Low Nicotine Content Cigarettes in Vulnerable Populations: Affective Disorders
Phase: PHASE2
Conditions: Tobacco Use Disorder
Sponsor: Brown University

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UNIVERSITY OF VERMONT CENTER ON TOBACCO REGULATORY SCIENCE 
 
 
PROJECT 3, STUDY 3 
LOW NICOTINE CONTENT CIGARETTES IN VULNERABLE POPULATIONS: AFFECTIVE DISORDERS 
STUDY PROTOCOL 
Version 37: 9 December 2022 

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Table of Contents 
 
1. Objective… ............................................................................................................................6 
2. Significance… ...................................................................................................................... 7 
2.1 Affective Disorders (AD) and Smoking ................................................................... 7 
2.2 Relevance of the project to the integrative theme and goals of the TCORS… ........ 8 
2.3 Relevance to the scientific domains and priorities of the FDA CTP… ..................... 8 
2.4 How study outcomes will improve scientific knowledge related to the 
manufacture, distribution and marketing of tobacco products ........................................8 
3. Rationale…..........................................................................................................................8 
3.1 Effects of Nicotine Reduction in Smokers with AD ...................................................8 
3.2 E-Cig Use ............................................................................................................. 10 
3.3 E-cig effects on smoking .......................................................................................10 
3.4 Mechanisms of e-cig effects ................................................................................. 11 
3.5 Importance of e-cig flavors effects ........................................................................ 11 
3.6 Products to be tested effects ................................................................................ 11 
3.7 Summary ............................................................................................................. 12 
4. Project Study Methods… ................................................................................................... 12 
5. Study Screening Procedures… .......................................................................................... 12 
5.1 Participants…....................................................................................................... 12 
5.2 Recruitment… ...................................................................................................... 12 
5.3 Informed Consent Process… ............................................................................... 13 
5.4 Screening Measures… ......................................................................................... 13 
5.5 Suicidality/Mental Health Monitoring… ................................................................ 16 
5.6 Inclusion/Exclusion Criteria… ............................................................................... 16 
5.7 Eligibility Determination… ................................................................................... 18 
6. Study Baseline Procedures............................................................................................... 19 
6.1 Visit scheduling requirements for baseline period… ............................................ 20 
6.2 Measures/Assessments… ................................................................................... 20 
6.3 E-Cigarette Training session (Baseline 2)… ....................................................... 22 
6.4 Interactive Voice Response… ............................................................................ 23 
7. Study Experimental Procedures… .................................................................................. 24 
7.1 Experimental Period… ...................................................................................... 24 
7.2 Experimental Visits Weeks 1, 3, 5, 7, 9, 11, 13 and 15 Procedures. .................. 24 
7.2.A Measures/ Assessments ..................................................................... 24 
7.3 Experimental Visits Weeks 2, 4, 6, 8, 10, 12, 14 and 16 Procedures ................ 25 
7.3.A Measures/Assessments ..................................................................... 25 
7.4 Interactive Voice Response System. ................................................................ 26 
7.5 Variable Incentive Program. ............................................................................. 26 
7.6 Product and Procedures Compliance Review Sessions. ................................... 28 
7.7 Quit Attempts During the Study Protocol ........................................................... 28 
7.7.A If a participant is currently abstaining from smoking with the intention 
to quit ...................................................................................................... 28 
7.7.B If a participant is planning to quit smoking, but has not initiated the quit 

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attempt. .................................................................................................... 29 
7.8 Abstinence Assessment Session. .................................................................. 29 
7.8.A Participants Who Meet Criteria for Abstinence. ................................. 29 
7.8.A.1 Measures/Assessments. .................................................... 29 
7.8.B Participants Who Do Not Meet Criteria for Abstinence. ..................... 30 
7.8.B.1 Measures/Assessments. .................................................... 30 
7.9. Participant Compensation .............................................................................. 30 
7.10 End of Study. ................................................................................................ 31 
7.11 30 Day Follow up Phone Call. ....................................................................... 31 
8. Study Randomization. ................................................................................................... 31 
8.1 Randomization Process. ................................................................................. 31 
8.2 Study Product Administration. ......................................................................... 32 
8.3 Guidelines for Reporting Other Nicotine Product Use. ..................................... 32 
8.4 Study Product Accountability. .......................................................................... 33 
9. Study 3 Statistical Methods and Sample Size. .............................................................. 33 
9.1 Statistical Methods. .......................................................................................... 33 
9.2 Sample Size..................................................................................................... 34 
10. Potential Risks of Participation. ................................................................................... 35 
10.1 Risks of Participation ..................................................................................... 35 
10.2 Avoiding Risk to Fetus................................................................................... 37 
10.3 Expected benefits of participation ................................................................... 37 
11. Protection Against Risk. ............................................................................................... 37 
11.1 Data Collection Protections. ........................................................................... 37 
11.2 Data Storage .................................................................................................. 38 
12. Adverse Events. .......................................................................................................... 38 
13. Withdrawal or Monitoring of Participants. ..................................................................... 39 
14. Data Safety Monitoring Board. ..................................................................................... 40 
15. Investigational Tobacco Product .................................................................................. 41 
16. Certificate of Confidentiality. ......................................................................................... 41 
17. Outcome Variables. .....................................................................................................42 
18. References. ................................................................................................................ 43 

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Abbreviations 
 
• 3HC: 3-hydroxycotinine 
• BAL: Breath alcohol levels 
• BDI: Beck’s Depression Inventory 
• BMI: Body Mass Index 
• BP: Blood pressure 
• BPM: Beats per minute 
• BRIEF-A: Behavioral Rating Inventory of Executive Function 
• CES: Cigarette Evaluation Scale 
• CO: Carbon monoxide 
• COT: Cotinine 
• CPD: Cigarettes per day 
• CPT: Cigarette Purchase Task 
• CPT: Continuous Performance Task 
• DAST: Drug Abuse Screening Test 
• DDT: Delay Discounting Task 
• D-KEFS: Delis-Kaplan Executive Function System 
• EDC: Electronic Data Capture 
• EQ-5D: Euro-Qol 
• FSPTCA: Family Smoking Prevention and Tobacco Control Act 
• FTND: Fagerström Test for Nicotine Dependence 
• GAD: Generalized Anxiety Disorder 
• HR: Heart rate 
• IVR: Interactive Voice Response 
• MDD: Major Depressive Disorder 
• MINI: Mini International Neuropsychiatric Interview 
• MNWS: Minnesota Nicotine Withdrawal Scale 
• NMR: Nicotine metabolite ratio 
• NNAL: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
• NNC: Normal nicotine content 
• NNN: N′-nitrosonornicotine 
• OASIS: Overall Anxiety Severity and Impairment Scale 
• OUD: Opioid Use Disorder 
• PANAS: Positive and Negative Affect Schedule 
• PHQ: Patient Health Questionnaire 
• PSS: Perceived Stress Scale 
• QSU: Questionnaire of Smoking Urges 
• RNC: Reduced nicotine content 
• SST: Stop Signal Task 
• TLFB: Timeline Follow Back 
• TPQ: Time Perspectives Questionnaire 
• VLNC: Very low nicotine content 
• WASI-II: Wechsler Abbreviated Scale of Intelligence-II 
• WISDM: Wisconsin Index of Smoking Dependence Motives 

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Project 3 Protocol 
 
 
 
1. OBJECTIVE 
 
 
While the prevalence of smoking in the US general population has declined over the past 50 
years, there has been little to no decline among people with mental health conditions. Affective 
disorders (ADs) are the most common mental health conditions in the US, and over 40% of 
people with ADs are current smokers.1 A national policy of reducing the nicotine content of 
cigarettes has the potential to reduce tobacco use, dependence, and related adverse health 
outcomes.2-4 Controlled trials in psychiatrically stable smokers have shown that extended use of 
very low nicotine content cigarettes (VLNCCs) results in reductions in cigarettes per day (CPD), 
cigarette dependence, and tobacco toxicant exposure, with few adverse consequences.5-8 
Furthermore, our research during UVM TCORS Phase 1 funding indicates that smokers with 
ADs respond to reductions in cigarette nicotine content with reductions in cigarette demand.9-10 
However, tobacco market conditions are likely to exert considerable influence over the extent to 
which that potential is realized. In particular, we hypothesize that the following conditions are 
likely to exert considerable influence over the potential effectiveness of a national nicotine 
reduction policy for cigarettes, particularly in smokers with ADs and other vulnerabilities to 
tobacco addiction: (1) whether alternative sources of non-combusted nicotine are readily 
available, and (2) whether these alternatives are available under conditions that optimize their 
appeal. 
The goal of the proposed trial is to experimentally model whether increasing the availability 
and appeal of an alternative, non-combusted source of nicotine (e-cigarettes) enhances the 
effects of reduced-nicotine cigarettes in smokers with ADs. Daily smokers with current ADs, 
recruited at University of Vermont and Brown University, will be randomized to one of the 
following four conditions: (1) normal nicotine content cigarettes (NNCCs) alone, serving as the 
control condition, (2) VLNCCs alone, (3) VLNCCs + nicotine e-cigarettes in only tobacco flavors 
(TF e-cigs), or (4) VLNCCs + nicotine e-cigarettes in preferred flavors (PF e-cigs). Participants 
will be asked to use only their assigned study products for 16 weeks. Outcome measures 
include total CPD, cigarette demand assessed by behavioral economics-based purchase tasks, 
craving, withdrawal, psychiatric symptoms, breath carbon monoxide (CO) and biomarkers of 
tobacco toxicant exposure. In Week 17, participants will receive incentives to abstain from 
cigarettes during a three-hour laboratory test session and we will assess the effects of study 
conditions on cigarette demand, craving and withdrawal. 
This research will address the following specific aims: Aim 1 (Primary): Compare the effects 
of (1) NNCCs alone, (2) VLNCCs alone, (3) VLNCCs + TF e-cigs and = (4) VLNCCs + PF e-cigs 
on total CPD in smokers with ADs. We hypothesize that at Week 16, total CPD will be reduced 
in a linear, graded manner (condition 4 > 3 > 2 > 1), with the largest reduction in the VLNCC + 
PF e-cig condition. Aim 2 (Secondary): Compare the effects of the four study conditions on 
cigarette demand, psychiatric symptoms, and biomarkers of smoke and tobacco toxicant 
exposure (CO, NNAL, PAHs) in smokers with ADs. We hypothesize that at Week 16, cigarette 
demand, CO, and toxicant biomarkers will have decreased in a linear, graded manner, with the 
largest reduction in the VLNCC + PF e-cig condition. We will characterize effects on psychiatric 
symptoms but are not testing specific hypotheses on these symptoms. Aim 3 (Exploratory): To 
explore the effects of the four study conditions on cigarette demand, craving, and withdrawal in 
smokers with ADs during the abstinence assessment period. 

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The integrative theme of this TCORS is vulnerable populations. The proposed research is 
highly relevant to the CTP’s scientific domains of Addiction and Behavior because it will address 
whether reducing the nicotine content of cigarettes reduces cigarette use, dependence, and 
product appeal, and whether these effects are enhanced by the availability of an appealing 
alternative source of non-combusted nicotine. It will address the Health Effects domain by 
assessing the effects of these conditions on tobacco toxicant exposure and a respiratory 
biomarker. The proposed study is significant and innovative because it will model how 
availability and appeal of e-cigs may moderate the effectiveness of a national reduced- nicotine 
policy for cigarettes in this understudied population. Finally, it is programmatic as it will build 
upon and extend the work that our team accomplished on VLNCCs in those with ADs during 
phase 1 of UVM TCORS funding. 
 
 
2. SIGNIFICANCE 
 
 
2.1. Affective Disorders (AD) and Smoking 
Each year, cigarette smoking kills almost half a million Americans and costs the US almost 
$300 billion in medical costs and lost productivity.11 While smoking rates in the general US 
population have declined over the past 50 years, there has been little to no decline among people 
with mental health conditions (MHCs), indicating that current tobacco control policies and 
treatments are not benefiting these smokers.1,12 Affective disorders (ADs), which include major 
depressive disorder and anxiety disorders, are the most common MHCs in the US; in 2015, 7% 
of US adults reported past-year major depressive disorder and 18% reported a past-year anxiety 
disorder.13 Over 40% of people with ADs are current smokers.1 Stated conversely, 22% of 
nicotine-dependent smokers report having a mood disorder and 23% report an anxiety disorder.14 
Smokers with ADs make as many cessation attempts as those without MHCs, but are more likely 
to relapse when they try to quit.15-18 Hence, ADs are associated with disproportionately high rates 
of tobacco-related disease and death.19, 20 
Similar transdiagnostic factors appear to underlie the low cessation rates in people with 
depression and anxiety disorders.21 Negative mood is a prominent feature of major depression 
and anxiety disorders22. Although long-term cessation is associated with improvements in mood,23 
smoking abstinence produces transient increases in negative mood that are reversed by 
smoking.24 Smokers with ADs report more severe effects of abstinence on negative mood than 
those without MHCs,25 and have stronger expectancies that smoking will reduce negative mood.26- 
28 Anhedonia (reduced capacity to experience pleasure from rewarding stimuli) may also 
contribute to smoking persistence in people with ADs. Anhedonia is a key symptom of depression 
and anxiety disorders and is associated with increased responsiveness to pharmacological 
reinforcers that potently release mesolimbic dopamine (DA).29 Consistent with this hypothesis, 
smokers with a history of major depression have greater smoking-induced DA release than those 
without depression,30 and overvalue cigarette reinforcement.31,32 Furthermore, nicotine can 
enhance the reinforcing effects of environmental stimuli.33,34 This may contribute to low cessation 
rates in smokers with ADs, as smokers with depression, but not those without MHCs, report 
greater enjoyment of activities in their natural environments while smoking.31 
A national nicotine reduction policy for cigarettes may be an effective regulatory approach to 
reducing cigarette dependence in smokers with ADs. The 2009 Family Smoking Prevention and 
Tobacco Control Act gave the Food and Drug Administration (FDA) the authority to regulate 
tobacco products as appropriate to protect public health, including limiting the nicotine content of 
cigarettes.35 An FDA-mandated reduction in the nicotine content of cigarettes to a minimally- 
addictive level could reduce tobacco reinforcement and dependence.3,36 This approach could be 
particularly beneficial to subpopulations of smokers who have less success with currently- 
available cessation treatments, such as people with ADs. Our work during the UVM TCORS 
phase 1 funding period, indicates that smokers with ADs, like smokers without MHCs, respond to 

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reductions in the nicotine content of cigarettes with reductions in cigarette demand and other 
measures of addiction potential. However, tobacco market conditions are likely to exert 
considerable influence over the extent to which the effects of reduced-nicotine cigarettes are 
realized in the natural environment. This may be particularly true of smokers with ADs, who are 
more sensitive to the effects of nicotine withdrawal than those without MHCs.37 Use of electronic 
cigarettes (e-cigs) is increasing sharply in the US, and it is important to consider the potential 
moderating effects of e-cig use on a reduced-nicotine policy for cigarettes. By providing an 
alternative source of nicotine, we believe that the availability of nicotinized e-cigs, and 
manipulations that increase their appeal (flavors), will enhance the ability of a national cigarette 
nicotine-reduction policy to decrease cigarette smoking, dependence and toxin exposure among 
smokers with ADs. 
2.2. Relevance of the project to the integrative theme and goals of the TCORS 
The integrative theme of the UVM TCORS is vulnerable populations, and its goals are to 
model the potential effects of tobacco product standards on product use in vulnerable populations, 
with the goal of reducing the risks of product use, dependence, and product-related adverse 
health outcomes. For the FDA to effectively execute its tobacco regulatory responsibilities, it must 
have sound scientific evidence on how product standards impact tobacco use in populations with 
high rates of tobacco dependence. This project will provide the FDA with evidence on the effects 
of a reduced-nicotine standard for cigarettes, alone and combined with another FDA-regulated 
product (e-cigs), on measures of cigarette use, demand, dependence, tobacco toxicant exposure 
and psychiatric symptoms in this vulnerable population. 
2.3. Relevance to the scientific domains and priorities of the FDA CTP 
The proposed research is highly relevant to the CTP’s scientific domains of Addiction and 
Behavior because it will address whether reducing the nicotine content of cigarettes reduces 
cigarette use, dependence, and product appeal, and whether these effects are enhanced by the 
availability of appealing alternative sources of non-combusted nicotine. It will address the Health 
Effects domain by assessing the effects of these conditions on tobacco toxicant exposure and a 
respiratory biomarker. 
2.4. How study outcomes will improve scientific knowledge related to the manufacture, 
distribution and marketing of tobacco products 
Study outcomes will directly inform scientific knowledge concerning the manufacture of 
tobacco products by demonstrating whether a reduction in the maximum nicotine content of 
cigarettes sold in the US to ≤ 0.4 mg nicotine/g tobacco would reduce smoking in this vulnerable 
population. The outcomes will also indicate whether continuing to allow the sale of e-cigs in 
characterizing flavors improves the efficacy of a reduced-nicotine standard for cigarettes on 
smoking reduction in this population. 
 
