Randomized Trial of Low Nicotine Cigarettes Plus Electronic Cigarettes in Smokers
Phase: NA
Conditions: Tobacco Dependence
Sponsor: Milton S. Hershey Medical Center

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HRP-592 - Protocol for Human Subject 
Research with Use of Test Article(s)
Protocol Title:
Randomized trial of low nicotine cigarettes plus electronic cigarettes in smokers
Principal Investigator:
Jonathan Foulds, PhD
Public Health Sciences
(717) 531-3504
jfoulds@psu.edu
Version Date:
1-13-25
Clinicaltrials.gov Registration #:
NCT04058717
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Table of Contents
1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Subject Numbers and Statistical Plan
9.0
Data and Safety Monitoring Plan
10.0
Risks
11.0
Potential Benefits to Subjects and Others
12.0
Sharing Results with Subjects
13.0
Subject Payment and/or Travel Reimbursements
14.0
Economic Burden to Subjects
15.0
Resources Available
16.0
Other Approvals
17.0
Multi-Site Study
18.0
Adverse Event Reporting
19.0
Study Monitoring, Auditing and Inspecting
20.0
Future Undetermined Research: Data and Specimen Banking
21.0
References
22.0
Confidentiality, Privacy and Data Management
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1.0
Objectives
1.1
Study Objectives
The long term goal of this project is to determine the likely health effects of very low nicotine content in 
cigarettes, in conjunction with availability of nicotine-containing electronic cigarettes (e-cigs) among 
smokers with mental health conditions (SMHC). This will be tested in a rigorous randomized controlled 
trial design. We plan to use a comprehensive set of measures of proven validity and reproducibility, 
including toxicant exposure, addiction and mental health to assess these effects.  The specific objective 
of this study is to recruit a cohort of 240 current exclusive daily SMHC (diagnosed using the MINI 
International Neuropsychiatric Interview) and to measure a comprehensive battery of  behavioral and 
health indicators at 4 and 8, 12 and 16 weeks after being randomized to use either normal nicotine 
content (NNC) Spectrum cigarettes (11.6 mg nicotine/cigarette) or very low nicotine content (VLNC) 
Spectrum cigarettes (0.2 mg nicotine/cigarette) while also having access to a JUUL e-cig (JUUL Labs, Inc.) 
containing either 0% or 5% nicotine strength e-liquids in a randomized double-blind, placebo-controlled 
2 by 2 design. Our central hypothesis is that key markers of harms to health (e.g. urinary NNAL, exhaled 
CO, measures of addiction, and mental distress) will be significantly improved among SMHC who are 
provided very low nicotine cigarettes and high nicotine e-cigs.  Study aims are:
Aim 1:  To determine whether SMHC have lower levels of markers of harm (e.g. urine NNAL, exhaled CO, 
measures of mental health) and cigarette addiction when switched to VLNC cigarettes, as compared 
with NNC cigarettes, at the end of the randomized phase (week 16).
Aim 2:  To determine whether SMHC have lower levels of markers of harm (urine NNAL, exhaled CO) 
and cigarette addiction when provided with nicotine-containing versus zero nicotine electronic 
cigarettes, at the end of the randomized phase (week 16).
Aim 3: To determine whether use of VLNC cigarettes increases the proportion of smokers who 
completely switch away from combustible tobacco use (no cigarette use in the past 7 days and CO < 
6ppm), as assessed (a) at the end of the randomized phase (week 16) and (b) 4 weeks after the end of 
the randomized phase of the trial (week 20), compared to those using NNC cigarettes. 
1.2
Primary Study Endpoints
The primary endpoint for the study is urinary NNAL concentration at Week 16. Urine NNAL is a 
biomarker that provides an accurate estimate of recent exposure to the lung carcinogen, NNK.
1.3
Secondary Study Endpoints
Secondary endpoints include exhaled CO, Kessler-6 score, and cigarette/e-cigarette dependence using 
Penn State Cigarette Dependence Index (PSCDI) and Penn State Electronic Cigarette Dependence Index 
(PSECDI), at week 16, and cigarette abstinence (no cigarette use in the past 7 days and CO < 6ppm) at 
week 20.
Additional endpoints include:
Health effects and toxicant exposure measures: Pulmonary Function Tests (PFT), Clinical COPD 
Questionnaire (CCQ), urinary CYMA (biomarker for acrylonitrile [volatile organic compound] exposure), 
3HPMA (biomarker for acrolein [volatile organic compound] exposure, cotinine (biomarker of nicotine 
exposure)  
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Mental health measures:  Center for Epidemiological Studies-Depression (CES-D), Overall Anxiety 
Severity and Impairment Scale (OASIS), Quick Inventory or Depressive Symptomatology (QIDS), 
Perceived Stress Scale (PSS)
Nicotine/Tobacco use and addiction measures:  daily cigarette use, daily e-cig use, Fagerstrom Test for 
Nicotine Dependence (FTND), Hooked on Nicotine Checklist (HONC), , Minnesota Nicotine Withdrawal 
Scale (MNWS)
2.0
Background 
2.1
Scientific Background and Gaps
Tobacco use remains the single biggest cause of preventable morbidity and mortality in the United 
States,(1) and cigarettes are by far the most commonly used tobacco product. For example, among all 
adults in the PATH Wave1 survey, 16% were daily users of cigarettes with the next most commonly used 
product being smokeless tobacco, at 1.8% of adults using daily.(2) A product standard for combustible 
tobacco products that limits the permissible nicotine content to a level that significantly reduces their 
addictiveness has the potential to significantly reduce the harms to public health from tobacco use in 
the United States.(3-5) The Family Smoking Prevention and Tobacco Control Act gave the FDA 
jurisdiction to implement such a product standard for cigarettes and other combustible tobacco 
products. The primary rationale for reducing the permissible nicotine content is to minimize the uptake 
and addictive use of cigarettes by new cohorts of young people.(6, 7) At the very least such a policy 
should not do harm to current smokers, particularly to vulnerable populations.  A number of studies of 
reduced nicotine content cigarettes have now taken place and we have recently completed our own 
trials.(5, 8-10) However, very few trials to date have provided evidence on two key questions where 
gaps in our scientific knowledge remain.  First, we do not know what the effects may be of immediate 
(as opposed to gradual) switching to VLNC cigarettes in SMHC. Second, when switching to VLNC 
cigarettes, no investigations have been conducted in a more realistic manner that enables systematic 
study of the effects of access to e-cigs.  This trial will be significant and innovative as it will be the first 
ever randomized controlled trial to provide evidence of immediate switching to VLNC cigarettes in 
SMHCs while systematically studying the impact of access to e-cigs. 
It has long been recognized that adults with mental health conditions are much more likely to smoke 
cigarettes than those without mental health conditions. Over time, those with mental health conditions 
are comprising a larger proportion of the remaining smokers.(11) For example, the current smoking 
prevalence among people without serious psychological distress fell from 20% in 2005 to 14% in 2015, 
whereas among people with serious psychological distress it stayed the same (42% vs. 41%) and actually 
increased for men.(12) The high smoking rates among people with mental health conditions is an 
important reason for large health disparities between people with serious mental health problems and 
those without, particularly in life expectancy.(13) Recent studies suggest that people with mental health 
conditions are similarly more likely to try, and to continue to use, e-cigs.(14, 15) For FDA to implement a 
reduced nicotine standard for combusted tobacco products it must possess reliable scientific data to 
estimate the likely public health effects in the real-world context of e-cig availability. In particular, FDA 
will need to know the health and addiction effects on SMHC. The proposed study will provide the data 
for this growing segment of the smoking population.  
Over the past 10 years, e-cigs have become increasingly popular in the U.S. where more than 79% of 
U.S. adults are currently aware of the devices and 3.7% are using one on a regular basis.(16) Current 
every-day or someday e-cig use is most prevalent among current smokers (15.9%) and recent ex-
smokers (22.0%) and is very uncommon among adult never cigarette smokers (0.4%).(16-18) E-cigs are 
battery-powered devices that heat and vaporize a liquid mixture (e-liquid), typically containing a vehicle 
such as propylene glycol (PG) and/or vegetable glycerin (VG) and often, but not always, nicotine and/or 
flavorings, to produce an aerosol that is inhaled by the user. E-cigs can expose users to several chemicals 
known to have adverse health effects including nicotine, carbonyls, and volatile organic compounds 
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(VOCs). The health effects of heated and aerosolized constituents of e-cig liquids, including solvents, 
flavors, and toxicants, are not completely understood.(19) However, some studies suggest e-cigs, when 
used exclusively, have a more favorable toxicity profile than tobacco cigarettes.(20, 21)  E-cigs have 
become increasingly popular among cigarette smokers, particularly SMHC. For example, in the PATH 
Wave 1 survey, cigarettes plus e-cigs was by far the most common pattern of combined use.(2) In a large 
population survey from 2015, people with a mental health condition were twice as likely to be current 
cigarette smokers and twice as likely to be current e-cig users as people without a mental health 
condition.(14) This study aims to assess the likely health effects of a product standard lowering the 
nicotine content of cigarettes in SMHC when having access to e-cigs.
It is highly likely that in a scenario in which FDA issued a product standard requiring only very low 
nicotine content in cigarettes, existing smokers may attempt to supplement their nicotine from 
alternative sources. Given the current prevalence of e-cig use among current and former smokers, they 
are a prime candidate for such a source. To date, most studies designed to evaluate the likely effects of 
a low nicotine product standard for cigarettes have required participants to only use the specially 
designed reduced nicotine content cigarettes without supplementation from their own cigarettes or any 
other nicotine sources.(4, 8) This was a reasonable research design, however it has become clear that a 
significant proportion of those allocated to smoke only VLNC cigarettes were non-compliant, as their 
cotinine concentrations could not realistically be obtained from smoking only VLNC cigarettes.(22, 23) It 
seems most likely that the participants “topped off” their nicotine levels by occasionally smoking normal 
nicotine cigarettes. In the real world, if a product standard requiring only VLNC in cigarettes were to be 
implemented it is likely that alternate nicotine products, such as e-cigs, would also be available, so it is 
important to examine the patterns of product use and the resulting effects on biomarkers of toxicant 
exposure in that situation.
An initial feasibility trial of the reduced nicotine standard randomized smokers to 8 weeks of either NNC 
cigarettes or VLNC cigarettes and provided participants with access to alternative nicotine sources 
(either a variety of non-combusted products or a variety that included combusted products).(24) In this 
study, e-cigs were the most commonly selected alternative nicotine products used in all groups, and 
those allocated to VLNC cigarettes used more alternative products, had greater reductions in smoking 
rates and greater reductions in NNAL and exhaled CO compared with NNC cigarettes.(24) These results 
support the presumption that a reduced nicotine standard for cigarettes will likely lead to increased use 
of e-cigs and suggests that access to non-combusted nicotine products may enhance the effects of VLNC 
cigarettes leading to reduced smoking and toxicant exposure. The Donny and Hatsukami research group 
(CENIC) is currently preparing to implement two funded trials of reduced nicotine cigarettes in the 
context of alternative nicotine availability.  However, there are no such trials focusing on the effects of 
VLNC cigarettes on smoking behavior and toxicant exposure specifically among SMHC, a vulnerable 
population that requires specialized investigations focused on how nicotine reduction may impact their 
mental health and smoking behavior.  The current trial is designed to provide this much needed 
evidence.      
2.2
Previous Data
Below, we summarize key relevant findings from our team’s recent research, which leads to both our 
interest and expertise in conducting this proposed study. 
Research on Reduced Nicotine Content Cigarettes. In our recently completed trial, participants were 
randomly assigned to smoke either (a) NNC cigarettes (11.6 mg/cig); or b) Reduced Nicotine Content 
(RNC) cigarettes where the nicotine content per cigarette is progressively reduced to 0.2 mg/cig in five 
steps over 18 weeks.  Participants were then offered the choice to either (a) quit smoking with 
assistance, (b) continue smoking the research cigarettes, or (c) return to their own cigarettes, and were 
followed up for a further 12 weeks.  After controlling for the baseline measure, plasma cotinine, exhaled 
CO and FTND score were all significantly lower at the end of randomized phase in the RNC group as 
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compared to the NNC group. Measures of nicotine dependence (mean cigarettes smoked per day, Penn 
State Cigarette Dependence Index) were significantly lower at the end of the randomized phase in the 
RNC group, as compared to the NNC group (p<0.003), whereas measures of psychiatric problems (CES-D 
depression score, QIDS depression score, OASIS anxiety score and MNWS nicotine withdrawal score) 
showed no significant change in the RNC group as compared to the NNC group. Analyses focusing on 
those participants who were compliant with exclusive use of research cigarettes throughout the 
randomized phase of the trial (in the RNC group having a reduction in mean cotinine from 245 ng/ml at 
visit 4 to 8 ng/ml at visit 10), found an almost identical pattern of results to the randomized phase 
completer analysis.
Treatment Choice: At the end of the randomized phase all participants were  given the choice of (a) quit 
smoking with assistance, (b) continue smoking the research cigarettes, or (c) return to their own 
cigarettes, before being followed up for a further 12 weeks. At the end of the treatment choice phase 
and the whole trial (12 weeks later), the RNC group was more likely to have quit smoking (18% [17/94] 
vs. 4% [4/94], p=0.004), based on intent-to-treat analysis including all 188 randomized participants, and 
validated by exhaled CO<9ppm. This study found that gradual switching to RNC cigarettes reduced 
dependence and toxicant exposure and enhanced smoking cessation.  In addition, there was no 
evidence that gradual switching may cause harms to the mental health of smokers with mood or anxiety 
disorders. 
Research on E-cigs. Our research on e-cigs has highlighted the important differences between different 
types of e-cig devices and liquids.(25) We have found that very few long term e-cig users continue to use 
the most popular starter “cig-a-like” brands that are approximately the same size and shape as a regular 
cigarette, as most either stop using e-cigs or transition to an advanced device characterized by a larger 
battery and a manual button.(26) Our survey studies suggested that continued use of an advanced 
generation e-cig device is at least partly driven by nicotine delivery (e.g., 77% switched to their current 
device in order to obtain a “more satisfying hit”).(26)
Both our NIH-funded Tobacco Center of Regulatory Science grant (P50-DA-036107) and our 
collaboration with the Virginia Commonwealth University TCORS (P50-DA-036105) have enabled us to 
explore new approaches for assessing the toxicity and addictive effects of electronic and tobacco 
cigarettes. For example, we used electron paramagnetic resonance spectroscopy (EPR) to measure free 
radicals in aerosols from different e-cigs, liquids, and “dry puffing”. The results demonstrated, for the 
first time, the production of highly oxidizing free radicals from e-cigs which may present a potential 
cardiopulmonary risk to e-cig users.(27) We have also undertaken laboratory studies comparing the 
nicotine absorption in experienced e-cig users using their own brands/liquids, with that of experienced 
cigarette smokers. We have published on the brain fMRI effects of the e-cigs,(28, 29) and perhaps the 
most significant result from these studies was the marked variability in nicotine absorption from 
different e-cigs, despite the fact that all were regular daily users using e-cigs with a nicotine 
concentration in the liquid of at least 12 mg/ml, and all used a standardized puffing protocol (30 puffs 
over 10 minutes). Results found some participants obtained cigarette-like nicotine absorption, others 
obtained almost no increase in blood nicotine level. 
When we analyzed the nicotine absorption by a-priori e-cig type categorizations it was clear that 
cigarette smokers obtained more consistently high and rapid nicotine absorption. Users of advanced e-
cigs also obtained significantly higher nicotine absorption than users of first generation or “cig-a-like” 
brands, who absorbed minimal nicotine. These laboratory results are consistent with our survey results, 
demonstrating that e-cig users are likely to gravitate toward devices with characteristics that result in 
more efficient and rapid nicotine absorption (such as a larger more powerful battery). Our team has also 
developed a new questionnaire to measure dependence on e-cigs. In a collaborative study with Yale and 
other TCORS on 1,009 e-cig users, the 10-item Penn State Electronic Cigarette Dependence Index 
(PSECDI) correlated +0.7 with a new e-cig version of the 22-item PROMIS Nicotine Dependence 
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items.(30)  In addition, in a large sample of current exclusive e-cig users recruited online (n=3609), we 
have used the PSECDI to demonstrate that regular e-cig users are less dependent on e-cigs than they 
retrospectively report having been on cigarettes prior to switching.(31) Recently, we replicated a similar 
pattern of results based on analysis of a comparison of nicotine dependence among exclusive daily e-cig 
users and exclusive daily cigarette smokers identified in a nationally representative sample recruited to 
the Wave 1 of the PATH study.(32)
In a collaborative TCORS project, we were one of two sites in a large randomized controlled trial to 
examine the effects of e-cigs on toxicant exposure.  Along with Virginia Commonwealth University,(33) 
this trial involves recruiting 520 smokers interested in reducing their smoking (not quitting) and 
randomizing to one of 4 conditions (a cigarette substitute, or an e-cig containing 0, 8 or 36 mg/ml 
nicotine liquid) including 12 visits over 9 months. The Penn State site has exceeded original recruitment 
targets and recruited 320 of the overall planned 520 participants in that trial. The trial includes a 
number of health risk measures, including NNAL (primary outcome), expired air carbon monoxide (CO), 
nicotine (via its metabolite cotinine in urine), biochemical and hematologic health indices such as C-
reactive protein (CRP), pulmonary function (via spirometry), and biomarkers of oxidative stress (e.g. 
glutathione). Main outcome results are currently being analyzed. 
2.3
Study Rationale
We believe that a product standard restricting the permissible nicotine content for cigarettes and other 
combustible products offers major potential public health benefits both by reducing cigarette uptake in 
future generations of young people and by reducing dependence, cigarette consumption and therefore 
toxicant exposure  among existing smokers. However, the effects of an immediate significant drop in 
cigarette nicotine content needs to be studied in SMHC because of their increased dependence on 
nicotine and vulnerability to nicotine withdrawal. In addition, the potential impact of e-cig availability in 
response to a reduced nicotine standard also needs to be evaluated due to the increasingly widespread 
use of e-cigs and their potential health effects.  We believe that by using a double-blind randomized-trial 
design with long term (16 weeks) access to both research cigarettes and e-cigs, and comprehensive 
biomarker measurement in smokers with a variety of current and recent mental disorders, we will be 
able to thoroughly assess the effects of switching to VLNC cigarettes in this vulnerable population in a 
more comprehensive manner than has previously been achieved. The outcomes of this novel project will 
directly inform FDA on the feasibility of a low nicotine standard for cigarettes in SMHC. 
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion Criteria
1.
Ages of 21–70
2.
Smoke >5 cigarettes per day for at least the prior 12 months 
3.
Smoke regular, filtered cigarettes or machine rolled cigarettes with a filter
4.
Exhaled CO measurement of ≥ 6 parts per million at baseline
5.
No serious cigarette smoking quit attempt or use of any FDA-approved smoking cessation 
medication in the prior 30 days (includes any nicotine replacement, varenicline, bupropion [used 
specifically as a quitting aid])
6.
No plans to quit smoking within the next 3 weeks
7.
History of a mental health condition like depression, anxiety, panic attacks, ADHD, schizophrenia, an 
eating disorder, or any other mental health condition and/or have a past history of receiving 
treatment, counseling or medication for a mental health condition
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8.
Must be willing to both switch to a different type of cigarette that may contain a different amount 
of nicotine and to try an e-cig to substitute for some of their cigarettes
9.
Must be willing and able to respond to contacts from study staff or attend visits over the study 
period (not planning to move, not planning extended vacation, no planned surgeries)
10. Must meet lifetime diagnostic criteria for a current or lifetime unipolar or bipolar mood disorder 
(e.g. major depressive disorder, major depressive episode, manic episode, hypomanic episode, 
bipolar disorder), an anxiety disorder (e.g. panic disorder, obsessive-compulsive disorder, post-
traumatic stress disorder, , agoraphobia, social anxiety disorder, generalized anxiety disorder), a 
psychotic disorder (e.g. mood disorder or other psychotic disorder), or an eating disorder (e.g. 
anorexia or bulimia) based on the MINI-International Neuropsychiatric Interview Standard (version 
7.0.2).(34) 
11. Able to read and write in English 
12. Able to understand and give informed consent
13. Access to a computer/smartphone with e-mail and a reliable internet connection
3.2
Exclusion Criteria
1.
Women who are pregnant and/or nursing or trying to become pregnant
2.
Unstable or significant medical condition in the past 3 months (e.g., recent heart attack or other 
serious heart condition, stroke, severe angina) 
3.
High blood pressure (systolic >159 mmHg or diastolic >99 mmHg during screening)
4.
Respiratory diseases (e.g., exacerbations of asthma or COPD, require oxygen, require oral 
prednisone), kidney (e.g., dialysis) or liver disease (e.g., cirrhosis), severe immune system disorders 
(e.g., uncontrolled HIV/AIDS, multiple sclerosis symptoms) or any medical disorder/medication that 
may affect participant safety or biomarker data
5.
Uncontrolled mental illness or substance abuse, or inpatient treatment for these in the past 
6 months
6.
Use of any non-cigarette nicotine delivery product (e.g., pipe, cigar, dip, chew, snus, hookah, e-cig, 
strips or sticks, IQOS) in the past 7 days  at screening
7.
Use of an e-cig for 5 or more days in the past 28 days or any use in the past 7 days at screening
8.
Use of marijuana for non-medical use or other illegal drugs/prescription drugs for non-medical use 
daily/almost daily or weekly in the past 3 months per NIDA Quick Screen
9.
Use of medical marijuana that is smoked (combusted) or use of recreational (illegal) THC vaping 
products
10. Any known allergy to propylene glycol or vegetable glycerin
11. Surgery requiring general anesthesia in the past 6 weeks
12. Unwilling to remain on one flavor of cigarette (regular or menthol) for the duration of the trial
13. Previous use of SPECTRUM research cigarettes in the past 6 months 
14. Other member of household currently participating in the study
15. History of a seizure disorder or had a seizure in the past 12 months
16. Currently taking or have taken medications prescribed to prevent seizures (such as Carbamazepine 
or Phenobarbital).  Using seizure medications for off-label use (indications other than treatment for 
seizures) will not be included as an exclusion, these will be assessed on a case-by-case basis
3.3
Early Withdrawal of Subjects
3.3.1
Criteria for removal from study
The PI reserves the right to remove a participant from the study for any reason, based on their 
discretion.
Criteria for withdrawal prior to randomization
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
Participant reports using non-cigarette nicotine products at Visit 2 AND Visit 3. 
Includes cigars, pipes, snuff, chew, hookah, electronic cigarette, marijuana, IQOS, or any 
other illegal smoked substance, or any other nicotine containing product.

