Comparing the Effects of Augmented Doses of Nicotine Replacement Therapy on Quitting Cigarettes and E-cigarettes
Phase: PHASE2
Conditions: Smoking Cessation, Electronic Cigarette Use, Cigarette Smoking
Sponsor: Medical University of South Carolina

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PROTOCOL TITLE 
Comparing the Effects of Augmented Doses of Nicotine Replacement Therapy 
on Quitting Cigarettes and E-cigarettes 
 
PRINCIPAL INVESTIGATOR 
Amanda M. Palmer, PhD 
 
 
 
1.0 Objectives / Specific Aims 
Tobacco use is one of the leading preventable causes of cancer-related morbidity and mortality in the 
US, and therefore remains a top priority for public health and cancer prevention research. The landscape 
of tobacco product use has shifted over the past decade, and research efforts should accommodate for 
these changes. Whereas smoking rates are declining, the use of electronic (e-)cigarettes is increasing. 
Although e-cigarettes may be used to help smokers quit cigarettes, many continue to use e-cigarettes 
without quitting smoking, thus identified as “dual users.” For these individuals, nicotine delivery from 
multiple product sources may increase nicotine dependence, which may result in more challenges with 
quitting both products. Importantly, any level of combustible tobacco use is detrimental to health and 
should be discouraged. Results from large representative surveys have estimated that over 60% of dual 
users want to quit; yet, there is a lack of data and intervention research to determine the most effective 
and acceptable treatments for dual smoking and e-cigarette cessation. Our prior pilot study showed that 
a standard dose (21mg patch, 4mg lozenge) of nicotine replacement therapy (NRT) may be an 
acceptable treatment option for users to quit e-cigarettes; however, dual users were unable to quit both 
products using this dose alone. The purpose of the present study is to determine if augmented doses of 
NRT will facilitate dual use cessation among a community sample of dual users. Dual users enrolled in 
the intervention will receive 1 of 3 NRT treatment doses: Arm A (21mg patch + 4mg lozenges); Arm B 
(21mg patch + 14mg patch + 4mg lozenges), or Arm C (2X21mg patches + 4mg lozenges). Results from 
this study will 1) provide preliminary data regarding which NRT dose may be appropriate for dual use 
cessation, 2) demonstrate the feasibility and acceptability of this intervention within the target population 
of interest.  
 
Aims and Hypotheses 
Aim 1: Evaluate, in a preliminary manner, the effect of augmented doses of NRT, compared to a standard 
dose, on outcomes from a dual use cessation attempt.  
Hypothesis: Higher instances of dual use abstinence days will be observed in the augmented dose 
groups (Arms B & C) as compared to the standard dose group (Arm A). 
Aim 2: Evaluate the feasibility, acceptability, and engagement with the treatment intervention.  
Hypothesis: There will be sufficient interest to complete study recruitment and procedures within the time 
limits of the funding.  
 
Results from the “CAN-DOSE: Cessation with Augmented Nicotine for Dual use Of Smoking and E-
cigarettes” study will provide preliminary insight into the effectiveness of NRT with a dual use population, 
and specifically, which dosage is best tolerated and utilized. These data will inform a future R-series 
application for a clinical trial for dual use cessation through enhanced doses of NRT. Treatment 
interventions to reduce the incidence of combustible tobacco use will benefit public health outcomes 
through cancer prevention.  
 
Medical University of South Carolina 
Protocol 

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2.0 Background 
Over the past several decades, tobacco control efforts have succeeded in reducing cigarette 
smoking prevalence, which has reduced the negative health effects of smoking on the population 
including cancer incidence and mortality1,2. Recent estimated from the Centers for Disease Control (CDC) 
Morbidity and Mortality Weekly Reports (MMWR) suggest that smoking prevalence among adults was 
down to 12.5% in 20203. However, overall prevalence of tobacco use has not declined as substantially, 
partially due to increasing rates of use of novel, alternative tobacco products. Specifically, use of 
electronic nicotine delivery systems (ENDS; i.e., electronic [e-]cigarettes, vaping) has been increasing. 
Both optimism and concern has arisen regarding the effect of these new products and their potential 
effects on public health4,5.  
E-cigarettes were initially marketed as an alternative to or means for smoking cessation, and they 
became popular amongst those currently smoking. Systematic reviews of the evidence show there is 
here is high certainty that e-cigarettes are just as effective as nicotine replacement therapy (NRT) for 
smoking cessation6. However, consistent with existing smoking cessation treatments, there is substantial 
room for improvement in quit rates. An unfortunate consequence of e-cigarette use, which differs from 
NRT outcomes, is that individuals who smoke and try to quit with e-cigarettes may progress to become 
“dual users” of both products7.  Some individuals who smoke may initiate e-cigarette use for reasons 
other than cessation, or alternatively, exclusive e-cigarette users may initiate cigarette smoking. It is 
estimated that in 2020, 39% of US e-cigarette users also smoked cigarettes, amounting to at least 2 
million dual users3,8. Most recently, devices containing salt-based, high nicotine solutions dramatically 
overtook the e-cigarette market by 15,000% from 2017-20229,10, which has likely increased the number 
of e-cigarette users and dual users.  
Cigarettes, on average, contain about 1.2mg of nicotine (~24mg per pack of 20 cigarettes). 
Nicotine-containing e-cigarette liquids may range anywhere from 3mg/ml to 50mg/ml and higher 
(common in disposable and cartridge devices); therefore, 1ml of nicotine liquid (a typical amount for one 
e-cigarette or refill) may contain more nicotine than a pack of cigarettes. Nicotine absorption 
pharmacokinetics is similar to that of smoking with some devices11. Whereas cigarettes are, in general, 
smoked one at a time during smoking sessions, e-cigarettes may be vaped throughout the day in several 
smaller sessions or used in longer puffing sessions similar to smoking.12 
 Both cigarettes and e-cigarettes deliver nicotine, a highly addictive substance, which contributes 
to sustained smoking and vaping behaviors. Adults who use e-cigarettes report health concerns, 
dependence, financial burden, social stigma, and discomfort with industry influence as reasons for 
wanting to stop their e-cigarette use13-15. Studies show that over half of adult cigarette smokers are 
interested in quitting16, and our has shown that 64.7% of dual users have plans to quit e-cigarette use17. 
Given that e-cigarette use is not completely harmless18,19, and any level of combustible tobacco use is 
harmful20 and poses a risk for the development of cancer, dual users should be a priority population for 
treatment. At minimum, the priority should be abstinence from combustible cigarettes, but abstinence 
from both products is ideal as to reduce any negative health effects that might occur. A specific emphasis 
on smoking relapse prevention is also warranted for this population. Our systematic review of e-cigarette 
cessation interventions showed that although it is clear that the majority of dual users want to quit, there 
are no empirically-supported interventions for dual use cessation21. In fact, most dual users attempt to 
quit unassisted (“cold turkey”) and are unsuccessful14. There is an urgent need to develop evidence-
based e-cigarette and smoking cessation interventions for this high priority population. 
In order to address the critical need for treatments to help people quit ENDS, clinical scientists 
may draw upon best practices for smoking cessation as a foundation for intervention development. 
Pharmacotherapy is a  well-established mechanism to promote long-term rates of smoking cessation22. 
Combined nicotine replacement therapy (NRT), which includes daily use of a patch alongside either 
lozenges or gum for breakthrough cravings, has demonstrated promise in enhancing smoking cessation 
outcomes23 and may be especially well-suited to help manage dual use withdrawal symptoms. That is, 
many dual users might significantly benefit from the combination of an extended-release nicotine patch 
and the ease of access to lozenges to help mitigate nicotine withdrawal symptoms in the moment.  