 
3. RATIONALE 
 
 
3.1. Effects of Nicotine Reduction in Smokers with AD 
Controlled trials of research cigarettes differing in nicotine content in general population 
samples have demonstrated that those who are switched to VLNCCs reduce their daily cigarette 
use, nicotine exposure, cigarette dependence, and tobacco toxicant exposure, with few adverse 
consequences.5-8 Given the low smoking cessation rates in smokers with ADs, it is important to 
consider whether these smokers experience benefits or negative consequences of nicotine 
reduction. Prior to the work accomplished by this TCORS during Phase 1 funding, few studies 
had examined effects of VLNCCs in smokers with ADs. Several laboratory studies in smokers 
with elevated depression or anxiety symptoms found that both VLNCCs and normal-nicotine 
cigarettes reduce craving and withdrawal and do not exacerbate depression or anxiety (reviewed 
by Gaalema et al.38). We recently conducted a secondary analysis of a large randomized clinical 

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trial that examined the effects of cigarettes varying in nicotine content over a 6-week period in 
non-treatment-seeking smokers, in which we examined whether those with higher vs. lower 
depressive symptoms at baseline differed with regard to their responses to cigarettes varying in 
nicotine content.39 We found that after 6 weeks of use, those who had used VLNCCs had lower 
smoking rates, nicotine dependence and craving than those who had used NNCCs, regardless of 
baseline depressive symptom score. Furthermore, those with elevated depressive symptoms at 
baseline who had been assigned to VLNCCs had lower depressive symptoms at Week 6 than 
those who had used NNC cigarettes. Importantly, 
biochemically-confirmed VLNCC compliance also did 
not differ by group. These findings provide support for 
the idea that a reduced-nicotine standard for cigarettes 
may reduce smoking, without worsening depressive 
symptoms, in smokers with elevated depressive 
symptoms. However, that study examined VLNCC 
effects in a non-clinical sample with elevated 
depressive symptoms, not those with diagnosed 
depression or anxiety disorders. 
To our knowledge, we are the first to report the 
effects of reduced-nicotine cigarettes on measures of 
cigarette reinforcement in smokers with ADs. In Study 
1, we examined the acute subjective and behavioral 
effects of cigarettes varying in nicotine content (15.8, 5.2, 2.4 and 0.4 mg nicotine/g tobacco) in 
smokers with Ads.9,10 In concurrent choice testing with the cigarettes available at an equal 
response effort, participants chose the higher over the lower nicotine content cigarettes across 
each of the six dose pairs consistent with reduced nicotine content cigarettes having lower 
addiction potential (below, left). The only difference between populations was at the 0.4 versus 
2.4 mg/g dose pair, where smokers with affective disorders chose the higher dose more often (p 
< .001), while disadvantaged women (p = .06) and those with opioid dependence (p = .91) did not 
exhibit a significant preference between those two doses (below, right). All doses decreased 
craving and withdrawal symptoms with no evidence of compensatory smoking. While the higher 
nicotine cigarettes were rated as more satisfying, increasing the response requirement to obtain 
these cigarettes reversed that preference. This observation has considerable tobacco regulatory 
implications. For example, allowing VLNCCs to be sold in common retail outlets while restricting 
sale of higher content cigarettes to more regulated stores would be predicted to shift preference 
towards the former. This same concept may also extend to regulatory efforts to shift preference 
from harmful combusted to less harmful non-combusted tobacco products. Overall, our results 
indicate that reducing the nicotine content of cigarettes reduces the relative reinforcing effects of 
smoking, and hence addiction potential, in smokers with ADs and other vulnerabilities to tobacco 
addiction. The 0.4 mg/g most robustly differed from the 15.8 mg/g dose in this population, 
supporting prior hypotheses about reducing nicotine content below 0.7 mg/g3. 
In Study 2, we are examining effects of cigarettes varying in nicotine content in smokers with 
ADs over a 12-week period. Preliminary results from 35 participants indicate that VLNCCs reduce 
smoking rates by >40% relative to NNCCs in Weeks 9-12 (see figure at right). However, while 
smokers with ADs reduce their smoking rates, few quit completely, similar to results seen in 
 

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general population samples.7 These findings set the stage for examining whether providing an 
alternative, non-combusted source of nicotine (e-cigs) enhances the efficacy of reduced-nicotine 
cigarettes in this population. 
3.2. E-Cig Use 
E-cigs consist of a cartridge containing an e-liquid solution of nicotine, propylene glycol (PG), 
vegetable glycerin (VG), flavoring, and other additives, which is heated with an atomizer that 
vaporizes the solution. First generation e-cigs resemble cigarettes (“cigalikes”) and are disposable 
or rechargeable, second generation products (such as the product that will be used in this study) 
often resemble pens and have refillable e-liquid reservoirs, and third generation devices have 
larger batteries, adjustable power delivery and replacement heating coils and wicks.40 Nicotine 
levels from e-cigs can be comparable to those from cigarettes, depending on e-cig characteristics, 
e-liquid nicotine content and user topography.41-44 Potential risks of e-cig use include exposure to 
low levels of carcinogens, toxicants, metals in the vapor, and cytotoxic effects of flavors.45,46 
However, toxin and carcinogen levels from e-cigs appear to be far lower than those from 
cigarettes. Hecht et al.47 reported that former smokers who had switched to e-cigs had 59-99% 
lower levels of 6 tobacco toxicant and carcinogen metabolites than ongoing smokers, comparable 
to reductions seen in smokers who had switched to nicotine lozenges.8 Another study found that 
NNAL, a metabolite of the tobacco carcinogen NNK, was reduced by 64% in smokers who had 
switched to e-cigs for two weeks, as was chest tightness.48 
E-cig use has increased sharply in the US, particularly among people with MHCs. A 2012 
national probability survey in >10,000 US adults found that people with MHCs (including ADs) 
were twice as likely to have ever used or to currently use e-cigs than those without MHCs.49 
Survey data from 2015 indicate a doubling of use since the Cummins et al. survey, and people 
with MHCs were still twice as likely to use e-cigs as those without MHCs (24.4% ever use, 11.4% 
current use).50 Of those with depression and anxiety disorders, 24-30% reported ever use and 11- 
13% reported current use.50 Two surveys also reported that likelihood of e-cig use was associated 
with psychiatric symptom severity or number of MHCs endorsed, suggesting a systematic 
relationship.50,51 Smokers in general report that their reasons for e-cig use are to quit or reduce 
smoking, to reduce cigarette craving and nicotine withdrawal, because e-cigs bother other people 
less than cigarettes, and because they can use e-cigs in places where smoking is forbidden.51-55 
Smokers with MHCs report similar reasons for use.56-59 
3.3. E-cig effects on smoking 
To date, clinical trials indicate effects of e-cigs on smoking reduction, but little effect on 
quitting.60-62 Modest effects on cigarette abstinence in these trials may have been due to use of 
first generation e-cigs that provided variable nicotine delivery and were subject to battery failure.63 
A trial using second generation e-cigs found cigarette abstinence rates of 34% after 8 weeks and 
21% 6 months later, with an overall 60% reduction in CPD.64 Few studies have examined the 
effects of e-cigs in smokers with ADs. Among hospitalized smokers with serious mental illness 
enrolled in a cessation trial, e-cig use increased during the trial but was not associated with 
smoking abstinence.65 Likewise, a survey in veterans found a strong association between MHCs 
and e-cig use, but no association with quitting.56 A secondary analysis of the Bullen et al. ASCEND 
trial60 found that mental health status did not moderate the effect of e-cigs on quitting.66 A pilot 
study in 21 smokers with psychotic disorders found that e-cig use decreased CPD.59 Both of the 
latter studies reported high rates of e-cig acceptability among smokers with MHCs.59,66 
We recently completed a pilot study in 18 smokers who were asked to switch to a second- 
generation e-cig with 18 mg/ml nicotine e-liquid for 6 weeks.67 All of those enrolled completed the 
study. Participants significantly reduced their CPD, breath CO levels, Fagerström Test for 
Cigarette Dependence scores, and increased their readiness to quit, all with large effect sizes 
(Cohen’s d’s ranging from 0.88 to 1.3). At a follow-up visit 4 weeks later, changes from baseline 
had been maintained with large effects sizes on all measures (Cohen’s d’s ranging from 0.8 – 

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1.1). This work demonstrates our experience and success with testing an e-cig similar to that 
which will be used in this study over a multi-week period. 
3.4. Mechanisms of e-cig effects 
E-cigs reduce cigarette craving and nicotine withdrawal symptoms.68 Although early studies 
found that e-cigs were less effective than cigarettes at reducing cigarette craving and 
withdrawal,60,69,70 second-generation e-cigs more effectively reduce craving and withdrawal under 
natural ad lib use conditions.41,64,71 E-cig effects on craving and withdrawal symptoms are 
determined by the extent to which e-cig are used by smokers; in turn, determinants of e-cig use 
include product appeal and reinforcing effects.72,73 
3.5. Importance of e-cig flavors 
More than two-thirds of adult e-cig users in 2013-2014 used a flavored e-cig.74,75 Flavors have 
been shown to substantially enhance the appeal and relative reinforcing effects of e-cigs76,77 and 
have been cited as a key feature of e-cigs affecting use among adults.75,78,79 Experimental studies 
show that flavors increase demand for e-cigs among cigarette smokers,80,81 particularly smokers 
who are not current e-cig users.81 Studies of e-cig users also highlight that flavors play an 
important role in their experience of the product82-84 and in reducing cigarette consumption and 
craving.83,85 Although a recent review on e-cigs and mental illness reported one study of flavors, 
which found no differential appeal in young adult smokers with mental illness in the VA,57 flavored 
(menthol) cigarette use is preferentially used among individuals with severe psychological 
distress86 and is associated with greater prevalence of both depression and anxiety in US young 
adults.87 Therefore, it warrants investigation whether providing e-cigs in preferred flavors 
increases e-cig use and the ability of e-cigs to substitute for cigarettes in smokers with ADs. 
 
3.6 Products to be tested 
Cigarettes to be assessed 
The cigarettes to be used in this study were made under an NIH contract with production being 
overseen by the Research Triangle Institute (referred to as “Spectrum cigarettes”). NIH currently 
has approximately 10 million of these cigarettes (of varying types) for research purposes. The 
cigarettes selected for the study span the range of yields likely to produce the hypothesized 
effects, as described above. Spectrum cigarettes are not currently commercially available, 
although they are similar in many ways to marketed cigarettes (e.g., similar manufacturing, filter, 
paper, etc.). 
 
E-cigarettes to be assessed 
Both the JUUL and the Vuse Solo will be used and assessed in this study. While JUUL will be 
offered to all participants, participants that are unwilling to use JUUL will be offered the Vuse 
Solo. 
JUUL is a commercially available closed system containing two components. One component 
contains a lithium-ion battery (200 mAh), nichrome coil heater, silica wick, and stainless steel 
vapor path. The other component is the prefilled e-liquid container that also serves as the 
mouthpiece. Each commercially available cartridge holds approximately 0.7 mL of e-liquid 
containing approximately 40 mg of nicotine or 5% nicotine by weight (NBW). A lower dose 
containing approximately 23 mg of nicotine per cartridge or 3% NBW is also marketed but will 
not be used in this study. All containers contain glycerol, propylene glycol, natural oils, extracts 
and flavors, nicotine, benzoic acid. We will not alter the e-liquid in any way. The research staff 
will distribute the e-liquid containers as purchased from the manufacturer. The JUUL apparatus 
and 5% NBW e-liquids that will be used are legally purchasable and have been as of August 8, 
2016. We will not alter them in any way. 
Vuse Solo is a commercially available closed system containing two components. The 
power/heating device includes a 270 mAh battery, silica wick, microchips, and sensor. The other 
component is the prefilled e-liquid container. Each commercially available cartridge holds 

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approximately 1 mL of liquid containing 48 mg of nicotine or 4.8% NBW. All containers contain 
vegetable glycerin, propylene glycol, reverse-osmosis water, glycerin, flavorings, and nicotine. 
The research staff will distribute the e-liquid containers as purchased from the manufacturer. 
The Vuse apparatus and e-liquid cartridges that will be used are legally purchasable and have 
been as of August 8, 2016. We will not alter them in any way. 
 
3.7. Summary 
Although smoking rates have declined in the overall US population, there has been little to no 
decline among people with ADs. A nicotine reduction strategy for combustible tobacco combined 
with e-cigarette availability may have complementary effects on smoking reductions and 
consequent tobacco-related health effects in this vulnerable population. This research is highly 
significant because it will model how the availability of e-cigs, a non-combusted nicotine product 
that is rapidly increasing in use among US smokers, impacts the effectiveness of a reduced- 
nicotine policy for cigarettes in this vulnerable population. It is responsive to the goals of the FDA 
in that the study conditions are designed to model real-world scenarios of possible harm reduction 
policies in a population that is vulnerable to smoking persistence. 
 
 
 
4. Project Study Methods 
 
This study will use a four-condition, parallel-groups research design. After a baseline period 
in which daily smoking rate and other baseline assessments are completed, participants will be 
randomly assigned to one of the following four conditions for a 16-week experimental period: (1) 
normal nicotine content cigarettes (NNCCs, 15.8 mg/g) alone, which serves as the control 
condition; (2) very low nicotine content cigarettes (VLNCCs, 0.4 mg/g) alone; (3) VLNCCs + 
tobacco-flavored nicotinized e-cigs (TF e-cig, 4.8 - 5.0% nicotine by weight, NBW, if they 
choose to use the Vuse or JULL devise, respectively); or (4) VLNCCs + preferred-flavor 
nicotinized e-cigarette (PF e-cig). 
 