Participant’s total cigarette consumption includes more than 10% of non-research 
cigarettes at Visit 3 

Participant has reduced their cigarette consumption by more than 50% compared to 
baseline (Visit 1) cigarettes per day (CPD) at Visit 2 or Visit 3.  This does not include 
situations of illness or other circumstances that would interfere with the participants’ 
normal smoking behavior. 

Participant must have smoked a total of 25 or more cigarettes in the past 6 days at 
Visit 2 and Visit 3. This does not include situations of illness or other circumstances that 
would interfere with the participants’ normal smoking behavior.  

Reporting a quit attempt
These circumstances of withdrawal may be taken on a case-by-case basis and actual 
withdrawal of the participant will be decided by the researcher.  For example, continuation in 
the study may be possible if the participant has acted in good faith during the study.
Criteria for general withdrawal
Participants may be discontinued by the PI at any point during the study for the following 
reasons:

Missing their randomization visit: If a participant misses Visit 3, the participant will be 
considered for withdrawal from the study. 

New pregnancy: Participants who report a new pregnancy at any point during the study 
will be withdrawn. (Except Visit 7; Note: no study products will be provided to the 
participant at Visit 7)

Suicide attempt: If at any time during the study it is discovered that a participant has 
made a suicide attempt, they will be withdrawn from the study. 

Cardiovascular disease (CVD) event requiring inpatient hospitalization: CVD 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). 

DVT/PE (deep vein thrombosis/pulmonary embolism, i.e., blood clots in the venous 
system) requiring inpatient hospitalization. 

Elevated blood pressure at any visit (systolic >159 mmHg or diastolic >99 mmHg). 

Adverse events related to e-cig use: Adverse events will be monitored at every study 
visit. 

Significant smoking rate increase compared to baseline: A participant will be 
withdrawn from the study if they meet BOTH of the following criteria (any visit prior to 
Visit 7):
o
The average cigarette per day (CPD) increase by more than 100% from the 
average CPD at Visit 1
o
The average of two consecutive expired breath carbon monoxide 
measurements increase according to the following: 

CO is greater than 50 ppm if CO at Visit 1 is <20 ppm.

CO is greater than 60 ppm if CO at Visit 1 is 20 – 34 ppm.

CO is greater than 70 ppm if CO at Visit 1 is 35 – 49 ppm.

CO is greater than 80 ppm if CO at Visit 1 is 50 – 60 ppm.
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
CO is greater than 90 ppm if CO at Visit 1 is 61 – 70 ppm.

CO is greater than 100 ppm if CO at Visit 1 is 71-80 ppm.

CO is greater than 110 ppm if CO at Visit 1 is 81-90 ppm.

CO is greater than 120 ppm if CO at Visit 1 is 91-100 ppm.

Worsening substance abuse in which the participant is behaving inappropriately at 
visits or demonstrates an inability to continue with the study. 

Any inpatient 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 (this could include recovery from a major 
surgery, worsening of psychiatric symptoms, etc.). 

Use of recreational (illegal) THC products that are vaped.

Participant choice: Participants may choose to remove themselves from the study by 
informing the research team verbally or in writing at any point during the study. 