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Additional benefits of NRT are that it is seldom used for longer than 1 year after quitting smoking24 and 
is generally well-tolerated. Our pilot trials of NRT for e-cigarette cessation and dual use cessation21,25 
have shown promise for NRT for vaping cessation; however, it was unclear if this dose of NRT was 
sufficient for dual users (see preliminary results below for a full explanation of the findings). Of note, we 
know of no other researchers conducting pharmacotherapy trials for dual users, making the proposed 
work especially novel.    
The purpose of the present study is to further investigate the successful smoking cessation 
intervention, NRT, for dual use cessation. Specifically, given the results of our prior pilot studies 
(described later in Preliminary Findings), the aim is to evaluate whether an augmented (increased) dose 
of NRT might be more effective in helping dual users achieve abstinence from both products. Prior 
research has shown that an increased NRT dose is an effective, well-tolerated treatment option for 
individuals who had not yet achieved abstinence from smoking22,26. Dual users who are interested in 
quitting will be randomized to receive 1 of 3 NRT treatment doses: Arm A (21mg patch, qd + 4mg lozenge 
prn [minimum of 5 & up to 20 per day]); Arm B (21mg patch + 14mg patch qd + 4mg lozenge prn [minimum 
of 5 & up to 30 per day]), or Arm C (2X21mg patches qd + 4mg lozenges prn [minimum of 5 & up to 40 
per day]). Throughout the course of treatment, dual users will report their tobacco use, medication use, 
and any side effects. Results from this preliminary study will give insight into NRT dosages that may be 
appropriate for future clinical trials of dual use cessation, as well as feasibility, acceptability, and 
engagement data for undergoing this type of treatment and the effects on cessation outcomes.  
Innovation 
This study includes several innovative elements that align with ACS and NCI’s aims to reduce 
cancer incidence and mortality. 1) As the previous literature has shown, many dual users who have tried 
to quit endorsed unsupported, “cold turkey” methods with limited success14,21. This project will serve as 
a foundation for future dual use cessation intervention development work. 2) Although testing an existing 
smoking cessation treatment (NRT) is not inherently novel, it is the best foundation for starting research 
on dual use cessation, which has a critical need for treatment development. Additionally, the augmented 
NRT doses have not, to our knowledge, been tested on dual users, thus representing a potentially 
significant impact in the treatment literature. 
Proof-of-concept.  
Proof-of-concept. We conducted a proof-of-concept feasibility study27 with 30 participants 
interested in quitting e-cigarettes (both dual and mono-users; for the purpose of this application, we will 
discuss results related to the dual users). This study included a qualitative interview followed by 
enrollment in a pilot trial. In the qualitative 
interview, participants were asked about 
why they were interested in quitting vaping 
and smoking. Primary motives for dual use 
included major themes surrounding health, 
cost, perceptions of friends and family, 
negative consequences of dependence, 
and stigma. Participants were then 
randomized (at a 1:2 ratio, respectively) to 
4-weeks of either 1) referral to the Quitline 
or 2) NRT + booklet of tips for quitting. The 
NRT dosage was the standard dose for 
someone smoking 1 pack of cigarettes per 
day: 4 weeks worth of 21mg patches and 
4mg lozenges. The booklet was a 
rudimentary adaptation of standard 
smoking cessation materials from the 
MUSC Tobacco Treatment Program28. 
Participants completed assessments 
Table 1. Abstinence outcomes 
 
Intervention (N=18) 
Control (N=12) 
 
Mono Use 
(N=10) 
Dual Use 
(N=8) 
Mono 
Use (N=5) 
Dual Use 
(N=7) 
End of Treatment (Day 28) 
E-cigarette abstinence  
4 (40%) 
2 (25%) 
0 
0 
E-cigarette change 
Reduced 
No change 
Increased 
 
2 (33.3%) 
4 (66.7%) 
0 
 
3 (50%) 
3 (50%) 
0 
 
1 (20%) 
4 (80%) 
0 
 
3 (42.8%) 
4 (57.1%) 
0 
Smoking abstinence  
- 
0 
- 
0 
Smoking change 
Reduced 
No change 
Increased 
 
0 
10 (100%) 
0 
 
1 (12.5%) 
7 (87.5%) 
0 
 
0 
5 (100%) 
0 
 
1 (14.2%) 
5 (71.4%) 
1 (14.2%) 
Follow-up (Day 56) 
E-cigarette abstinence  
3 (30%) 
2 (25%) 
1 (20%) 
1 (14.2%) 
E-cigarette change 
Reduced 
No change 
Increased 
 