 
 
5. Study Screening Procedures 
 
5.1. Participants 
Participants will be men and women, ages 21 – 70 years, with a current diagnosis of an 
affective disorder, defined as a major depressive disorder, dysthymic disorder, generalized 
anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, or panic disorder 
with or without agoraphobia based on the Mini Neuropsychiatric Interview (MINI) which uses 
DSM-5 criteria, OR Lifetime diagnosis of one of the above based on MINI with a self-report of 
currently receiving treatment for one of these disorders prescribed psychoactive medication, 
behavioral therapy, etc.). Additionally, they must be sufficiently literate to complete the research 
tasks, be in good physical health without serious illness or change in health in past three months, 
and have the technological capabilities to complete weekly face-to-face video assessments and 
the compatibility to use ico Smartphone Smokerlyzers for assessing breath carbon monoxide 
(CO) levels. Study inclusion and exclusion criteria are detailed below. 
5.2. Recruitment 
Using an intent-to-treat analysis approach, we require 53 randomized per condition (212 total) to 
test our primary aims. We estimate 10% attrition between enrollment and randomization based on 
UVM TCORS Phase 1 research, and will therefore enroll up to 59 per condition (236 total). In 
addition, we will pilot test with up to 20 participants (10/site) for a total of 256 participants (90 at 
Brown, 166 at UVM). Potential participants will respond to community advertisements (local 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
13 
 
 
newspapers, community bulletin boards, lab Facebook page, Facebook ads, lab website, center 
website, behavioral health centers, Craigslist, city buses, etc.) that contain a study description, 
link to an online survey and the name and phone number of the Research Assistant. Participants 
can choose to complete the pre-screening questionnaire online or by phone. At UVM, individuals 
recruited from online sources will be directed to a UVM-hosted recruitment website where they 
will have the opportunity to select which research studies interest them. They will then be 
redirected to a brief online screener to assess eligibility. The Patient Health Questionnaire-488 
will be used to screen for probable mood or anxiety disorder. This 4-item instrument, which 
comprises the first 2 items of the Patient Health Questionnaire 9-item(PHQ-9) scale89 and the first 
2 items of the Generalized Anxiety Disorder 7-item (GAD-7) scale90 measures the two core DSM- 
IV criteria for major depressive disorder and generalized anxiety disorder, respectively. The 
PHQ–4 begins with the stem question: “Over the last 2 weeks, how often have you been bothered 
by the following problems?” and each item is scored from 0 (“not at all”), 1 (“several days”), 2 
(“more than half the days”), or 3 (“nearly every day”). Therefore, the total score on this composite 
measure ranges from 0 to 12. A total score of 3 for the 2 anxiety items or the 2 depression items, 
plus questions querying past treatment for depression or anxiety, will be used to identify probable 
cases. If deemed eligible, those who complete the online questionnaire will be called by the 
Research Assistant to further discuss the study. The RA will read a script briefly explaining the 
study. Participants will be informed that this is not a smoking cessation program, and that smoking 
cessation services are available in the community independent of their decision to participate in 
this study. If interested, they will be invited to participate in the first portion of the screening 
interview. Research assistants will inform eligible participants that the screening will occur over 
video chat, and will assist the participant with setting up an appropriately secure video 
platform.Those who call into the laboratory will be read a script briefly explaining the study. After 
verbal informed consent is received, the participants will be asked questions over the phone to 
determine initial eligibility. 
During this first portion of the screening, the participant will complete questionnaires through 
REDCap online while the research assistant is present over video chat or phone to deliver 
instructions and to answer any questions. The participant will then answer interviewer-administered 
questionnaires over video chat. Participants who did not yet set up their video platforms will do so 
with the research assistant before beginning any questionnaires. Participants will be instructed to 
have picture identification (e.g. driver’s license) available to show the staff. If participants anticipate 
not having acceptable ID, staff should consult with the project coordinator or study PI. Initial study 
eligibility will be determined after data are collected from this visit. Participants who meet initial 
study eligibility will be scheduled for the second portion of the screening. 
Before the second portion of the screening occurs, eligible participants will receive the 
equipment necessary to use for collecting physiological measurements. Participants will be asked 
to pick up this equipment via curbside pickup at our clinic (UVM University Health Center, UHC), 
which will consist of participants calling staff once they arrive at UHC and staff coming out to give 
participants a bag/box containing the following equipment: a Smokerlyzer; an audio jack adapter 
for the Smokerlyzer if necessary; a blood pressure cuff; an oximeter; a thermometer; a urinary 
cotinine dipstick; urine cups with attached temperature test strips; a pregnancy test strip (if 
applicable) and urine toxicology test strips or a saliva toxicology test. Participants (and staff) will 
be asked to use cloth face coverings when exchanging product. If participants arrive via car, staff 
will drop this bag on the hood of the participant’s car while the participant remains in the car 
Participants may be invited to come inside to pick up this equipment if the participant is asked to 
wait for this exchange. All participants must pass a COVID19 screening before entering the building. 
If there is any waiting that needs to occur inside the building, the participant will wait inside one of 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
14 
 
 
our five highly ventilated smoking chambers. If there happens to be no space in the smoking 
chambers, the participant will be told that they cannot come up to the clinic until space is available. 
After each use, the all of the surfaces in the smoking chambers will be cleaned with 70% or greater 
of alcohol solution by staff wearing a mask and gloves, as well as all of the door handles. If the 
participant uses the bathroom while they are in the clinic, the bathroom surfaces and handles will 
be wiped down after use by staff while masks and gloves are worn. Participants who are using the 
smoking chambers at any point in the study to wait for product or equipment exchange will remain 
in the chambers until a staff member comes to knock on the door to let them out. In this way, we 
can avoid people coming into close contact with each other in the larger room that contains the 
smoking chambers. A minimum of 6 feet of distance will be maintained for all staff and participants 
at all times. For participants who come to the clinic, a commercial courier will deliver this equipment 
to them before the second portion of the screening. 
If at any point the Smokerlyzers are not available for distribution, we will conduct the CO test 
curbside before or after participants are invited inside and the courier service will not be available. 
Research Assistants will bring down the CO monitor when they bring the rest of the equipment to 
the participant. While maintaining 10 feet of distance and wearing gloves, staff will explain how the 
CO monitor works. Once the participant is ready, staff will press the button to obtain the 
measurement and will set the CO monitor down and will back away 10 feet. The participant will then 
come to pick up the device and will blow into the monitor. After the participant completes the test, 
they will set down the monitor and back up 10 feet and staff will retrieve the monitor. After every use, 
staff will wipe down the CO monitor with disinfectant wipes and hydrogen peroxide wipes. When 
using the monitor, a D-piece (a portable valve filter) must be placed into the monitor and then the 
single use plastic mouthpiece is placed into the D-piece. The monitor has built in SteriTouch 
technology to ensure optimum infection control, and the D-pieces filter out 99.9% of airborne bacteria 
and greater than 97% of viruses for excellent infection control. Each participant will be assigned their 
own D-piece to use throughout the study, and no D-piece will ever be shared among participants. 
Participants will gently exhale into the D-piece for the breath carbon monoxide reading. Participants 
will be instructed only to exhale through the device, not to inhale..D-piece technology also includes 
a one-way valve that prevents air from being drawn back from the monitor. D-pieces will also be 
wiped down after each use with disinfectant wipes and hydrogen peroxide wipes and stored in a 
container at the lab. 
Once participants have received the necessary equipment to complete the physiological 
portion of the screening, the research assistant will initiate a video call with the participant. During 
this call, the participant will be instructed on how to use the equipment and then will be asked to 
use the equipment to obtain the following physiological readings: blood pressure, heart rate, 
oxygen saturation, temperature, and breath CO levels. Participants will also be asked to collect 
a urine or saliva sample during the visit. If a saliva sample is collected, the participant you will 
provide the saliva sample over video chat while the staff observes. If a urine sample is collected, 
staff will ask participant to bring this urine sample to the video screen after collection to perform 
a urine toxicology test and a pregnancy test (if applicable). These urine cups will have 
temperature strips affixed to ensure that the sample is valid. Participants who have a carbon 
monoxide level of less than or equal to 8 will also be asked to use the urinary cotinine dipstick to 
determine whether they are positive for cotinine. The participant will obtain the physiological 
readings and perform the tests and then will hold the results of the test up to the camera so that 
the research assistant can interpret and record the readings on REDCap, Potential participants 
will also be instructed to have handy a pack of their usual brand cigarettes, all prescription 
medications they are currently taking and identification (example, driver’s license) during this 
second portion of screening visit. If participants anticipate not having acceptable ID site staff 
should consult with the project coordinator or study PI. 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
15 
 
 
A participant must complete his/her two-part screening session within 30 days of completing 
the pre-screening questionnaire. If the participant is not able to complete the two-part screening 
visit in that timeframe, he/she will need to complete the pre-screening questionnaire again. 
 
5.3. Informed Consent Process: 
Before beginning the informed consent process, potential participants will need to produce 
identification as described above. The interviewer will confirm the age and identity of the 
participant. If the participant is not between the ages of 21 and 70, he/she will be dismissed 
without payment. During the first portion of the screening session, study information will be 
presented and documentation of the participant’s informed consent via electronic signature on 
REDCap will be required prior to participating in the screening session. In order to ensure 
adequate informed consent, participants will be asked to read the first several lines aloud (to 
determine literacy) and will then be given ample time to read the consent document. If the 
interviewer suspects the participant is not literate, he or she will have them continue reading 
further to confirm. Inability to read and comprehend written study materials will result in ineligibility 
and the interviewer will inform the participant that they are not eligible. Only after the participant 
and the researcher are fully satisfied that the participant understands the purpose of the study, 
the confidentiality of the data, the procedures, the risks/benefits and his/her rights as a research 
participant will the consent form be signed and the participant undergo screening procedures. 
 
5.4. Screening Measures 
Those who consent will be screened for eligibility using the following measures: 
The following physiological measures will be collected and entered directly into REDCap 
by the interviewer: 
 
1) Expired breath carbon monoxide (CO) levels will be assessed using an ico Smokerlyzer 
Smartphone Monitor (Covita -for remote collection) or a Bedfont CO monitor (for curbside 
collection), a reliable and valid measure of recent smoking. 
a. Urinary cotinine test strips will be used to asses cotinine levels if a participant's 
carbon monoxide reading is less than or equal to 8 ppm. 
2) A urine or saliva toxicological screen will be performed to assess the presence of illicit 
drugs including up to the following drugs: marijuana, cocaine, opiates, oxycodone, 
benzodiazepines, 
barbiturates, 
amphetamines, 
methadone, 
buprenorphine, 
methamphetamines, MDMA and PCP. Participants who fail the drug screen for drugs 
other than marijuana or their prescribed opioid medication may reschedule the interview 
but will need to be re-consented to ensure they have received adequate informed consent. 
They will be excluded if they are positive for drugs (other than marijuana or prescribed 
medications as determined by PI on a case-by-case basis) the second time. 
3) Urine Pregnancy Test (HCG detection) will be performed for all participants. 
4) Blood pressure and heart rate will be measured using an automated blood pressure 
monitor and a finger pulse oximeter to help the licensed medical professional determine 
final participant eligibility. Participants will be told if their blood pressure is in an abnormal 
range and advised to see a doctor by research staff. The research staff will also submit a 
medical event form for the LMP to review along with a Blood Pressure and Heart Rate 
Symptom Checklist form to ascertain details of the symptomatology for the LMP to review. 
In severe cases, the LMP may also choose to call the participant to follow-up and/or 
withdraw the participant from the study if necessary. All of these procedures are 
documented in our Blood Pressure/Heart Rate Collection: Standard Operating Procedure 
form which we can submit to the IRB if the Committee deems necessary. 
5) Body temperature, respiratory rate and oxygen saturation will be added as physiological  
measures based on the CDC recommendations and those of Dr. David Kaminsky.  

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
16 
 
 
https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung- 
disease/healthcare-providers/index.html 
 
 
The following screening assessment will be administered on paper as an interview: 
1) The Mini International Neuropsychiatric Interview (MINI) 7.070 
 
The following screening assessments will be administered as an interview and then will be entered directly into 
REDCap by the interviewer: 
1) The MINI Plus Modules 
2) The MINI suicide subscale94 to evaluate suicide risk. 
3) MINI Follow-up Questionnaire (if applicable) 
4) Tobacco Use History and Exposure Questionnaire, which measures variables such as 
smoking amount, cigarette brand, age of initiation of smoking, number of quit attempts, 
duration of quit attempts and duration of smoking. 
5) Smoking Cessation Therapy Use Questionnaire 
6) Time Since Last Cigarette Questionnaire 
7) Medical History Questionnaire to assess current diagnoses, symptoms and past health 
problems. 
a. Medications will be recorded directly onto the Concomitant Medications form in REDCap. 
8) Drug Abuse Screening Test (DAST-10), which assesses quantity and frequency of 
alcohol and drug use (12 month and 1 month version) 
 
The following screening assessments will be completed by the participant directly in 
REDCap, except where noted otherwise: 
1) Demographic History Questionnaire, which will assess age, gender, ethnicity, race, 
education, income, marital status, and employment history. 
2) Alcohol Use Questionnaire---based on the Alcohol Use Disorders Identification Test95 (12 
month and 1 month version) 
3) Drug Use Questionnaire---based on the Drug Abuse Screening Test96 (12 month and 1 
month version) 
4) Fagerström Test for Nicotine Dependence (FTND)97; 
5) Wisconsin Inventory of Smoking Dependence Motives-Brief Scale (WISDM)97 will be 
administered to assess nicotine dependence severity. 
6) Penn State Electronic Cigarette Dependence Index99; 
7) Smoking Stages of Change Algorithm100; 
8) Identifying Information Form will include the participant’s REDCap Subject Identifier, 
name, address (including the county of residence), email address, phone number, age, 
date of birth, and social security number (if applicable). 
a. This form will be entered into the ‘Identifying Information Access Database’. 
• Each site will have a separate ‘Identifying Information Access Database’. 
• Identifying information will not be shared with other sites. Each site is 
responsible for maintaining confidentiality of this information. 
• 
Identifying information will be kept in a locked file cabinet (source 
document) and in a password protected Access Database (electronic 
version) separate from all other study data. 
9) Beck Depression Inventory (BDI-II)91, to assess depressive symptoms. 
(This form has been updated on 1.29.20 so as to use the BDI-II. The BDI-II will be used instead of the BDI so that the data  
collected will be directly comparable to other projects using the BDI-II). 
10) Overall Anxiety Severity and Impairment Scale92(OASIS); to assess frequency and 
severity of anxiety symptoms. 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
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11) COVID19 Symptom Questionnaire 
12) Respiratory Symptom Questionnaire will be administered to assess respiratory health 
 
