puffs per day with the study device and until you feel 
85 
comfortable using the device) using the device before visit 2. In the subsequent vaping 
86 
sessions, you will use a study e-cig pre-filled with e-liquid. Each vaping session will 
87 
include a standardized, 5-minute, 10-puff vaping bout (30 seconds between each puff) 
88 
followed by 30 minutes of ad libitum (as desired) vaping. 
89 
 
90 
During the vaping sessions, measures of vaping behavior (topography) will be assessed. 
91 
 
92 
You will not be allowed to eat or drink (other than water) during the vaping sessions, but 
93 
you will be allowed to have a light snack prior to placement of the IV and vape session 
94 
starting. If you choose Option B you can eat and drink during the 3-hour 
95 
washout/downtime periods. 
96 
 
97 
4.   How long will I be in the study? 
98 
 
99 
You will be in this study up to 6 months depending on what study schedule you choose, 
100 
A or B, how your visits are scheduled and your ability to remain abstinent prior to each 
101 
visit. 
102 
 
103 
Option A: Over this period, your first visit will last up to 3 hours and then 8 subsequent 
104 
visits that will last up to 2 hours each. 
105 
 
106 
Option B: Over this period, your first visit will last up to 3 hours and there will be 4 
107 
subsequent visits that will last up to 6 hours each. 
108 
 
109 
There may be anticipated circumstances under which your participation may be 
110 
terminated by the investigator without regard to your consent. Examples of when this 
111 
may happen are, if you are not following the study requirements, become pregnant during 
112 
the study, or for any other reason we feel your participation is not in your best interest or 
113 
the study’s best interest. 
114 
 
115 
You can stop participating in this study at any time. However, if you decide to stop 
116 
participating in the study, we encourage you to talk to the researcher first. 
117 
 
118 
5. Can I stop being in the study? 
119 
 
120 

CONSENT & 
AUTHORIZATION 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2020C0169 
IRB Approval date:  12.04.2020 
Version:  5.0 
 
 
Page 4 of 11 
3Form date: 
05/17/2019  
 
You may leave the study at any time.  If you decide to stop participating in the study, 
121 
there will be no penalty to you, and you will not lose any benefits to which you are 
122 
otherwise entitled.  Your decision will not affect your future relationship with The Ohio 
123 
State University.  
124 
 
125 
16. What risks, side effects or discomforts can I expect from being in the 
126 
study? 
127 
 
128 
Survey Risks 
129 
Some people feel uncomfortable answering questions about smoking or their health. You 
130 
may choose to select “Refuse to answer” as your response. Since these surveys will be 
131 
administered through the University approved Research Electronic Data Capture 
132 
(REDCap) system, any information collected will be in a secure database accessible only 
133 
to authorized study staff.  
134 
 
135 
Reproductive Risks for Women 
136 
If you are a female, you must not be and should not become pregnant nor breastfeed an 
137 
infant while on this study.  Using cigarettes or e-cigarettes while pregnant or breastfeeding 
138 
may involve risks to an embryo, fetus or infant, including birth defects which are currently 
139 
unforeseeable. In order to reduce your risk of pregnancy, you or your partner should use 
140 
one or more acceptable methods of birth control regularly and consistently while you are 
141 
on this study. 
142 
 
143 
If you become pregnant or suspect that you are pregnant during this study, you should 
144 
immediately inform the study personnel.  We will conduct a pregnancy test at each visit to 
145 
ensure that you are not currently pregnant. The study product may be discontinued until 
146 
the result of the pregnancy test is known. If pregnancy is confirmed, you may be 
147 
withdrawn from the study. Payment for all aspects of obstetrical, child, or related care will 
148 
be your responsibility. 
149 
 
150 
Blood Draws 
151 
There is a slight risk of discomfort, bruising, or infection with a blood draw. Your blood 
152 
will be drawn by trained research staff.  
153 
 
154 
Lung/Carbon Monoxide Tests 
155 
The breath and lung carbon monoxide tests are not associated with risks, but repetitive 
156 
testing within a short time frame may cause dizziness or shortness of breath.  
157 
 
158 
E-cigarette Devices 
159 
All of the products in our study are currently available for purchase in stores; however, 
160 
there was no FDA evaluation of these devices prior to their being commercially available. 
161 
As a result, we do not know the long-term safety, risks, or if these devices contain 
162 
ingredients that are known to be toxic to humans.  
163 