3 (30%) 
4 (40%) 
0 
 
2 (33.3%) 
4 (66.7%) 
0 
 
0 
4 (80%) 
0 
 
4 (57.1%) 
3 (42.8%) 
0 
Smoking abstinence   
- 
0 
- 
0 
Smoking change 
Reduced 
No change 
Increased 
 
0 
10 (100%) 
0 
 
2 (25%) 
6 (75%) 
0 
 
0 
5 (100%) 
0 
 
2 (28.5%) 
4 (57.1%) 
1 (14.2%) 

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reporting e-cigarette use and smoking at end of treatment (EOT) and 1-month follow up. In 6 months, 
we enrolled 30 participants; 24 (80%) of whom completed the EOT survey and 18 (60%) who 
completed follow-up. As shown in Table 1, following treatment, 33.3% (6/18) of the intervention 
group that received NRT was able to quit vaping whereas 0% in the control group did (3-day point 
prevalence). Notably, no dual users quit smoking; that is, some discontinued their e-cigarette use but 
continued to smoke. Some dual users were able to reduce their e-cigarette use and/or smoking, and 
only one had increased their smoking. Another important observation from this study was that 
individuals who 
achieved abstinence 
from vaping self-
reported using NRT 
more than those who 
were not abstinent 
(see Table 2).  
 
 
Altogether, these preliminary studies support the current application in 1) There is substantial 
interest in quitting dual use, as evidenced by results from national surveys as well as the recruitment 
and retention in the proof-of-concept study; 2) It is unclear what dose of NRT might be the most 
beneficial for those wishing to quit smoking and vaping; 3) Participants who achieved abstinence from 
vaping tended to use more NRT, which suggests a dose-response relationship between medication use 
and outcomes; 4) adherence to dual NRT was low and needs to be explicitly encouraged.   
 
3.0 Interventions to Be Studied 
 
The purpose of the present study is to further investigate the successful smoking cessation 
intervention, NRT, for dual use cessation. Specifically, given the results of our prior pilot study, the aim 
is to evaluate whether an augmented (increased) dose of NRT might be more effective in helping dual 
users achieve abstinence from both products. Prior research has shown that an increased NRT dose is 
an effective, well-tolerated treatment option for individuals who had not yet achieved abstinence from 
smoking20,24. In this intervention study, participants who are dual users of cigarettes and e-cigarettes who 
are interested in quitting both products will be recruited. Participants will be randomized into 1 of 3 
treatment conditions, each receiving a 4-week (28 day) supply of NRT: Arm A (21mg patch, qd + 4mg 
lozenge prn [minimum of 5 & up to 20 per day]); Arm B (21mg patch + 14mg patch qd + 4mg lozenge prn 
minimum of 5 & [up to 30 per day]), or Arm C (2X21mg patches qd + 4mg lozenges prn [minimum of 5 & 
up to 40 per day]). Additionally, participants will receive a supportive booklet, adapted from smoking 
cessation materials currently in use by the MUSC Tobacco Treatment Program, with tips and strategies 
for how to go about quitting vaping and smoking. Participants will complete weekly surveys to report on 
their medication use, tobacco use, and other quitting-related variables. Following completion of the 28-
day treatment, participants will be sent follow-up surveys at 1 month (Day 56). Results from this 
preliminary study will give insight into NRT dosages that may be appropriate for future clinical trials of 
dual use cessation, as well as feasibility, acceptability, and engagement data for undergoing this type of 
treatment and the effects on cessation outcomes. 
 
4.0 Study Endpoints. 
 
Primary Endpoint: 
Days of dual use abstinence (Day 28, Day 56): The primary outcome of interest is the number of days 
participants self-report abstinence from both e-cigarettes and smoking. These data will be derived from 
daily surveys that query about the previous day’s e-cigarette use (yes/no, estimated number of times 
Table 2 
Intervention (N=18) 
 
Abstinent 
(N=6) 
Not abstinent  
(N=12) 
Abstinent vs Not 
T , p, d 
# days using any NRT 
22.67 (2.88) 
7.83 (8.67) 
-5.36, <.001, -2.01 
# days using NRT patch 
19.50 (4.76) 
6.58 (4.76) 
-3.23, <.01, -1.61 
# days using NRT lozenge 
11.33 (7.06) 
3.91 (5.96) 
-2.35, <.05, -1.17 
# days using combined NRT 
8.16 (6.49) 
2.66 (5.75) 
-1.83, .08, -0.92 

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vaped, estimated amount of cartridge/refill used) and cigarette smoking (yes/no overall, number of 
cigarettes smoked). Non-responders and missing data will be coded as not abstinent.  
Secondary Endpoints: 
Reduction (Day 28, Day 56): In addition to number of days of complete dual product abstinence, we will 
use baseline and daily survey data (described above) to calculate the reduction of e-cigarette use and 
smoking between groups from baseline to end of treatment.  
Safety (Day 28): To further assess differences in acceptability and response to the treatment doses, 
adverse events between groups will be evaluated. NRT side effects will be captured during daily diary 
assessments using the Systematic Assessment for Treatment Emergent Events (SAFTEE)29.  
Feasibility/Acceptability (Day 28): Feasibility and acceptability endpoints will be determined by the 
proportion of eligible subjects able to be contacted who subsequently enroll, the proportion of enrolled 
subjects who complete the Day 28 survey, and the proportion of enrolled subjects who complete ≥80% 
of their daily surveys during the treatment period. Participants will report satisfaction and helpfulness of 
the intervention at the end of treatment (Day 28). 
 
5.0 Study Population / Inclusion and Exclusion Criteria 
 
We aim to recruit 45 participants (15 in each group: A, B, and C). Inclusion criteria include: 1) age 18+; 
2) daily nicotine-containing e-cigarette user (25+ days per previous month); 3) e-cigarette use 5+ 
times/day; 4) e-cigarette use > 1year; 5) smoking >1 cigarette on 5-7 days per week 6) interest in 
quitting smoking and e-cigarette within the next month (>7 on 10-point scale); 7) willingness to use 
NRT; 8) able to receive text messages/email, and 8) mailing address in SC.  
 