In the event that the REDCap website is not functioning, the assessments will be administered 
aloud and participant answers will be recorded securely. The interviewer will enter the data into 
REDCap when it resumes functioning properly. This information should be recorded in the ‘End of 
Visit Evaluation Form’. 
5.5. Suicidality/Mental Health Monitoring 
Participants who endorse suicidal intention in the past month or a suicide attempt in the past 
6 months as indicated on the BDI (score > 1 on question 9) or MINI suicide subscale (endorse 
question 4 and/or 5 on the MINI suicide subscale or question 6 on the MINI suicide subscale 
with suicide attempt in the past 6 months) or answer “yes” to question A3g on the MINI 
Neuropsychiatric interview and symptoms have occurred in the past two weeks will be 
assessed by a clinician for eligibility and possible intervention. The research staff member will 
contact a licensed clinician for evaluation. In the event that no clinician is available, staff will 
put the participant in contact with the National Suicide Prevention Lifeline at 1-800-273- 
8255. They will also contact the Study Coordinator and Site PI to inform them of the situation 
as soon as possible. Additionally, they will contact the Project Coordinator to inform her of the 
situation. The participant will be paid $25 (+$25 bonus if applicable) and provided with local 
mental health resources. Post enrollment, any report of suicidal ideation or attempt by a 
participant will be grounds for immediate withdrawal from the study. 
5.6 Inclusion/Exclusion Criteria 
Inclusion Criteria: 
 
1) Men and women ages 21-70, 
2) Past-year: MDD, dysthymic disorder, generalized anxiety disorder, post-traumatic stress 
disorder, obsessive-compulsive disorder, or panic disorder with or without agoraphobia, 
based on MINI structured interview, OR Lifetime diagnosis of one of the above based on 
MINI with a self-report of currently receiving treatment (prescribed psychoactive 
medication, behavioral therapy, etc.), 
3) Report smoking ≥ 5 cigarettes per day for the past year, 
4) Provide an intake breath CO sample >8 ppm, (if ≤ 8 ppm, then urinary-cotinine strip must 
be positive) 
5) Be without current substance abuse/dependence other than nicotine, 
6) Be sufficiently literate to complete the research-related tasks, 
7) Be in good physical health without serious illness or change in health in the past three 
months as determined by the licensed medical professional at each site, 
8) Have appropriate equipment to complete face-to-face video assessments and use ico 
Smartphone Smokerlyzer Monitors. For those who do not have a Smartphone, staff will 
explore potential alternate plans (e.g., project-provided inexpensive Android phone) 
 
Exclusion Criteria: 
 
1) Exclusive use of roll-your-own cigarettes, 
2) Planning to quit smoking in the next 30 days, 
3) A quit attempt in the past 30 days resulting in greater than 3 days of abstinence, 
4) Significant use of other tobacco or nicotine products within the past month (more than 9 
days in the past 30). 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
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5) Positive toxicology screen for any of the following drugs: cocaine, opiates, methadone, 
oxycodone, 
buprenorphine, 
benzodiazepines, 
barbiturates, 
amphetamines, 
methamphetamines, MDMA and PCP 
a. Marijuana will be tested for but will not be an exclusionary criterion. Participants 
will be discouraged from smoking marijuana during the study. 
b. Participants with valid prescriptions for opiates, benzodiazepines, barbiturates, or 
amphetamines will not necessarily be excluded. 
c. Participants failing the toxicology screen will be allowed to re-screen once. These 
participants will need to be re-consented before being rescreened to ensure they 
have received adequate informed consent. 
6) Self-report of binge drinking alcohol (more than 9 days in the past 30 days, 4/5 drinks in a 
2 hour period in females/males), 
7) Systolic blood pressure < 90 or ≥ 160 mmHg 
a. Participants failing for blood pressure will be allowed to re-screen once. 
8) Diastolic blood pressure < 50 or ≥ 100 mmHg 
a. Participants failing for blood pressure will be allowed to re-screen once. 
9) Breath CO > 80 ppm, 
10) Heart rate is greater than or equal to 115 bpm or less than 45 bpm 
a. Participants failing for heart rate will be allowed to re-screen once. 
11) Currently seeking treatment for smoking cessation, 
12) Being pregnant, trying to become pregnant, or nursing, or not report using a form of 
approved birth control if applicable determined by the Project Medical Director 
13) Have used nicotine replacement, bupropion or other pharmacotherapies as cessation aids 
in the past month (bupropion will be allowed for treatment of depression), 
14) Unstable psychiatric conditions (psychiatric medication changes in the past 4 weeks), 
15) Symptoms of psychosis, dementia or mania, 
16) Suicidal ideation in the past month (score > 1 on the BDI question 9 or endorse question 
4 and/or 5 on the MINI suicide subscale), 
17) Reporting a plan or attempt to commit suicide, which is assessed on question A3g of the MINI
Neuropsychiatric Interview Major Depressive Episode Module. Thoughts of suicide without an intent or
plan is not an exclusion criteria, 
18) Suicide attempt in the past 6 months (endorse question 6 on the MINI suicide subscale 
with suicide attempt in the past 6 months), 
19) Participation in another research study in the past 30 days, 
20) Co- habitation with any research participant who has or is participating in the current 
study, 
21) Daily use of e-cigarettes in the past month (defined as 6 – 7 days per week)._ 
22) Oxygen saturation of < 90% 
23) Reporting positive symptoms for COVID19 
 
Individuals under age 21 are excluded because they cannot legally buy cigarettes. Those with 
unstable medical, psychiatric, or medication conditions (as determined by the licensed medical 
professional) are excluded as these symptoms could affect a participant’s ability to complete the 
study. Examples include but are not limited to the following: angina, stroke, heart attack which 
occurred since phone screening, blood clots in the arms or legs for which the individual is 
undergoing active medical treatment, cancer requiring active chemotherapy or radiation therapy, 
severe shortness of breath caused by conditions such as uncontrolled asthma, COPD, or 
arrhythmia, active untreated infection such as pneumonia, active untreated endocrine disorder 
such as hyperthyroidism. We will exclude those currently seeking smoking treatment and those 
who plan to quit in the next 30 days, as participation in this study may not lead to reductions in 
smoking. We will exclude pregnant or nursing women and women of reproductive potential who 
are unwilling to use acceptable forms of birth control throughout the study if applicable determined 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
19 
 
 
by the Project Medical Director. We will also exclude anyone with current or recent alcohol or drug 
abuse problems as these factors could independently affect smoking behavior during the study. 
Individuals with baseline CO readings greater than 80 ppm, those with heart rate or blood 
pressure readings that are out of range (systolic: 90-159 mmHg; diastolic: 50-99 mmHg; HR: 45- 
114 bpm) and anyone who has attempted suicide in the past six months will be excluded from the 
study for safety concerns. Individuals who smoke ‘roll your own’ cigarettes exclusively will be 
excluded from the study because we will be unable to standardize their baseline smoking 
behavior. Individuals who have reported daily use of e-cigarettes in the past 30 days will be 
excluded as they may not be compliant with experimenter-provided e-cigarettes. Individuals who 
have recently participated in a research study will be excluded as participation may have changed 
their smoking patterns, which may preclude a stable smoking baseline. Because participants are 
required to complete portions of the protocol independently, they will need to be able to 
independently read and comprehend the study materials. 
 
5.7. Eligibility Determination: 
The research assistant will review the entire screening assessment battery for initial eligibility 
determination, confirming the participant meets the above described inclusion/exclusion criteria. 
All eligibility criteria that are not related to physiological measurements will be assessed during 
the first portion of the screening visit, and all criteria related to physiological measurements will 
be determined during the second portion of the screening. The final eligibility of the participant 
will be determined by a licensed medical professional (MD,DO, NP, PA, Master’s prepared RN 
or CRN) at each site after reviewing the Medical History Questionnaire, BDI, Mini Neuropsychiatric 
Interview, and the MINI suicide subscale. The licensed medical professional may meet with a 
participant if available and think it necessary for eligibility determination. He/she will sign off on 
eligibility prior to the first baseline visit. If the licensed medical professional determines the 
participant is not medically eligible to participate in the study, has current symptomatology that 
would interfere with interpretation of the data, or is unlikely to complete the study he/she will inform 
the research assistants who will contact the participant prior to the first baseline visit. The licensed 
medical professional will not need to review the medical history forms of participants who are 
ineligible for other, non-medical reasons. 
If a participant fails the urine or saliva toxicology screen due to a prescription medication 
he/she is taking, then he/she will not be automatically excluded. The interviewer will make note of 
this when he/she submits the forms to the licensed medical professional for final eligibility 
determination. 
Once all the screening procedures have been completed, researchers will pay participants 
$25 (+$25 bonus if applicable) for their time as long as they pass the drug tests and meet the 
minimum requirements for carbon monoxide or urinary cotinine levels. Participants will be paid 
after the completion of the study visit. If participants are deemed ineligible at any point in the 
screening, the participant will be paid after determined ineligible. Marijuana will be tested for but 
will not be an exclusionary criterion. If a participant does not pass the drug test but has a current, 
valid prescription that would explain the failed test he/she will not be automatically excluded and 
will still receive the visit payment. Participants who meet all other eligibility criteria, sans the 
medical criteria, will be scheduled for the first baseline visit. 
At the end of the screening session, the researcher will complete the End of Visit Evaluation 
Form. This will allow the researcher to make note of any problems encountered during the visit 
and to assess the truthfulness of the participant in regards to self-report of tobacco use. 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
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6. Study Baseline Procedures 
 
 
This study will use a one-week, two-session baseline period to collect baseline individual 
difference measures and monitor daily usual-brand smoking behavior. At Baseline 1 or within 1 
business day of the Baseline 1 visit, participants will be provided their usual brand cigarettes to 
smoke, equivalent to 150% of their daily smoking rate. Participants will be encouraged to come to 
the lab to pick up their usual brand cigarettes in a curbside exchange after they complete the 
questionnaires and physio for the BL1 visit. Those who cannot come to the lab will receive product 
via a commercial courier. A time line follow back (TLFB) will be used during the period between 
Baseline 1 and Baseline 2 to assess the daily cigarette use for the first 7 days the participant has 
product. The participant must have received their UB cigarettes from the lab before the 7-day 
assessment period starts, and Baseline 2 must occur at least 7 days after the participant receives 
their usual brand cigarettes from the lab. If the baseline period extends past seven days and if the 
participant has run out of product, participants will need to purchase their own usual brand cigarettes. 
Use of a two session baseline period will ensure stability of daily smoking reports, reduce reactivity 
to the daily cigarette monitoring, and reduce participant burden. During the two baseline sessions, 
participants will complete subjective questionnaires. Each visit will last approximately two to four 
hours. At the end of each baseline session, the researcher will complete the End of Visit Evaluation 
Form,. This will allow the researcher to make note of any problems encountered during the visit and 
to assess the truthfulness of the participant in regards to self-report of tobacco use. Participants will 
also be supplied with saliva test equipment and urine collection equipment during the Baseline 1 
product exchange so that they can collect saliva and first void urine samples during the Baseline 2 
visit. 
For the Baseline 1 visit and all subsequent visits, the participant will be sent a REDCap link 
within 15 minutes of the start of the scheduled visit to complete all of the non-interviewer 
administered questionnaires. The participant will complete these questionnaires on their own but can 
have the research assistant present on a video call if they desire. Before beginning the physiological 
assessment portion of the visit over video call, the research assistant must review the participant’s 
questionnaire responses for that visit. Participants will be compensated after the completion of the 
study visit and when the participant has received their new product. 
At Baseline 2 and all subsequent visits, after the participant has answered the questionnaires and 
has completed the physiological portion of the visit over video call, participants will be asked to 
come to the lab for exchange of product and biological samples. Participants will bring in their used 
and unused product from the previous visit as well as a first-void urine sample for assessing tobacco- 
related toxin exposure and a salivary sample for assessing nicotine metabolism rate on applicable 
visits (BL2, Week 8 and Week 16) using equipment that was provided at the previous visit. 
Participants will be instructed to call the RA at the office when they get to the clinic to ensure that 
there is enough space in the smoking chambers to house all participants while abiding by safety 
guidelines as detailed on page 14 of the protocol. All participants must pass a COVID19 screening 
before entering the building. When invited into the lab, the participant will be shown to a smoking 
chamber and will instructed to place their bag of product outside of the chamber. The participant 
will wait here while the RA processes and returns product through the randomization database. Then 
the RA will dispense new product and bring the bag back to the participant. When the RA deems it 
safe for the participant to exit the chamber, the RA will instruct the participant that they can leave. 
The RA will instruct the participant to observe social distancing measures during this exchange, 
providing clarification if necessary. If a participant forgets their first-void urine sample at the 
Baseline 2 visit, staff will ask participant to come back to the clinic with their first void urine sample 
before exchange of product occurs. If participant is unable to return to the clinic with their first void 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
21 
 
 
sample, staff can arrange to meet the participant off campus to pick up their urine sample and to give 
participant their study product. Distancing and safety measures as described above must be observed. 
For participants who cannot make it to UHC, special arrangements will be made to enable use of the 
randomization database and product return/distribution procedures to the extent possible. Each 
week, during - or scheduled as nearly as possible to – a virtual visit, a complete accounting of the 
participant’s product inventory will be taken and processed remotely through the randomization 
database. The participant will separate product based on its type (e-cigarette or combustible 
inventory) and status (used/unused), and the RA will process return characteristics through the 
database accordingly. The RA will clarify barcode characteristics with the participant when legibility 
is compromised. The participant will be instructed to keep unused product in their possession, but 
to exchange any used product with the courier who will deliver newly dispensed replacement 
products within 48 hours. 
Product that will be given to participants for the Baseline 2 visit cannot be given/sent to 
participants until 7 days have passed following completion of the Baseline 1 visit. We will need to 
calculate baseline smoking rate during this 7-day period and so participants cannot have access to 
any blinded study product or e-cigarettes before this 7-day period has ended. 
 