CONSENT & 
AUTHORIZATION 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2020C0169 
IRB Approval date:  12.04.2020 
Version:  5.0 
 
 
Page 5 of 11 
3Form date: 
05/17/2019  
 
 
164 
16. What benefits can I expect from being in the study? 
165 
 
166 
If you agree to take part in this study, there may or may not be direct medical benefit to 
167 
you. We hope that the information learned from this study will help us to understand how 
168 
nicotine form, concentration, and flavor affects people’s vaping behaviors and health. 
169 
 
170 
8.   What other choices do I have if I do not take part in the study? 
171 
 
172 
You may choose not to participate without penalty or loss of benefits to which you are 
173 
otherwise entitled. 
174 
 
175 
9.   Will my study-related information be kept confidential? 
176 
 
177 
Efforts will be made to keep your study-related information confidential.  However, there 
178 
may be circumstances where this information must be released.  For example, personal 
179 
information regarding your participation in this study may be disclosed if required by state 
180 
law.   
181 
 
182 
Also, your records may be reviewed by the following groups (as applicable to the 
183 
research): 
184 
• 
Office for Human Research Protections or other federal, state, or international 
185 
regulatory agencies; 
186 
• 
U.S. Food and Drug Administration; 
187 
• 
The Ohio State University Institutional Review Board or Office of Responsible 
188 
Research Practices; 
189 
• 
The sponsor supporting the study, their agents or study monitors; and 
190 
• 
Your insurance company (if charges are billed to insurance). 
191 
 
192 
We will work to make sure that no one sees your survey responses without approval. But, 
193 
because we are using the Internet, there is a chance that someone could access your online 
194 
responses without permission. In some cases, this information could be used to identify 
195 
you. Your data will be protected with a code to reduce the risk that other people can view 
196 
the responses. The Ohio State University will keep your information in password 
197 
protected databases and locked research files in a secure environment and will protect it to 
198 
the full extent of the law. 
199 
 
200 
The NIH has issued a Certificate of Confidentiality for this study. This Certificate 
201 
provides extra protection for you and your study information, documents, or samples 
202 
(blood, tissue, etc.). The Certificates are issued so that we cannot be required to disclose 
203 
any identifiable, sensitive information collected about you as a part of this study in a 
204 
lawsuit or legal proceeding. We are also prevented from releasing your study information 
205 

CONSENT & 
AUTHORIZATION 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2020C0169 
IRB Approval date:  12.04.2020 
Version:  5.0 
 
 
Page 6 of 11 
3Form date: 
05/17/2019  
 
without your consent. This is a layer of protection over and above the already existing 
206 
protections in place for you and your information, documents, or samples. 
207 
However, these protections do not apply in some situations. For example, we may have to 
208 
release your information if a law requires us to do so, the Agency that is funding this 
209 
study requests the information, or if the FDA tells us to release this information. We may 
210 
also use your information to conduct other scientific research as allowed by federal 
211 
regulations. 
212 
Study information that has health implications may be placed in your medical record 
213 
where authorized employees may see the information. Further, authorized requests for 
214 
your records (medical record release for continuity of care) may result in research-related 
215 
information being released. 
216 
Please talk to your study team, or contact the Office of Responsible Research Practices at 
217 
614-688-8641, if you have questions. 
218 
 
219 
If this study is related to your medical care, your study-related information may be placed 
220 
in your permanent hospital, clinic, or physician’s office records. Authorized Ohio State 
221 
University staff not involved in the study may be aware that you are participating in a 
222 
research study and have access to your information.  
223 
 
224 
If we find information that significantly impacts your health, we will share it with you. 
225 
You will be provided with any new information that develops during the course of the 
226 
research that may affect your decision whether or not to continue participation in the 
227 
study. 
228 
   
229 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
230 
required by U.S. law.  This website will not include information that can identify you.  At 
231 
most, the website will include a summary of the results.  You can search the website at 
232 
any time. 
233 
 
234 
10. Will my de-identified information and bio-specimens be used or shared for 
235 
future research? 
236 
 
237 
Yes, it/they may be used or shared with other researchers without your additional 
238 
informed consent.  De-identified information does not include any details that could make 
239 
it possible for others to recognize you. 
240 
 
