Impact of E-cigarette Training on Puff Patterns, Cigarette Smoking, and Health Outcomes Among Smokers With COPD
Phase: NA
Conditions: Pulmonary Disease, Chronic Obstructive, Tobacco Smoking
Sponsor: University of Kansas Medical Center

 
KUMC – HRPP- 03/12/2015 
 
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University of Kansas Medical Center  
RESEARCH PROTOCOL INVOLVING HUMAN SUBJECTS  
TEMPLATE WITH GUIDANCE 
 
Version date: 04/29/2022  
Principal Investigator: Eleanor Leavens, PhD 
Study Title: Impact of e-cigarette training on puff patterns, cigarette smoking, and health outcomes 
among smokers with COPD 
Co- Investigator(s): Nicole Nollen, PhD; Edward Ellerbeck, MD; Matthew Mayo, PhD; Jennifer 
Woodward, MD; Sandra Billinger, PT, PhD, FAHA 
 
 
I. 
Purpose, Background and Rationale 
A. Aim and Hypotheses  
Nearly 9 out of 10 chronic obstructive pulmonary disease (COPD) deaths in the United States 
(US) are attributed to smoking. Most (>90%) smokers with COPD are interested in quitting but 
success rates are very low; only about 12% are able to quit with FDA-approved medications as 
part of a clinical trial and far fewer (<5%) quit following brief advice to quit. An alternative 
approach for smokers who cannot or will not quit with first-line therapies is tobacco harm 
reduction, or transitioning smokers to potentially less harmful products (e.g., e-cigarettes). E-
cigarettes (ECs), when used consistently and exclusively, help smokers quit and reduce tobacco-
related harms. This is particularly true for smokers with COPD who report significant reductions 
in COPD exacerbations, improved lung function, and quality of life after switching to ECs. 
However, the extent of harm reduction is directly related to the degree of switching (i.e., 
reduction in CPD). Most smokers who transition to ECs make a partial switch to EC (i.e., dual 
users) and, while they experience harm reduction benefits relative to continued smoking, the 
benefit is less than those who completely switch. To reduce harm among high-risk smokers with 
COPD who are unable to quit with first-line therapies, there is an urgent need to understand 
how training smokers on the optimal EC puff pattern can be optimized to facilitate a complete or 
predominant pattern of EC use among smokers with COPD. The alternative for these smokers is 
continued smoking of, arguably, the most harmful tobacco product on the market and imminent 
disease progression. 
 
Our long-term goal of our research is to decrease tobacco-related disease burden among high-
risk smokers unable to quit using standard methods. The overall objective of this application is 
to evaluate the impact of EC training on changes in puff patterns, nicotine craving and exposure, 
cigarette smoking, and improvements in COPD-related health effects among smokers with COPD 
who have been unable to quit smoking using pharmacotherapy. Our central hypothesis is that 
training on optimal puff behavior with ECs (compared to brief advice to switch to ECs) will result 
in a greater proportion of patients predominantly using ECs and a greater reduction in COPD-
related health effects. Furthermore, greater dose of intervention will result in amplified effects. 
Our central hypothesis has been formulated on the basis of our preliminary data, which suggest 
that 1) smokers with COPD have a particularly difficult time quitting, 2) smokers with COPD 
have high levels of interest in using ECs, and 3) predominant EC users engage in distinct puff 
patterns compared to continued smokers; this puff pattern can be ‘trained’ and results in higher 
rates of switching to EC. 
 

 
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Smokers with COPD, stratified by EC naïve and current dual users, who are unwilling to make a 
pharmacotherapy-assisted quit attempt but that are willing to use ECs will be randomly assigned 
to receive 1) brief advice to switch to ECs at baseline, 2) a single session of training on optimal 
EC puffing and use at baseline, or 3) enhanced EC training on optimal EC puffing and use at 
baseline, day 3, and wks 4, 8, and 12. Participants will complete a human laboratory 
assessment of EC use patterns and a complementary 12-week RCT of real-world smoking and 
EC use patterns. The human lab trial will be conducted over two visits to assess acute changes 
in puff patterns and nicotine craving and exposure. The RCT will provide real-world data on 
changes in cigarette smoking, COPD-related health effects, and EC puff patterns. 
 
1. Our specific aims are: 
Aim 1: Understand differences in acute (i.e., in-lab) changes in puff patterns (i.e., puff 
duration), cigarette craving, and nicotine exposure from pre- to post-EC training/brief 
advice between smokers who received brief advice versus EC training (single episode and 
enhanced EC training arms combined). Smokers who receive EC training will show 
greater increases in puff duration compared to brief advice (H1a), greater reductions in 
cigarette craving compared to brief advice (H1b), and greater increases in nicotine 
exposure compared to brief advice (H1c).  
Aim 2: Determine the longer-term impact of EC training and training dose on switch 
patterns (i.e., % predominant EC users), health effects (i.e., changes in cardiovascular 
health, functional activity, lung function) and puff patterns. In a dose response pattern, 
enhanced EC training will result in the greatest proportion of predominant EC users at 
Wk12 (H2a), the greatest improvements in health outcomes at Wk12 (H2b), and the 
greatest increases in puff duration from baseline to Wk12 (H2c) followed by single 
session training and brief advice.  
 
B. Background and Significance 
Cigarette smoking among patients with chronic obstructive pulmonary disease 
(COPD): Over one third of smoking-related deaths are a result of COPD and up to 90% of COPD 
cases are caused by smoking.1 COPD is associated with profoundly reduced quality of life due to 
symptoms including wheezing and sleep disturbance.2 Therefore, the benefits of quitting 
smoking and symptom reversal are enormous for this population. Despite these potential 
benefits, about 40% of patients with COPD continue to smoke.3 The majority of smokers with 
COPD report interest in quitting smoking4 but when offered pharmacotherapy, only 12-14% 
succeed in a sustained quit, indicating that smokers with COPD have a very difficult time 
quitting.5 
 