6.1. Visit scheduling requirements for baseline period: 
Participants will be required to schedule the Baseline 1 visit within 30 days of the completion 
of their screening visit. If a participant still wants to be in the study after 30 days, he/she will need 
to be re-screened. The participant will need to be re-consented but will maintain the original 
REDCap Subject Identifier. The ideal target window separating Baseline 1 and Baseline 2 is 
between 7 and 12 days. The minimum is 7 days and the maximum is 21 days. If the participant 
does not complete the visit within 21 days, then he/she will not be rescheduled and will be 
discontinued from the study. 
6.2. Measures/Assessments 
 
The following physiological measures will be collected and recorded directly into REDCap 
by the interviewer: 
1) CO 
2) Blood Pressure 
3) Heart Rate 
4) Body temperature 
5) Oxygen saturation 
6) Respiratory rate 
7) Urine or Saliva Toxicology 
8) Urine Pregnancy test (if applicable, to be performed every 2 weeks) 
 
The following assessments will be administered as an interview at Baseline 1 and 
entered directly into REDCap by the interviewer at the end of the visit: 
1) Concomitant Medications Form 
2) Health Changes Questionnaire, which will assess any weekly health changes, 
3) Time Since Last Cigarette Questionnaire 
 
The following assessments will be administered at Baseline 1 and completed by the 
participant directly in REDCap: 

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1) BDI 
2) OASIS 
3) Respiratory Symptom Questionnaire 
4) COVID19 Symptom Questionnaire 
5) Wisconsin Inventory of Smoking Dependence Motives-Brief Scale (WISDM) will be 
administered to assess nicotine dependence severity. 
6) Perceived Health Risks Rating101, a measure of the perceived addictive potential and other 
health risks associated with cigarettes; 
7) Perceived Stress Scale (PSS)101, assessing the degree to which life situations are 
perceived as stressful; 
8) Positive and Negative Affect Scales (PANAS)102, a measure of changes in positive and 
negative mood; 
9) Respiratory Health Questionnaire, a UVM measure of cough, shortness of breath and 
other respiratory symptoms; 
10) Minnesota Nicotine Withdrawal Scale (MNWS)103, a measure of nicotine withdrawal; 
11) Questionnaire of Smoking Urges-brief scale - Usual Cigarette (QSU)104, which measures 
the urge to smoke; 
12) Vaping Craving Questionnaire105, which measures the urge to vape; 
13) Cigarette Evaluation Scale – Usual Cigarette (CES)106, which measures responses to 
cigarettes (e.g., reward, satisfaction); 
14) Vaping Evaluation Scale (VES), which measures responses to taping (e.g. reward, satisfaction) 
15) Cigarette Purchase Task – Usual Brand Version (CPT)107, a self-report analogue of a 
progressive-ratio schedule that measures the relative reinforcing efficacy of cigarettes by 
querying how many of that day’s cigarette they would consume in a day at varying prices. 
This task will indicate whether prolonged VLNC cigarette use reduces cigarette demand 
and increases sensitivity to increases in cigarette costs; 
16) Snaith-Hamilton Pleasure Scale (SHAPS)110. 
 
All participants will also be asked to select their top three flavors of e-cigarette liquid from a list read to 
them by the RA. This question will be asked in preparation for giving flavored pods to participants who 
are randomized into the flavored e-cigarette condition. This information will be recorded directly into 
REDCap. Participants will be asked to rate these top three flavors based on either previous experience 
with these flavors or to indicate how much they believe that they will like or dislike the flavors. 
 
Physiological measures collected at Baseline 2 will be entered directly into REDCap by 
the interviewer: 
 
1) CO 
2) Blood Pressure 
3) Heart Rate 
4) Body temperature 
5) Oxygen saturation 
6) Respiratory rate 
7) Urine or Saliva Toxicology 
8) Urine Pregnancy (if applicable; to be performed every two weeks) 
The following assessments will be administered as an interview at Baseline 2 and then 
entered directly into REDCap by the interviewer: 
1) Concomitant Medications Form 

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2) Health Changes Questionnaire 
3) Time Since Last Cigarette Questionnaire 
 
The following assessments will be administered at Baseline 2 and completed by the 
participant directly in REDCap: 
1) BDI 
2) OASIS 
3) COVID19 Symptom Questionnaire 
4) Respiratory Symptom Questionnaire 
5) MNWS 
6) WISDM 
7) PANAS 
8) QSU (usual brand) 
9) Vaping Craving Questionnaire 
10) CES (usual brand) 
11) Vaping Evaluation Scale 
12) CPT (usual brand) 
13) Snaith-Hamilton Pleasure Scale (SHAPS) 
14) E-Cigarette flavor rating questionnaire 
a. Participants will rate only the flavors that they received from staff for this visit 
 
In the event that the REDCap website is not functioning, the assessments will be administered 
aloud and participant answers will be recorded securely. The interviewer will enter the data into 
REDCap when it resumes functioning properly. This information should be recorded in the ‘End of 
Visit Evaluation Form’. 
1)  for each picture as they appear on the screen. 
 
 
6.3 E-cigarette Training Session (Baseline 2): 
Participants assigned to an e-cig condition will be told that they will be provided with a JUUL. 
If a participant indicates an unwillingness to use the JUUL device, the research assistants will 
offer the participant the Vuse Solo as alternative device. If the participants does not wish to 
use either device, he or she would be ineligible for the study. 
Participants in the e-cigarette conditions will be given e-cigarette pods BEFORE the training 
session occurs. These pods will be either picked up at the lab (preferred) or delivered to the 
participant 1 to 2 days before their Baseline 2 visit occurs. Participants randomized to the e- 
cigarette conditions will be notified before their Baseline 2 visit (but after the 7-day period 
following Baseline 1) and informed of their e-cigarette condition. Participants randomized to the 
flavored condition will be given pods of up to three flavors of their choice. Staff will calculate how 
many total pods participants will be given at this time based on their smoking rate, and 
participants will be able to choose the proportion of each flavor that they would like to receive. 
The e-cigarette training session will occur over video chat after the physiological 
measurements have been collected. The first 30 minutes of the training session will consist of 
the participant being taught how to use, charge, and replace pods/cartridges for their e- 
cigarette of choice. Participants will first try their JUUL using the tobacco flavor, and then 
decide which device they would like to use for the duration of the study. If desired, participants 
are able to choose a preferred device to use without testing both e-cigarettes. At this point, 
participants who are in the tobacco-only flavor condition will conclude their training session. 
For all visits following Baseline 2, participants in the preferred flavor condition are permitted 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
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to take up to three flavors home per week, but can choose to take less than three flavors if 
desired. Participants will take home their chosen pods or cartridges of up to three flavors until 
next visit. Participants will be able to change their flavors at only one point in the study if they 
desire. Participants will only be allowed to take home three flavors at one time. Participants will 
be given an E-cigarette instructional manual that reviews the e-cigarette training done at this 
visit. Participants will be encouraged to call with any device issues. 
 
6.4. Interactive Voice Response System: 
At the end of the first baseline visit, participants will be trained to use the Interactive Voice 
Response (IVR) System, which will contact participants each day throughout the study and ask 
about their smoking behavior as well as withdrawal symptoms the week before and after Baseline 
2. We will also review the IVR adherence incentive program, which consists of $1 per call plus a 
$10 bonus for seven consecutive calls. 
The IVR system is operated by TeleSage (https://telesage.com/about/). To be enrolled in the 
IVR system, research staff will enter the participant’s initials, telephone number, subject identifier, 
and visit dates into the IVR TCORS website. Identifying information (initials and telephone 
numbers) will not be extracted as part of the data by the bioinformatics group. Please refer to 
TeleSage’s privacy statement and HIPAA compliance form for additional information. 
 
Baseline 2 biological specimens: 
1) Urine sample for smoking biomarker assessment: 
Participants will be asked to provide a urine sample (first void of the day) at the second 
baseline session and to post-randomization weeks 8 and 16 for biomarker assessment. 
Biomarker analysis will provide nicotine and carcinogen exposure outcome measures and 
verify compliance with VLNC cigarettes. Samples will be stored at -80C. Urine samples 
will be analyzed for total nicotine (cotinine plus its glucuronide conjugate, a useful measure 
of daily nicotine exposure), the tobacco-specific nitrosamine 4-methylnitrosamineo-1-(3- 
pyridyl)-1-butanol (NNAL), and metabolites of 4 polycyclic aromatic hydrocarbons (PAHs), 
which are biomarkers of tobacco smoke carcinogens and decrease upon tobacco 
cessation or reduction. Anatabine is a minor alkaloid that is reduced in users of VLNC 
cigarettes and e-cigs. Therefore, anatabine levels in samples from those assigned to the 
VLNCC, VLNCC +TF e-cig and VLNCC+PF e-cig conditions should be lower than levels 
from those in the NNCC condition. These analyses will be performed by the Murphy lab 
at the University of Minnesota. 
2) Saliva Samples for smoking biomarker assessment: 
We will collect a saliva sample at the second baseline session and post-randomization 
weeks 8 and 16 for analysis of nicotine metabolite ratio (NMR; ratio of 3-hydroxycotininine 
[3 HC] to cotinine [COT]), a phenotypic marker of nicotine metabolic rate. Analyses of 
these samples will be performed by the Tyndale lab. 
 
Biomarker shipping and storage: 
Biomarkers will be shipped quarterly to the University of Vermont Laboratory for Clinical 
Biochemistry Research (Tracy Lab). The Tracy Lab will serve as a central repository for all 
biomarker specimens and will be responsible for distributing specimens to the appropriate labs 
on a quarterly basis. Urine samples will be analyzed and stored at the University of Minnesota 
Murphy Lab. The saliva samples will be analyzed and stored at the University of Toronto Tyndale 
Lab. 
 
 
 
7. Study Experimental Procedures 
 

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7.1. Experimental Period: 
Participants will be seen weekly throughout the 16-week experimental period. Weeks 4, 8, 12, 
16 and the abstinence visit will take approximately 2-4 hours each. All other sessions will last 
approximately 2 hours If a participant has a positive urine or saliva toxicology test or is visibly 
intoxicated as determined by slurred speech, swaying, or stumbling, the session will be 
rescheduled until a negative test result is obtained and intoxication is not present. As a part of 
each experimental visit, participants will be asked to come to UHC for a product exchange. All 
participants must pass a COVID19 screening before entering the building. Participants will be 
instructed to contact the RA at the office when they get to the clinic to ensure that there is enough 
space in the smoking chambers to house all participants while abiding by safety guidelines as 
detailed on page 14 of the protocol. All participants must pass a COVID19 screening before 
entering the building. When invited into the lab, the participant will be shown to a smoking 
chamber and will instructed to place their bag of product outside of the chamber. The participant 
will wait here while the RA processes and returns product through the randomization database. 
Then the RA will dispense new product and bring the bag back to the participant’s smoking 
chamber and leave it on the ground in front of the chamber. When the RA deems it safe for the 
participant to exit the chamber, the RA will instruct the participant that they can leave. The RA will 
instruct the participant to observe social distancing measures during this exchange, providing 
clarification if necessary. At the end of each experimental session, the researcher will complete 
the End of Visit Evaluation Form, which will be filed in the participant’s binder. This will allow the 
researcher to make note of any problems encountered during the visit and to assess the 
truthfulness of the participant in regards to self-report of tobacco use and compliance to study 
procedures. 
 
Visit scheduling requirements for experimental period: 
The ideal scheduling window between each visit is 7 days based on the date of the Baseline 
2 Visit. For additional scheduling requirements, refer to the ‘Scheduling Visits SOP’. If a participant 
misses a visit and is unable to reschedule during the window (± 3 days), that visit will not be 
‘made-up’ in the future. All measures that were not completed will be considered missing data 
and will not be collected during future visits. If a visit mistakenly occurs outside of the designated 
window, this is a protocol deviation. A ‘Non-Medical Event Form’ will need to be completed. 
Additionally, each visit should occur at approximately the same time of day ± 2 hours. 
If a participant is not able to attend his/her Week 16 visit, then it should be rescheduled even 
if it is outside of the scheduling window. This will be documented as a protocol deviation. 
7.2. Experimental Visits Weeks 1, 3, 5, 7, 9, 11, 13, and 15 Procedures 
7.2.A. Measures/Assessments 
Physiological Measures Collected and entered directly into REDCap by the interviewer: 
 
1) CO 
2) Blood Pressure 
3) Heart Rate 
4) Body temperature 
5) Oxygen saturation 
6) Respiratory rate 
7) Urine or Saliva Toxicology 
8) Urine Pregnancy test (if applicable, to be performed every 2 weeks) 
The following assessments will be administered as an interview and will be entered 
directly into REDCap by the interviewer: 
1) Concomitant Medications 

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2) Medical Event Form, if applicable 
3) Health Changes Questionnaire 
4) Time Since Last Cigarette Questionnaire 
 
The following assessments will be completed by the participant directly in REDCap: 
1) BDI 
2) OASIS 
3) COVID19 Symptom Questionnaire 
4) Respiratory Symptom Questionnaire 
5) MNWS 
6) Snaith-Hamilton Pleasure Scale (SHAPS) 
In the event that the REDCap website is not functioning, the assessments will be administered 
aloud and participant answers will be recorded securely. The interviewer will enter the data into 
REDCap when it resumes functioning properly. This information should be recorded in the ‘End of 
Visit Evaluation Form’. 
7.3. Experimental Visits Weeks 2, 4, 6, 8, 10, 12, 14, and 16 Procedures: 
7.3.A Measures/Assessments 
Physiological measures collected and entered directly into REDCap by interviewer: 
 
1) CO 
2) Blood Pressure 
3) Heart Rate 
4) Body temperature 
5) Oxygen saturation 
6) Respiratory rate 
7) Urine or Saliva Toxicology 
8) Urine Pregnancy test (if applicable) 
 
The following assessments will be administered as an interview and will be entered into 
REDCap by the interviewer at the end of the visit: 
1) Concomitant Medications 
2) Medical Event Form, if applicable 
3) Health Changes Questionnaire 
4) Time Since Last Cigarette Questionnaire 
 
The following assessments will be completed by the participant directly in REDCap: 
1) BDI 
2) OASIS 
3) COVID19 Symptom Questionnaire 
4) Respiratory Symptom Questionnaire 
5) MNWS 
6) QSU (usual brand) 
7) QSU (study cigarette) 
8) Vaping Craving Questionnaire 
9) CES (usual brand) 
10) CES (study cigarette) 
11) Vaping Evaluation Scale 

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12)  PANAS 
13) Cigarette Purchase Task - Usual Brand Cigarette Version (weeks 4, 8, 12 and 16 only) 
14) Cigarette Purchase Task – Study Cigarette Version (weeks 4, 8, 12 and 16 only) 
15) Cross-price Elasticity Task109- e-cigarettes and combustible cigarettes (weeks 4, 8, 12 
and 16 only) (for e-cigarette experimental conditions only) 
16) Penn State Electronic Cigarette Dependence Index (weeks 8 and 16 only) 
17) Respiratory Health Questionnaire (weeks 8 and 16 only) 
18) FTND (weeks 8 and 16 only) 
19) Perceived Health Risks Questionnaire (weeks 8 and 16 only) 
20) Smoking Stages of Change Algorithm and Contemplation Ladder (weeks 8 and 16 only) 
21) WISDM – Brief Scale 
22) Snaith-Hamilton Pleasure Scale (SHAPS) 
23) Drug Use Questionnaire – 1 month version (weeks 8 and 16 only) 
24) Perceived Stress Scale (weeks 8 and 16 only) 
25) Alcohol Use Questionnaire – 1 month version (weeks 8 and 16 only) 
26) E-cigarette flavor rating questionnaire (weeks 4, 8, 12 and 16 only) 
 
In the event that the REDCap website is not functioning, the assessments will be administered 
aloud and participant answers will be recorded securely. The interviewer will enter the data into 
REDCap when it resumes functioning properly. This information should be recorded in the ‘End of 
Visit Evaluation Form’. 
 