Participant behavior: 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, appears/admits to 
giving away/selling study products, consistently loses study products etc., then the PI 
can withdraw him/her from the study at the PI’s discretion. 
3.3.2
Follow-up for withdrawn subjects
If participants are withdrawn from the study for any of the reasons noted above prior to 
randomization, they will be replaced until a total of 240 participants have been randomized to 
the study. Subjects who withdraw themselves or are withdrawn from the study at a visit will be 
asked to complete the study visit including a questionnaire regarding the reasons for dropping 
out.  
For participants who withdraw themselves from the study, they will be asked if we can follow up 
with them at the week 16 visit.  We will contact them via one call, message, and letter to 
complete the week 16 visit.  If they wish not to be contacted to complete the week 16 visit, they 
will not be contacted.  
If participants are lost to follow-up (i.e. simply do not respond to calls or letters without formally 
withdrawing) one final attempt will be made to contact them for the week 16 visit via one call, 
message and letter. If they complete the week 16 visit they will also be invited to the final (week 
20) visit. 
4.0
Recruitment Methods
4.1
Identification of subjects
Recruitment for this study will be facilitated through IRB STUDY00002213 (Study name:  Call Routing 
Screener) which will also serve as the initial recruitment point of contact.  We will also use Studyfinder 
to identify participants.  Studyfinder is a web-based recruitment tool for Penn State researchers, 
managed and sponsored by Penn State Clinical Translational Science Institute (CTSI).  The study team is 
enrolling subjects with mental health disorders.  
This study will also identify subjects through the Penn State Health electronic medical record.  Penn 
State EIM will release a data report of patients who have been diagnosed with nicotine dependence and 
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either depression or generalized anxiety. Only those who have had a patient visit in the past 3 years will 
be included.  The report will include patient contact information (i.e. phone number, email address, and 
address).  Researchers will reach out to potential participants through these avenues to let them know 
about the study opportunity.  
4.2
Recruitment process
The methods of recruitment for this study are included in IRB STUDY00002213 in addition to 
Studyfinder.  Interested volunteers will call the study center number (or fill out the survey online) to 
complete the eligibility script and questions for IRB STUDY00002213. If a participant’s responses match 
this study’s specified inclusion criteria they will be forwarded to research staff for further screening.  In 
addition, if a participant matches this study’s specified inclusion criteria from the questions in IRB 
STUDY00002213, they will be emailed a recruitment message with details about this study (see 
recruitment email uploaded under Recruitment Materials).    Researchers will also identify potential 
participants from the EIM data report generated from the EMR.
The coordinator will attempt to call a participant for screening into this study.  If the coordinator cannot 
connect with the participant through phone, they will follow up the phone call with a text message.  The 
text message will state the researcher’s purpose of the phone call and if the participant is interested in 
hearing details about the study, they can text the phone number back with a convenient time for the 
coordinator to call.  The purpose of the text message is to determine the best time to contact 
participants based on their schedule.  
4.2.1
How potential subjects will be recruited.
Recruitment for this study will be facilitated through IRB STUDY00002213.  Details on how 
participants will be recruited and recruitment materials are in IRB STUDY00002213.  Our study details 
will also be listed on Studyfinder.  Participants who qualify for this study that are recruited through IRB 
STUDY00002213 will receive a recruitment email message with details of this study.
4.2.2
Where potential subjects will be recruited.
Recruitment for this study will be facilitated through IRB STUDY00002213. Details on where 
participants will be recruited are in IRB STUDY00002213.  Potential participants will also be recruited 
through Penn State’s Studyfinder website (studyfinder.psu.edu).
4.2.3
When potential subjects will be recruited.
Recruitment for this study will be facilitated through IRB STUDY00002213. Details on when 
participants will be recruited are in IRB STUDY00002213.  While enrollment is open, details of the study 
will be listed on Studyfinder.
4.2.4
Describe the eligibility screening process and indicate whether the screening process will 
occur before or after obtaining informed consent. Screening begins when the investigator 
obtains information about or from a prospective participant in order to determine their 
eligibility.  In some studies, these procedures may not take place unless HIPAA Authorization 
is obtained OR a waiver of HIPAA Authorization when applicable for the screening procedures 
is approved by the IRB.  
1.
Call Routing Screener in IRB STUDY00002213 (Phone or online survey): We will consider 
the screening process and eligibility questions in IRB STUDY00002213 as Screening #1. This 
process includes a brief phone or online survey screening to determine basic eligibility for 
any of our study center protocols. Based on their answers to the questions participants will 
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be routed to this study.  Then, participants will complete the screening for this study in two 
additional steps. 
2.
Project Screener 1 (Phone, Email, Text): Participants will be contacted by researchers via 
phone, email, or text to complete the Project Screener 1.  Those contacted via phone will 
complete the screening questions over the phone with the researcher, while those 
contacted by email or text will be provided a REDCap link to complete the screening 
questions online on their own . A full script and screening questions specific to this study are 
in the “Consent Forms and Recruitment Materials” section of the IRB application. If a 
participant has met basic eligibility criteria, they will be scheduled to come into the study 
center for their first visit.
The data collected from screening will be kept to understand reasons why people cannot 
participate.  Data may be used for future research.  All data will be de-identified before 
future use.
3.
Project Screener 2 (In person at Visit 1): At Visit 1 they will be re-screened using Screener 1.  
If the participant’s answers have changed from the phone screener (Screener 1) and they 
are no longer eligible, they will be informed that they cannot participate. If they remain 
eligible, they will be consented to the study and further screened for eligibility. A full script 
and screening questions are uploaded in the “Consent Forms and Recruitment Materials” 
section of the IRB application.
5.0
Consent Process and Documentation 
5.1
Consent Process:
Check all applicable boxes below:
 Informed consent will be sought and documented with a written consent form [Complete Sections 
5.2 and 5.6] 
 Implied or verbal consent will be obtained – subjects will not sign a consent form (waiver of 
written documentation of consent) [Complete Sections 5.2, 5.3 and 5.6] 
  Informed consent will be sought but some of the elements of informed consent will be omitted or 
altered (e.g., deception). [Complete section 5.2, 5.4 and 5.6] 
 Informed consent will not be obtained – request to completely waive the informed consent 
requirement. [Complete Section 5.5]
5.2
Obtaining Informed Consent 
5.2.1
Timing and Location of Consent 
When participants attend Visit 1, they will have the study explained to them in detail, have the 
opportunity to ask questions, and then will be asked to sign the consent form. This will take 
place in a private clinic room at the Penn State Clinical Research Center.
Procedures during COVID-19:
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We will use the verbal consent obtained during the Phone Screener 1 for the Remote Visit 1 
procedures.  At the in-person Visit 2 we will collect written consent.  They will have the study 
explained to them in detail, have the opportunity to ask questions, and then will be asked to 
sign the consent form. This will take place in a private clinic room at the Penn State Clinical 
Research Center.
5.2.2
Coercion or Undue Influence during Consent 
Once potential study volunteers are identified, they will be given information about the study 
and offered the opportunity to participate. The researchers obtaining consent will be instructed 
to clearly indicate that the participant’s enrolling in the trial is purely voluntary and the 
researchers will not offer comments about whether they believe the participant should enroll in 
the study or not. Given the number of contacts and visits involved in the study protocol, the 
compensation provided to the participant is modest.
5.3
Waiver of Written Documentation of Consent 
5.3.1
Indicate which of the following conditions applies to this research:
  The research presents no more that minimal risk of harm to subjects and involves no 
procedures for which written consent is normally required outside of the research context.
OR
  The only record linking the subject and the research would be the consent document and the 
principal risk would be potential harm resulting from a breach of confidentiality. Each subject 
will be asked whether the subject wants documentation linking the subject with the research, 
and the subject’s wishes will govern. (Note: This condition is not applicable for FDA-regulated 
research. If this category is chosen, include copies of a consent form and /or parental 
permission form for participants who want written documentation linking them to the 
research.)
OR
  If the subjects or legally authorized representatives are members of a distinct cultural group 
or community in which signing forms is not the norm, that the research presents no more 
than minimal risk of harm to subjects and provided there is an appropriate alternative 
mechanism for documenting that informed consent was obtained.  (Note: This condition is not 
applicable for FDA-regulated research.) 
Describe the alternative mechanism for documenting that informed consent was obtained:
For participants determined to be eligible, a study visit will be made where they will complete 
a written consent form.
5.3.2
Indicate what materials, if any, will be used to inform potential subjects about the research 
(e.g., a letter accompanying a questionnaire, verbal script, implied consent form, or summary 
explanation of the research)
A verbal phone script will be used to inform potential subjects about the research and is 
uploaded in the Screener 1 document under Local Site Documents Question 2. 
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5.4
Informed consent will be sought but some of the elements of informed consent will be omitted or 
altered (e.g., deception).
5.4.1
Indicate the elements of informed consent to be omitted or altered
N/A
5.4.2
Indicate why the research could not practicably be carried out without the omission or 
alteration of consent elements
N/A
5.4.3
Describe why the research involves no more than minimal risk to subjects.
N/A
5.4.4
Describe why the alteration/omission will not adversely affect the rights and welfare of 
subjects.
N/A
5.4.5
If the research involves using identifiable private information or identifiable biospecimens, 
describe why the research could not be practicably be carried out without using such 
information or biospecimens in an identifiable format.
N/A
5.4.6
Debriefing 
N/A
5.5
Informed consent will not be obtained – request to completely waive the informed consent 
requirement
N/A
5.5.1
Indicate why the research could not practicably be carried out without the waiver of consent
N/A
5.5.2
Describe why the research involves no more than minimal risk to subjects.
N/A
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5.5.3
Describe why the alteration/omission will not adversely affect the rights and welfare of 
subjects.
N/A
5.5.4
If the research involves using identifiable private information or identifiable biospecimens, 
describe why the research could not be practicably be carried out without using such 
information or biospecimens in an identifiable format.
N/A
5.5.5
Additional pertinent information after participation
N/A
5.6
Consent – Other Considerations 
5.6.1
Non-English-Speaking Subjects
N/A
5.6.2
Cognitively Impaired Adults
5.6.2.1 Capability of Providing Consent
N/A
5.6.2.2
Adults Unable to Consent
N/A
5.6.2.3 Assent of Adults Unable to Consent
N/A
5.6.3
Subjects who are not yet adults (infants, children, teenagers) 
5.6.3.1 Parental Permission
N/A
5.6.3.2 Assent of subjects who are not yet adults
N/A
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
Check all that apply:
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Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable]
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable]
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3]
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3]
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3]
6.2
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
6.2.1
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual
6.2.1.1
Plan to protect PHI from improper use or disclosure
Information is included in the Research Data Plan Review Form
6.2.1.2
Plan to destroy identifiers or a justification for retaining identifiers 
All study data will be retained indefinitely.
6.2.2
Explanation for why the research could not practicably be conducted without access to and 
use of PHI
Screener 1 will be used to check eligibility criteria (date of birth), and when participants are 
screened, their contact information will be used to follow-up about scheduling and for 
appointment reminders. This requires that we have complete contact (name, phone number, 
address) information.
6.2.3
Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization
In order to screen the participants prior to inviting them into the study center, the investigators 
are conducting a phone screen to determine if the participants are likely to be eligible for the 
study.
Procedures during COVID-19:  In order to minimize in person face-to-face participant contact we 
are conducting Visit 1 study procedures remotely (Remote Visit 1) and written consent is not 
obtainable until in-person Visit 2.
6.3
Waiver or alteration of authorization statements of agreement
Protected health information obtained as part of this research will not be reused or disclosed to any 
other person or entity, except as required by law, for authorized oversight of the research study, or for 
other permitted uses and disclosures according to federal regulations. 
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The research team will collect only information essential to the study and in accord with the ‘Minimum 
Necessary’ standard (information reasonably necessary to accomplish the objectives of the research) per 
federal regulations. 
Access to the information will be limited, to the greatest extent possible, within the research team. All 
disclosures or releases of identifiable information granted under this waiver will be accounted for and 
documented.
7.0
Study Design and Procedures
7.1
Study Design
We propose to conduct a parallel-group, randomized, double-blind, 2-by-2 controlled trial in which 240 
current SMHC will be randomized to one of 4 groups: 1) normal nicotine content cigarettes (NNCs) and 
nicotine containing e-cigs; 2) NNCs and zero nicotine e-cigs; 3) very low nicotine content cigarettes 
(VLNCs) and nicotine containing e-cigs 4) VLNCs and zero nicotine e-cigs.  
After baseline phases on own cigarettes (one week) and NNCs (2 weeks), participants will be 
randomized to one of these four groups and will attend visits every 4 weeks for 16 weeks, at which point 
the main study outcome measures will be assessed. All participants will be followed up with a study visit 
4 weeks after the final randomized visit to identify whether they have continued to use e-cigs/cigarettes 
and to assess their motivation in smoking abstinence.
7.2
Study Procedures
All study visits will occur in a private clinic room in the Penn State Clinical Research Center.
Procedures during COVID-19:
Visits 1, 6, and 8 will be done remotely either over Penn State Health Zoom or over the telephone. Questionnaires will 
be administered via e-mailed or texted link to REDCap, and completed on the participant’s own computer/cell-phone, 
with their answers securely saved in REDCap. All other study visits will occur in a private clinic room in the Penn State 
Clinical Research Center.
Once in-person research is allowed again, the study will return to previously approved procedures.
Based on the restrictions set by the Dean (Participant mask removal must PAUSE for all observational 
studies at the College of Medicine), the study team will no longer perform exhaled CO or PFT tests 