Electronic cigarettes (ECs) and tobacco harm reduction for smokers with COPD: 
Evidence indicates that ECs are less harmful compared to combustible cigarettes.6 In their 
consensus statement, the National Academies for Science, Engineering, and Medicine concluded 
that there is “conclusive evidence” that completely switching to ECs reduces smokers’ exposure 
to toxicants carcinogens, or cancer-causing substances.6 While there are no long-term studies of 
cancer risk due to EC use, mounting evidence from in vivo and in vitro studies suggests reduced 
cancer risk from ECs compared to cigarettes.1,2 For smokers that are unable or unwilling to quit 
combustible smoking, the question is whether ECs offer a reduction in harm (not elimination of 
harm) compared to cigarettes. For smokers that are unable or unwilling to quit nicotine and tobacco 
use, completely switching to ECs likely reduces their cancer-risk.3 Moreover, smokers with smoking 
attributable diseases, like COPD, who already experience a heightened risk due to continued 
smoking, may experience the greatest benefit from making a complete switch from combustible 
cigarettes to ECs.4 In randomized trials, ECs have resulted in better quit rates compared to 
control and NRT.7,8 In a prospective, non-randomized study of COPD smokers who switched to 
ECs or continued smoking, EC users showed a significant reduction in COPD exacerbations and 

 
KUMC – HRPP- 03/12/2015 
 
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improvements in lung function and measures of quality of life.9 These data indicate ECs may be 
a promising harm reduction tool for smokers with COPD that have been unable to quit. 
 
Factors associated with successful switching: One primary factor that predicts successful 
switching is EC puff behavior. The experience of vaping differ significantly from the experience 
of smoking cigarettes, resulting in a learning curve to achieve sufficient nicotine delivery. Cross-
sectional studies of exclusive EC users indicate that they are able to extract more nicotine from 
ECs compared to naïve or dual users.10-12 Existing research shows that smokers who successfully 
switch to ECs take longer puffs compared to those who only partially switch, suggesting that 
smokers who are successful in switching naturally learn how to effectively puff on an EC. It 
remains unknown whether smokers can be trained on optimal puff behavior.  
 
 
C. Rationale 
 
Studies by our team13 and others show that smokers who achieve predominant or exclusive EC 
use have unique puff patterns compared to continued smokers (i.e., greater puff duration).13-16 
Smokers who switch to ECs and become predominant or exclusive EC users adapt their puff 
patterns within 1 week by taking longer, slower puffs.14 While no studies have examined 
methods for training smokers on optimal topography, one study showed that a slight variation in 
instructions to switch resulted in reduced smoking.15   
 
This study is innovative in the following ways. First, the study will enroll a high-risk population 
of smokers that is not only understudied but stands to experience marked improvements in 
health and quality of life from quitting smoking. The alternative for these smokers is continued 
smoking of the most harmful tobacco product on the market and imminent disease progression. 
Second, the concept of providing training on optimal use of ECs is innovative. Despite evidence 
that those who successfully switch to ECs show distinct topography patterns compared to EC 
“failures”, no studies have attempted to train on optimal use. This strategy pulls from the NRT 
literature17,18 and posits that a similar form of training on “optimal” use will increase EC 
effectiveness of facilitating switching and reduce smokers’ tobacco-related harm. 
 
D. ECs and E-liquid  
 
The Evolv Reflex EC (Figure 1) will be used for the proposed study. Our team 
has conducted three validation studies with the device and embedded 
software. It is both a highly effective EC and a topography device that tracks 
and stores all facets of information about the participant’s use of the product, 
including puffing topography which we view as a great strength. See Figure 2 for 
an example of the topography feedback provided by the device. The device has 
the capacity to store 4 weeks of data between in-person visits. We will use the 
eScribe topography software available specifically for this device. In addition, we 
will use a secondary topography device (eTop 
device) during in-person lab-based 
visits in order to correlate topography from the two 
devices. Our team has used the eTop device in 
numerous past trials. The Reflex device is a pod-based 
device and is compatible with nicotine salt and freebase 
nicotine e-liquid. We will use commercially available 
nicotine salt e-liquid in 5% nicotine concentration. The 
e-liquid has been tested by Drs. Salathe and Kim at 
KUMC Department of Internal Medicine to 
independently confirm the e-liquid concentration is 
within 1% of the advertised levels. We considered other 
concentrations but chose 5% because it is the most commonly used concentration among 
Figure 1. Reflex EC 
Figure 2. Example topography 

 
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market leaders like JUUL, has demonstrated high appeal5 and cigarette-like levels of nicotine 
delivery among smokers,5-8 and high rates of switching.9 For the human lab portion of the study, 
participants will be provided a pre-filled pod for each visit. For the RCT, we will provide pre-filled 
pods in 4-week increments. If participants cannot tolerate the Evolv Relfex, we will offer a 
choice of JUUL or Vuse devices. JUUL and Vuse are pod based systems. We will offer menthol or 
tobacco flavors in 5% or 3% concentration. 
 
 
II. 
Research Plan and Design 
 
A. Study Objectives: The overall objective of this application is to evaluate the impact of EC 
training on changes in puff patterns, nicotine craving and exposure, cigarette smoking, and 
improvements in COPD-related health effects among smokers with COPD who are unable to 
quit smoking using pharmacotherapy. 
B. Study Type and Design: The proposed study is an open label randomized clinical trial of EC 
training and training dose among smokers with COPD. Smokers with COPD (n=45) stratified 
by EC use history (naïve vs. current use) will be randomized (1:1:1) to receive brief advice 
to switch to ECs, single session EC training, or enhanced EC training. Participants will 
complete an in-lab assessment of pre-intervention EC puff patterns followed by intervention 
and a follow-up assessment of resultant changes in EC puff patterns. Visits will be separated 
by a standard minimum 24-hour washout period. Participants will complete a final 
assessment of EC puff patterns at Wk 12. Immediately following completion of the second 
human lab visit, participants will receive 12 weeks of EC and assistance with switching, 
based on treatment allocation. Participants will complete in-person follow-up assessments 
throughout the 12-week switch period and those in the enhanced training arm will receive 
ongoing training. 
 