Biological Samples to be collected: 
1) First void urine sample (Weeks 8 and 16 only) 
2) Saliva sample (Weeks 8 and 16 only) 
7.4. Interactive Voice Response System: 
Participants will continue to use the IVR system on a daily basis throughout the experimental 
period to record the number of study cigarettes smoked per day, measurement of e-cig use and 
use of non-study cigarettes or other tobacco products. Measurement of e-cig use will be collected 
by asking two questions: how many daily e-cigarette episodes occurred, where one episode 
consists of around 10-15 puffs or up to approximately 10 minutes, and what proportion of pods 
and/or cartridges were used per day. Participants will also be asked to log how many flavors of e- 
cigs they used per day. During the first week after Baseline 1, the IVR system will collect information 
about mood and withdrawal symptoms. 
7.5. Variable Incentive Program: 
An incentive program has been developed with the goal of improving attendance at 
scheduled assessment sessions, compliance with using only study-provided tobacco products, 
and encouraging honest self-reports regarding all nicotine/tobacco use. 
Briefly, participants will receive a total of seven tickets for each weekly visit they attend 
after randomization (Visits 03-18, weeks 1-16). In total, participants could earn 112 valid tickets 
across the 16 visits. Participants will be instructed that these tickets correspond to attendance 
(one ticket), honest reporting (one ticket), compliance in bringing back used and unused 
pods/cartridges (two tickets) and adherence to using only the assigned study product (three 
tickets). Participants who do not bring back all of their unused study product and used 
packaging will be told that they may not be eligible to earn the two compliance tickets. 
Participants will be further instructed that all of the tickets that they receive “could” be eligible for 
entry into a monthly drawing for prizes, but that only tickets that are “validated” will be eligible for 
prizes. 
Since it is prohibitively expensive to test urine samples each week for each participant 
and because it is currently not feasible to detect with reasonable precision non-compliance 

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based on biomarkers in the two higher nicotine group, we plan to only validate the attendance 
tickets. Hence, each participant who attends their regularly scheduled weekly session will have 
a total of seven validated tickets entered into the monthly drawing. 
To convey the message that we may be validating honest reporting and use of only 
study-provided products, a bogus pipeline of sorts, we will tell the participants that a composite 
assessment of the measures that we collect MAY be used to validate the amount of nicotine 
and tobacco products that they are using. So there is some minor deception involved, but 
technically we could conduct urine toxicology testing for both purposes. Hence, if the urine 
toxicology testing is presented as something that MAY be done for validation purposes, we feel 
that any deception is relatively minor. For scientific/economic reasons we are just electing to 
restrict validation to attendance. 
Nevertheless, we will debrief all participants upon the completion of the trial. We will inform 
them that the incentive program was based exclusively on attendance due to the relatively high 
cost of urine toxicology testing and other practical problems with shipping the urines for prompt 
testing. 
Drawings will be conducted on the 1st of each month. Validation will be performed by 
staff who have no participant interaction and are not blind to condition. Any ticket drawn will be 
eligible for an incentive as the only true contingency is for attendance. There will be no mention 
of the basis for earning incentives (i.e., whether the ticket was for attendance, honesty, 
adherence). Participants will simply be informed that he or she earned an incentive from the 
drawing. 
Each drawing will be independent (without replacement); consequently, some 
participants will not win a prize and others may win more than one during the study if more than 
one of their tickets is drawn. After confirming winners, the remaining tickets from each month 
will be discarded (i.e., tickets will only be entered into one drawing). The monthly prize amounts 
are detailed below. 
We estimate based on the 2 ½ years we think it will take to complete this study, that 
participants will win an average of approximately $65 in prizes or an additional $5.50 per week 
per participant. 
 
Grand Prize (1): $500 cash 
Second Prize (1): $200 cash 
Third Prize (5): $10 cash 
 
7.6. Product and Procedures Compliance Review Sessions: 
At each visit, Baseline 2 through Week 16, participants will be counseled about their use of 
the study cigarettes and assigned e-cigarette (if applicable). Participants will be asked about any 
concerns or obstacles associated with use of the study cigarettes and assigned e-cigarette (if 
applicable). The importance of honest self-reporting will be stressed. Participants will be told that 
they will not be penalized for use of other nicotine or tobacco products and that it is crucial for 
them to report any use of these products. If difficulties are encountered, participants will be asked 
why they think they are experiencing difficulties (e.g., taste, withdrawal symptoms) and to 
problem-solve how to deal with these difficulties in order to meet the protocol requirements. 
Additionally, participants will be counseled about their IVR completion, visit attendance, task 
engagement and product accountability. Refer to the ‘Product and Procedures Compliance 
Review Sessions SOP’ for more information. 
7.7. Quit Attempts During the Study Protocol: 
At each weekly session, we will ask each participant if s/he is currently abstaining from 
smoking with the intention of quitting and whether s/he is planning to quit smoking prior to 
his/her next scheduled visit. If a participant is currently abstaining from smoking with the 
intention to quit, we will encourage the participant to continue abstaining, schedule them for 

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weekly visits, and provide them with NCI’s Clearing the Air manual and local smoking 
cessation resources. We will give them the option of taking study product(s) home but not 
require that they take them, and if they do take the product(s) home we will suggest that they 
put the product(s) away at home so as to remove these cues from view. We will ask the 
participant to contact staff if they lapse and would like to receive study product(s) prior to 
his/her next visit. If a participant is planning to quit but has not initiated a quit attempt, we will 
ask if s/he has identified a quit date and if so what the date is, provide them with the Clearing 
the Air manual and local smoking cessation resources, provide them with the study product(s), 
and recommend that they put the product(s) away out of view on the quit date. 
For those in a condition including e-cigarettes, we will defer to the participant’s interests 
in continuing to use e-cigarettes as part of their quit attempt. Those who indicate that they will 
continue to use them will be given their same weekly supplies base on their baseline smoking 
rate. Those who indicate that they are planning to abstain from both combusted and non- 
combusted tobacco, we will honor that request. As we state above about combusted cigarettes, 
if participant changes his or her mind about resuming e-cigarette use, they can contact us and 
obtain their weekly supply. 
 
 
7.7.A. If a participant is currently abstaining from smoking with the intention to quit: 
• Encourage participant to continue abstaining from smoking 
• Schedule the participant for normal weekly visits, but no puff topography 
• 
Provide the participant with the ‘Clearing the Air’ manual and local smoking cessation 
resources 
• 
Give the participant the option to receive study product rather than require him/her to take 
the product 
• 
If the participant choses to receive the study product have him/her sign a form 
acknowledging that cigarette availability could be detrimental to the quit attempt. 
Recommend that he/she put the product “away” at home as to avoid unwanted cues to 
smoke. 
• 
If the participant chooses not to receive the study product, have him/her contact the lab if 
he/she lapses and would like to pick up or be mailed the study product prior to his/her next 
visit. 
7.7.B. If a participant is planning to quit smoking, but has not initiated the quit attempt: 
• Ask if he/she has identified a target quit date and, if so, what that target date is 
• Provide the participant with the ‘Clearing the Air’ manual and local smoking cessation 
resources 
• Provide the participant with the study product as usual. Recommend that on the target 
date he/she put the product “away” at home as to avoid unwanted cues to smoke. 
 
7.8. Abstinence Assessment Session: 
After the week 16 visit, participants will be required to attend one additional visit the 
following day. During this visit, participants will have been encouraged to abstain from smoking 
until their next scheduled visit (approximately 24 hours later). The abstinence assessment 
session should be scheduled no less than 18 hours and no more than 30 hours after the Week 
16 visit. Abstinence will be verified by an expired breath carbon monoxide level of less than or 
equal to 6 parts per million (ppm). This session will allow us to determine whether the 
experimental cigarettes and e-cigarette use (for the e- cigarette conditions) have reduced the 
effects of abstinence on these measures relative to the control conditions. If the participant 
does NOT meet abstinence criteria, he/she will only receive 
$20 for the visit. Those who do meet abstinence criterion will do concurrent choice session 

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detailed below. 
 
7.8.A Participants Who Meet Criteria for Abstinence 
7.8.A.1 Measures/Assessments 
Physiological measures collected and entered directly into REDCap by the interviewer at 
the end of the visit: 
 
1) CO 
2) Blood Pressure 
3) Heart Rate 
4) Body temperature 
5) Oxygen saturation 
6) Respiratory rate 
7) Urine or Saliva Toxicology 
 
The following assessments will be administered as an interview and will be entered 
directly into REDCap by the interviewer: 
1) Concomitant Medications 
2) Medical Event Form, if applicable 
3) Health Changes Questionnaire 
4) Time Since Last Cigarette Questionnaire 
 
The following assessments will be completed by the participant directly in REDCap: 
1) BDI 
2) OASIS 
3) COVID19 Symptom Questionnaire 
4) Respiratory Symptom Questionnaire 
5) MNWS 
6) PANAS 
7) QSU-brief - Usual Cigarette 
8) QSU-brief - Study Cigarette 
9) Vaping Craving Questionnaire 
10) Cigarette Purchase Task - Usual Brand Cigarette Version 
11) Cigarette Purchase Task - Study Cigarette Version 
12) E-cigarette Purchase Task- E-cigarette Version 
13) Snaith-Hamilton Pleasure Scale (SHAPS) 
 
In the event that the REDCap website is not functioning, the assessments will be administered 
aloud and participant answers will be recorded securely. The interviewer will enter the data into 
REDCap when it resumes functioning properly. This information should be recorded in the ‘End 
of Visit Evaluation Form’. 
 
7.8.B. Participants Who Do Not Meet Criteria for Abstinence 
7.8.B.1 Measures/Assessments 
Participants who do NOT meet abstinence criteria will be required to complete the 
following assessments: 

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1) CO 
2) Blood Pressure 
3) Heart Rate 
4) Body temperature 
5) Oxygen saturation 
6) Respiratory rate 
7) Urine or Saliva Toxicology 
 
The following assessments will be administered as an interview and entered directly into REDCap by the 
interviewer: 
1) Concomitant Medications 
2) Health Changes Questionnaire 
3) Medical Event Form, if applicable 
4) TLFB 
 
The following assessments will be completed by the participant directly in REDCap: 
1) BDI 
2) OASIS 
3) COVID19 Symptom Questionnaire 
4) Respiratory Symptom Questionnaire 
 
7.9. Participant Compensation: 
Participants will receive $25 plus a $25 bonus for completing each screening visit on time as 
scheduled. Payment for the first screening session will be made upon its completion. Payment 
for the second screening session will be made regardless of enrollment as long as the 
participant passes the drug test and meets the minimum requirements for carbon monoxide or 
urinary cotinine levels. Participants who do not pass the drug test or who are visibly intoxicated 
as determined by slurred speech, swaying, or stumbling will not be able to complete the visit 
and will be asked to take another test several days after the first positive. If they are negative 
for the second test, they will be eligible to participate, and if they are positive the for the second 
text they will be excluded. Participants will receive $100 for each study visit from Baseline 1 to 
Week 16. Participants will also have a chance to earn an additional $20 bonus for every study 
visit that is completed on time as scheduled starting at Week 1 and ending at Week 15. 
Participants can receive up to $120.00 for the abstinence session ($20 if participant does not 
achieve abstinence, $120 if participant reaches abstinence), $40 for biochemical verification of 
abstinence at 30 day follow up visit, and up to $306 for completing daily IVR reports of study 
cigarette and other nicotine and tobacco use. There will also be a $150 bonus distributed at 
Week 16 for completing the study. Participants who do not complete the entire study will 
receive compensation for the sessions that they do complete. Total compensation for 
completing Study 3, including study visit payments, daily IVR calls and end of study bonus is 
$2816. As mentioned above, participants will have a chance to earn additional incentives for 
compliance, honesty and attendance through urine testing. Participants will be given a debit 
card at the beginning of the study (during the second portion of the screening visit) and 
compensation for each visit will be automatically transferred to the card after they complete that 
visit. If debit cards are unavailable, participants will be paid via an alternate method (i.e. cash or 
check). 
 
7.10. End of Study: 
After a participant has completed all study procedures and has been paid for participation the 
research assistant will read the following script and give the participant the Clearing the Air 

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Manual. 
“If you’ve reduced your smoking during this study, we encourage you to continue these reductions 
or even consider quitting. We would like to provide you with some resources should you decide 
to try to abstain from smoking (give “Clearing the Air” and hotline information). Please also feel 
free to consult with your physician and use any medications he/she deems appropriate. We will 
call you in approximately 30 days to ask about your smoking since leaving the study. There is no 
right answer and we know how difficult quitting can be. Please just answer honestly. The call will 
take less than 5 minutes. Thanks again for your participation.” 
The following assessments will be administered using REDCap: 
1) End of Study Questionnaire 
 
7.11. 30 Day Follow up Phone Call: 
Participants will receive a follow-up phone call between 25 and 35 days after the abstinence 
assessment session to assess their smoking patterns. The phone questionnaire will last less 
than five minutes. The questionnaire will ask if the participant is still smoking, how much and 
whether he/she has attempted to quit smoking since the end of the study. Participants will 
receive 5 variable incentive program lottery tickets for completing the call as compensation. 
Those who report abstinence will be invited to complete biochemical verification and be 
compensated $40 for doing so. Abstinence will be achieved by a carbon monoxide reading of 6 
parts per million (ppm) or under. A urine sample may also be collected to be sent to the lab for 
analysis. Additionally, any Medical Event Forms that remain open from the last session will be 
discussed. If the participant became pregnant during the study, this would have been recorded 
as a medical event. During this phone call, the research assistant will confirm her due date. 
This event will remain open until delivery. At that time the licensed medical professional will 
contact the participant to ask a few questions about the baby’s health and will update the 
Medical Event Form. 
Once a participant has completed all study procedures and all open events have been 
closed, the PI or Project Manager will review the participant’s record and sign a form indicating 
study completion for that participant. 
 
 
 
8.0 Study Randomization 
 
 
8.1 Randomization Process 
The lead statistician will create a randomization schedule for each of the two sites, 
amounting to 150% of expected enrollment at each site. The excess randomization codes will 
be used in the event that a site will have to enroll extra participants due to unexpectedly slow 
enrollment at another site. The nicotine doses will be identified by letter code and only 
Administrative Core personnel with no participant contact will have the link between the 
statistician’s letter code and dose assignments. There will be no blinding of e-cigarette 
conditions. The Administrative Core will maintain the randomization schedule and the link 
between the alphabetic code and treatment assignment securely. A second sealed copy will be 
secured in a separate building to protect against loss related to fire or other unforeseen events. 
The University of Vermont will be responsible for removing all identifying information from 
cigarettes received from the Research Triangle Institute (RTI), labeling each carton with a blind 
code, assigning product using this blind code based on the randomization schedule being 
provided by the UVM Biostatistics Core, and shipping cigarettes and e-cigarettes to each site as 
needed based on recruitment. Each site will be responsible for tracking product received and 
distributed to participants, collecting unused product from participants, and returning unused 
cigarettes and e-cigarettes to UVM. The participants, investigators and study staff will not have 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
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knowledge of which product is given to a participant or whether different participants received 
the same or different product. 
 
8.2 Study Product Administration 
During the experimental period, participants will be provided with a 14-day supply of research 
cigarettes equivalent to 150% of their daily smoking rate. Those in the e-cigarette conditions will 
also be provided with a 14-day supply of e-cigarettes equivalent to their daily smoking rate. This 
rate will be calculated at Baseline 2 and will be an average daily smoking rate based on the IVR 
data that reports on the usage for the first seven days following the day of the first baseline visit. 
This will ensure adequate availability of cigarettes in the numerous locations participants may 
typically keep a supply (home, work, vehicle, etc.) as well as avoid expending the entire supply if 
they miss a scheduled visit. Participants will be instructed to use the research cigarettes for 12 
weeks, at which point they are to discontinue product use. 
If there is prior knowledge a participant will be missing a visit (i.e. planned vacation, laboratory 
closure, etc.), then the participant will be provided with an adequate supply of cigarettes to make 
up for the missed visit(s). The participant will be given a 21-day supply if one visit is going to be 
missed and a 28-day supply if two visits are going to be missed. 
 