during visits.  With this modification there will be no need for participants to take off their mask during 
study visits.  Once the restrictions are lifted, the study team will go back to collecting these samples 
during the study visit.
Visit 1 (Week -3)
During Visit 1, participants will be screened in person using Screener 2.  They will be asked to 
provide photo ID to verify the age given in Screener 2.  If the participant meets eligibility using 
Screener 2 they will be asked to provide informed consent.  Informed consent will be obtained 
by research staff. During this process, the usual discussion of procedure, risks, side effects, 
confidentiality, voluntary participation, and right to refuse participation without prejudice will 
be explained to the participant. Participants must be capable of understanding the nature of this 
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study, its potential risks, discomforts and benefits before signing consent. Participants will 
receive a signed copy of the form.   
Once the informed consent is obtained the following information will be collected to determine 
the final eligibility in accordance with inclusion/exclusion criteria mentioned above:
1.
Measure exhaled CO
2.
Obtain urine sample for pregnancy determination for women of child-bearing potential 
(those who have had a period in the past 12 months) and who have not had a hysterectomy
3.
Obtain medical and concomitant medication histories
4.
NIDA Drug Screener
5.
Measure vital signs (blood pressure and heart rate)
6.
Administer all modules in the Mini International Neuropsychiatric Interview (MINI) and 
current suicide risk assessment (see MINI Standard (version 7.0.2) document).  Researchers 
will administer the MINI mental health diagnostic tool electronically through the nView 
Health online application.   Procedure for suicide risk at screening: If a participant scores ≥9 
on the MINI suicide module the Psychiatric Medical Monitor (Dr. Ahmad Hameed) will be 
contacted.  The researcher will discuss the score with the Psychiatric Medical Monitor and 
they will determine if the participant’s enrollment into study is appropriate.  
If a participant does not meet eligibility they will be compensated for their travel.  
If a participant meets all the eligibility criteria they will be asked to complete questionnaires via 
an electronic survey in REDCap or administered by a study coordinator.  See Table 1 for 
questionnaires and biomeasures collected at this visit.  Participants will be given a laptop with 
access only to the internet and an individualized REDCap survey will be opened so they can 
complete direct data entry.  The study staff will review the study guidelines and provide 
participants with instructions on how to keep track of the number of their usual brand cigarettes 
smoked each day for one week by using a cigarette log.  All participants will be asked to refrain 
from using non-study tobacco/nicotine products or other smoked products during the study, but 
are encouraged to report the use of these products to the study staff.  The next study visit will 
be scheduled for one week later.  Participants will receive a print out of their upcoming study 
contacts and visits.  Participants will be compensated for completing the study visit and 
procedures.
Table 1: Time and events schedule with measures, questionnaires, and biomarkers 
Phase
Baseline
Randomized
Follow 
up
Study Visit Number
1
2
3
Phone
4
5
6
7
8
Study Week Number
-3
-2
0
1
4
8
12
16
20
Measures/Questionnaires
Study and Non-Study Product Use
E-cig and Cigarette Use log
X
X
X
X
X
X
X
X
Cigarette liking scales (35)
X
X
X
E-cig Patterns of Use, E-cig Side Effects, E-cig Evaluation, E-cig 
Dependence (PSECDI), 
X
X
X
X
X
E-cig Perceived Health Risk Rating
X
X
X
E- cig details
X
Basic participant and smoking characteristics
Demographics (including Social Determinates of Health [SDOH])
X
Tobacco use history, cigarette details
X
Medical History
X
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NIDA Drug Use (36)
X
X
AUDIT-C(37, 38)
X
X
Environmental tobacco smoke questionnaire (39)
X
Cigarette Perceived Health Risk 
X
X
X
X
Nicotine dependence (FTND, HONC, PSCDI (31, 40, 41))
X
X
X
X
X
X
X
Nicotine Use Disorder
X
X
PROMIS Dependence
X
X
Minnesota Nicotine Withdrawal Scale (42)
X
X
X
X
X
X
X
Questionnaire of Smoking Urges (QSU) (43, 44)
X
X
X
X
X
X
Confidence to Quit
X
X
Mental Health and Wellbeing
MINI International Neuropsychiatric Interview (MINI) (34)
X
Kessler K6 scale (45, 46)
X
X
X
X
X
X
X
CES-D, QIDS (depression) (47) (48)
X
X
X
X
X
X
Overall Anxiety Severity Impairment Scale (OASIS) (49)
X
X
X
X
Perceived Stress Scale (50)
X
X
X
X
Positive and Negative Syndrome Scale (PANSS-6) (51)
X
X
X
X
X
X
Clinical COPD questionnaire (CCQ) (52)
X
X
X
X
X
X
PROMIS Sleep Disturbance Short Form (53)
X
X
X
X
INTERHEART and WI-PREPARE (55, 56)
X
Biomeasures
Weight (57)
X
X
X
X
X
X
Height
X
Waist and hip circumference (57)
X
X
Blood Pressure, Pulse (58, 59)
X
X
X
X
X
X
X
Exhaled CO
X
X
X
X
X
X
X
X
Pulmonary function test (spirometry) (60)
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
Adverse events (61)
X
X
X
X
X
X
X
X
Biomarkers
Urine: NNAL,  Acrylonitrile (CYMA) Acrolein (3-HPMA) (20, 62, 63)
X
X
X
Pregnancy test
X
X
X
X
Procedures during COVID-19:
Remote Visit 1 (Week -3)
Remote Visit 1 will occur over Zoom or the telephone.  During Remote Visit 1, participants will 
be screened using Screener 2.  If the participant meets eligibility using Screener 2 the following 
information will be collected over Zoom or the telephone to determine eligibility in accordance 
with inclusion/exclusion criteria mentioned above:
1.
NIDA Drug Screener
2.
Obtain medical and concomitant medication histories
3.
Administer all modules in the Mini International Neuropsychiatric Interview (MINI) and 
current suicide risk assessment (see MINI Standard (version 7.0.2) document).  Researchers 
will administer the MINI mental health diagnostic tool electronically through the nView 
Health online application.   Procedure for suicide risk at screening: If a participant scores ≥9 
on the MINI suicide module the Psychiatric Medical Monitor (Dr. Ahmad Hameed) will be 
contacted.  The researcher will discuss the score with the Psychiatric Medical Monitor and 
they will determine if the participant’s enrollment into study is appropriate.
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If a participant meets the eligibility criteria they will be asked to complete questionnaires via an 
electronic survey in REDCap.  See Revised Table 1 for questionnaires collected at this visit.  
Biomeasures will not be taken.  The study staff will review the study guidelines and provide 
participants with instructions on how to keep track of the number of their usual brand cigarettes 
smoked each day for one week by using a cigarette log.  All participants will be asked to refrain 
from using non-study tobacco/nicotine products or other smoked products during the study, but 
are encouraged to report the use of these products to the study staff.  The next study visit will 
be scheduled for one week later.  
Questionnaires for Visit 2 outlined in Revised Table 1 will be sent to the participant via a survey 
link before the in-person Visit 2.  Participants will be encouraged to complete the questionnaires 
2 hours before the Visit 2, but will have up to 24 hours to complete them after the visit.  
Revised Table 1: Time and events schedule with measures, questionnaires, and biomarkers during COVID-19
Phase
Baseline
Randomized
Follow 
up
Study Visit Number
R1
2
3
Phone
4
5
R6
7
R8
Study Week Number
-3
-2
0
1
4
8
12
16
20
Measures/Questionnaires
Study and Non-Study Product Use
E-cig and Cigarette Use log
X
X
X
X
X
X
X
X
Cigarette liking scales (35)
X
X
X
E-cig Patterns of Use, E-cig Side Effects, E-cig Evaluation, E-cig 
Dependence (PSECDI), 
X
X
X
X
X
E-cig Perceived Health Risk Rating
X
X
X
E- cig details
X
Basic participant and smoking characteristics
Demographics (including Social Determinates of Health [SDOH])
X
Tobacco use history, cigarette details
X
Medical History
X
NIDA Drug Use (36)
X
X
AUDIT-C(37, 38)
X
X
Environmental tobacco smoke questionnaire (39)
X
Cigarette Perceived Health Risk 
X
X
X
X
Nicotine dependence (FTND, HONC, PSCDI (31, 40, 41))
X
X
X
X
X
X
X
Nicotine Use Disorder
X
X
PROMIS Dependence
X
X
Minnesota Nicotine Withdrawal Scale (42)
X
X
X
X
X
X
X
Questionnaire of Smoking Urges (QSU) (43, 44)
X
X
X
X
X
X
Confidence to Quit
X
X
Mental Health and Wellbeing
MINI International Neuropsychiatric Interview (MINI) (34)
X
Kessler K6 scale (45, 46)
X
X
X
X
X
X
X
CES-D, QIDS (depression) (47) (48)
X
X
X
X
X
X
Overall Anxiety Severity Impairment Scale (OASIS) (49)
X
X
X
X
Perceived Stress Scale (50)
X
X
X
X
Positive and Negative Syndrome Scale (PANSS-6) (51)
X
X
X
X
X
X
Clinical COPD questionnaire (CCQ) (52)
X
X
X
X
X
X
PROMIS Sleep Disturbance Short Form (53)
X
X
X
X
INTERHEART and WI-PREPARE (55, 56)
X
Biomeasures
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Weight (57)
X
X
X
X
X
Height
X
Waist and hip circumference (57)
X
X
Blood Pressure, Pulse (58, 59)
X
X
X
X
X
Exhaled CO
X
X
X
X
X
X
Pulmonary function test (spirometry) (60)
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
Adverse events (61)
X
X
X
X
X
X
X
X
Biomarkers
Urine: NNAL,  Acrylonitrile (CYMA) Acrolein (3-HPMA) (20, 62, 63)
X
X
X
Pregnancy test
X
X
X
X
Note: R indicates remote visit
Visit 2 (Week -2)
Participants will be asked for their cigarette log from the prior week and to complete 
questionnaires for Visit 2 outlined in Table 1. Measures will be completed electronically on a 
participant computer via REDCap or administered by a study coordinator. Participants will be 
given a laptop with access only to the internet and an individualized REDCap survey will be 
opened so they can complete direct data entry.  Biomeasures will be obtained (e.g., pulmonary 
function tests, weight, height, waist and hip, exhaled CO, blood pressure, pulse) as outlined in 
Table 1. Participants will be given SPECTRUM research cigarettes containing a normal amount of 
nicotine (11.6 mg/cigarette) matching the flavor (regular or menthol) of their usual brand of 
cigarettes to smoke for the next two weeks. Participants will receive cigarette logs to fill out 
their cigarettes smoked per day.  The number of research cigarettes provided will be 130% of 
baseline cigarettes per day in order to reduce the chance of running out. This amount may be 
changed throughout the study according to recent consumption. Participants will be asked to 
return all opened, unopened and empty cigarette packs to the study center at each visit.  All 
participants will be asked to refrain from using non-study tobacco/nicotine products or other 
smoked products during the study, but are encouraged to report the use of these products to 
the study staff.  Participants will be compensated for completing the study visit and procedures.
Procedure for suicide risk at all visits where QIDS questionnaire is administered:  If participants 
indicate an answer of > 0 on item 12 of the QIDS questionnaire, the MINI Suicide module will be 
administered.  Scores of ≥ 9 on the MINI Suicide module will require an assessment with a 
licensed clinician to document a clinical plan and a determination of retention or termination 
from the study.
Procedures during COVID-19:
Visit 2 will be completed in-person.  Participants will be screened for COVID-related symptoms 
using a modified version of the Patient Screening Questions from the Penn State Health website. 
The written informed consent process will take place in person using the paper Consent Form 
HRP-580 uploaded in the “Consent Forms and Recruitment Materials” section of the IRB 
application.  During this process, the usual discussion of procedure, risks, side effects, 
confidentiality, voluntary participation, and right to refuse participation without prejudice will 
be explained to the participant. Participants must be capable of understanding the nature of this 
study, its potential risks, discomforts and benefits before signing consent. Participants will 
receive a signed copy of the form.
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Participants will be asked to provide photo ID to verify the age given in Screener 2.  They will 
have to complete the final eligibility requirements at this visit in accordance with the 
inclusion/exclusion criteria mentioned above:  
1.
Obtain urine sample for pregnancy determination for women of child-bearing potential 
(those who have had a period in the past 12 months) and who have not had a hysterectomy
2.
Measure exhaled CO
3.
Measure vital signs (blood pressure and heart rate) 
Participants will be asked for their cigarette log from the prior week. Additional biomeasures will 
be obtained (e.g., pulmonary function tests, weight, height) as outlined in Revised Table 1. 
Participants will be given SPECTRUM research cigarettes containing a normal amount of nicotine 
(11.6 mg/cigarette) matching the flavor (regular or menthol) of their usual brand of cigarettes to 
smoke for the next two weeks. Participants will receive cigarette logs to fill out their cigarettes 
smoked per day.  The number of research cigarettes provided will be 130% of baseline cigarettes 
per day in order to reduce the chance of running out. This amount may be changed throughout 
the study according to recent consumption. Participants will be asked to return all opened, 
unopened and empty cigarette packs to the study center at each visit.  All participants will be 
asked to refrain from using non-study tobacco/nicotine products or other smoked products 
during the study, but are encouraged to report the use of these products to the study staff.  
Participants will be compensated for completing the study visit and procedures.
Procedure for suicide risk at all visits where QIDS questionnaire is administered:  If participants 
indicate an answer of > 0 on item 12 of the QIDS questionnaire, the MINI Suicide module will be 
administered.  Scores of ≥ 9 on the MINI Suicide module will require an assessment with a 
licensed clinician to document a clinical plan and a determination of retention or termination 
from the study.
Visit 3 (Week 0)
Participants will be asked for their cigarette log from the prior week and to complete 
questionnaires outlined in Table 1. Measures will be completed electronically on a participant 
computer via REDCap or administered by a study coordinator. Participants will be given a laptop 
with access only to the internet and an individualized REDCap survey will be opened so they can 
complete direct data entry.  Biomeasures will be obtained (e.g., pulmonary function tests, 
weight, exhaled CO, blood pressure, pulse) as outlined in Table 1. Urine samples will be 
collected at this visit.  A pregnancy test will be given to women of childbearing potential.
Participants who complete the Baseline Phase and are eligible to continue in the study will enter 
the Randomized Phase. They will be randomized to either  continue to smoke the same NNC 
SPECTRUM (11.6 mg nicotine) research cigarettes they smoked in the Baseline Phase or  switch 
to VLNC SPECTRUM research cigarettes (0.2 mg nicotine) AND also be randomized to either a 
nicotine-containing (5% nicotine liquid) or placebo (0% nicotine liquid)  JUUL e-cig (JUUL Labs, 
Inc.). Participants will receive a 4-week supply of research cigarettes (130% of baseline daily 
consumption) and e-liquid pods to last 28 days until the next appointment. They will be shown 
how to use the e-cig and how to charge it. Participants may be shown videos from the JUUL 
website (https://www.juul.com/learn/device) for more information on how to use and charge 
the device called, ‘How to use JUUL’ and ‘How to set up your JUUL Device’.  We will also give 
them a handout called JUUL E-Cigarette Instructions.  Within the JUUL device packaging there is 
a paper insert with instructions and information.  This insert will be given to the participant 
when we give them the JUUL device.  The study staff will give participants e-cig and cigarette 
use logs and instruct them to record daily use. Participants will be encouraged/provided advice 
to substitute some of their cigarettes with their e-cigarette.  
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All participants will be asked about their use of other nicotine/tobacco products and if they 
vaped/smoked any other substances other than nicotine/tobacco as this could affect the urine 
biomarkers collected during the study (e.g. carbon monoxide and cotinine levels). Participants 
will also be reminded to only use research cigarettes and not commercial brand cigarettes, as 
well as only using the e-liquid pods received by researchers.  Participants will be compensated 
for completing the study visit and procedures.
Between Visits 3 and 4 participants will receive a daily online REDCap survey (named E-cigarette 
and Cigarette Use Log (Online Survey Version) under Participant Entered Measures) via a text 
message to their cell phone with a link to the survey using the Twilio services.  The survey will 
ask about the number of e-cig uses, number of cigarettes smoked, and any non-study cigarettes 
smoked.  During the first week of the online survey, participants will also be asked about 
nicotine withdrawal symptoms.  If participants do not have a reliable cell phone and internet 