Participants will remain abstinent from nicotine/tobacco for 12 hours prior to each study 
visit. Abstinence will be verified by eCO (>12 ppm.24 Self-report will be used for EC 
abstinence, as there is currently no objective, reliable measure to verify non-use of these 
products within the time the participants will be in the lab. Participants will be provided the 
device of their choice with either tobacco or menthol flavored e-liquid or pods. Participants 
will puff ad libitum for 30 minutes to establish baseline levels. Throughout the session, puff 
topography will be measured. Blood sampling for changes in nicotine levels will occur at -5 
minutes (pre-vaping session) and +30 minutes (immediately post-session). At the end of 
Human Lab Visit 1, participants will receive training on the EC based on intervention 
allocation. Human Lab Visit 2 will be identical to Visit 1 but will not include additional EC 
training. Human Lab Visit 3 (~Wk 12) will be identical to Visit 2 and will measure longer-
term changes in EC puff patterns. The Evolv Reflex EC has the capacity to track and store 4 
weeks of data about a participant’s use of the product and puffing topography between in-
person visits. eScribe topography software will be used for the device. The JUUL and Vuse 
devices do not collect data.  Because daily use of EC is consistently one of the best predictors 
of exclusive EC use,10  we will reinforce this pattern across sessions within the enhanced EC 
training arm and problem-solve barriers related to daily use.  
 
Figure 1: Overall study flow 

 
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C. Sample size, statistical methods, and power calculation 
1. 45 eligible smokers with COPD will be stratified by EC use history (naïve vs. current use) 
and randomized (1:1:1) to receive brief advice to switch to ECs, single session EC 
training, or enhanced EC training. Randomization will be determined by computer-
generated random numbers. After baseline data collection has been completed, the 
research assistant will select the sequential study ID number to determine the 
randomization assignment. 
 
2. This is an open-label trial. There is no blinding involved. 
 
3. Based upon preliminary data, the standard of change in puff duration over two weeks 
was 1.5 seconds per puff. Assuming a common standard deviation across groups, 15 
participants will allow us to obtain a 95% CI with a margin of error of 0.76 for the mean 
change for brief advice. In the acute phase (i.e., human lab visits 1 and 2), the single 
episode and enhanced EC training arms will have the same amount of intervention and 
will be combined. Thus, 30 participants will allow us to obtain a 95% CI with a margin of 
error of 0.54 for the mean change in puff duration in the combined intervention groups. 
We also wish to estimate the proportion of subjects who are predominant or complete 
switchers at Week 12. Fifteen participants in each group will allow us to estimate the 
95% CI for the proportion of switchers in each group with a margin of error no greater 
than 0.25. This data will allow us to determine the sample size needed for a fully 
powered randomized trial. For the purposes of the current study, we will need 15 
complete cases for each group. Due to potential attrition, we will recruit up to 22 
participants per group. We will discontinue recruitment when we have 15 complete cases 
per group.  
 
 
D. Subject Criteria (See Vulnerable Populations appendix, if applicable): Participants 
will be adult smokers ≥21 years old and diagnosed with COPD. The study will be open to 
both men and women. We have chosen to focus on participants with COPD who are unable 
to quit smoking using pharmacotherapy because their unique smoking profile places them at 
a high-risk population of smokers that is understudied and stands to experience marked 
improvements in health and quality of life from quitting smoking. Women who are pregnant, 
plan to become pregnant, or are breastfeeding will be excluded from the study because 
tobacco products will be provided, and smoking is associated with low birth weight and 
premature labor. Children and those <21 years old will be excluded because the minimum 
age for purchasing tobacco products is 21 years old. 
 
1. Inclusion criteria: 
 
Smokers:  
COPD, ≥21 years old, speak and understand English, smoke on >25 of the last 30 
days for the past 3 months, willing to switch from cigarettes to the study e-cigarette 
for the duration of the study. Have tried but failed to quit smoking in the last year, 
unwilling to make a pharmacotherapy-assisted quit attempt in the next 30 days, 

 
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willing to complete six in-person study visits, willing to have blood drawn, have 
reliable transportation to attend all in-person assessments, have a working phone 
number, and plan to remain in the Kansas City area for the full duration of the trial. 
 
Dual users:  
COPD ≥21 years old, speak and understand English, smoke on ≥15 days of the last 
30 days for the past 3 months, willing to switch from cigarettes and their own e-
cigarette to the study e-cigarette for the duration of the study, use an EC on >15 
days of the last 30 days for the past 3 months, have tried but failed to quit smoking 
in the last year, unwilling to make a pharmacotherapy-assisted quit attempt in the 
next 30 days, willing to complete six in-person study visits, willing to have blood 
drawn, have reliable transportation to attend all in-person assessments, have a 
working phone number, and plan to remain in the Kansas City area for the full 
duration of the trial. 
 
2. Exclusion criteria: 
 
Smokers:  
Use of tobacco products other than cigarettes including e-cigarettes in the past 30 
days, current use of cessation medications, pregnant, planning to become pregnant, 
or breastfeeding, recent history of cardiovascular or pulmonary events in the past 3 
months, household member current or previously enrolled in the study, weekly use of 
an EC over the last 6 months 
 
Dual Users:  
Use of tobacco products other than cigarettes and e-cigarettes in the past 30 days, 
current use of cessation medications, pregnant, planning to become pregnant, or 
breastfeeding, recent history of cardiovascular or pulmonary events in the past 3 
months, household member current or previously enrolled in the study  
 
3. Withdrawal/Termination criteria:  
 
Participants will be instructed to present to the lab nicotine deprived (12 hours abstinent) 
for the first study visit. If participants present to the first study visit with an eCO >12 
ppm or they report other nicotine use on two separate study visits, they will be 
withdrawn from the study (i.e., participants will be rescheduled one time).    
 
4. Participants will not be allowed to participate in another research study that aims to alter 
their tobacco use during this research study.  
 
 
E.  Specific methods and techniques used throughout the study  
 
1. Laboratory tests: At the beginning and end of the vaping session at Human Lab visits 1, 
2, and 3 (~week 12), blood will be collected for nicotine analysis via a blood draw from 
the participant’s arm. If deemed necessary by the study nurse (CRU staff) or by the 
participant, an IV catheter may be placed for blood draws. Blood sampling for changes in 
nicotine levels will occur at -5 minutes (pre-vaping session) and +30 minutes 

 
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(immediately post-session). No more than 7 mL of blood will be drawn per draw (≤14 mL 
per visit). Blood will be processed and analyzed for nicotine and cotinine levels.    
 