Exclusion criteria includes medical conditions contraindicated to NRT use (including pregnancy, past 
month myocardial infarction, current cardiac arrhythmia, current angina, uncontrolled vascular disease, 
or medical conditions in which consumption of phenylalanine is contraindicated, including 
Phenylketonuria [PKU] and allergy to phenylalanine), individuals reporting current use of other nicotine-
containing products and/or smoking cessation medications, those who vape non-nicotine substances, 
and individuals unable to consent (e.g. significant cognitive deficit, non-English speaking). These 
criteria were used in the proof-of-concept study25 which recruited at an acceptable pace. Exclusion 
criteria, including health information, will be ascertained via self-report on the online pre-screener. We 
have requested a waiver of signed consent for this assessment. 
 
Pregnancy status will be ascertained via self-report on the online pre-screener. In addition, we will ask 
participants if they are sexually active and if they are using any type of contraceptive method (with a list 
of available options). If female participants are deemed eligible (i.e., not pregnant and not engaging in 
unprotected sex) and schedule an intake, they will be mailed a pregnancy test. They will be told they 
will not complete the test until after they have consented to the study and agree to continue. During 
consent, discuss the exclusion criteria for pregnancy, as well as review risks of medication use as it 
pertains to pregnancy. Following consent, during the initial intake assessment, we will conduct the 
pregnancy test. The participant will perform the pregnancy test at home and report results to the 
research staff via sending a photo of the test (if doing consent over phone) or showing the test on video 
(if consenting via video call). If the test is negative, we will continue with the rest of the study 
procedures. 
 
We will not be enrolling vulnerable populations, specifically pregnant women, children, prisoners, or 
institutionalized individuals. We also will not enroll subjects incapable of providing their own consent.  
Should a potential subject present where there is a concern about their ability to understand study 
procedures and provide meaningful consent, their cognitive status and understanding of the study will 
be evaluated by the investigative team.  If there is any concern that the individual may be impaired, 
they will not be eligible for participation and not enrolled in the study.  The rationale will be provided to 

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the individual as well as his or her family members.  Referrals for further evaluation, including urgent or 
emergent evaluation, will be made as needed and clinically warranted.  
 
6.0 Number of Subjects 
We aim to recruit 45 participants (15 in each group: Arm A (21mg patch, qd + 4mg lozenge prn 
[minimum of 5 & up to 20 per day]); Arm B (21mg patch + 14mg patch qd + 4mg lozenge prn [minimum 
of 5 & up to 30 per day]), or Arm C (2X21mg patches qd + 4mg lozenges prn [minimum of 5 & up to 40 
per day]). We will use all possible methods to recruit until each arm is full. 
 
7.0 Setting 
We will use exclusively remote/telehealth procedures as detailed below. Data will be stored on MUSC 
Box or OneDrive folders which will only be shared with study staff. Any paper copies of data will be 
stored in a locked office in the HCC building.  
 
8.0 Recruitment Methods 
Advertising will be done online through a variety of media outlets seeking dual users motivated to quit. 
Participants will be screened online for eligibility. Potential participants will complete a pre-screening 
survey that is linked in the ad. If the individual is deemed eligible, the research staff will conduct a 
screening appointment via the web/mobile phone with the participant to confirm eligibility. After 
confirming eligibility, the research staff will conduct a full consent and intake via the tele-consent 
platform (i.e., Doxy.me or other HIPAA compliant tele-video conferencing software) or a link to a 
REDCap consent form.  
 
This research study will use remote/telehealth procedures as detailed below, consistent with our 
Tobacco Treatment Program procedures at our institutions. 
 
9.0 Consent Process 
 
When interested participants enter into the online screening survey via REDCap, they will be provided 
with information about the purpose of the screening survey, including what information will be collected, 
and how it will be kept private. Participants will be aware that they will be providing contact information 
and health information on this survey, which will only be used for research study eligibility purposes and 
will be kept secure. Participants have the option to stop the screening survey at any time. Upon review 
of the provided information, participants will provide consent to screening by selecting the appropriate 
option on REDCap, which will be recorded as consent (signature waived). Eligible participants will be 
contacted following the screening to consent into the study as outlined below.  
 
Participants will have 2 options to consent into this study: 1) remote consent via a virtual procedure 
(i.e., Doxy.me or other HIPAA compliant tele-video conferencing software), or 2) remote electronic 
consent (e-consent) via REDCap combined with a phone call. Informed consent will be maintained in 
each, allowing (requiring) discussion with study staff to ensure full understanding. In each option, 
participants will schedule a remote consent “visit” with research staff and will be encouraged to be in a 
private location during the call. Participants will be provided with a copy of the consent form 
electronically, which they can review on their own. Research staff will review the consent form with 
participants during the visit, allowing for any participant questions to be answered. The participant will 
be encouraged to take as much time as needed to review the consent form prior to enrolling in the 
study. Participants will also be notified that they will receive a signed copy of the consent form for their 
personal records to reference in the future. 
 
Remote consent via doxy.me: This essentially is video or telephone facilitated live discussion with study 
staff and potential study participant. After the initial determination of study eligibility, assessed online in 

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our secure survey, participants will be asked about their capacity for doxy.me procedures, including 
access to a computer with a webcam and speakers, and compatible internet browser (doxy.me is 
currently optimized for Google Chrome & Firefox, with planned expansion to additional browsers). For 
those who have the required hardware and software for doxy.me, we will offer this option and follow 
IRB-approved procedures as per precedent. All doxy.me signed consent forms will be saved as pdf files 
within our study records; the participant also gets an electronic copy. Research staff will then have the 
participant complete the baseline questionnaire.   
 