access they will complete the information on paper logs.
Procedures during COVID-19:
Visit 3 will be completed in-person. Participants will be screened for COVID-related symptoms 
using a modified version of the Patient Screening Questions from the Penn State Health website. 
Questionnaires for Visit 3 outlined in Revised Table 1 will be sent to the participant via a survey 
link before the in-person visit.  Participants will be encouraged to complete the questionnaires 2 
hours before the visit, but will have up to 24 hours to complete them after the visit.  Participants 
will be asked for their cigarette log from the prior week.  Biomeasures will be obtained (e.g., 
pulmonary function tests, weight, exhaled CO, blood pressure, pulse) as outlined in Revised 
Table 1. Urine samples will be collected at this visit.  A pregnancy test will be given to women of 
childbearing potential.
Participants who complete the Baseline Phase and are eligible to continue in the study will enter 
the Randomized Phase. They will be randomized to either continue to smoke the same NNC 
SPECTRUM (11.6 mg nicotine) research cigarettes they smoked in the Baseline Phase or switch 
to VLNC SPECTRUM research cigarettes (0.2 mg nicotine) AND also be randomized to either a 
nicotine-containing (5% nicotine liquid) or placebo (0% nicotine liquid)  JUUL e-cig (JUUL Labs, 
Inc.). Participants will receive a 4-week supply of research cigarettes (130% of baseline daily 
consumption) and e-liquid pods to last 28 days until the next appointment. They will be shown 
how to use the e-cig and how to charge it. Participants may be shown videos from the JUUL 
website (https://www.juul.com/learn/device) for more information on how to use and charge 
the device called, ‘How to use JUUL’ and ‘How to set up your JUUL Device’.  We will also give 
them a handout called JUUL E-Cigarette Instructions.  Within the JUUL device packaging there is 
a paper insert with instructions and information.  This insert will be given to the participant 
when we give them the JUUL device.  The study staff will give participants e-cig and cigarette 
use logs and instruct them to record daily use. Participants will be encouraged/provided advice 
to substitute some of their cigarettes with their e-cigarette.  
All participants will be asked about their use of other nicotine/tobacco products and if they 
vaped/smoked any other substances other than nicotine/tobacco as this could affect the urine 
biomarkers collected during the study (e.g. carbon monoxide and cotinine levels). Participants 
will also be reminded to only use research cigarettes and not commercial brand cigarettes, as 
well as only using the e-liquid pods received by researchers.  Participants will be compensated 
for completing the study visit and procedures. 
Between Visits 3 and 4, participants will receive a daily online REDCap survey (named E-cigarette 
and Cigarette Use Log (Online Survey Version) under Participant Entered Measures) via a text 
message to their cell phone with a link to the survey using the Twilio services.  The survey will 
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ask about the number of e-cig uses, number of cigarettes smoked, and any non-study cigarettes 
smoked.  During the first week of the online survey, participants will also be asked about 
nicotine withdrawal symptoms.  If participants do not have a reliable cell phone and internet 
access they will complete the information on paper logs.
Phone Call (Week 1)
Study staff will call participants to check in on their use of the study cigarettes/e-cig, remind 
them to use the study products, document any adverse events, and remind them to fill out their 
e-cigarette and cigarette use log on paper and through the online surveys.  If any data on the e-
cigarette and cigarette use log online survey is missing it will be collected over the phone with 
the participant.
Visit 4-7 (Weeks 4, 8, 12, 16)
Participants will return their e-cig and cigarette use log, and have a comprehensive set of 
measures recorded according to the visit (Table 1).  Measures will be completed electronically 
on a participant computer via REDCap or administered by a study coordinator. Participants will 
be given a laptop with access only to the internet and an individualized REDCap survey will be 
opened so they can complete direct data entry.  Women of child bearing potential will be 
retested for pregnancy at Visits 5 and 7.  
The study staff will give participants e-cig and cigarette use logs and instruct them to record 
daily use at each visit.  All participants will be asked about their use of other nicotine/tobacco 
products and if they vaped/smoked any other substances other than nicotine/tobacco at each 
visit as this could affect the urine biomarkers collected during the study (e.g. carbon monoxide 
and cotinine levels).  Participants will be encouraged/provided advice to substitute some of their 
cigarettes with their e-cigarette. 
Participants will receive a 4-week supply of research cigarettes (130% of daily consumption) and 
e-liquid pods to last approximately 28 days until the next appointment. Participants will be 
asked to return all opened, unopened and empty cigarette packs and all used/unused e-liquid 
pods to the study center at each visit in order to monitor use.  
At Visit 7, participants will return all used and unused research cigarette packs. No more 
cigarettes will be given.  Participants will be allowed to keep their e-cig and unused e-liquid pods 
until the next visit.  Participants will return their e-cig and cigarette use logs. Urine samples for 
biomarkers will be taken.  Participants will complete all biomeasures and questionnaires 
outlined in Table 1.  Participants will be advised to quit smoking completely and provided with 
the quitline number and sources of free/low cost nicotine replacement therapy (NRT) (see  
Cigarette Smoking Cessation Tools handout document).  The Surgeon General booklet will also 
be give (see the Consumer Surgeon General Report Booklet document). Participants will be 
asked about their plans to either (a) go back to their own cigarettes only (b) go back to own 
cigarettes but supplement with an e-cig, (c) continue using an e-cig only, or (d) quit tobacco/e-
cigs completely. Participants will be compensated for completing the study visit and procedures.
A study pulmonologist was added to the study team.  We will be monitoring lung function using 
pulmonary function testing that will be completed at Visits 4-7. Any significant worsening (10% 
worsening or greater) in pulmonary function will be documented as an adverse event.  These 
adverse events will be reviewed by the Safety Monitors in a timely manner.  In cases where the 
Safety Monitor suspects that a participant may be having a respiratory adverse event related to 
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the study product, a study pulmonologist will be consulted. The pulmonologist will make any 
needed medical recommendations and a determination regarding whether the participant is 
able to continue with the study.  For more urgent and/or serious adverse events, the Safety 
Monitor and/or the study pulmonologist will be consulted and immediate medical attention will 
be sought if needed.  
Procedures during COVID-19:
Visits 3-5 and 7 will be completed in-person.  Participants will be screened for COVID-related 
symptoms using a modified version of the Patient Screening Questions from the Penn State 
Health website. Remote Visit 6 will be completed remotely over Zoom or the telephone.  
Questionnaires for visits outlined in Revised Table 1 will be sent to the participant via a survey 
link before the in-person visit.  Participants will be encouraged to complete the questionnaires 2 
hours before the visit, but will have up to 24 hours to complete them after the visit.  Participants 
will return their e-cig and cigarette use log.    Biomeasures will be taken as outlined in Revised 
Table 1.  No biomeasures will be collected at Remote Visit 6.  Women of child bearing potential 
will be retested for pregnancy at Visits 5 and 7.  
The study staff will give participants e-cig and cigarette use logs and instruct them to record 
daily use at each visit.  All participants will be asked about their use of other nicotine/tobacco 
products and if they vaped/smoked any other substances other than nicotine/tobacco at each 
visit as this could affect the urine biomarkers collected during the study (e.g. carbon monoxide 
and cotinine levels).  Participants will be encouraged/provided advice to substitute some of their 
cigarettes with their e-cigarette. 
Participants will receive a 4-week supply of research cigarettes (130% of daily consumption) and 
e-liquid pods to last approximately 28 days until the next appointment.  At Visit 5, participants 
will receive an 8-week supply of e-cigarettes and cigarettes due to Remote Visit 6 being a 
remote visit.  Participants will be asked to return all opened, unopened and empty cigarette 
packs and all used/unused e-liquid pods to the study center at each visit in order to monitor use.  
At Visit 7, participants will return all used and unused research cigarette packs. No more 
cigarettes will be given.  Participants will be allowed to keep their e-cig and unused e-liquid pods 
until the next visit.  Participants will return their e-cig and cigarette use logs. Urine samples for 
biomarkers will be taken.  Participants will complete all biomeasures and questionnaires 
outlined in Revised Table 1.  Participants will be advised to quit smoking completely and 
provided with the quitline number and sources of free/low cost nicotine replacement therapy 
(NRT) (see Cigarette Smoking Cessation Tools handout document).  The Surgeon General 
booklet will also be given (see the Consumer Surgeon General Report Booklet document). 
Participants will be asked about their plans to either (a) go back to their own cigarettes only (b) 
go back to own cigarettes but supplement with an e-cig, (c) continue using an e-cig only, or (d) 
quit tobacco/e-cigs completely. Participants will be compensated for completing the study visit 
and procedures.
A study pulmonologist was added to the study team.  We will be monitoring lung function using 
pulmonary function testing that will be completed at Visits 4, 5, 7. Any significant worsening 
(10% worsening or greater) in pulmonary function will be documented as an adverse event.  
These adverse events will be reviewed by the Safety Monitors in a timely manner.  In cases 
where the Safety Monitor suspects that a participant may be having a respiratory adverse event 
related to the study product, a study pulmonologist will be consulted. The pulmonologist will 
make any needed medical recommendations and a determination regarding whether the 
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participant is able to continue with the study.  For more urgent and/or serious adverse events, 
the Safety Monitor and/or the study pulmonologist will be consulted and immediate medical 
attention will be sought if needed.  
Follow-up Visit 8 (Week 20)
All participants will be followed up at a visit 4 weeks after their last visit of the Randomized 
Phase in order to find out their cigarette/e-cig consumption and any attempts in abstinence 
after participating in the randomized portion of the trial. Participants will return any final e-cigs 
and e-liquid pods to the study team by either dropping them off to the researcher or scheduling 
a pick up time with the researcher.  If neither of these options can be arranged the participants 
will be advised how to properly dispose the products themselves.  Participants will complete an 
exhaled CO measurement plus all measures listed in Table 1. Participants will be compensated 
for completing the study visit procedures.  
Procedures during COVID-19:
Remote Visit 8 will be completed remotely over Zoom or the telephone.  All participants will be 
followed up 4 weeks after their last visit of the Randomized Phase in order to find out their 
cigarette/e-cig consumption and any attempts in abstinence after participating in the 
randomized portion of the trial. Questionnaires for visits outlined in Revised Table 1 will be sent 
to the participant via a survey link before the in-person visit.  Participants will be encouraged to 
complete the questionnaires 2 hours before the visit, but will have up to 24 hours to complete 
them after the visit. Participants will return their e-cig and any e-liquid pods in a pre-paid 
envelope addressed to the study site.  In cases where participants report being abstinent from 
cigarettes in the past 7 days at Visit 8, we will verify with a carbon monoxide reading (which bio-
chemically validates abstinence). We will plan to send individual CO monitors for participants 
that can be mailed to the participant’s house. Participants will use the personal devices to 
complete a CO measurement while on ZOOM with the researcher.  Participants will be 
compensated for completing the study visit procedures.
Unscheduled Visits
If a participant requires additional study product (e.g., cigarette packs, e-cig pods), or if the e-cig 
fails, they may call the research center to schedule a time to obtain additional products (in-
person).  
Appointment Reminders
Phone call, text, and email reminders will be used throughout the study to remind participants 
of their next visits (approximately 1-2 days prior). Also, visit time/date confirmation and study 
center directions will be emailed/mailed to the participant prior to Visit 1 (see First Appointment 
Reminder document).  For participants who allow us to contact them through phone and text 
messaging, the study team will be using Google Voice to call or text participant reminders of the 
study visit and reminders to complete the study surveys with the REDCap survey link.  Google 
Voice is phone service that allows researchers to communicate with participants without 
revealing their personal phone numbers.  The study team will save participants phone number 
with their study ID.  Participants will be told not to share PHI through this phone number.  
Biospecimen Processing 
All urine samples collected will be stored and analyzed in the project biomarkers core lab led by 
Dr. John Richie. 
Data Collection via Phone
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If participants are unable to attend an in-person study visit, the researcher will attempt to 
collect data over the phone. Participants will not be compensated for data provided through this 
method.
Missed Visit Procedures 
Participants will be called at least once to reschedule a missed Visit 1. For participants who do 
not show up for any other in-person visit, up to 3 phone/email attempts will be made to contact 
them to reschedule their appointment.   
7.3
Duration of Participation
The participants who complete all study contacts will participate for a total of 23 weeks.  
7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
7.4.1
Description
Research cigarettes (SPECTRUM) used in the study are provided by the NIDA Drug Supply 
Program (Notice Number NOT-DA-14-004). They are available from the Research Triangle 
Institute (RTI, North Carolina) with the same additives as commercial cigarettes but contain 
varying levels of nicotine. The cigarettes come in either menthol or non-menthol cartons. Each 
carton includes 10 packs of cigarettes with 20 cigarettes per pack.  The physical characteristics, 
chemical profiles and pharmacokinetics of the research cigarettes have been well characterized 
(66-68). 
We will use JUUL e-cigs purchased from JUUL Labs, Inc. The JUUL e-cig is a closed-system device 
that contains 2 main components- a disposable pod that contains liquid and a heating coil, and a 
USB-rechargeable battery.  The disposable pods contain 0.7 mL of e-cig liquid and contain either 
0% or 5% nicotine strength by weight.  The device is rechargeable with a USB charging dock.  
The JUUL e-cig device meets battery and electrical testing standards.  The safety features of 
JUUL include breath activation to prevent the device from turning on accidentally and a low 
power setting that limits its peak temperature. 
We had originally proposed to use the NIDA Standardized Electronic Cigarette (SREC) because 
(a) it is available with a placebo matching the nicotine variety (b) it has known nicotine 
pharmacokinetics (mean Cmax = 17.7 ng/ml after 10 puffs in 4.5 minutes) and (c) it is known to 
deliver low concentrations of toxicants relative to both cigarettes and some other e-cigs(69, 70). 
In a laboratory study of chemicals emitted by SREC here at Penn State, we concluded that 
“Overall, SREC was more efficient at aerosol and nicotine production than both Blu and Vuse. In 
terms of carbonyl and free radical levels, SREC delivered lower or similar levels to both other 
devices.”(69)   However, the e-cig company manufacturing the NIDA SREC product has 
experienced technical difficulties as it moved from producing small numbers of this e-cig to 
manufacturing a large number of e-cigs for numerous clinical trials. We cannot use this product 
until these problems have been resolved. Our NIH program officer agreed with us that in this 
ongoing situation, for this protocol (which is not required to use the SREC device), it makes 
sense to use JUUL.