Human Laboratory Assessments (see Table 1 for timing):  
Topography will be used to objectively and passively measure EC puff patterns. 
Topography is a measure of substance self-administration11,12 and has been used 
successfully 
by our team 
in past 
trials.13-16 
Topography 
will be used 
in three 
ways: 1) in 
lab-based 
EC vaping 
sessions as 
an outcome 
variable, 2) 
within the 
intervention 
as outlined 
above, and 
3) in the 
natural environment throughout the RCT.  
Nicotine boost. At all three visits, blood samples will be collected at -5 (baseline) and 
+30 minutes (post-session). Samples will be analyzed according to standardized 
methods by Dr. Na Zhang at KUMC. Blood will be analyzed for nicotine levels to assess 
nicotine “boost” (i.e., change in nicotine level pre- to post-session) achieved during the 
EC sessions.  
eCO will be measured at final screening and all human lab visits. A >50% reduction in 
eCO from initial screening will indicate compliance with 12-hour abstinence from 
smoking.17 eCO is collected by having the participant take a deep breath in and hold it for 
15 seconds and then exhaling into a straw. 
Cigarette craving/withdrawal. The self-reported Tiffany-Drobes Questionnaire on 
Smoking Urges – brief (QSU-brief)18,19 and Minnesota Nicotine Withdrawal Scale 
(MNWS)20 will measure changes in cigarette craving and nicotine withdrawal from pre- to 
post-session.  
Other self-report assessments. The modified self-reported Cigarette Evaluation Scale 
(mCES)21 will assess subjective effects and sensory experiences at the end of each 
session. Participant’s intentions for future use (e.g., purchase, use) of ECs will be 
assessed using a 4-item measure.  
 
RANDOMIZED TRIAL OF EC TRAINING 
RCT Assessments (see Table 1 for timing): 
Cigarette smoking. Cigarette smoking will be assessed at W0, W4, W8, and W12 using 
the Timeline Followback (TLFB)22,23 in which individuals report on number of cigarettes 
per day (CPD) in the past 7 days.  
eCO levels will be used to biochemically confirm smoking status. eCO <6 ppm will 
indicate a complete switch.24 
Respiratory health and lung function. The COPD assessment test (CAT)25 is a COPD-
specific 8-item questionnaire designed to assess impairment in health status of COPD 
patients. Participants will complete the CAT at baseline and Wks 4, 8, and 12 to assess 
changes in self-reported respiratory health. Lung function will be assessed via 
spirometry.  
 
Table 1. Measures by timepoint 
 
 
Human Lab 
 
RCT 
Measure 
SCRN 
V1 
V2/W0 
W4 
W8 
W12 
V3 
Topography* 
 
X 
X 
X 
X 
 
X 
Nicotine boost 
 
X 
X 
 
 
 
X 
eCO 
X 
X 
X 
X 
X 
X  
 
7-day TLFB 
X 
X 
X 
X 
X 
 
X 
Health effects 
 
 
 
 
 
 
 
Spirometry 
 
X 
 
 
 
 
X 
COPD Gold Staging  
X 
 
 
 
 
 
X 
CAT 
X 
 
 
X 
X 
 
X 
Pulse wave velocity 
 
X 
 
 
 
 
X 
Beat to beat blood pressure 
 
X 
 
 
 
 
X 
6MWD 
 
X 
 
 
 
 
X 
Other self-report 
 
 
 
 
 
 
 
Cigarette craving/withdrawal 
 
X 
X 
 
 
 
X 
mCES 
 
 
 
X 
 
 
X 
Subjective effects of EC 
 
X 
X 
 
 
 
X 
Behavioral intentions 
X 
 
 
X 
 
 
X 
Notes. Topography measured throughout 12-week switching period 

 
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6-minute walk distance (6MWD)26,27 will assess changes in functional activity. The 
6MWD assesses an individual’s overall ability to conduct everyday activities and will be 
conducted at baseline, W4 and W12. This measure is particularly responsive to change in 
smokers with COPD.  Specifically, improvements in 6MWD have been found within xx 
weeks of smoking reduction in smokers with COPD [ref]. 
Changes in cardiovascular functioning will be measured using Pulse Wave 
Velocity,28,29 a sensitive measure of arterial stiffness that shows rapid (~1 month) 
changes with switching to ECs, at baseline and W12. In addition, we will assess changes 
in beat-to-beat blood pressure from baseline to W12. Beat-to-beat blood pressure is a 
sensitive measure of blood pressure and vascular elasticity. Measures of cardiovascular 
functioning will be conducted by Dr. Sandra Billinger and her team. These measures are 
sensitive to changes in smoking and vaping status and are associated with downstream 
health outcomes that result from smoking, such as cardiovascular disease. 
 
2. Study Procedures:  
a. Initial Screening: The initial screening will review inclusion/exclusion criteria by 
phone or online screener. Those eligible will be scheduled to complete an in-
person visit within 14 days. 
b. Final Screening (Day 0): Participants will be instructed to smoke and vape as 
they normally would before the final screening. Final eligibility screening will be 
conducted in-person and will consist of a pregnancy test, exhaled carbon 
monoxide (eCO), providing evidence of EC use (bring EC to visit; dual users only), 
and obtaining informed consent. Participants will complete carbon monoxide (CO) 
measurement to confirm current smoking status (CO > 12 ppm). CO is collected 
by a simple, non-invasive breath test that involves the participant holding their 
breath for ~15 seconds and then exhaling into a straw connected to the CO 
monitor. Cigarette smoking will be assessed using the Timeline Followback (TLFB) 
in which individuals report on number of cigarettes per day (CPD) in the past 7 
days. To assess baseline self-reported respiratory health, participants will 
complete the COPD assessment test (CAT). The modified Cigarette Evaluation 
Scale (mCES) will assess subjective effects and sensory experiences at the end of 
the session. Participant’s intentions for future use (e.g., purchase, use) of ECs will 
be assessed using a 4-item measure. Participants will sample two e-liquid flavors 
(Menthol and Tobacco) to establish preference. Participants will go home with 
their device and e-liquid of choice to practice at home. Participants will complete 
baseline measures. Participants will be compensated $10 for the final screening. 
c. Human Lab Visit 1 (1-14 days after Final Screening): At Human Lab Visit 1, 
participants will be re-screened according to inclusion/exclusion criteria. 
Pregnancy exclusion will be confirmed at each visit. They will be instructed to 
remain nicotine abstinent for 12 hours prior to the visit. Participants will complete 
CO measurement to confirm tobacco/nicotine abstinence. Participants will be 
provided with an overview of the study, and complete additional baseline self-
report measures. Self-report will be used for EC abstinence, as there is currently 
no objective, reliable measure to verify non-use of these products within the time 
the participants will be in the lab. Cigarette smoking will be assessed using the 
TLFB in which individuals report on number of CPD in the past 7 days. Participants 
will be provided the device of their choice and pre-filled pod of their preferred e-
liquid flavor. Participants will puff ad libitum for 30 minutes to establish baseline 
topography levels. Throughout the session, pre-intervention puff topography will 
be measured via a pressure sensor attached to the device/product and by the 
integrated topography software within the EC. This will not require anything 
additional of the participant. Blood sampling for changes in nicotine levels will 
occur at -5 minutes (pre-vaping session) and +30 minutes (immediately post-
session). Self-reported levels of cigarette craving and withdrawal will be measured 