241 
11. What are the costs of taking part in this study? 
242 
 
243 
There is no cost to you if you participate in this study. 
244 
 
245 
12. Will I be paid for taking part in this study? 
246 

CONSENT & 
AUTHORIZATION 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2020C0169 
IRB Approval date:  12.04.2020 
Version:  5.0 
 
 
Page 7 of 11 
3Form date: 
05/17/2019  
 
 
247 
By law, payments to participants are considered taxable income. 
248 
 
249 
You will receive the following compensation for your time: 
250 
 
251 
Option A   
 
 
 
Option B 
252 
Visit 1: $50 
 
 
 
Visit 1: $50 
253 
Visit 2: $50 
 
 
 
Visit 2: $100 
254 
Visit 3: $50 
 
 
 
Visit 3: $125 
255 
Visit 4: $50 
 
 
 
Visit 4: $150 
256 
Visit 5: $75 
 
 
 
Visit 5: $175 
257 
Visit 6: $75 
258 
Visit 7: $75 
259 
Visit 8: $75 
260 
Visit 9: $100 
261 
 
262 
 
263 
The maximum amount you can potentially earn by end of study if you follow study 
264 
instructions is $600. 
265 
 
266 
Payments will be made using the Greenphire ClinCard to increase accountability and 
267 
facilitate ease of payment.   
268 
 
269 
13. What happens if I am injured because I took part in this study? 
270 
 
271 
If you suffer an injury from participating in this study, you should notify the researcher or 
272 
study doctor immediately, who will determine if you should obtain medical treatment at 
273 
The Ohio State University Wexner Medical Center.   
274 
 
275 
The cost for this treatment will be billed to you or your medical or hospital insurance. The 
276 
Ohio State University has no funds set aside for the payment of health care expenses for 
277 
this study.  
278 
 
279 
14. What are my rights if I take part in this study? 
280 
 
281 
If you choose to participate in the study, you may discontinue participation at any time 
282 
without penalty or loss of benefits.  By signing this form, you do not give up any personal 
283 
legal rights you may have as a participant in this study. 
284 
 
285 
You will be provided with any new information that develops during the course of the 
286 
research that may affect your decision whether or not to continue participation in the 
287 
study. 
288 
 
289 

CONSENT & 
AUTHORIZATION 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2020C0169 
IRB Approval date:  12.04.2020 
Version:  5.0 
 
 
Page 8 of 11 
3Form date: 
05/17/2019  
 
You may refuse to participate in this study without penalty or loss of benefits to which 
290 
you are otherwise entitled. 
291 
 
292 
An Institutional Review Board responsible for human subjects research at The Ohio State 
293 
University reviewed this research project and found it to be acceptable, according to 
294 
applicable state and federal regulations and University policies designed to protect the 
295 
rights and welfare of research participants. 
296 
 
297 
15. HIPAA AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR 
298 
      RESEARCH PURPOSES  
299 
 
300 
I. 
What information may be used and given to others? 
301 
 
302 
• Past and present medical records; 
303 
• Research records; 
304 
• Records about phone calls made as part of this research; 
305 
• Records about your study visits; 
306 
• Information that includes personal identifiers, such as your name, or a number 
307 
associated with you as an individual; 
308 
• Laboratory and other test results 
309 
• Diaries and questionnaires 
310 
• Records about any study drug you received; and 
311 
• Records about the study device.  
312 
II. 
Who may use and give out information about you? 
313 
 
314 
Researchers and study staff.   
315 
 
316 
III. Who might get this information? 
317 
 
318 
• The sponsor of this research.  “Sponsor” means any persons or companies that are: 
319 
• working for or with the sponsor; or  
320 
• owned by the sponsor. 
321 
• Authorized Ohio State University staff not involved in the study may be aware that 
322 
you are participating in a research study and have access to your information; 
323 
• If this study is related to your medical care, your study-related information may be 
324 
placed in your permanent hospital, clinic, or physician’s office record; 
325 
• Others: National Cancer Institute 
326 
 
327 
IV. 
 Your information may be given to: 
328 
  
329 

CONSENT & 
AUTHORIZATION 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2020C0169 
IRB Approval date:  12.04.2020 
Version:  5.0 
 
 
Page 9 of 11 
3Form date: 
05/17/2019  
 
• The U.S. Food and Drug Administration (FDA), Department of Health and Human 
330 
Services (DHHS) agencies, and other federal and state entities; 
331 
• Governmental agencies in other countries; 
332 
• Governmental agencies to whom certain diseases (reportable diseases) must be 
333 
reported; and  
334 
• The Ohio State University units involved in managing and approving the research 
335 
study including the Office of Research and the Office of Responsible Research 
336 
Practices. 
337 
• Researchers and laboratories outside of the Ohio State University. 
338 
 