The reasons for selecting JUUL are the same as reasons we originally selected the SREC, (a) it is 
available with a placebo matching the nicotine variety (b) it has known nicotine 
pharmacokinetics (baseline-adjusted mean Cmax = 15.4 ng/ml after 10 puffs in 4.5 minutes, as 
compared with 20.1 ng/ml from a Pall Mall cigarette(71)) and (c) it is known to deliver low 
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concentrations of toxicants relative to both cigarettes and some other e-cigs (72). Our own lab 
here at Penn State studied JUUL in a similar manner to SREC and concluded that “These findings 
suggest that oxidative stress and/or damage resulting from JUUL use may be lower than that 
from cigarettes or other e-cig devices.” Other labs, independent of JUUL, have studied the JUUL 
product and come to very similar conclusions: “JUUL's nicotine-normalized formaldehyde and 
total aldehyde yields are lower than other previously studied ECIGs and combustible 
cigarettes.”(73). One of the key advantages of JUUL is that it has a built-in temperature-
controlled circuit that prevents the temperature of the liquid from exceeding 215°C. In other e-
cigs overheating of the coil as the liquid in the wick runs low is one factor suspected of causing 
higher toxicant emissions (but still far lower than cigarettes). JUUL’s design avoids this.
Finally, in September 2019, FDA announced a new deadline for all e-cigarette manufacturers to 
apply for the right to continue to stay on the market (September 9, 2020). These Pre-market 
Tobacco Product applications (PMTAs) require all manufacturers to provide FDA with a very 
comprehensive set of information about their product, including marketing plans. It is likely that 
only the major e-cig manufacturers will be capable of submitting acceptable PMTAs to legally 
stay on the market after September 9, 2020. While it is impossible to know the outcome of that 
process, we need to select a product to use in our trial that appears likely to remain on the 
market in the foreseeable future, and so that is another reason for selecting JUUL.
7.4.2
Treatment Regimen
At Visit 2, all participants will be given Normal Nicotine Cigarettes (11.6 mg nicotine/cigarette) 
to use for 2 weeks.  At Visit 3, participants will be randomized into one of the 4 arms described 
below: 
5% Nicotine E-cig
 0% Nicotine E-
cig 
Normal Nicotine Cigarettes (NNCs) 
(11.6 mg nicotine/cigarette)
Arm 1
Arm 2
Very Low Nicotine Cigarettes  
(VLNCs) (0.2 mg nicotine/cigarette)
Arm 3
Arm 4
Participants will be provided with these products starting at Visit 3 (Week 0) and continue to use 
these products ad libitum through Visit 7 (Week 16).
7.4.3
Method for Assigning Subject to Treatment Groups
Eligible participants will be allocated to one of the four conditions using a blocked 
randomization with a 1:1:1:1 ratio of condition assignments via REDCap.  The randomization 
table will be created by the study statistician and only unblinded staff will have access to it.
7.4.4
Subject Compliance Monitoring
Compliance will be monitored throughout the trial by a) daily product use logs; b) product 
accountability logs where the amount of product dispensed will be recorded and unused 
products collected and recorded; and c) questionnaires administered during study contacts 
regarding the use of other tobacco or nicotine products.  Any problems that arise or are 
anticipated will be discussed and problem-solved with the coordinator.  Furthermore, exhaled 
CO measurements will be collected throughout the study to verify smoking intensity and 
exposure levels.
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7.4.5
Blinding of the Test Article
Research cigarettes:  An unblinded staff member will receive and remove all identifiers from 
cigarette cartons and replace them with our own blind code labels. The blind code labels will be 
unique to each carton and correspond to a nicotine dose level.  There are no identifiers on 
individual packs of cigarettes. The blinded researcher will not be involved in the packing and 
labelling of the research cigarettes.
E-cigs: The e-cig products will be received by unblinded staff who will appropriately package the 
pods and e-cig parts (device+charger) into packs/kits for the participants. The kits will have 
assigned numbers corresponding to a nicotine dose level, and the participants will be randomly 
assigned to a kit number at the randomization visit. The blinded researcher will not be involved 
in the packing and labelling of the kits.
All other study personnel, including lab staff, will remain blinded until the last randomized 
participant completes Visit 8.
7.4.6
Receiving, Storage, Dispensing and Return 
7.4.6.1
Receipt of Test Article 
Research cigarettes:  Experimental cigarettes will be provided free of 
charge to the investigators via the NIDA Drug Supply Program (Notice 
Number NOT-DA-14-004). They will be shipped in boxes to Penn State from 
the Research Triangle Institute. The boxes will contain cartons of 
cigarettes- 10 packs in each carton with 20 cigarettes in each pack. Each 
carton is packaged by nicotine content and menthol (green)/non-menthol 
(blue) flavoring. 
E-cigs: The JUUL device will be purchased from JUUL Labs, Inc. in its 
standard packaging and shipped to Penn State and will be received by 
unblinded staff. Pre-filled, sealed, disposable pods containing 0.7 mL of e-
cig liquid will also be purchased from JUUL Labs, Inc. The research team will 
maintain the certificates of analysis or lot information for the JUUL 
products used in the study.
7.4.6.2
Storage
Research cigarettes:  Cigarettes will be stored in standard freezers at Penn 
State in a locked space that is only accessible by unblinded research staff 
involved in our studies.  A service provided by Penn State will monitor and 
record the temperature of the freezers.
E-cigs: Devices and e-liquids will be stored at room temperature at Penn 
State in a locked space that is only accessible by unblinded research staff 
involved in our studies. A service provided by Penn State will monitor and 
record the temperature/humidity of the room.
7.4.6.3
Preparation and Dispensing
All receiving, sorting, blinding of the study products will be done in secure, 
locked space for unblinded research staff at Penn State Hershey.   
Research cigarettes:  Once the cigarettes are received, they will be blinded 
by the unblinded study staff with unique blind codes.  At Visit 3, following 
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confirmation of eligibility for randomization, staff will use blind codes to 
dispense the cartons to participants.  Staff will prepare a bag of cigarette 
packs that will be given to the study coordinator for the participant.  The 
blinded researchers will not be involved in the packing and labeling of the 
cigarettes.
E-cigs:  The pods will come pre-filled in sealed packages. They will be 
prepared for participants by unblinded staff and stored with unique 
identifiers. Unblinded staff will appropriately package kits containing two 
JUUL devices and a supply of pods for the participants. At Visit 3, following 
confirmation of eligibility for randomization, participants will be randomly 
assigned a kit number. The blinded researchers will not be involved in the 
packing and labeling of the kits.
7.4.6.4
Return or Destruction of the Test Article
Research cigarettes: Participants will be instructed to return all research 
cigarette packs at the next in-person visit, regardless of whether they are 
empty, unopened or partially used. Any unused research cigarettes that 
are returned from the participant at the end of the study will be destroyed 
on site according to the general policy for drug disposal by the 
Investigational Drug Pharmacy.
E-cigs:  Participants will be instructed to return all used and unused e-liquid 
pods to the study at each in-person visit to monitor use. We will ask 
participants to return the e-cig to the study site at the last in person visit 
and we will dispose of it on-site.  Any unused pods that are returned at the 
last in person visit will be destroyed on site according to the general policy 
for drug disposal by the Investigational Drug Pharmacy.  
Procedures during COVID-19:
Participants will receive a pre-paid envelope at Visit 7 to return all of their 
unused pods and e-cig to the study site.  Any unused pods and e-cigs will 
be destroyed on site according to the general policy for drug disposal by 
the Investigational Drug Pharmacy.  
7.4.6.5
Prior and Concomitant Therapy
Concomitant medications will be collected at baseline and regularly 
throughout the trial to monitor participant health conditions.
Participants taking varenicline, bupropion or nortriptyline as a smoking 
cessation medication in the prior month will be excluded from the study. 
Participants taking bupropion or nortriptyline for depression management 
and who expect to continue use of the medication throughout the trial will 
be eligible to participate. Additionally, participants who are prescribed 
bupropion or nortriptyline for depression management at any point during 
the study will be eligible to continue with the study. Medications related to 
certain medical conditions that are exclusions to the study, such as COPD 
and current heart conditions, will serve to alert the study staff of the 
presence of these conditions during screening. Once the participant is 
entered into the randomized double blind phase of the study, there are no 
other medications that will interfere with the participant’s ability to 
participate.
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8.0
Subject Numbers and Statistical Plan
8.1
Number of Subjects
We plan to enroll 300 participants in order to randomize 240 participants (60 in each of the four study 
arms).
8.2
Sample size determination
For the sample size calculation, we have used data for completers of our recent randomized controlled 
trial(8) to estimate magnitude of effects for the primary endpoint (NNAL, pmol/mg creatinine).  
Additionally, we have used data from Donny et al.’s trial [Table Supplement 15] (5).  Based on their 
paper, the difference in log NNAL between the 0.4 mg/g group (sample size 96) and the 15.8 mg/g group 
(sample size 100) is log(0.78)= -0.248 with a confidence interval of log(c(0.64, 0.96)) = (-0.446, -0.0408). 
Based on this, the within group standard deviation of log NNAL is 0.562. Combining the above two 
datasets, we shall assume that the effect size is 58% of the size of the standard deviation in the sample 
size calculation, slightly larger than reported above because our trial will have 16 weeks of follow-up. Let 
arm 3 of the trial be the group to which arms 1, 2 and 4 will each be compared. To adjust for multiple 
comparisons, the type one error level alpha is taken to be .05/3=0.017. The sample size of 60 subjects in 
each of the 4 arms is needed to provide 80% power of detecting a difference between any three arms 
and arm 3. In addition this trial will have over 95% power, at a 5% type 1 error rate, to detect the same 
effect on abstinence found in our recent RCT of VLNCs one month after the end of the randomized 
phase (20.2% in those randomized to VLNCs vs. 6.4% in those randomized to NNCs).
8.3
Statistical methods
Basic baseline statistics including means (standard deviations) and frequency distributions (percentages) 
will be reported for demographic characteristics, smoking characteristics, nicotine dependence, and 
nicotine and toxicant exposure. Characteristics will be reported by the four treatment arms to identify 
treatment arm imbalances. Numerical baseline characteristics will be compared among four arms using 
ANOVA tests or nonparametric Kruskal-Wallis tests when appropriate. Categorical variables will be 
compared using chi-square tests or Fisher’s exact tests. The focus of the statistical analysis will be the 
difference between four trial arms in terms of the biomarkers of toxicity and health effects. Analyses will 
be conducted in two approaches, which will address our research questions in two different angles. The 
first approach is a simplified and streamlined one, the longitudinal measurements of these biomarkers 
over the 16-week period will be summarized by using just the baseline (visit 3, pre-randomization) and 
final (visit 7, end of randomization period) measurements. Analysis of Covariance (ANCOVA) models will 
be used to compare the final measurements among the four arms, while the baseline measurements 
will be treated as controlled covariates in the modelSpecifically, the comparisons between arms 1 and 3 
and between arms 2 and 4 answer whether switching to very low nicotine cigarettes  leads to lower 
markers of harm as compared to continuing on normal nicotine cigarettes. This addresses specific Aim 1. 
Furthermore, we will study if this reduction is the same when combined with 5% nicotine e-cigs (arms 1 
and 3) and combined with placebo e-cigs (arms 2 and 4). Similarly, comparison between arm 1 and arm 
2 reveals if access to nicotine versus placebo e-cigs impacts these biomarkers. This will address Aim 2. In 
particular, we will test if the arm 3 has the best outcome as stipulated in Aim 2. These analyses will be 
conducted using ANCOVA models with interaction terms between traditional cigarettes (normal nicotine 
vs. very low nicotine) and e-cig (5% vs. 0%).  Appropriate transformation may be done on some of the 
outcome variables (for example log-transformation) to make sure the underlying statistical assumptions 
are all satisfied. Note that for NNAL, one of our main biomarkers of toxicity; it can only be analyzed 
using the first approach due to the limitation of number of measures.  
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The second approach for biomarker analysis will use the longitudinal data analysis to model all the 
repeated measurements of these biomarkers over the entire 16 weeks. Their trajectories will be plotted 
for each of the 4 arms. Linear mixed-effect models will be used to model the biomarker measurements 
on the following predictors: time after randomization (X1, which can be measured in weeks (continuous 
or visit number (categorical)), normal vs. low nicotine cigarettes (X2), 5% nicotine e-cig vs. placebo e-cig 
(X3), the interaction between cigarette and e-cig (X2*X3), and the interaction between X1 and X2, X3, 
X2*X3. In particular, the three-way interaction of X1, X2 and X3 indicates an interaction between 
cigarette type (NNC versus VLNC) and e-cig type (nicotine versus placebo) on their effect on the change 
of these markers of harms to health over time. Note that the time variable (X1) can be treated as either 
categorical or continuous, which will lead to different statistical models – growth curve model vs 
repeated-measure ANOVA models. If X1 is treated as categorical, then the estimated means and 95% 
confidence interval (CI) values of the outcome variables will be reported using tables. If X1 is treated as 
continuous, then the point estimates and 95% CI of the coefficients (rate of changes) will be reported. 
The baseline (before randomization) measures of the outcome variables will be included in the model as 
a controlled covariate. Family-wise type-I error rate due to multiple comparisons will controlled at the 
visit level (if X1 is treated as categorical) using Bonferroni method. Again, appropriate transformation of 
the outcome variable may be carried out – similar to the first approach.
Intent-to-treat (ITT) principle will be adopted for the analyses in both approaches.  Additionally, the 
measurements of tobacco use and addiction and measurements of mental health will be monitored and 
summarized, and will be compared across these arms in a similar statistical fashion as described above.    
Self-reported compliance will be reported for all participants. For participants in arm 4 (VLNC plus 
placebo ecigs) their compliances will be further evaluated using biomarkers. Comparison on the 
outcome variables will be made between compliers vs non-compliers within arm 4 participants only.  All 
analyses will be conducted using statistical software SAS version 9.4 or higher (SAS Institute, Cary, NC, 
USA) and R Programming language version 3.6.1 or higher (R Foundations). All tests will be two-sided 
and the statistical significance level to be used is 0.05.
Adjusted models will evaluate the treatment effect while adjusting for covariates, such as gender, age, 
race, SDOH scoring, and other baseline factors.
9.0
Data and Safety Monitoring Plan
9.1
Periodic evaluation of data
The PI and research staff will be responsible for the daily oversight of subject safety.  Subjects will be 
seen by research staff while in the study that will assess adverse events and take appropriate medical 
actions if necessary.  The Safety Monitor will review AEs on a weekly basis and study staff will discuss 
subject’s experiences during meetings when necessary.  The Safety Monitor will consult with the study 
pulmonologist (Dr. Rebecca Bascom) on respiratory related adverse events.  In addition, the study 
statistician will prepare a cumulative report of all data points listed below for the Data and Safety 
Monitoring Committee to review every 6 months after recruitment begins.
9.2
Data that are reviewed
The Data and Safety Monitoring Report will include:

Accrual and retention

Baseline sociodemographic characteristics 

Adverse events and serious adverse events

Protocol deviations/violations

Participants’ ability to achieve study requirements
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
Significant changes in mental health status including suicidal ideation

Changes in psychological measures of anxiety and depression (OASIS and QIDS)

Changes in cigarette consumption from baseline

Exhaled carbon monoxide increase from baseline

Changes in lung function via pulmonary lung function tests

Changes in lung function via the Clinical COPD questionnaire
9.3
Method of collection of safety information
Safety data and adverse event information will be collected at study visits and entered directly into 
REDCap.  Every study visit, participants will be asked a series of standard questions that would trigger an 
assessment for an adverse event to be documented. Adverse event information can also be given 
voluntarily by participants between study visits. An adverse event log will be used to document the 
description of the adverse event including, start/stop dates of event, type, grade, attribution to the 
study treatment, expected/unexpected, and action taken.
9.4
Frequency of data collection
Adverse event information and safety data will be collected at each study visit but can be reported at 
any time during the study.  
9.5
Individuals reviewing the data
A committee will be established to review the data that will include:
 
1.
Julio Fernandez-Mendoza, Ph.D., Department of Psychiatry and Behavioral Health,
Penn State College of Medicine*
2.
Erika Saunders, M.D., Department of Psychiatry and Behavioral Health, Penn State
College of Medicine
3.
David Rabago, M.D., Department of Family and Community, Penn State College of
Medicine 
*DSM Committee Chair
The committee will review the report and make appropriate recommendations to continue research as 
is, continue research with modification, or discontinue research in the event of significant efficacy issues 
or unacceptable adverse events. A copy of the committee’s review of the Data and Safety Monitoring 
Report will be shared with Penn State IRB and any other appropriate regulatory bodies. 
9.6
Frequency of review of cumulative data
A Data and Safety Monitoring Report with cumulative data will be generated every 6 months after 
recruitment begins.  
9.7
Statistical tests
Basic descriptive statistical methods will be used to analyze the safety data to determine whether harms 
are occurring.  Changes from the baseline in cigarette consumption, exhaled carbon monoxide, 
pulmonary function, and mental health measures will be calculated.  In addition, the accrual and 
retention-dropout rate, completion rate, and the proportions of adverse events (AE) and serious adverse 
events (SAE) will be generated. 
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9.8
Suspension of research
Due to the low risk of the study treatment, it is unlikely that there will be a need to suspend the 
research. However, should the committee identify any issues after reviewing the cumulative data, these 
recommendations will be followed.
10.0
Risks
Switching cigarette brands: Before being randomized in the study you will switch from your usual brand of 
cigarettes to study cigarettes that are similar in nicotine to your own brand of cigarettes to smoke for 2 weeks. 
The cigarettes you are given throughout this study may have different characteristics (i.e. nicotine level, 
ventilation, length, etc.) than your usual brand. So you could experience symptoms related to different strength 
or sensory effects from the study cigarettes, such as harshness in your throat or chest.
Increased compensatory smoking: Participants may be given cigarettes that have very low levels of nicotine in 
them which may lead to compensatory smoking and in turn increased levels of toxicant exposure. In prior 
studies, compensatory smoking was minimal and higher levels of toxicant exposure were generally not 
observed. Cigarette consumption and exhaled carbon monoxide will be monitored throughout the trial.
E-cig use: There may be some unknown risks related to the use of e-cigs. The most common side effects 
associated with using an e-cig are changes in taste, dehydration, mucus in throat/sinus, dry mouth, dry cough, 
throat irritation, mouth irritation, sore throat, mouth ulcers, dizziness, headache, nausea, and hiccups. 

E-cig liquid contains vegetable glycerin, propylene glycol, and flavorings. It is possible that 
participants may have an allergy to one of more of these ingredients. Participants with known 
allergies to these substances will be excluded from the study. The most common reported 
allergic reaction to these substances is contact dermatitis (or rash). 

There are reports that some people who use e-cigarettes have experienced seizures, with most 
involving youth or young adult users.  Participants with a history of seizures or take medications 
to prevent seizures will be excluded from the study.