 
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using the Tiffany-Drobes Questionnaire on Smoking Urges – brief (QSU-brief) and 
Minnesota Nicotine Withdrawal Scale (MNWS) pre- and post-session. The mCES 
will assess subjective effects and sensory experiences at the end of each session. 
Participant’s intentions for future use (e.g., purchase, use) of ECs will be assessed 
using a 4-item measure.  At the end of the baseline vaping session, participants 
will be randomized and enrolled (stratified on EC history) to one of three study 
arms in a 1:1:1 fashion: 1) Brief Advice, 2) Single Episode Training, 3) Enhanced 
EC Training. See the Training Guild for Researcher for specific training. For the 
Brief Advice study arm, participants will be given brief advice to switch to the EC 
and basic instructions on use of the EC and refilling pods. Participants will view 
their topography post-intervention via the Escribe software while they puff. Based 
on our preliminary data, trained research staff will give feedback on puff 
parameters shown to differ between complete switchers and switch “failures” – 
puff duration, flow rate, inter-puff interval, and puff number. The session will last 
~30 minutes. For the Enhanced EC training study arm, participants will receive 
the same training as the Single Episode Training arm. Participants will be asked to 
set a switch date using the Action Planning form. Participants will take the EC 
device home and use it as much or as little as they would like before the next 
visit. Lung function will be assessed via spirometry. At the end of the visit, a 6-
minute walk distance (6MWD) test will be done to assess the participant’s overall 
ability to conduct everyday activities. Baseline cardiovascular functioning will be 
measured using Pulse Wave Velocity, a sensitive measure of arterial stiffness that 
shows rapid (~1 month) changes with switching to ECs. Baseline beat-to-beat 
blood pressure will be measured to assess blood pressure and vascular elasticity. 
Participants will be compensated $50 for this visit. 
d. Human Lab Visit 2 / RCT Visit – Week 0 (1-5 days after Human Lab Visit 
1): Human Lab Visit 2 will occur 1-5 days after Human Lab Visit 2. Human Lab 
Visit 2 will be identical to Visit 1 but will not include any training, 6MWD test, or 
cardiovascular assessment. The purpose of this visit is to assess changes in 
topography following training at visit 1. Participants will be compensated $50 for 
this visit. 
e. Between Week 0 and Week 4: Participants will be provided with the device of 
their choice and pre-filled pods to use between visits for the real-world switch 
period. If chosen,  the Evolv Reflex EC device will collect and store 4 weeks of 
data on the participant’s EC use patterns and puffing topography. The JUUL and 
Vuse devices do not collect data. Research staff will conduct a brief phone check 
in with all participants on their switch date. During this call, a trained research 
assistant will assess tobacco and nicotine use since the last visit and will briefly 
trouble shoot barriers to switching to the e-cigarette.  
f. 
RCT Visit – Week 4: At Week 4 topography data will be downloaded from the EC 
and reviewed. In addition, participants will return their used and unused pods 
which will be weighed to assess e-liquid consumption between visits. Those in the 
Brief Advice and Single Session Training arms will not receive additional training. 
For those in the Enhanced Training arm, they will receive additional real-time 
feedback on their puff patterns. This arm is intended to mimic the level of support 
provided to smokers making a quit attempt using traditional quit smoking 
strategies and to determine the minimum level of support necessary to achieve a 
pattern of predominant EC use. Our approach with this arm is intentionally flexible 
to match the needs of each participant over the course of behavior change. For 
the purposes of rapport-building and continuity of care, attempts will be made to 
have participants meet with the same staff member each session. For participants 
in all study arms, the following will be done. Topography will be used to objectively 
and passively measure EC puff patterns. Participants will again complete eCO 
measurement to confirm smoking status. Cigarette smoking will be assessed using 
the TLFB in which individuals report on number of CPD in the past 7 days. To 