Remote e-consent via REDCap: This is similar to above doxy.me procedures but without the video 
connection, replaced by live phone call.  Participants will link to a REDCap-delivered consent document 
and will have a concurrent phone discussion with study staff who will provide further details on the 
study and answer any questions. Like doxy.me procedures above, these will likely be scheduled with 
potential participants in advance, i.e., through a consent appointment. The individual would 
electronically sign the consent form, and this then becomes a part of the research record, and like 
above the participant is given an electronic version of the consent to retain.   
 
For all the above procedures, and throughout the study, we maintain a phone line to support anyone 
who calls with questions. Anyone who completes a consent form will comprise the consented sample. 
However, the sample is reduced further to those with whom we can establish phone contact (Day 0; 
weekly follow-up surveys will begin the following day); i.e., the enrolled sample. This enrolled sample is 
the intent-to-treat sample. 
Although the mode of consent may differ across participants (i.e., doxy.me vs. teleconsent) we have 
taken steps to ensure that all participants will be fully informed of study procedures, including 
risks/benefits of participation, prior to providing signed consent. We ensure that all potential participants 
discuss the study with an IRB-approved consenter prior to providing signed consent.  
 
10.0 Study Design / Methods 
 
A target of 45 dual users across South Carolina will be recruited through various media outlets. 
Advertising will solicit vapers motivated to quit. Dual users will consent to be screened online for study 
eligibility, including potential for pregnancy. Pregnancy status and health conditions contraindicated to 
NRT (past month myocardial infarction, current cardiac arrhythmia, current angina, uncontrolled 
vascular disease, or medical conditions in which consumption of phenylalanine is contraindicated, 
including Phenylketonuria [PKU] and allergy to phenylalanine) will be ascertained via self-report on the 
online pre-screener. In addition, we will ask participants if they are sexually active and if they are using 
any type of contraceptive method (with a list of available options). If female participants are deemed 
eligible (i.e., not pregnant and not engaging in unprotected sex) and schedule an intake, they will be 
mailed a pregnancy test. They will be told they will not complete the test until after they have consented 
to the study and agree to continue. During consent, we will discuss the exclusion criteria for pregnancy, 
as well as review risks of medication use as it pertains to pregnancy and the aforementioned medical 
conditions.  
 
If the participant qualifies, research staff will schedule a time to complete the interview and baseline 
assessment battery. Following consent, during the initial intake assessment, we will conduct the 
pregnancy test on applicable participants. If the test is negative, we will continue with the rest of the 
study procedures. Participants will then be randomized to study arm (Arm A (21mg patch, qd + 4mg 
lozenge prn [minimum of 5 & up to 20 per day]); Arm B (21mg patch + 14mg patch qd + 4mg lozenge 
prn [minimum of 5 & up to 30 per day]), or Arm C (2X21mg patches qd + 4mg lozenges prn [minimum 
of 5 & up to 40 per day]). Participants will be provided with a 28-day supply of NRT by mail and a self-
help booklet (which includes instructions for medication use) and instructions to select a target quit date 
within 1 week. Research staff will contact the participants upon receipt of the materials and obtain the 

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target quit date. Participants in both groups will receive a brochure with information for contacting the 
SC QuitLine. During the 28-days of treatment, participants will be sent daily monitoring surveys asking 
about e-cigarette use, cigarette smoking, NRT, and quit attempts during the previous day. One month 
following the receipt of the materials, participants will complete an assessment battery. All assessment 
procedures will be completed via approved remote data collection platforms (e.g. REDCap). 
Participants will have the option to receive all study-related surveys (through REDCap) via text 
message or via email. No identifying information will be included on the texts/emails.  
 
Randomization. Participants will be randomized to one of the following NRT conditions: Arm A (21mg 
patch, qd + 4mg lozenge prn [minimum of 5 & up to 20 per day]); Arm B (21mg patch + 14mg patch qd + 
4mg lozenge prn [minimum of 5 & up to 30 per day]), or Arm C (2X21mg patches qd + 4mg lozenges prn 
[minimum of 5 & up to 40 per day]). Randomization to the intervention groups will be stratified on 
dependence score as follows: Participants will complete both the Roswell ENDS Nicotine Dependence 
Scale (Roswell eND30; e-cigarette dependence) and the Fagerström Test for Nicotine Dependence 
(FTND31; smoking dependence). Both scales have score ranges from 0 (no dependence) – 10 (high 
dependence). Consistent with cutoffs for the Roswell eND scale, participants will be stratified by low 
dependence (0-5) or high dependence (6-10) based on their highest score on either scale.  
 
Treatments. All treatment procedures will be conducted remotely (e.g., online, through mail). 
Intervention: Following randomization, participants will be instructed to select a quit day (Day 0) 
within the next week at which time they will commence using NRT. Participants will be sent a supportive 
text message reminder on that date (“Today is your quit date! Make sure to use your medications and 
written materials to help you. You got this!”).  
NRT medications. Following consent, participants randomized to the combined intervention will 
be mailed their 28-day supply of NRT. All participants will be encouraged to use the highest dose sent to 
them based on their randomization. A specific emphasis will be made on instructing participants to use 
both patches and lozenges concurrently. We will allow participants to engage in dose reductions 
naturalistically if they feel they need to, which will be captured through the daily surveys. Although this 
medication has not been formally tested for ENDS cessation, with the exceptions of our small pilot 
studies19,23, it is the first line treatment for cigarette cessation. For this reason, we believe it is a safe and 
acceptable pharmacotherapy to use for this intervention. We will monitor adverse events. 
Behavioral Support. A brief, informational booklet will be provided to participants that discusses 
how to plan and engage in a quit attempt of all tobacco products used. This will be adapted from currently 
used treatment manuals utilized by the MUSC Tobacco Treatment Program with clinical patients. This 
booklet will also provide information regarding the SC QuitLine, a freely available public service that 
provides tobacco cessation counseling and medication over the phone or through mobile/web platforms. 
Participants will be informed about the services the QuitLine offers as well as how to contact this service. 
 
Daily Monitoring. During the 28-days of treatment, all participants will be sent daily monitoring surveys 
(described later). All assessment procedures will be completed via approved remote data collection 
platforms (e.g., texting via Redcap). To increase retention, we will call participants who do not respond 
for >3 days.  
 