8.3 Guidelines for Reporting other Nicotine Product Use 
Participants will be asked to refrain from use of other non-study cigarettes during the study 
period. If participants have to use another nicotine product, they will be told to use a non- 
combustible product (gum, patch, etc.). Additionally, they will be told there is not a penalty for use 
of non-study products, and that it is crucial for them to report any use of non-study tobacco 
products. Throughout the baseline and experimental periods, an Interactive Voice Response 
(IVR) system will be used on a daily basis to record the number of study cigarettes and non-study 
cigarettes used the previous day. During the baseline and first experimental week, participants 
will also answer daily IVR questions about their mood. Participants will be seen weekly for 
assessments. Brief standardized review sessions focusing on compliance with the study 
cigarettes and other study procedures will be provided at each visit. 

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8.4 Product Accountability: 
Participants will be required to keep track of all the products provided to them. Therefore, they 
will be instructed to return all unused products and empty cigarette packs e-liquid pods/cartridges 
to the laboratory each week. Research staff will complete the ‘Product Accountability Log’ as they 
process participants’ product. Any discrepancies in the product dispensed versus product 
returned will be discussed and recorded in the log. Research staff will weigh all opened e-cigarette 
pods/ cartridges that the participant returns at all visits to determine how much e-liquid was used 
since the participant was last seen. Empty cigarette packs and e-liquid pods/cartridges will not be 
saved. Unused cigarette packs and e-liquid pods/cartridges will be re-distributed to the 
participants during Weeks 1-15. During Week 16, remaining unused cigarettes and e-cigarette 
pods/cartridges returned by the participants will be collected by the research staff. 
Participants who report running out of cigarettes or e-liquid pods/cartridges prior to a scheduled 
weekly visit will be allowed to come in for an unscheduled visit to obtain more research cigarettes. 
To determine whether a rate change for cigarettes is necessary, we will look at the past two CO 
levels as compared to the Baseline 2 CO. If the CO trend is consistent with the self-report of 
smoking all of the allotted cigarettes then a rate increase will be granted. The participant will then 
receive cigarettes at a rate of 175% of their daily smoking rate. The maximum increase is 200% of 
their daily smoking rate. To determine whether a rate change for e-cigarettes is necessary, we will 
monitor the amount of e-cigarette use the participant is reporting and showing through product 
return along with any unscheduled visits. The investigator may grant an e-cigarette rate increase 
in increments of 25%. The maximum increase for e-cigarettes will be 200% of their baseline weekly 
e-cigarette dispensation rate. 
If participants lose more than two packs of cigarettes and/or pods/cartridges and require 
an unscheduled visit to the laboratory to supplement their supply, they will be told the next time 
they lose more than two packs they will have to wait until their next scheduled appointment to 
receive more cigarettes. 
 
9. Study 3 Statistical Methods and Sample Size 
 
 
9.1 Statistical Methods 
Continuous outcomes will be summarized by mean, standard deviation, median and range. 
Categorical outcomes will be summarized by frequencies and percentages. Skewed continuous 
outcomes will be log- or square-root transformed as appropriate. Variables measured at each 
baseline visit will be averaged and the average will be used as the baseline measurement. As we 
expect conditions to be balanced on important baseline characteristics due to randomization, our 
primary analysis for all endpoints will not be adjusted for potential confounders. However, a 
secondary analysis will be completed for all outcomes adjusting for demographic characteristics 
(e.g., age), that we have found to be important in prior studies. Potential moderators (e.g., SSRI 
vs. non-SSRI antidepressant, depression vs. anxiety disorders, BMI above or below 30) will be 
explored by adding that term and the moderator-by-condition term to the model. We will examine 
age group and gender as potential moderators in a similar fashion. 
Participants will be randomized in equal probability to one of the four conditions, with 
randomization stratified by site and menthol cigarette status. All analyses will follow the intent- 
to-treat principle (i.e. subjects will be analyzed according to condition assignment, regardless of 
compliance). The Primary Aim will examine the effects of condition on total CPD (study product 
and non-study product). CPD will be analyzed by week (mean over all days in a seven-day 
period) using a mixed model to account for repeated measures from the same individual. 
Models will include baseline CPD as a covariate. Using a mixed model also allows us to 
include the effect of study site as a random effect. Additional analyses conducted using data 
collected at the end of the study will use orthogonal comparisons to test for a linear trend in the 
decrease in CPD, such that VLNCC + PF e-cig > VLNCC + TO e-cig > VLNCC > NNCC, with 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
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the largest reduction in the VLNCC + PF e-cig condition. As we expect that differences among 
conditions for some of the outcomes may not follow a linear pattern, we will use related 
planned comparisons to test for threshold effects, specifically contrasting the NNCC condition 
to all three VLNCC conditions, and NNCC to the two VLNC + e-cigarette conditions.. Analysis 
of cigarette demand, smoke exposure and tobacco carcinogens (Aim 2) as well as additional 
outcomes, including subjective effects, will be analyzed in a similar manner. Because 
Exploratory Aim 3 is based on abstinence-induced effects and will be examined using data 
collected at a single visit at Week 17, analysis will be based on an analysis of co-variance 
model. In addition to the effect of condition, we will include important covariates noted above. 
Exploratory analyses will also be conducted combining data collected from three of the 
vulnerable populations (disadvantaged women of childbearing age, opioid dependent 
individuals, individuals with AD) to explore potential differences in effects of study condition 
across these populations. This will be done with the addition of the effects of population and 
population-by-condition terms to the models described above. Study staff will make every effort 
to minimize missing data, and results of our ongoing trial suggest that this will be minimal. We 
will examine the missing data pattern, and if it is missing at random, will use all data available, 
without imputation. 
permutation tests.121 
 
9.2 Sample Size 
Sample size was determined using NQuery Advisor based 
on hypothesis tests related to Aim 1, specifically to detect a 
significant difference between the study conditions (NNCC, 
VLNCC, VLNCC + TO e-cigs, VLNCC + PF e-cigs) on total 
cigarettes per day (CPD). The primary statistical approach will 
be repeated measures ANOVAs but required sample sizes 
were calculated focusing on expected outcomes at Week 16. 
This sample size estimate is intentionally conservative and 
calculated based on one outcome at one time point; however, 
given the repeated measures nature of our data, we will have 
correlated observations within subjects. Thus, with the given 
sample sizes we will achieve the stated power to detect 
differences of even lesser magnitude than stated or planned. 
Our sample size determination is based on preliminary results 
from our current trial and results from a large randomized 
clinical trial of cigarettes varying in nicotine content.7 Note that 
Table 2. Observed effect sizes 
 
Outcome 
Observed 
between-group 
ES (15.2 vs. 0.4 
mg/g) 
CPD 
0.81 
Craving 
0.20 
FTND 
0.42 
Breath 
CO 
0.33 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
36 
 
 
the between-group effect size is defined as the difference of study condition means divided by the 
common standard deviation. A sample size of 53 participants per condition will provide 80% power 
to detect an effect size of 0.60 for all pair-wise comparisons, with a two-sided type 1 error rate of 
0.05. This is smaller than that found in our on-going study to date for CPD and smaller than the 
effect sizes reported by Hatsukami et al.8 for all measures except breath CO. In addition, this 
sample size provides greater thn 95% power to detect a linear dose-response effect across the 
four experimental conditions. Becase we have relied only on outcomes at Week 16, our proposed 
sample sizes are somewat conservative, but we believe this is appropriate for this 
study given that the effects of VLNC cigarettes in this population, particularly in combination with 
e-cigarettes, are completely unknown. The sample size above assumes a 15% loss to follow-up, 
consistent with our experience in the current study. We will increase our overall sample size to 
232 in order to allow pilot testing in a group of 20 participants. 
 
 
10. Potential Risks of Participation 
 
 
10.1 Risks of Participation 
1) Survey Questionnaires. This interview will include questions about your medical and 
psychiatric histories, drug and alcohol use and history, breath tests for cigarette and 
alcohol use, urine or salivary tests of illicit drug use and pregnancy, and questionnaires 
about your mood. Answering these personal questions could make you uncomfortable. If 
you report thoughts of killing yourself or other indicators of suicidality, a study clinician 
will come to talk to you. You may also request to see a study clinician if you are in 
discomfort and would like help and/or referrals for mental health resources. 
 
2) Breach of Confidentiality: The risk of the interview is loss of privacy if other people find out 
the results. 
 
3) Undue Influence: Undue influence is a possible risk due to monetary compensation for 
participating in these studies. The likelihood of this risk is low because the compensation 
is commensurate with the amount of time and effort required for these studies. 
 
4) Drug Testing: A breach of confidentiality could occur and other people could learn of the 
participant’s drug use. 
 
5) Obtaining Blood Pressure and Heart Rate. The blood pressure cuff may cause minimal 
discomfort. In obtaining blood pressure we may find a participant to have abnormal blood 
pressure and/or heart rate. If participant’s blood pressure is abnormal, we will inform the 
participant of this, and participant may be advised to see a doctor, and may also be 
contacted by our study doctor. Also, smoking and nicotine can affect the cardiovascular 
system, which may result in changes in blood pressure and/or heart rate. 
 
6) Smoking Cigarettes: All cigarettes are detrimental to a person’s health and can lead to 
significant medical problems including: 
a. Cardiovascular Diseases: Coronary heart disease, heart attack, stroke, peripheral 
vascular disease, reduced blood circulation, abdominal aortic aneurysm 
b. Respiratory Diseases: Emphysema, bronchitis, and chronic airway obstruction 
Cancers: Cancer of the lung, bladder, cervix, esophagus, kidney, larynx, mouth, 
pancreas, throat, and stomach; leukemia 
c. Metabolic Diseases: Type 2 Diabetes 
d. Other Health Risks Associated with Smoking: Including but not limited to infertility, 
lower bone density in postmenopausal women, and hip fracture in women 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
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e. Death 
 
7) Smoking Study Cigarettes. All cigarettes are harmful to a person's health and can lead 
to cardiovascular (heart) disease, respiratory (lung) disease, cancer and other health 
problems. In addition to the above medical problems, you may experience some minor 
negative health effects such as headaches. You may also experience smoking 
withdrawal symptoms, which are listed below. In addition, due to the altered nicotine 
levels, there could be a change in your use of cigarettes including the manner in which 
you inhale the smoke. Smoking the study cigarette does not necessarily provide any 
less risk than your usual brand of cigarette and could pose increased health risks. 
 
8) Using Study E-cigarettes. E-cigarettes are devices that heat nicotine to produce an 
aerosol. The health effects of e-cigarettes are still unclear, but appear to be less than 
that for tobacco cigarettes. Most e-cigarette users have lower nicotine levels than when 
they smoked regular cigarettes. Some e-cigarette users, especially those who use both 
e-cigarettes and regular tobacco cigarettes as well as youth and young adults, can have 
increased nicotine levels. In some rare cases, these use patterns have been associated 
with seizures. Whether this would occur with the concurrent use of very low nicotine 
cigarettes is unclear. E-cigarettes users very often maintain addiction to nicotine, but 
this addiction appears to be somewhat less than that from tobacco cigarettes. Abruptly 
quitting e-cigarettes could cause withdrawal symptoms similar to those from quitting 
tobacco cigarettes (see below) but slightly less severe. The most common side effects 
include dry mouth, irritation of the throat and mouth, and mild cough. The JUUL and 
Vuse e-cigarettes we will be providing have not been well-studied but appear to be of 
similar risk to other e-cigarettes. You may have heard that e-cigarettes, or "vapes," can 
explode and seriously injure people. Although they appear rare, these explosions are 
dangerous. The exact causes of these incidents are not yet clear, but some evidence 
suggests that battery-related issues may lead to vape explosions. In order to prevent e- 
cigarette related injuries, keep your e-cig away from other metal objects, never charge 
your e-cig with a phone or tablet charger, don’t charge your e-cig overnight or leave it 
charging unattended, and stop using the e-cig if the batteries get damaged or wet. 
Always keep e-cig liquid out of kids’ and pets’ reach and sight after use. If we learn 
about additional risks of e-cigarettes during the study, we will inform you of these risks. 
 
Mood and Psychiatric Symptom Changes. You may experience smoking withdrawal 
symptoms during this study. These symptoms can include anger, anxiousness, 
craving for a cigarette, depressed mood, difficulty concentrating, frustration, 
increased appetite, impatience/impulsivity, irritability, restlessness, sleep problems, 
and weight gain. These feelings can be uncomfortable and can last a couple of 
weeks, but usually are of minimal risk. In addition, if you have a past history of 
anxiety, depression, or alcoholism, it is possible withdrawal could cause substantial 
increases in depression and anxiety symptoms, but this appears to be rare. At each 
visit, we will ask you how you feel. If you or we think that being in this study is putting 
your mental health at risk, we may have you meet with an on-site clinician and/or 
stop participating in the study. Further, if you report thoughts of killing yourself or 
other indicators of suicidality, a study clinician will come to talk to you. You may also 
request to see a study clinician if you are in discomfort and would like help and/or 
referrals for mental health resources. 
 
9) Returning to Regular Smoking: It is possible that if participants return to smoking their 
usual brand of cigarette at the end of the study they may experience mild and transient 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
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nausea, dizziness, and lightheadedness. 
 
10) Risk to Fetus. To avoid risks to a fetus, it is important that you are not pregnant 
during this study. Avoiding sexual activity is the only certain method to prevent 
pregnancy. However, if you choose to be sexually active, you should be using 
approved forms of birth control if applicable determined by the Project Medical 
Director, including but not limited to prescribed birth control pills, patch, ring, 
injections, implants or intrauterine device (IUD) or an appropriate “double barrier” 
method. If you choose to be sexually active during this study, pregnancy could 
still result even with the use of these birth control methods. 
 
 
10.2 Avoiding Risks to Fetus: 
If participants choose to be sexually active, they should use an appropriate “double barrier” 
method of birth control (such as female use of a diaphragm, or contraceptive sponge, in addition 
to male use of a condom) or the female should be using prescribed “birth control” pills, patch, ring, 
injections, implants or intrauterine device (IUD) if applicable determined by the Project Medical 
Director. If a participant endorses a “double barrier” method, our medical professional will speak 
to the participant to confirm which methods will be used during the duration of the study. 
Participants will be tested for pregnancy every two weeks beginning at screening through the last 
study visit. If a participant becomes pregnant during the study, she will be withdrawn from the 
study. Approximately 30 days after being withdrawn or having a positive pregnancy test at the last 
study visit, the research staff will call the 
participant to confirm her due date. The licensed medical professional will follow-up with the 
participant after delivery to ask questions about the baby’s health. 
 
10.3 Expected benefits of participation: 
There are no benefits from participating in the study. The information obtained from this 
study may ultimately help the Food and Drug Administration decide how best to regulate nicotine 
and tobacco products with the goal of improving public health. 
 