339 
V. 
Why will this information be used and/or given to others? 
340 
 
341 
• To do the research;  
342 
• To study the results; and  
343 
• To make sure that the research was done right.   
344 
 
345 
VI. 
 When will my permission end? 
346 
 
347 
There is no date at which your permission ends. Your information will be used 
348 
indefinitely. This is because the information used and created during the study may be 
349 
analyzed for many years, and it is not possible to know when this will be complete. 
350 
 
351 
VII. May I withdraw or revoke (cancel) my permission? 
352 
 
353 
Yes. Your authorization will be good for the time period indicated above unless you 
354 
change your mind and revoke it in writing. You may withdraw or take away your 
355 
permission to use and disclose your health information at any time. You do this by 
356 
sending written notice to the researchers. If you withdraw your permission, you will not 
357 
be able to stay in this study. When you withdraw your permission, no new health 
358 
information identifying you will be gathered after that date. Information that has already 
359 
been gathered may still be used and given to others. 
360 
 
361 
VIII. What if I decide not to give permission to use and give out my health 
362 
information? 
363 
 
364 
Then you will not be able to be in this research study and receive research-related 
365 
treatment.  However, if you are being treated as a patient here, you will still be able to 
366 
receive care. 
367 
 
368 
IX. 
 Is my health information protected after it has been given to others? 
369 
 
370 

CONSENT & 
AUTHORIZATION 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2020C0169 
IRB Approval date:  12.04.2020 
Version:  5.0 
 
 
Page 10 of 11 
3Form date: 
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There is a risk that your information will be given to others without your permission. Any 
371 
information that is shared may no longer be protected by federal privacy rules. 
372 
 
373 
X. 
May I review or copy my information? 
374 
 
375 
Signing this authorization also means that you may not be able to see or copy your study-
376 
related information until the study is completed.   
377 
 
378 
16. Who can answer my questions about the study? 
379 
 
380 
For questions, concerns, or complaints about the study, or if you feel you have been 
381 
harmed as a result of study participation, you may contact Profile Study staff at 1-844-744-
382 
2447. 
383 
 
384 
For questions related to your privacy rights under HIPAA or related to this research 
385 
authorization, please contact a privacy officer at 614-293-4477. 
386 
 
387 
For questions about your rights as a participant in this study or to discuss other study-
388 
related concerns or complaints with someone who is not part of the research team, you 
389 
may contact the Office of Responsible Research Practices at 1-800-678-6251. 
390 
 
391 
If you change your mind about taking part in this study, you can contact Profile Study 
392 
staff by phone at 1-844-744-2447. Staff may ask if you want to withdraw from the entire 
393 
study or parts of it. 
394 
 
395 
 
396 
397 

CONSENT & 
AUTHORIZATION 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2020C0169 
IRB Approval date:  12.04.2020 
Version:  5.0 
 
 
Page 11 of 11 
3Form date: 
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Signing the consent form 
398 
 
399 
I have read (or someone has read to me) this form and I am aware that I am being asked to 
400 
participate in a research study.  I have had the opportunity to ask questions and have had them 
401 
answered to my satisfaction.  I voluntarily agree to participate in this study. 
402 
 
403 
I choose study schedule Option A _____ 
 
I choose study schedule Option B _____ 
404 
 
405 
I am not giving up any legal rights by signing this form.  I will be given a copy of this form. 
406 
 
407 
 
 
 
 
Printed name of participant 
 
Signature of participant 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
 
 
 
 
Printed name of person authorized to consent for 
participant (when applicable) 
 
Signature of person authorized to consent for participant  
(when applicable) 
 
 
 
 
 
AM/PM 
Relationship to the participant 
 
Date and time 
 
 
408 
Investigator/Research Staff 
409 
 
410 
I have explained the research to the participant or his/her representative before requesting the 
411 
signature(s) above.  There are no blanks in this document.  A copy of this form has been given 
412 
to the participant or his/her representative. 
413 
 
414 
 
 
 
 
Printed name of person obtaining consent 
 
Signature of person obtaining consent 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
415 
Witness(es) - May be left blank if not required by the IRB 
416 
 
417 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
418