Follow-up. At the end of treatment (Day 28), research staff will contact the participant to complete an 
assessment battery. Four weeks after this (Day 56), a final follow-up assessment battery will be 
administered. Those who report abstinence from smoking will be mailed a remote carbon monoxide 
monitor (iCO) to complete and return. To increase retention, surveys will be sent via text and email, and 
we will call participants who do not respond within 1 week.  
 
Measures. Dual users who enroll in the study will first complete an assessment battery.  
 

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Assessments 
 
• 
Demographics (Baseline): Demographics will include sex, gender, sexual orientation, race, 
ethnicity, age, income, education, marital status, and health insurance status.  
• 
E-cigarette Use History (Baseline): At baseline participants will report e-cigarette use history 
(length of e-cigarette use, device, flavor, why they started, past quit attempts), current weekly use 
rates (days per week, estimated times per day, estimated puffs per day, length that a 
cartridge/refill lasts) and details about their specific product typically used (type, flavors, nicotine 
content, size of cartridge/refill).  
• 
Cigarette Use History (Baseline): Participants will report retrospective (lifetime) and current 
weekly (past 7-day) use of cigarettes, including length of time smoking, brand smoked, cigarettes 
per day, and quit attempts.  
• 
Motivation and Confidence to quit (Baseline, Days 28, 56): Participants will be asked to rate on a 
scale of 1-10, 10 being highest, their level of motivation and confidence in their upcoming quit 
attempt. If still using ENDS/smoking at end of treatment or follow-up, this will be re-assessed.  
• 
Expectancies (Baseline). Expectancies for e-cigarette use will be measured using the Short Form 
Vaping Consequences Questionnaire (S-VCQ)32 and expectancies for smoking will be measured 
using the Smoking Consequences Questionnaire (SCQ)33.  
• 
Dependence (Baseline, Days 28, 56). Participants will complete the Roswell eND Scale30, which 
has been validated to measure dependence on individuals seeking to quit ENDS use, as well as 
the Fagerström Test of Nicotine Dependence (FTND)34.  
• 
Daily monitoring survey (Treatment [Days 1-28]): In addition to the primary endpoints above, daily 
surveys will ask about the previous day: attempts to quit e-cigarettes/smoking, cravings to vape 
(Vaping Craving Questionnaire35), cravings to smoke (Questionnaire of Smoking Urges36), and 
NRT use (number of patches and/or lozenges used). Participants will also be asked if they used 
the supportive booklet or engaged with the Quitline, and length of each interaction. 
• 
Withdrawal (Treatment [Days 1-28]): Symptoms of withdrawal will be measured using the Brief 
Wisconsin Inventory of Smoking Dependence Motives (WISDM) scale34.  
• 
Timeline Follow-Back (TLFB; Days 29-56): On Day 56, a study staff member will conduct a TLFB37 
assessment to capture vaping, smoking, and NRT use over the previous month.  
• 
Carbon Monoxide (Day 28, Day 56): Participants who report abstinence from cigarette smoking 
will be sent an iCO to provide samples at each timepoint. TLFB data will be used to cross-
reference self-reported product use. 
 
Participant compensation. Participants will be compensated $25 for each the baseline, end of 
treatment, and follow-up assessments. Participants can earn up to $60 more for daily survey 
completion (biweekly payments as follows: $10 for 1-4 completed, $15 for 5-6, $20 for 7-11, $25 for 12, 
$30 for 13-14). Participants will be compensated with $20 for each CO sample provided (up to 2). To 
improve retention, participants who complete >85% (27 out of 31) of assessments will receive a bonus 
payment of $25. The maximum that someone in this study can earn if they complete all aspects of the 
study is $200. Participants will be offered electronic payments via ClinCard. 
 

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# of Assessments Completed in 2 weeks 
Amount paid (Bi-weekly) 
1-4 
$10 
5-6 
$15 
7-11 
$20 
12 
$25 
13-14 
$30 
 
 
11.0 Data Management 
 
 
Power analyses were performed using PASS 2022 v 22.0.4. Forty-five subjects will be randomly allocated 
1:1:1 to treatment arm (A, B or C) using permuted block randomization with block sizes of 3 or 6. 
Randomization will be stratified by level of dependence (low vs high). The primary endpoint is a binary 
indicator of abstinence (yes or no) measured daily for 28 (56) days from treatment initiation. Generalized 
estimating equations (GEEs) will be used to model the log odds of abstinence as a function of treatment 
arm. Separate models will be fit to evaluate abstinence in the first 28 or 56 days. Following best practice 
for covariate adjustment, level of dependence (stratification variable) will be included as a model 
covariate. We will assume a compound-symmetric working correlation structure, but all final estimates 
and inference will be based on the robust sandwich estimator. Finally, we will conform with the intention-
to-treat principle and therefore anticipate no issues secondary to missing data. The probability of 
abstinence in each treatment arm, differences in abstinence probabilities between treatment arms, and 
corresponding 90% confidence intervals will be estimated based on the fitted model. These estimates 
will then be used to construct model-based point and interval estimates of the average number of days 
abstinent in the first 28 (56) days from treatment initiation by multiplying by a factor of 28 or 56 as 
appropriate. As an additional analysis, we will include time (continuous) and arm-by-time interaction to 
evaluate temporal trends. Finally, we will investigate gender-related treatment effect heterogeneity by 
including sex and arm-by-sex interaction terms. However, sample size is small, and we consider such 
models to be purely exploratory. Fig 1 shows the power to detect a difference in the probability of 
abstinence between two groups of size 15 measured at 28 timepoints, where the probability of abstinence 
in group 1 is 10% (Fig 1A) or 15% (Fig 1B), the probability of abstinence in group 2 ranges from 30% to 
50%, and inference is based on GEE Wald tests with two-sided α = 0.1. Null abstinence rates ranging 
from 10 to 15% are justified based on preliminary data presented in this application. With no preliminary 
data to estimate the intra-cluster correlation (ICC), we considered a broad range of ICC values (0.2 to 
0.5). 

