Conditions: Nicotine Dependence, Cigarettes
Keywords: Nicotine addiction Cigarette smoking Nicotine patches E-cigarettes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 94
Healthy volunteers: no

Brief summary:
This study plans to investigate whether using electronic cigarettes (e-cigarettes) or skin patches containing nicotine affects switching from smoking conventional combustible (burning) cigarettes.

Detailed description:
This study proposes to assess the relative role of nicotine dose and route of delivery in affecting successful switching from combustible cigarettes to e-cigarettes, as well as concomitant reductions in ad libitum cigarette smoking and exposure to harmful and potentially harmful constituents of combustion. The strategy will be to assess adoption of e-cigarette use and concomitant reduction in ad libitum smoking of subjects' usual brands of cigarettes over an 8-week period, during which they will receive nicotine or non-nicotine e-cigarettes, and nicotine skin patches. The nicotine patches will not be used as a therapeutic treatment in this study, but rather as a way to manipulate the nicotine dose, while varying the rate and route of nicotine delivery. Behavioral or "habit" aspects of e-cigarette use will be controlled for by the groups receiving non-nicotine e-cigarettes. Initially the study design included placebo patch control conditions, but due to limitations in budget and period of support, enrollment in these these arms was discontinued. All participants currently receive active nicotine patches.

Arms:
arm 1: Participants will receive e-cigarettes containing nicotine and nicotine patches (21mg/24hr) and will be asked to switch from cigarette use to use of the study e-cigarettes for eight weeks. arm 2: Participants will receive e-cigarettes not containing nicotine and nicotine patches (21mg/24hr) and will be asked to switch from cigarette use to use of the study e-cigarettes for eight weeks. arm 3: Participants will receive e-cigarettes containing nicotine and placebo patches (21mg/24hr) and will be asked to switch from cigarette use to use of the study e-cigarettes for eight weeks. arm 4: Participants will receive e-cigarettes not containing nicotine and placebo patches (21mg/24hr) and will be asked to switch from cigarette use to use of the study e-cigarettes for eight weeks.

Interventions: intervention 1: Nicotine patch intervention 2: Placebo patch intervention 3: E-cigarettes intervention 4: Non-nicotine e-cigarettes
Intervention descriptions: intervention 1: Participants will wear the nicotine patch daily while switching from cigarette use to use of e-cigarettes for eight weeks. intervention 2: Participants will wear the placebo patch daily while switching from cigarette use to use of e-cigarettes for eight weeks. intervention 3: Participants will use e-cigarettes containing nicotine while switching from cigarette use to use of e-cigarettes for eight weeks. intervention 4: Participants will use e-cigarettes not containing nicotine while switching from cigarette use to use of e-cigarettes for eight weeks.

Protocol document:
Prot_SAP_001.pdf: 
The Role of Nicotine Dose and Route of Delivery in Affecting Adoption of E-
cigarettes and Reducing Exposure to Toxic Combustion Products
Document Date: May 9, 2022
NCT03492463


DUHS IRB Application (Version 1.31)
General Information
*Please enter the full title of your protocol:
The Role of Nicotine Dose and Route of Delivery in Affecting Adoption of E-cigarettes and 
Reducing Exposure to Toxic Combustion Products
 
 
*Please enter the Short Title you would like to use to reference the study:
ENDS-Switch
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study.
 
 
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Dept?
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Assign key study personnel (KSP) access to the protocol
* Please add a Principal Investigator for the study:
(Note: Before this study application can be submitted, the PI MUST have completed CITI training)
 
Rose, Jed
 
3.1 If applicable, please select the Key Study personnel: (Note: Before this study application can be submitted, all Key 
Personnel MUST have completed CITI training)
* Denotes roles that are not recognized in OnCore. Please select an appropriate role that is recognized in all clinical 
research applications (iRIS, OnCore, eREG, etc.)
 
A) Additional Investigators, Primary Study Coordinator (CRC), and the Primary Regulatory 
Coordinator (PRC):
Claerhout, Susan 
 Primary Regulatory Coordinator
Davis, James 
 Co-PI
B) All Other Key Personnel
Campbell, David 
 Other*
N


Claerhout, Susan 
 Research/Physician Assistant
Maultsby, Linda 
 Other*
Melcher, Betsy 
 Research/Physician Assistant
Mukhin, Alexey 
 Other*
Pallin, Kendra 
 Clinical Research Specialist/Study Assistant
Thomas, Leah 
 Other*
*Please add a Study Contact:
 
Campbell, David 
Claerhout, Susan 
Rose, Jed 
The Study Contact(s) will receive all important system notifications along with the Principal 
Investigator. (e.g., The study contact(s) are typically the Principal Investigator, Study Coordinator, 
and Regulatory Coordinator.) 
 