 
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assess changes in self-reported respiratory health, participants will complete the 
CAT. Lung function will be assessed via spirometry. Self-reported levels of 
cigarette craving and withdrawal will be measured using the Tiffany-Drobes QSU-
brief and MNWS. The mCES will assess subjective effects and sensory experiences 
at the end of each session. Participant’s intentions for future use (e.g., purchase, 
use) of ECs will be assessed using a 4-item measure. At the end of the visit, 
participants will be provided another 4-week supply of pre-filled pods and 
encouraged to continue their switch. Participants will be compensated $20 for this 
visit. 
g. Between Week 4 and Week 8: Participants will be provided with another 4-
week supply of pre-filled pods to use between visits for the real-world switch 
period. The Evolv Reflex EC device will collect and store 4 weeks of data on the 
participant’s use and puffing topography. The JUUL and Vuse devices do not 
collect data. 
h. RCT Visit – Week 8: Procedures at the Week 8 the visit will closely mirror Week 
4 visit. Used and unused returned pods will be weighed. Topography data will be 
downloaded and reviewed. Those from the Enhanced EC Training study arm that 
have not achieved optimal topography or predominant EC use will receive real-
time feedback on their puff patterns. Participants will again complete eCO 
measurement to confirm smoking status. Cigarette smoking will be assessed using 
the Timeline Followback (TLFB). To assess changes in self-reported respiratory 
health, participants will complete the CAT. Lung function will be assessed via 
spirometry. Self-reported levels of cigarette craving and withdrawal will be 
measured using the Tiffany-Drobes Questionnaire on Smoking Urges – brief (QSU-
brief) and Minnesota Nicotine Withdrawal Scale (MNWS). The modified Cigarette 
Evaluation Scale (mCES) will assess subjective effects and sensory experiences at 
the end of each session. Participant’s intentions for future use (e.g., purchase, 
use) of ECs will be assessed using a 4-item measure. Participants will be 
compensated $20 for this visit. 
i. 
Between Week 8 and Week 12: Participants will again be provided with 4 
weeks of pre-filled pods to use between visits for the real-world switch period. The 
Evolv Reflex EC device will collect and store 4 weeks of data on the participant’s 
use and puffing topography. The JUUL and Vuse devices do not collect data. 
j. 
RCT Visit – Week 12: Participants will smoke and vape as they normally would. 
Participants will complete eCO measurement to confirm smoking status. Because 
the eCO is the only measure needed for this visit, visit location will be flexible. 
Visits will be conducted as determined by location and abilities of the study 
participant. Participants will be compensated $10 for this visit. 
k. Human Lab Visit 3: Human Lab Visit 3 (Week 12) will be identical to Visit 1 
(above) but will not include any training. The visit is intended to measure longer-
term changes in EC puff patterns. Participants will be instructed to remain 
abstinent from nicotine and tobacco for 12 hours prior to the study visit. 
Participants will complete eCO measurement to confirm tobacco/nicotine 
abstinence. To assess changes in self-reported respiratory health, participants will 
complete the CAT. Lung function will be assessed via spirometry. Self-reported 
levels of cigarette craving and withdrawal will be measured using the Tiffany-
Drobes QSU-brief and MNWS. The mCES will assess subjective effects and sensory 
experiences at the end of each session. Participant’s intentions for future use 
(e.g., purchase, use) of ECs will be assessed using a 4-item measure. At the end 
of the visit, a 6-minute walk distance (6MWD) test will be done to assess the 
participant’s overall ability to conduct everyday activities. Baseline cardiovascular 
functioning will be measured using Pulse Wave Velocity, a sensitive measure of 
arterial stiffness that shows rapid (~1 month) changes with switching to ECs. 
Baseline beat-to-beat blood pressure will be measured to assess blood pressure 
and vascular elasticity. Participants will be compensated $50 for this visit. 

 
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l. 
Monthly for 3 months post active study completion – phone follow up with 
participant. 
 
3. Due to COVID-19 and the need to keep patients and researchers safe, we may use 
Zoom, a HIPAA compliant, university approved video conferencing software, during the 
visit. This will allow the participant to smoke freely (unmasked) while the researcher can 
watch and communicate with the participant via video conferencing from outside the 
clinic room. We will only enter the room when necessary and will ensure the participant is 
masked when research staff are present.  
4. All procedures, tests, and visits are being performed solely for research purposes and are 
not billable to insurance.  
5. Samples will be labeled with a unique participant and study identification numbers, 
participant initials, visit date, and timepoint (-5, +30) and only members of Dr. Leavens 
and Zhang’s teams will have access to the samples. Samples will be disposed of one 
month after the final report is sent out to the Principal Investigator. 
6. Timeline: We anticipate that this study will last 1 year (12 months; See Table 2 for 
timeline). We expect to recruit 5 participants in the third month of Q1 and 18 participants 
in each Q2 and Q3 and 4 participants in the final quarter. This accrual rate is 
commensurate with our past studies.  
 
Table 2. Study timeline by quarter 
 
 
F. Risk/benefit assessment:  
1. Physical risk: The potential risks for this study are minimal. There is a slight risk of 
discomfort, bruising and infection with blood draw. Blood will be drawn by trained 
research staff. IVs will be placed and blood draws will be conducted by an RN or LPN. 
Sterile instruments will be used for blood draws, the participants skin will be cleaned with 
an alcohol wipe at the site of the needle stick. Participants will complete no more than 
two study visits in a seven-day period. 
2. Psychological risk: Risks for participants include those associated with the inconvenience 
of participation including answering surveys, providing blood samples, and completing 
multiple visits. To minimize the inconveniences associated with study participation we will 
review all data collection instruments and study procedures to minimize the number of 
items in our instruments and improve the accessibility and convenience of our study 
procedures.  We may use several methods to enhance convenience to participants, 
including offering study visits throughout the day. Another risk is feeling pressured to be 
in the study, which we will track in order to monitor and will report as an adverse event. 
Finally, although very unlikely, some questions may make participants uncomfortable; 
participants are not required to answer questions they do not wish to. 
3. Social risk: None 
4. Economic risk: None 
5. Potential benefit of participating in the study  
a. There are no direct benefits to participants for participating in this study 
b. If shown to be effective, our study could, in the future, benefit smokers with 
COPD who are unable to quit smoking using FDA-approved medications by helping 
them switch to a potentially less harmful product.  

 
KUMC – HRPP- 03/12/2015 
 
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c. The researchers hope that the information gathered from this research may be 
useful in informing interventions for smokers unable to quit and to therefore 
benefit public health. 
G. Location where study will be performed: All study visits will be completed at the Clinical 
Research Unit – Rainbow. During study visits where cardiovascular functioning is measured, 
participants will also visit Dr. Billinger’s laboratory (KUMC campus; Hemenway Bldg; G002). 
All data will be directly entered into an electronic data capture system (i.e., RedCap or 
CRIS), therefore minimizing the use of paper records.  If paper records are generated, they 
will be stored in locked file cabinets.  Only study staff will have access to the locked records 
and the secure online electronic data capture system.   
H. Collaboration (with another institution, if applicable): N/A 
I. Single IRB Review for a Multi-site study (if applicable): N/A 
J. Community-Based Participatory Research (if applicable): N/A 
 
K. Personnel who will conduct the study, including: 
1. Indicate, by title, who will be present during study procedure(s):  
Personnel on the project include: Eleanor Leavens (PI), Nikki Nollen (co-I), Edward 
Ellerbeck (co-I), Sandra Billinger (co-I), Jennifer Woodward (co-I and study physician), 
Matthew Mayo (biostatistician), Tricia Snow (lead study coordinator), Terri Tapp 
(research assistant), Olivia Funk (research assistant), Leah Lambart (GRA), Dan Li 
(regulatory staff), CRU staff 
2. Primary responsibility for the following activities, for example:  
a. Determining eligibility: Eleanor Leavens, Nikki Nollen, Tricia Snow, Leah Lambart, 
Olivia Funk 
b. Obtaining informed consent: Eleanor Leavens, Leah Lambart, Olivia Funk 
c. Providing on-going information to the study sponsor and the IRB: Eleanor 
Leavens,  
d. Maintaining participant's research records: Eleanor Leavens, Tricia Snow, Matt 
Mayo, Olivia Funk, Leah Lambart 
e. Completing physical examination: N/A 
f. Taking vital signs, height, weight: CRU staff, Sandra Billinger and staff 
g. Drawing / collecting laboratory specimens: CRU staff 
h. Performing / conducting tests, procedures, interventions, questionnaires: Eleanor 
Leavens, Tricia Snow, Leah Lambart, Olivia Funk, CRU staff 
i. Completing study data forms: Eleanor Leavens, Tricia Snow, Leah Lambart, Olivia 
Funk 
j. Managing study database: Matt Mayo, Tricia Snow, Eleanor Leavens, Nikki Nollen, 
Leah Lambart 
 