 
 
 
11. Protection Against Risk 
 
 
11.1 Data Collection Protections 
Research data without identifiers will be maintained in a locked file cabinet and on 
password-protected computers in the research staff workplace, with only code numbers 
identifying subjects. Study consent forms and the linkage between the participants’ names and 
codes will be stored in a locked file cabinet inside a locked office. Interviews with participants 
will be conducted in private rooms. Urine or saliva samples for drug and pregnancy tests and 
tobacco exposure biomarkers will be obtained in a private bathroom within the laboratory 
suite. 
Subjective measures will be administered electronically. The biostatistics and data-management 
team will provide consistent data-management practices for all data in the Center. Using 
REDCap, which is housed on the University of Vermont Medical Center’s HIPAA-compliant 
computing system, will maximize validity and reliability of data. REDCap is a secure, web-based 
system that accommodates local and remote data collection by each project team, and allows 
for data entry work-flow monitoring and data quality control monitoring by biometry staff. The 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
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RedCap database for this project will be hosted on the UVMCOM servers. In addition, data will 
be collected from participants on a daily basis using an interactive voice recognition system 
(IVR) developed and hosted by TeleSage Inc (www.telesage.com, Chapel Hill, NC). TeleSage is 
a company with expertise on gathering patient-centered outcomes tracking data for 
mental health clinical and research institutions. TeleSage has developed and hosted 
behavioral health-related research software systems using IVR and Web-based 
technologies and is leader in  behavioral health  outcomes tracking technologies.For 
data integrity, data entry windows will follow the structure of paper forms as much as possible to 
allow for ease of entry, and will use predefined choices to minimize errors when possible. Data 
quality monitoring will be facilitated with periodic down loads and analysis using a variety of 
common statistical program format such as SAS, Stata, R, and SPSS. Quality control 
procedures will be conducted for all data collected, including analysis of missing data and logic 
checks for out of range and other anomalous values. This secure electronic data gathering and 
transmission plan, overseen by the experienced biostatistical team, will minimize opportunities 
for breaches of confidentiality. Biological samples for nicotine and carcinogen biomarker 
analysis will be marked with participant ID, stored in the locked laboratory suite, and sent to a 
laboratory for analysis on a quarterly basis. 
All information collected as part of this study will be accessible only to research staff. No 
information will be shared with participants’ clinicians unless the participant requests this in 
writing. All investigators and staff have undergone (and any new staff will undergo) human 
subjects’ ethics training as required by UVM and are fully conversant with relevant ethical 
principals around confidentiality. Assessments, consenting and study procedures will be closely 
supervised by the PI. 
The sponsors (NIDA/FDA) as well as the Institutional Review Board and regulatory 
authorities could be granted direct access to original medical and research records for 
verification of clinical trial procedures and/or data. If this is required, it will be done under 
conditions that will protect privacy to the fullest extent possible consistent with laws relating to 
public disclosure of information and the law-enforcement responsibilities of the agency. 
11.2 Data Storage: 
Data will be stored locally at each site. Long-term storage of all study data, for at least 7 years 
after study completion, will be at the University of Vermont. 
 
 
 
 
12. Adverse Events 
 
 
The research assistant will ask about adverse events at each session, using a form that 
assesses the nature, severity, duration, action taken, and outcome of study-related adverse 
events. AEs will be captured from the time of first study cigarette. Participants will be given 
contact cards to inform us of events that occur between study contacts. Any AE that remains 
open will be reviewed and closed at an interview conducted 30 days after the study completion 
date (completers) or when the study should have ended had the participant completed the study 
(dropouts and those withdrawn by investigator). 
All procedures will be monitored to ensure that they conform to the approved protocol. In 
addition, monitoring will be done of all unforeseen circumstances that might arise and affect 
safety; of all reports of serious adverse events as defined in 38 CFR 46 (death, new or 
prolonged hospitalization, persistent or significant disability/incapacity); of other significant 
adverse events (adverse events that lead to drop out by the participant or termination by the 
investigator); of unexpected adverse events resulting from the study, and of expected adverse 
events. 
Any SAE will be brought to the attention of the site PIs as soon as possible and not longer 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
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than 24 hours. Any AE or SAE that is both unexpected and related to study participation will be 
reported to the IRB within 7 days of the event. The local IRB will make a determination as to 
whether additional reporting requirements are needed. IRB actions will be reported to the 
funding agency by the PIs no less than annually and more frequently as recommended by the 
local IRB. Any SAEs will be summarized in the yearly Progress Reports to the funding agency, 
including a review of frequency and severity. All SAEs will be followed through ongoing 
consultation with the physician caring for the patient until they resolve, result in death, or 
stabilize and are not expected to improve. The study staff will be in close contact with 
participants and health care providers throughout the study to monitor for potential unanticipated 
problems. Any unanticipated problems will be discussed at the weekly research staff meetings 
and reported as required to the local IRB. 
 
13. Withdrawal or Monitoring of Participants 
 
 
For the participant’s protection, participants will be withdrawn immediately from the study 
if any of the following occur: 
1) Cardiovascular disease (CVD) event: Typically includes MI (heart attack), PTCA 
(angioplasty/stenting), bypass surgery, stroke, peripheral vascular disease (arterial 
blockages in arms or legs leading to procedure or surgery). Less common CVD problems 
would be new cardiac arrhythmias (e.g., new atrial fibrillation) or new valvular disease 
(e.g., mitral or aortic regurgitation). 
2) DVT/PE (deep vein thrombosis/pulmonary embolism, i.e., blood clots in the venous 
system). 
3) Suicide Attempt: A participant will be withdrawn if he/she attempts suicide at any time 
during participation in the study. 
4) Psychiatric Hospitalization: A participant will be withdrawn if he/she is hospitalized for 
psychiatric reasons at any time during participation in the study. 
5) Pregnancy: If participant indicates she is pregnant or has a positive pregnancy test at any 
time during the study, she will be withdrawn from the study, and this event will remain 
open until delivery. At that time the licensed medical professional will contact the 
participant to ask a few questions about the baby’s health and will update the open 
‘Medical Event Form’. A positive pregnancy test at Week 16 will trigger a ‘Medical Event 
Form’ to be completed but will not result in withdrawal since she is no longer receiving 
study product. 
6) Expired breath carbon monoxide increase: A participant will be withdrawn from the study 
if the average of two consecutive CO readings during the same visit is 100 ppm or greater. 
7) Marked increase in smoking: A participant will be withdrawn from the study if he/she meets 
BOTH of the following criteria for two consecutive weeks 
a. Cigarette per day increase: The average CPD increases by more than 100% from 
the average CPD during baseline. 
b. Expired breath carbon monoxide increase: If the average of two consecutive CO 
measurements in the same visit is 
i. CO is greater than 50 ppm if CO at Baseline 1 is <20 ppm. 
ii. CO is greater than 60 ppm if CO at Baseline 1 is 20 – 34 ppm. 
iii. CO is greater than 70 ppm if CO at Baseline 1 is 35 – 49 ppm. 
iv. CO is greater than 80 ppm if CO at Baseline 1 is 50 – 64 ppm. 
v. CO is greater than 90 ppm if CO at Baseline 1 is 65 – 80 ppm. 
c. Note: If the second consecutive visit is the last study visit, then the participant 
would not be withdrawn from the study. 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
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8) If a participant is discharged from or discontinues his or her methadone or buprenorphine 
treatment, they will be discontinued from the study. 
 
The following will be monitored and can lead to the participant being withdrawn by the PI 
or Licensed Medical Professional: 
1) Cigarettes per day increase: Continued participation will be evaluated by the site PI if the 
average number of cigarettes per day (CPD) increases by more than 100% from the 
average CPD during baseline as determined by CPD at Baseline 2. 
2) Blood pressure (BP) or heart rate (HR) changes: If any of the following occur post- 
enrollment: 1) BP is at or above 160/100 or below 90/50, or 2) HR is at or above 115 bpm 
or below 45 bpm a manual blood pressure and heart rate measurement will be taken after 
10 minutes have passed. If the manual reading is still out of range, a ‘Blood Pressure and 
Heart Rate Symptom Checklist’ and ‘Medical Event Form’ will be completed, and the 
participant will be monitored by the medical professional. 
3) Expired breath Carbon Monoxide increase: If the average of two consecutive CO 
measurements meets the criteria below then the ‘Medical Event Form’ will be completed 
and the participant will be monitored by the medical professional. 
a. CO is greater than 50 ppm if CO at Baseline 1 is <20 ppm. 
b. CO is greater than 60 ppm if CO at Baseline 1 is 20 – 34 ppm. 
c. CO is greater than 70 ppm if CO at Baseline 1 is 35 – 49 ppm. 
d. CO is greater than 80 ppm if CO at Baseline 1 is 50 – 64 ppm. 
e. CO is greater than 90 ppm if CO at Baseline 1 is 65 – 80 ppm. 
4) Any hospitalization or debilitation in which participation in the study could be detrimental 
to the recovery process. This will be self-reported by the participant and will be reviewed 
by the site PI and medical professional to determine whether continued participation in the 
study is appropriate. 
5) If a participant is behaving in an inappropriate or threatening manner, admits to lying about 
eligibility criteria, is participating in other smoking research studies that could affect the 
primary outcome measures, etc., then the PI can withdraw him/her from the study at the 
PI’s discretion. 
6) If a participant fails to attend regularly scheduled research assessment visits or comply 
with the research procedures or schedule, then the PI can withdraw him/her from the study 
at the PI’s discretion. 
7) Increase in psychiatric symptoms: Exacerbation in symptoms noted during the study (i.e., 
change in BDI category from mild to moderate or moderate to severe) will trigger review 
by the study’s licensed medical professional. The PI will withdraw the participant upon the 
licensed medical professional’s recommendation. 
 
 
14. Data Safety Monitoring Board 
 
 
A Data and Safety Monitoring Board (DSMB) has been established to monitor safety 
outcomes and will be comprised of four members. The DSMB will be chaired by Kevin Delucchi, 
PhD., Professor in Residence of Biostatistics in Psychiatry at the University of California San 
Francisco and Director of the Quantitative Core of the San Francisco Treatment Research Center; 
Eden Evins, MD, MPH., Cox Family Professor of Psychiatry at Harvard Medical School and 
Director of Center for Addiction Medicine at Massachusetts General Hospital; Ari Kirshenbaum, 
Ph.D., Professor of Psychology at Saint Michael's College who he teaches courses in 
psychopharmacology and neuroscience, and currently has grants from NIH and NSF for work in 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
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human behavioral pharmacology and his grant-funded work focuses on cognitive and behavioral 
responses to nicotine and cannabinoids; and Elisabeth Johnson, Ph.D., who has over twenty 
years of clinical experience in women’s health and pediatrics, including caring for women with 
substance use disorders. 
 
Conflict of Interest 
None of the board members will be otherwise affiliated with the center and each member will 
complete a conflict of interest disclosure form prior to each meeting. Ad hoc specialists may be 
invited to participate as non-voting members at any time if additional expertise is desired. 
 
Monitoring Activities and Frequency of Meetings 
The DSMB will set their own agenda and decisions about monitoring; e.g. how frequently to 
monitor, what threshold requires changes to protocol or stopping the study, and whether to view 
raw or analyzed data. The DSMB will be given FDA and EMEA guidelines for DSMBs and recent 
reviews on DSMBs. A brief report will be generated from each meeting for the study record and 
forwarded to each of the study site’s Institutional Review Boards (IRB) and NIDA’s Program 
Officer with the progress report. The DSMB will be available to convene outside of the regular 
meetings, if necessary. If concerns should arise regarding a particular subject, or any troublesome 
trends in the experiences of participants, they will make appropriate recommendations for 
changes in protocol, as needed. The project investigators will continue to examine safety data, 
blind to study condition, in case they wish to make study modifications. Before modifications 
are made, they will inform the DSMB and request their comments. 
 
Communication Plan to IRB, NIDA, and FDA (if applicable) 
All IRBs, the FDA and the NIDA’s Program Officer will be informed of any significant action 
taken as a result of the Data and Monitoring Board’s findings. Study Participants will be informed 
of any changes in risk. 
 
Protection of Confidentiality 
For DSMB meetings only de-identified data, including blinded study site and condition type, 
will be provided to the board. All data and discussion during the meeting will be confidential. 
 
 
 
 
15. Investigational Tobacco Product 
 
 
The University of Vermont Center on Tobacco Regulatory Science will complete an 
Investigational Tobacco Product (ITP) application with the FDA to cover the experimental 
cigarettes being used in this study. This application encompasses both Project 3 sites. 
 
 
16. Certificate of Confidentiality 
 
 
To help protect the participant’s privacy, Dr. Stephen Higgins, PhD, will obtain a Certificate of 
Confidentiality from the national Institute on Drug Abuse. With this certificate, the researchers 
cannot be forced to disclose information that may identify the participants, even by a court 
subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings. The researchers will use the Certificate to resist any demands for information that 
would identify the participants, except as explained below. The Certificate cannot be used to resist 
a demand for information from personnel of the United States Government that is used for auditing 
or evaluation of federally funded projects or for information that must be disclosed in order to meet 
the requirements of the Federal Food and Drug Administration (FDA). 
The Certificate of Confidentiality does not prevent the participant or a member of their family 

CHRMS (Medical) #19-0128 Approved: 1/23/2023 
43 
 
 
from voluntarily releasing information about themselves and their involvement in the research. If 
an insurer, employer or other person obtains the participant’s written consent to receive research 
information, then the researcher may not use the Certificate to withhold that information. 
The Certificate of Confidentiality does not prevent the researchers from disclosing 
voluntarily, without consent, information that would identify the individual as a participant of the 
research project in instances such as evidence of child abuse or a participant's threatened 
violence to self or others. 
 
 
 
17. Outcome Variables 
 
 
Primary Endpoints for Study 3: 
1) Cigarette Smoked per Day (CPD) 
2) Nicotine Dependence Severity 
Secondary Endpoints for Study 3: 
1) Measures of adherence: non-study cigarette use, drop-out rate 
2) Measures of psychiatric symptoms: BDI, OASIS 
3) Measures of discomfort/dysfunction: MNWS, QSU 
4) Measures of other health-related behaviors: breath alcohol, urine or salivary drug screen, 
TLFB-drug use, Alcohol Use Questionnaire, Drug Use Questionnaire, weight 
5) Measures of nicotine/tobacco dependence: FTND, WISDM 
6) Measures of tobacco exposure: CO, total nicotine equivalents, NNN, NNAL, minor 
alkaloids 
7) Measures of intention to quit: Stages of Change, Contemplation Ladder 
8) Measures of compensatory smoking: puff topography, filter analysis 
9) Measures of other tobacco use: TLFB-other tobacco 
10) Measures of cigarette characteristics: CES, Cigarette Purchase Task 
11) Measures of cardiovascular function: heart rate, blood pressure, urine 11-dehydroTXB2 
12) Measures of perceived risk: Perceived Health Risk Questionnaire 
13) Safety outcome variables: Adverse Events (AEs), Serious Adverse Events (SAEs) 

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44 
 
 
 
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