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Please see additional criteria and information in the policy titled “Reliance on the IRB of Another Institution, 
Organization, or an Independent IRB" on the 
.
IRB web site
Regular Study Application - Most common. The IRB will determine if the study is eligible for expedited 
review or requires full board review upon submission. 
Application for Exemption from IRB Review - Includes Exempt, Not Human Subject Research, & Not 
Research. 
External IRB Application - Any study using an external IRB as the IRB-of-Record. 
Trainee Research While Away from Duke - Research conducted by medical students overseen by the 
Office of Curriculum & other student/trainee research away from Duke. 
Individual Patient Expanded Access, Including Emergency Use - Use of an investigational product 
under expanded access, including emergency use of an investigational drug or biologic or emergency 
use of an unapproved device.  
 
Conflict of Interest
Do any of the participating study investigators or other key personnel (or their immediate family/significant 
other) have a financial or intellectual interest in, or are receiving compensation from, the sponsor or the 
drugs, devices or technologies used in this research?


 Yes   
 No
Has this conflict been disclosed to the Duke COI Committee?
 Yes   
 No
Are any key personnel an inventor of any of the drugs, devices or technologies used in this research?
 Yes   
 No
Have you filed an Inventor Disclosure Form?
 Yes   
 No
Do any key personnel have or anticipate (within the year) any financial relationships (e.g., consulting, 
speaking, advisory boards, patents, equity, options) that could be perceived to overlap or present a conflict 
of interest with the current research?
 Yes   
 No
Describe the overlap:
Rose Research Center provides clinical trials services to JUUL Labs.  Given his relationship with JUUL, Dr. 
Rose will not be permitted to serve as PI on Duke research that may result in direct commercial 
advancement of JUUL products. It is not legal to use Duke's non-profit resources to advance the 
commercial prospects of a for-profit entity unless the research is performed in such a manner that the 
Public Benefit is assured. While he can in general perform research in fields of science that may ultimately 
be useful to companies, he will not be permitted to act as PI for any research that results in a direct 
commercial advancement of JUUL products. The Research Integrity Office (RIO) has reviewed Dr. Rose's 
NIH grants, and he may continue to serve as the Duke PI on the NIH award which uses the JUUL e-
cigarettes and formulated cartridges.
Do any key personnel have a conflict of interest management plan (issued by the Duke University School of 
Medicine Research Integrity Office) with this company?
 Yes   
 No
If Yes, please give the name(s) of the relevant personnel.
Dr. Jed Rose
 
Oversight Organization Selection
CRU (Clinical Research Unit) or Oversight Organization Selection:
Please select the CRU.
Psychiatry
The Clinical Research Unit that takes responsibility for this study.
More information on CRUs can be found on the Duke Office of Clinical Research (DOCR) website, 
http://docr.som.duke.edu
Questions concerning CRU selection should be directed to docr.help@dm.duke.edu.
For questions about the Campus Oversight Organization, please visit Campus Oversight 
.
Organization


List all Key Personnel on the study who are outside Duke:
Note: You will also need to attach the documentation of Human Subjects Certification for each 
individual, if they have completed the certification somewhere other than Duke.
If outside key personnel will have access to Duke PHI, a data transfer agreement AND 
external site IRB approval (or IRB authorization agreement) will be needed.  See HRPP 
policy Use of Research Data by Former Duke Students or Former Duke Faculty and 
Employees
In the panel below, “PHI” is Protected Health Information.
       Entry 1       
Name
Study Role
Email Address
Institution / Organization
Will he/she have access to 
Duke P.H.I.?
  Yes   
  No
Is he/she an unpaid 
volunteer at Duke on the 
study?
  Yes   
  No
Indicate the Protocol source below:
The protocol source is the author of the protocol. If the protocol is a joint authorship between multiple 
sources, select the primary author. 
An IRB fee may be assessed for all research that is supported by for-profit entities and requires full board 
review. For additional information, see the IRB fees section of the IRB web site
PI initiated 
Commercial / Industry (for-profit entity) initiated 
Federal Government initiated 
Cooperative Group Initiated 
Foundation (non-profit group) initiated 
Other 
 