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All studies: 
Several steps will be taken to safeguard the confidentiality of subjects and their data. From the original 
data collected from participants, any identifying information will be removed, put into another file 
(described later), and all participants will be given a study number. Coded data will be stored in digital 
databases (Box folder). The names of participants will not be associated with this data and 
assessments will be maintained according to participant study number. A master list connecting 
participant study numbers to participant names and other identifying data will be kept in a locked file 
cabinet where it can only be accessed by senior level project staff. OnCore records will be maintained 
for each participant. Any information published as a result of the study will be such that it will not permit 
identification of any participant. 
 
Right to privacy for participation in this research will be protected through coding of data and proper 
storage of research records. Consistent with mandated reporting requirements for health providers, we 
advise participants that in the case of child abuse or neglect, threat of injury to self or others, or 
intention to destroy property, that we may need to intervene and report that information to the proper 
authorities. Subjects will be informed of this limit to confidentiality as it is stated in the informed consent 
document. 
 
The data will be stored in a locked room for 6 years after the final data is collected. The PI and the 
research staff will have access to PHI. Organizations that have a responsibility for protecting human 
participants, including the MUSC IRB, may have access to subjects’ records containing PHI. 
Additionally, the funding source may have access to subjects’ records containing PHI. 
 
12.0 Provisions to Monitor the Data to Ensure the Safety of Subjects 
Sources of Material: Forty-five individuals will be enrolled in the current project. The assessments will 
be collected only after obtaining informed consent, and for research purposes only. These records will 
be kept by Dr. Palmer in password protected confidential electronic files with restricted access.  
   
Confidentiality Procedures: As the PI, Dr. Palmer will assure all procedures protecting study data 
designed to guard subject confidentiality conform to the MUSC Research Protection Program 
requirements.  Additionally, the MUSC IRB must approve all procedures before the study can begin.  All 
data will be stored securely in locked offices or laboratories accessible only by study staff. Further, all 
information that could potentially identify a subject directly is removed from all study data.  This will be 
replaced with a unique identifier code.  The key to linking the code to subject identity will be kept 
Fig. 1 Power to detect a two-group difference in abstinence (P2 – P1) for (A) P1 = 0.1 or (B) 
P1 = 0.15 across ICC values ranging from 0.2 to 0.5. 

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separately from study data, in a locked file. Only study staff involved in clinical recruitment and 
assessment will have access to individually identifiable private information.  All other study staff will only 
have access to the coded identifier. 
 
Adverse Events:  
Given that this is a very low risk study assessing a behavioral intervention and a medication (nicotine 
patches and lozenges) that is so safe it has been available over-the-counter since 1996, we do not 
expect serious adverse events. Please see section 14 “Risks to Subjects” for more research on the 
safety of NRT, augmented doses of NRT, and NRT for vaping cessation.  
 
Adverse Events: 
Participants will have the phone numbers of the PI Dr. Amanda Palmer (843-792-1413) and 
will be prompted to contact her if an adverse event occurs. If a participant contacts the 
research team due to an adverse event, the event will be appropriately addressed, and the 
event will be reported per the IRB standard procedures and criteria below. Adverse events will 
also be tracked via daily and monthly assessments, where they will be able to rate the incident 
as mild, moderate, or severe. The research staff, with the guidance of Dr. Palmer and Dr. 
Emily Ware will track the relatedness of the incident to study medication. The variables that we 
will encourage the pharmacist and PI to assess include severe reports of the following 
symptoms (listed symptoms of nicotine overdose per package insert): nausea, salivation, 
abdominal pain, sweating, headache, diarrhea, dizziness and weakness. We will determine if 
any adverse events result in dropouts or are serious according to FDA guidelines. Following 
the report of an adverse event and consultation with Dr. Ware, the participant will be contacted 
to discuss modifying their NRT usage. 
Adverse events will be defined and graded for risk as follows: 
 
Coding of Severity: 
0 = No adverse event or within normal limits 
1 = Mild adverse event 
2 = Moderate adverse event 
3 = Severe, resulting in psychiatric or medical hospitalization 
4 = Life-threatening adverse event 
5 = Fatal adverse event 
 
Coding of Attribution will be made for adverse events grade 3 and above (ie, serious adverse events): 
1 = Unrelated to study interventions 
2 = Unlikely relationship to study interventions 
3 = Possible relationship to study interventions 
4 = Probable relationship to study interventions 
5 = Definite relationship to study interventions 
The FDA’s definition of serious adverse events (21 CFR 312) will be used. Serious Adverse 
Events include any untoward medical occurrence that at any dose results in death or the 
immediate risk of death, hospitalization, or the prolonging of an existing hospitalization, 
persistent or significant disability/incapacity or a congenital anomaly/birth defect, new cancer, 
or medication overdose. 

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Serious adverse events, whether unanticipated or anticipated, will be reported immediately 
(within 24 hours) to the MUSC Institutional Review Board. The PI will evaluate the adverse 
event and determine whether the adverse event affects the Risk/Benefit ratio of the study and 
whether modifications to the protocol or the consent procedures are required. 
Unanticipated problems involving risk to subjects or others (defined as an event that is is 1] 
unexpected, 2] related or possibly related and 3] serious) will be reported to the IRB no later 
than 10 working days after the event or notification to the research team that the event has 
occurred. The reported information will include: a description of the event, the date of 
occurrence, whether it is a local or outside report, how the event affected the rights, safety or 
welfare of the subject or others, current status of MUSC subjects, and any planned changes or 
modifications to the project as a result of the event. 
Any participants' experiences of unanticipated adverse events will be reported on an annual 
basis to the MUSC Institutional Review Board. 
 
14.0 Risks to Subjects 
 
The main study procedures include completion of questionnaires and using NRT, both of which are 
generally considered minimal risk procedures.  Although these procedures do carry slight risk, the 
primary risks of the study is loss of confidentiality. There is also a risk that the treatment the study 
participant is randomized to may prove to be less effective than the other study treatment or other 
available treatments. 
 