L. Assessment of Subject Safety and Development of a Data and Safety Monitoring 
Plan 
 
1. Elements of the plan include: 
The current study does not pose more than minimal risk. We continue to closely monitor 
the situation. To address this concern, we will obtain informed consent, closely monitor 
AEs and SAEs and promptly report any that occur. Dr. Woodward will provide medical 
oversight. The Evolv Reflex EC will be used for the proposed study. The Reflex device is a 
commercially available pod-based device and is compatible with nicotine salt and 
freebase nicotine e-liquid. We will use commercially available nicotine salt e-liquid in 
~5% nicotine concentration. If participants cannot tolerate the Evolv Relfex, we will offer 

 
KUMC – HRPP- 03/12/2015 
 
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a choice of JUUL or Vuse devices. JUUL and Vuse are pod based systems. We will offer 
menthol or tobacco flavors in 5% or 3% concentration.  
2. We will protect participants and minimize risks by using the strict exclusion criteria and 
careful monitoring of AEs. AEs will be tracked during regularly scheduled visits or through 
spontaneous reports made by participants. Drs. Leavens, Nollen, and Woodward will be 
made aware of unexpected or serious AEs within 24 hours of the first report by 
participants; all other AEs will be reviewed weekly by Dr. Leavens and discussed at 
regular meetings with Dr. Woodward. SAEs will be reported to the KUMC IRB within 24 
hours of first awareness of the event. Unexpected adverse events that are related to the 
study products will be reported to KUMC IRB within 5 working days of first awareness of 
the event if the event is not serious and within 24 hours of first awareness if the event is 
serious. Unexpected adverse events that are unrelated to the study products will be 
reported to the KUMC HSC during yearly routine event reporting. Dr. Woodward will 
determine relatedness for each reported AE. SAEs will be defined as any event 
experienced by a study subject while using the study device that is fatal, life-threatening 
(subject was at risk of death from the event as it occurred), disabling or incapacitating, 
requires inpatient hospitalization or prolongs a current hospitalization, or required 
intervention to prevent permanent impairment or damage.   
3. In the case of AEs, participants will be reminded of the voluntary nature of the study and 
be allowed to discontinue participation without negative consequences. In the case of 
SAEs related to use of study products, participation will be discontinued. 
4. We will follow up with participants three months post treatment.  
 
 
III. 
Subject Participation 
 
A. Recruitment: 
1. Our team has a record of successful recruitment of smokers that spans three decades. 
Our team has completed 7 large-scale, NIH-funded trials and recruited over 3,000 
smokers in the past decade. Moreover, according to TUKHS patient database, there are 
over 3,700 smokers with COPD within Family Medicine alone. Based on this history and 
the available patient population, our enrollment goal of 45 smokers and e-cigarette users 
is comfortably feasible. Participants will be recruited through clinic (KUMC Department of 
Family Medicine), community-based efforts (e.g., flyers, face-to-face), and social media 
platforms including Facebook, Instagram, and Craigslist. Flyers will be placed around 
KUMC/TUKHS for patients to take.  We will use the KUMC HERON and KUMC KUCC C3OD 
databases and the TMC/O2 electronic medical records to identify smokers. We will then 
send letters to patients on behalf of physicians (with prior physician approval) informing 
them of the study. In the letter, participants will be given the option to opt out of future 
study contact. Potential participants that do not opt out will be contacted by phone to 
assess interest in study enrollment/eligibility. We will also use the Frontiers registry to 
identify adult smokers who have agreed to be contacted for research. We will also use 
radio ads, word of mouth, and our existing pool of participants from prior studies. We will 
post the study to the KUMC Intranet list of current studies for KUMC employees. 
Additionally, participants are currently being screened for other research studies 
conducted by our team. Those who have completed studies or who are ineligible for other 
studies being conducted will be informed about the current study and offered the 
opportunity to be screened.   
 
2. Recruitment methods are described above. Recruitment will be conducted by members of 
the study team. Recruitment will be overseen by Dr. Leavens. Initial screening will be 
conducted over the phone and by redcap survey.  
 
3. Advertisements and flyers that will be used for recruitment are attached. Advertisements 
and flyers will be handed out to potential participants by the study team and will be 
placed in clinics at KUMC/TUKHS. 

 
KUMC – HRPP- 03/12/2015 
 
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4. Letters sent on behalf of physicians will be mailed directly to patients to inform them of 
the study. Within one week of mailing letters, study staff will make follow-up calls to 
patients who did not opt out and offer initial screening. 
B. Screening Interview/questionnaire: The screening will be conducted by self-report via a 
redcap survey and eligibility will be verified by phone and at the initial in-person study visit 
(i.e., final enrollment). Participants will also have the option to complete initial screening 
completely by phone. The screening questionnaire will address the general 
inclusion/exclusion criteria as listed above. Only participants who have expressed interest 
will be screened. Prior to screening, participants will be given a brief overview of the study 
and informed that we need to collect some information to learn whether they may be eligible 
for the research. They will be informed that completion of the screening interview is 
voluntary, and they can discontinue screening at any time. Participants will be asked to 
provide consent for screening. 
C. Informed consent process and timing of obtaining of consent 
1 
Consent procedures will be conducted by trained members of the research team. Prior to 
consent, participants will be provided a detailed and comprehensive overview of study 
procedures.  
 
2 
Individuals interested in the proposed study and deemed to be initially eligible will meet 
the research assistant at the Clinical Research Unit – Rainbow. Each individual will be 
given a copy of the consent form and as much time as they need to review its contents. 
After the consent form is read, both the individual and the research assistant will review 
the consent form together and the potential participant will be encouraged to ask 
questions. Each individual will be reminded that participation in the study is completely 
voluntary. The consenting process will take place in a private location. 
 