There have been some reports of serious lung illnesses among those who used e-cigarettes, and 
even some cases of death as a result.  The cause of all deaths has not been identified.  The 
investigations being conducted by the Centers for Disease Control and Prevention (CDC) and the 
Food and Drug Administration (FDA) have found that the majority of people experiencing these 
illnesses were using e-cigarette products that contained tetrahydrocannabinol (THC) and/or 
products that were bought off the street and not from retail establishments.  The e-cigarette 
products used in this study do not contain THC and were bought from manufacturers where 
quality testing and control is performed.  Nonetheless, participants will be advised to call their 
doctor immediately if they experience cough, shortness of breath, chest pain, nausea, vomiting, 
diarrhea, or fever after using their e-cigarette.  Participants will be told to only use the e-
cigarette and liquid pods (cartridges) given to them by the researchers and to not tamper with 
their e-cigarette or use other liquids with the e-cigarette device.
Nicotine addiction: Participants may be given an e-cig that contains nicotine, which is an addictive substance. 
The amount of nicotine they receive from this product depends on what product they are given and how 
they use it. 
Nicotine withdrawal symptoms: Ceasing nicotine may result in nicotine withdrawal symptoms (e.g., irritability, 
anxiety, restlessness, depressed mood, increased appetite, fatigue, insomnia/sleep problems, 
impatience, headache, difficulty concentrating). It is possible that nicotine withdrawal symptoms could 
affect a pre-existing mental health condition.  These symptoms will be monitored at each visit. 
New pregnancy or intention to become pregnant: Nicotine, from cigarettes and from e-cigs, is known to be 
harmful to the developing human fetus. Women who are pregnant or are nursing a child may not 
participate in this research study. Females capable of becoming pregnant will be administered a 
pregnancy test prior to beginning the research. Participants must agree to take reasonable and 
necessary precautions against becoming pregnant during the period of the investigation. 
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Spirometry: Risks associated with spirometry may include shortness of breath, dizziness, headache, and on rare 
occasions fainting while doing the breathing test. Every effort will be made to limit these effects during 
the procedure. Participants with medical conditions that may place them at increased risk are being 
excluded. 
Loss of confidentiality: There is a risk of loss of confidentiality if information is obtained by someone other than 
the investigators. Precautions will be taken to prevent this including direct coding of data in REDCap. 
Randomization in clinical trials: Participants will be assigned to a research intervention by chance. The research 
intervention they receive may prove to have more side effects than the other research intervention(s). 
Questionnaires: It is possible that some of the questions in the questionnaires may make participants 
uncomfortable. They will be instructed that they are free to skip any questions that make them 
uncomfortable. In addition, participants will be provided with a list of phone numbers for organizations 
that can provide information and referrals should they need them.
11.0
Potential Benefits to Subjects and Others 
11.1
Potential Benefits to Subjects
There is no guaranteed direct benefit to the individuals who participate in this study. However, those 
who participate and switch completely to the e-cig may have less exposure to tobacco-related toxicants 
as a result of their participation. In addition, they may reduce their dependence on traditional 
cigarettes.
11.2
Potential Benefits to Others
Society as a whole will benefit from the research because it is expected to provide important 
information on tobacco-related health markers while also providing information on the effects of using 
e-cigs and smoking reduction strategies.
12.0
Sharing Results with Subjects
This study is not designed to diagnose any disease or condition. However, if during the course of conducting 
clinical procedures (e.g., blood pressure, pulmonary function test), a participant is found to have a result outside 
of clinical norms, the result will be discussed with the participant at the visit where the result is identified.  This 
information will be written in the Critical Value Letter so that it can be shared with the participant and/or their 
doctor.  If a woman tests positive for pregnancy, the results will be shared with the participant, they will be 
withdrawn from the study, and they will be advised to follow up with their doctor for prenatal medical care. 
Overall study results will not be shared with participants.  
A Participant Randomization email will be sent to all participants who were randomized in the study.  The email 
will state their randomization assignments for both the study cigarettes and e-cigarette/pods.  They will be told 
if study cigarettes either contained normal nicotine or very low nicotine and if the e-cigarette pods either 
contained nicotine or zero nicotine.
13.0
Subject Payment and/or Travel Reimbursements
Compensation for study participation is outlined in the Payment Table below. The total possible payment is 
$550. Payments will be issued on the Greenphire ClinCard.
Payment Table
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Study Visit #
Visit 
Completion
Transportation 
(in-person 
visits)
Incentive
Total
1
$0
2
$60
$20
$80
3
$60
$20
$80
4
$60
$20
$80
5
$60
$20
$80
6
$60
$60
7
$60
$20
$80
8
$60
$30
$90
                                                                               Total possible:
$550
14.0
Economic Burden to Subjects
14.1
Costs
There are no costs that subjects will be responsible for related to the research.
14.2
Compensation for research-related injury
It is the policy of the institution to provide neither financial compensation nor free medical treatment 
for research-related injury. In the event of injury resulting from this research, medical treatment is 
available but will be provided at the usual charge. Costs for the treatment of research-related injuries 
will be charged to subjects or their insurance carriers.
15.0
Resources Available 
15.1
Facilities and locations
All participant visits will take place in the Penn State Hershey Clinical Research Center.
Procedures during COVID-19:
All in-person visits will take place in the Penn State Hershey Clinical Research Center.  Remote visits will 
take place over the telephone or Penn State Health Zoom.
15.2
Feasibility of recruiting the required number of subjects
Generally, those with mental health conditions have a higher smoking prevalence than the general 
population (32% with mental illness, 23.3% without mental illness).  Additionally, the estimated smoking 
prevalence in 2017 in Pennsylvania was 19%.  
We had success in recruiting and screening for our recently completed trial on SMHC(8), where 
participants were required to meet diagnostic criteria for a mood or anxiety disorder on the MINI 
International Neuropsychiatric Interview (MINI).(34)  For this planned trial we have chosen to include 
those with these plus additional mental health conditions so the sample is more broadly representative 
of the wider group of potentially vulnerable smokers.
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15.3
PI Time devoted to conducting the research
Dr. Foulds has no clinical responsibilities and so the majority of his time is devoted to research, including 
this project. He is funded at 20% time for this study.
15.4
Availability of medical or psychological resources
All of our participants will be seen by appropriately trained research staff and research nurses in the 
Clinical Research Center while in the study. We have established a protocol for assessing suicide risk that 
requires the availability of a licensed psychiatrist to evaluate participants if they indicate any score on 
the MINI suicide ≥ 9 at screening or follow-up. Any score on the QIDS questionnaire > 0 will trigger the 
study staff to complete the MINI Suicide module. Scores ≥ 9 on the MINI will trigger a psychiatric 
assessment. Any urgent health problem will require accompanying the participant to the ER, which is 
located in the same building.
Procedures during COVID-19:
If a psychiatric assessment is triggered during a remote visit, the study psychiatrist will contact the 
participant over the phone or Zoom.
15.5
Process for informing Study Team
All members of the study team will have completed all necessary training and documentation will be 
collected. The project will also have a shared workspace to upload project specific documentation, for 
example, training documents, SOPs, IRB documents, and current protocols.  Regular team meetings will 
be conducted where study procedures, questions, and issues will be discussed and resolved.
16.0
Other Approvals
16.1
Other Approvals from External Entities
The FDA will require submission and approval of an Investigational Tobacco Product (ITP) application for 
use of the study products. 
16.2
Internal PSU Committee Approvals
Check all that apply:
  Anatomic Pathology – Penn State Health only – Research involves the collection of tissues or use of 
pathologic specimens. Upload a copy of “HRP-902 - Human Tissue For Research Form” in CATS IRB. 
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA 
or gene therapy).
  Clinical Laboratories – Penn State Health only – Collection, processing and/or storage of extra tubes 
of body fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids 
that had been collected for clinical purposes but are no longer needed for clinical use. Upload a copy 
of “HRP-901 - Human Body Fluids for Research Form” in CATS IRB. 
  Clinical Research Center (CRC) Advisory Committee – All campuses – Research involves the use of 
CRC services in any way.
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  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest.
  Radiation Safety – Penn State Health only – Research involves research-related radiation 
procedures. All research involving radiation procedures (standard of care and/or research-related) 
must upload a copy of “HRP-903 - Radiation Review Form” in CATS IRB. 
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE.
  Scientific Review – Penn State Health only – All investigator-written research studies requiring 
review by the convened IRB must provide documentation of scientific review with the IRB 
submission. The scientific review requirement may be fulfilled by one of the following: (1) external 
peer-review process; (2) department/institute scientific review committee; or (3) scientific review by 
the Clinical Research Center Advisory committee.  NOTE: Review by the Penn State Health Cancer 
Institute (PSCI) Protocol Review Committee or the PSCI Disease Team is required if the study 
involves cancer prevention studies or cancer patients, records and/or tissues. For more information 
about this requirement see the IRB website.
17.0
Multi-Site Study
N/A
17.1
Other sites 
N/A
17.2
Communication Plans
N/A
17.3
Data Submission and Security Plan
N/A
17.4
Subject Enrollment
N/A
17.5
Reporting of Adverse Events and New Information
N/A
17.6
Audit and Monitoring Plans
N/A
18.0
Adverse Event Reporting
18.1
Adverse Event Definitions
For drug studies, incorporate the following definitions into the below responses, as written:
Adverse event
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related
Adverse reaction
Any adverse event caused by a drug
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Suspected adverse 
reaction
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reaction implies a lesser degree 
of certainty about causality than “adverse reaction”.

Reasonable possibility.  For the purpose of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.
Serious adverse 
event or Serious 
suspected adverse 
reaction
Serious adverse event or Serious suspected adverse reaction: An adverse event 
or suspected adverse reaction that in the view of either the investigator or 
sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Life-threatening 
adverse event or 
life-threatening 
suspected adverse 
reaction
An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the Investigator (i.e., the study site 
principal investigator) or Sponsor, its occurrence places the patient or research 
subject at immediate risk of death.  It does not include an adverse event or 
suspected adverse reaction that had it occurred in a more severe form, might 
have caused death.
Unexpected 
adverse event or 
Unexpected 
suspected adverse 
reaction.  
An adverse event or suspected adverse reaction is considered “unexpected” if 
it is not listed in the investigator brochure, general investigational plan, clinical 
protocol, or elsewhere in the current IND application; or is not listed at the 
specificity or severity that has been previously observed and/or specified.
For device studies, incorporate the following definitions into the below responses, as written:
Unanticipated 
adverse device 
effect
Any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or IDE application (including a supplementary plan 
or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects.
18.2
Recording of Adverse Events
Research subjects will be routinely questioned about adverse events at in-person study visits.  Adverse 
event data will be directly coded into REDCap.
All adverse events (serious or non-serious) and abnormal test findings observed or reported to study 
team believed to be associated with the study drug(s) or device(s) will be followed until the event (or its 
sequelae) or the abnormal test finding resolves or stabilizes at a level acceptable to the investigator.
An abnormal test finding will be classified as an adverse event if one or more of the following criteria are 
met:

The test finding is accompanied by clinical symptoms

The test finding necessitates additional diagnostic evaluation(s) or medical/surgical intervention; 
including significant additional concomitant drug treatment or other therapy
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NOTE: Simply repeating a test finding, in the absence of any of the other listed criteria, does not 
constitute an adverse event.

The test finding leads to a change in study drug dosing or discontinuation of subject 
participation in the clinical research study

The test finding is considered an adverse event by the investigator.
In addition, we will be monitoring lung function throughout the study using pulmonary function testing. 
Any significant worsening (10% worsening or greater) in pulmonary function will be documented as an 
adverse event.
18.3
Causality and Severity Assessments
The Safety Monitors will promptly review documented adverse events and abnormal test findings on a 
weekly basis to determine 1) if the abnormal test finding should be classified as an adverse event; 2) if 
there is a reasonable possibility that the adverse event was caused by the study drug(s) or device(s); and 
3) if the adverse event meets the criteria for a serious adverse event. For more urgent and/or serious 
adverse events, the Safety Monitor will be available for consultation by phone or immediate medical 
attention will be sought (i.e. Emergency room). The Safety Monitor will then make any needed medical 
recommendations and a determination regarding whether the participant is able to continue with the 
study. In cases where the Safety Monitor suspects that a participant may be having a respiratory adverse 
event related to the study, a pulmonologist (Dr. Bascom) will be consulted. The pulmonologist will make 
any needed medical recommendations and a determination regarding whether the participant is able to 
continue with the study. 
If the investigator’s final determination of causality is “unknown and of questionable relationship to the 
study drug(s) or device(s)”, the adverse event will be classified as associated with the use of the study 
drug(s) or device(s) for reporting purposes.  If the investigator’s final determination of causality is 
“unknown but not related to the study drug(s) or device(s)”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history.
18.4
Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
18.4.1 Written IND/IDE Safety Reports
N/A
18.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions
N/A
18.5
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) possibly, probably, or definitely related to the research procedures. Harms 
(adverse events) will be submitted to the IRB in accordance with the IRB policies and procedures.
18.6
Unblinding Procedures
If an adverse event requires the subject to be unblinded, the unblinded study personnel will be able to 
provide that information as needed. Otherwise, participants will not be unblinded to their e-
cig/cigarette product allocation. 
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18.7
Stopping Rules
No formal a priori statistical stopping rules will be used for interim monitoring of the primary or 
secondary endpoints. Analyses will be performed and comprise of endpoints associated with safety and 
study integrity (i.e. recruitment rate, completion rate, rates of SAEs/AEs, changes in cigarette 
consumption/exhaled carbon monoxide from baseline), and any other variables that are requested from 
the Data and Safety Monitoring Committee. A bi-annual summary report of these analyses will be 
prepared by the study statistician for the committee to review. The committee will use these reports as 
the primary basis assessing data quality and subject safety, and if necessary making recommendations 
of amendment to the protocol or stopping the trial.
19.0
Study Monitoring, Auditing and Inspecting
19.1
Study Monitoring Plan
19.1.1 Quality Assurance and Quality Control
The overall responsibility for data quality and study conduct lies with the PI.  Data will be 
collected from participants and coded directly by either using the REDCap survey tool 
(participant entered data) or through REDCap data entry forms (researcher entered data).  The 
codes that link the name of the participant and the study ID will be kept confidential in REDCap. 
Any paper forms (consent) will be securely locked in the research offices of the PI.  Any 
additional data that is generated (i.e., electronic PFT), will be stored electronically on the PHS 
server in password protected files.
Study data will be managed using REDCap (Research Electronic Data Capture). REDCap is a 
secure web application designed to support data capture for research studies, providing user-
friendly web-based case report forms, real-time data entry validation (e.g. for data types and 
range checks), audit trails and a de-identified data export mechanism to common statistical 
packages (SPSS, SAS, Stata, R/S-Plus). The system was developed by a multi-institutional 
consortium which includes The Pennsylvania State University and was initiated at Vanderbilt 
University. The database is hosted at the Penn State Hershey Medical Center and College of 
Medicine data center, which will be used as a central location for data processing and 
management. REDCap data collection projects rely on a thorough study-specific data dictionary 
defined in an iterative self-documenting process by all members of the research team. This 
iterative development and testing process results in a well-planned data collection strategy for 
individual studies. 
REDCap is HIPAA compliant. Data are stored on a secure server; data in REDCap are encrypted; 
access to the database requires authentication (a unique username and password); data are 
accessed based on the individual’s role on the project; every interaction with the data is logged, 
creating an audit trail.
Data quality tools included in REDCap will be utilized to identify incorrect data types, out of 
range data and outliers.  Data that will be entered by participants directly will be reviewed for 
completeness. Out of range values will be identified immediately when the participants are 
completing online data forms to reduce keying errors.
19.1.2 Safety Monitoring
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The Principal Investigator will confirm that all adverse events (AE) are correctly entered into the 
AE case report forms by the coordinator; be available to answer any questions that the 
coordinators may have concerning AEs; and will notify the IRB, FDA, sponsor and/or DSMB of all 
applicable AEs as appropriate. 
The Research Coordinator will complete the appropriate report form and logs; assist the PI to 
prepare reports and notify the IRB, FDA and/or DSMB of all Unanticipated Problems/SAE’s.
The Safety Monitors (Dr. Ahmad Hameed and Dr. Christopher Sciamanna) are licensed medical 
professionals who will make the final assessments and causality of AEs.  They will be available to 
answer any questions concerning AEs.  In cases where the Safety Monitor suspects that a 
participant may be having a respiratory adverse event related to the study, the study 
pulmonologist will be consulted. 
20.0
Future Undetermined Research: Data and Specimen Banking
20.1
Data and/or specimens being stored
Specimens (urine) collected during the study will be banked for future undetermined research.  
Specimens will be stored with a participant ID code attached along with the visit number and date.  All 
other identifiable data associated with the ID code will be retained in REDCap.  
Questionnaire data collected during the study that is used for future undetermined research will be de-
identified.  
20.2
Location of storage
Specimens will be stored in freezers in the locked lab spaces of Dr. Foulds in the Cancer Institute.  
Questionnaire data will be stored within REDCap.  
20.3
Duration of storage
Questionnaire data and specimens will be stored indefinitely.  
20.4
Access to data and/or specimens
The lab managers, technicians, study coordinators, and PI will have access to the freezer rooms where 
the specimens will be stored. The researchers will have access to the stored data in REDCap, although 
role-specific rights will be granted as minimally necessary.
20.5
Procedures to release data or specimens
Investigators who are interested in obtaining specimens and/or data from this project for ancillary 
studies will first be required to submit a detailed written proposal to Dr. Foulds. If the proposal is 
approved, only de-identified data will be released to the investigator. 
20.6
Process for returning results
Investigators will be required to provide the results to the study team and PI.  
21.0
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22.0
Confidentiality, Privacy and Data Management 
See the Research Data Plan Review Form
STUDY00012579
Approval: 1/23/2025