1. Breach of confidentiality:  There is the potential risk of breach of confidentiality of laboratory 
information.  The Co-PIs have experience as an investigator dealing with such sensitive information 
and has experience assuring that data is adequately protected.  Safeguards to protect 
confidentiality include locked records and firewalls around password-protected electronic data, and 
all study data being coded, with the key linking the code with a subject’s identity being kept in a 
separate, locked file. 
 
2. NRT  
 
Daily diary surveys will monitor for AEs related to the NRT. If a participant endorses an adverse 
side effect, they will be contacted by research staff to determine the degree of the event and make 
recommendations regarding continuing product use as recommended by the TTP Clinical 
Pharmacist Dr Emily Ware. These will be recorded as a part of the study file.  
 
2.1 Nicotine patches and lozenges: Exclusion criteria will include endorsement of history of any of 
the following medical conditions that are contraindicated for patch use: myocardial infarction, 
arrhythmias, angina, vascular disease, or medical conditions in which consumption of phenylalanine 
is contraindicated. 
 
The most common side effects from nicotine patch are skin irritation, insomnia, and headache or 
nausea.  Nicotine lozenges may cause side effects, including sore throat, indigestion, gas, and 
nausea.  
2.2 Combined use of any NRT product and tobacco product 
 
Our study allows participants to sample individual NRT products while attempting to quit smoking and 
vaping.  Thus, participants could be using NRT products concurrently (same day) as smoking or 

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vaping. This could result in nicotine intoxication; i.e. nausea, dizziness, headache, stomachache, 
etc38. In a prior study for cigarette smokers, participants completed a nicotine intoxication scale, and 
Drs. Toll and Carpenter found no evidence of nicotine intoxication when gum and cigarettes were In 
a review of prior smoking reduction studies, it was found that most participants did not have higher 
than normal cotinine levels with concurrent use of cigs and NRT, and there were few AEs reported39.  
 
Our participants will be encouraged to avoid vaping and smoking at the same time as wearing the 
patch or using the lozenge.  
 
2.3 Augmented doses of NRT  
This study utilizes augmented doses of NRT; that is, participants may be recommended to a dosing 
schedule that is higher than the labeled recommendations on the box. One reason for doing this is to 
address the elevated levels of nicotine consumption seen in dual users of cigarettes and e-cigarettes.  
One study40 asked dual users about how their dependence changed from smoking only to dual use. 
Most dual using participants reported feeling higher nicotine dependence and believed themselves 
to be using more nicotine than when they were exclusively smoking. For this reason, it makes sense 
to utilize higher doses of NRT than standard recommended doses for exclusive smoking cessation. 
In fact, for some individuals who are heavy smoking or have difficulty quitting, higher doses of NRT 
have been endorsed in the literature.  
 
The Cochrane review41 of NRT showed benefit for increasing NRT doses above the standard dose, 
particularly for those smoking at higher rates or who have failed to quit in the past repeatedly. A 2013 
review of methods for enhancing NRT efficacy found that increasing the dosage of NRT or adjusting 
the dosage based on higher dependence showed favorable outcomes for smoking cessation23. Other 
reviews42 and studies26,43 have also demonstrated favorable outcomes of high-dose NRT compared 
to controls, some utilizing doses as high as 84mg43. Importantly, these studies and reviews failed to 
show increased incidents of serious adverse events related to increased NRT use. Results of studies 
of high-dose NRT have been so consistently reported that clinical practice guidelines22 for smoking 
cessation recommend higher doses of NRT for individuals who smoke based on characteristics such 
as dependence (See Chapter 6, part B: Medication Evidence and Table 3.8). Given the recent 
proliferation of e-cigarette use in the US (e-cigarettes are the second most common tobacco product 
used among adults, with nearly half of those using e-cigarettes also reporting smoking), it is important 
to continue extending these findings to dual tobacco product users as is called for in the reviews23,42.  
 
Some (but not all) studies of high dose NRT have shown an increased prevalence of non-serious side 
effects, including sleep disturbance, nausea, dizziness, headache, and skin irritation at patch 
application site42. Participants will be encouraged to report any adverse effects to the research staff, 
who will consult with our Clinical Pharmacist and provide recommendations for dosage alterations as 
appropriate. We will record all AEs and have plans to evaluate differential safety profiles of each 
dosage arm (see section 4.0; Secondary endpoints).  
 
2.4 NRT for e-cigarette use 
Recently published reviews21,44,45 of vaping cessation interventions provide preliminary evidence for 
the effectiveness, acceptability, and safety of NRT for e-cigarette use. Also see proof of concept 
study25 for which the present proposal was based off of and showed minimal adverse events of NRT 
for dual use cessation.  
 
Nicotine replacement therapy is a recommended treatment for pharmacists by the Therapeutic 
Research Center46. Dr. Ware uses these guidelines to treat patients in the Tobacco Treatment 
Program at MUSC.  
 

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Our participants will be encouraged to report any adverse effects to the research staff, who will consult 
with our Clinical Pharmacist and provide recommendations for dosage alterations as appropriate. We 
will record all AEs and have plans to evaluate differential safety profiles of each dosage arm (see 
section 4.0; Secondary endpoints).  
 
3. Randomization. There is a risk that the treatment the study participant is randomized to may prove to 
be less effective than the other study treatment or other available treatments.  
4. Pregnancy. NRT use is contraindicated during pregnancy. Participants will be aware that they should 
discontinue use of NRT medications if they become pregnant during the course of the study. 
Participants will be instructed to inform research staff if they become pregnant during the course of 
the study. They will be permitted to continue in other study procedures (e.g., surveys) but will be 
explicitly discouraged from continuing to use study medications.  
 
16.0 Drugs 
The NRT for research participants will be stored at room temperature in a location accessible to 
research staff. Once a participant enrolls into the study, the medication, in the original packaging, will 
be mailed in the to the participant (overnight via fedex) after they have completed the baseline 
assessment. We will include medication instruction sheets that detail how to properly use the 
medications and what to do about side effects. If side effect are reported, either through the daily 
surveys or directly to research staff, suggested alterations of dosages will be done with the MUSC HCC 
TTP Clinical Pharmacist Dr. Emily Ware.  
 
 
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