3 
We do not anticipate recruitment of subjects with compromised cognitive abilities and/or 
decisional impairment. However, if questions regarding a participant’s ability to provide 
informed consent arise, Dr. Leavens will determine whether the subject is able to give 
informed consent. 
D. Alternatives to Participation: The alternative to participation is not participating, 
continuing to smoke cigarettes as usual, obtaining EC on their own, attempting to quit using 
FDA-approved pharmacotherapy, attempting to quit cold turkey. 
E. Costs to Subjects: There are no costs to participants. All tests, procedures, and visits are 
being performed solely for research purposes and are not billable to insurance companies. 
F. How new information will be conveyed to the study subject and how it will be 
documented: We have plans to publish data from this study in aggregate but will not 
provide any individualized feedback to patients. 
G. Payment, including a prorated plan for payment: Participants will receive $10 for final 
screening. Eligible participants who complete study procedures will receive $50 for each of 
the human lab visits, and $20 for each of the week 4 and 8 RCT visits. In addition, 
participants will be compensated $10 for the week 12 visit. Participants who complete all 
study procedures will earn $210.  
H. Payment for a research-related injury: N/A 
IV. 
Data Collection and Protection 

 
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A. Data Management and Security:  Confidentiality will be maintained by assigning each 
participant a study identification number and numerically coding all data. The association of 
the ID-code and the participant’s name will be kept by Tricia Snow in a locked file cabinet. 
The screening questionnaire and all survey data will be directly entered into RedCap or CRIS 
and accessible only by study staff. Any paper copies of records will be kept in a locked filing 
cabinet in offices that are kept locked when unoccupied.  Only summaries of group data will 
be reported in any publications or presentations, with no identification of individuals.  
Because identifiable information will be collected, participant privacy will be maintained 
throughout the duration of the study by adhering to the regulations set forth by the HIPAA 
Privacy Rule.  More specifically, identifiable information will not be released without written 
authorization of the participant.  Mobile devices will not be used for data collection or 
storage. Identifiable data will not be sent outside of KUMC. 
 
B. Sample / Specimen Collection:  No more than 7 mL of blood will be collected per blood 
draw (7 mL per draw x 2 draws per visit x 3 visits = 42 mL total during study). All samples 
will be de-identified and labeled with a study identification number. Blood samples will be 
aliquoted into two separate vials. Samples will be stored at the Bioanalytical Laboratory at 
the Rainbow Clinical Research Center. Samples will be accessible only to members of the 
study team. Results from biomarker analyses will be de-identified and shared only with 
members of the research team. Any resulting publications will present the data in aggregate; 
individual participants will not be identified. Samples will be disposed of one month after the 
final report is sent out to the Principal Investigator.  
C. Procedures to protect subject confidentiality:  Confidentiality will be maintained by 
assigning each participant a study identification number and numerically coding all data.  All 
biological samples and survey data will be labeled with the study identification number and 
never with the participants name or other identifiable information.  The association of the 
ID-code and the participant’s name will be kept by Dr. Leavens in a locked file cabinet and 
will only be accessible to members of the study team. 
D. Quality Assurance / Monitoring:  All data will be directly entered into our electronic data 
capture system (i.e., RedCap or CRIS) that contains edit checks to control the quality and 
completeness of data entry. Completeness of data entry will be automatically verified before 
each assessment is completed. The electronic data capture system is behind the KUMC 
secure firewall with role-based access that is HIPAA and human subjects compliant. There 
are no plans for ongoing third-party monitoring. 
V.Data Analysis and Reporting 
A. Statistical and Data Analysis: The purpose of this pilot is to build a body of preliminary 
evidence and determine effect sizes for a fully powered R01 trial. To assess Aim 1, we will 
obtain means and SD for each variable at V1 and V2 and calculate mean change and SD of 
the change. Given that there is no difference at this stage in singe and enhanced training 
arms, data for these arms will be combined. We will then construct 95% CIs on the change 
of each of these variables for treated and control groups. Obtain CI on the difference in the 
change between the two groups on each of these variables which will allow us to determine 
the short-term impact of training on outcome variables. To assess Aim 2, we will be able to 
estimate the proportion of subjects that fall into each of the switch patterns across the three 
treatment groups. Specifically, we will construct CIs on the proportion of predominant EC 
users. This would give us the data to determine effect sizes for the fully powered R01 trial. 
We will obtain means and SDs for each variable (i.e., health effects, puff patterns) at Wk0 
and Wk12 and calculate mean change and SD of the change. We will then construct 95% CIs 
on the change of each of these variables for the three arms. We will obtain CI on the 
difference in the change between the three groups on each of these variables which will 
allow us to determine the longer-term impact of training on the outcome variables. Given the 
pilot nature of the study, we have limited ability to assess variables that may affect our 

 
KUMC – HRPP- 03/12/2015 
 
Page 16 of 17
 
 
 
endpoints of interest, but initial correlations and associations will be examined to see if any 
of the variables (e.g., stratification variables including EC use history, gender) are related to 
our endpoints of interest. 
B. Outcome: The primary study endpoint is changes in puff duration from pre- to post-EC 
training/brief advice between smokers who received brief advice versus EC training (single 
episode and enhanced EC training arms combined).  We hypothesize that smokers who 
receive EC training will show greater increases in puff duration compared to brief advice, 
greater reductions in cigarette craving compared to brief advice, and greater increases in 
nicotine exposure compared to brief advice. Additionally, enhanced EC training will result in 
the greatest proportion of predominant EC users, the greatest reduction in COPD-related 
health effects, and the greatest increases in puff duration. 
C. Study results to participants: Study results will not be shared with research participants. 
D. Publication Plan: We plan to publish results in appropriate tobacco and public health 
journals such as Addiction, Tobacco Control, Nicotine and Tobacco Research, etc. In addition, 
results will be presented at regional, national, and international conferences. 
 
VI. 
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those of tobacco smoke. Tob Control. Aug 4 2017;doi:10.1136/tobaccocontrol-2017-053808 
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Wagener TL, Leavens EL, Mehta T, et al. Impact of flavors and humectants on waterpipe tobacco smoking topography, 
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