Sponsor and Funding Source
Add all funding sources for this study:
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Details
Sponsor Name
Sponsor Type
Contract 
Type:
Project 
Number 
Award 
Number 
National Institute on Drug 
Abuse 
Federal Government 
Grant 
 
 
Sponsor Name:
National Institute on Drug Abuse 
Sponsor Type:
Federal Government 
Sponsor Role:
Funding
Grant/Contract Number:
P50DA027840 
Project Period:
From:08/15/2015   to:05/31/2020 
Is Institution the Primary Grant 


Holder:
Yes 
Contract Type:
Grant 
Project Number:
 
Award Number:
 
Grant Title:
Center for Adaptive Treatment of Cigarette Addiction 
PI Name:
(If PI is not the same as identified 
on the study.)
 
Explain Any Significant 
Discrepancy:
 
Principal Investigator 
Duke 
Grant 
 
 
Sponsor Name:
Principal Investigator 
Sponsor Type:
Duke 
Sponsor Role:
Protocol Control Data Coordination Monitoring Coordinating 
Center;
Project Period:
From:08/15/2015   to:05/31/2020 
Is Institution the Primary Grant 
Holder:
Yes 
Contract Type:
Grant 
Project Number:
 
Award Number:
 
Grant Title:
 
PI Name:
(If PI is not the same as identified 
on the study.)
 
Explain Any Significant 
Discrepancy:
 
Is this a federally funded study?
 Yes   
 No
Does this study have any of the following?
Industry sponsored protocol
Industry funded Duke protocol
Industry funded sub-contract from another institution
Industry provided drug/device/biologic
SBIR/STTR funded protocol
 
  Yes   
  No
As part of this study, will any samples or PHI be transferred to/from Duke to/from anyone other than the 
Sponsor, a Sponsor subcontractor, or a Funding Source?
  Yes   
  No
Is the Department of Defense (DOD) a funding source?


  Yes   
  No
For Federally funded studies:
Is your funding subject to, and does it comply with, the funding agency's policy for data sharing?
  Yes   
  No
Enter the Grant Number or Other Federal Agency Proposal or Application Number:
P50DA027840
Note: The Federal Funding Agency ID Number is the Sponsor's grant number assigned to your project and 
available on your Notice of Award (example: R01HL012345).
 
If known, enter the SPS (Sponsored Projects System) number if applicable:
230139
In the Initial Submission Packet, attach the following:
(1) The entire grant, or an explanation of why a grant is not needed. 
(2) NIH institutional Certificate form related to data sharing (if applicable).
The entire grant is needed so that it may be reviewed against the protocol for concordance.
Have you successfully synced your protocol to OnCore by clicking the ‘Sync Data Over API’ button at the top 
of this page?
Please verify that the protocol has been created in OnCore before submitting this application for PI Signoff.
 
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I may have forgotten! I'll click it again right now, just to be sure, and verify it was successfully sent by 
logging into OnCore. 
 
Mobile Devices and Software
Does this study involve the use of a software or a mobile application?
  Yes   
  No
List all software, including third party (non-Duke) and mobile apps, that will be utilized for ascertainment, 
recruitment, or conduct of the research/project: (eg, MaestroCare, DEDUCE):
Microsoft Access is used for logging subject information (Enrollment Log, Visit Log, etc.); this database is 
designed and maintained by the CRC (Al Salley, al.salley@duke.edu), and data are entered by key 
personnel. Main phone number: (919) 668-5055.
The Study Team will design CRFs in REDCap. Study participants will complete some study questionnaires 
on REDCap. Questionnaires will be completed within REDCap on a desktop computer in the office. The 
technician will log on to the REDCap site and will open the questionnaires for the subjects. Subjects will 
only have access to their questionnaires. Access to any other websites will be blocked by Psychiatry 
Information Technology. Remote participants will complete all surveys/questionnaires online via REDCap.


Other questionnaires will be completed on paper forms which were designed in Microsoft Word and Excel 
2010.
 
 
We intentionally do not record calls and we do not allow for generic user input or long 'voicemail' style 
inputs. We require callers spell and pronounce their names and key in a telephone number to prevent 
excess unnecessary information from being collected.
Zoom will be used to verify the identity and date of birth of participants.  It will also be used to verify CO 
readings.  Zoom calls will not be recorded. 
 
Multi-site Research
Is this a multi-site study?
  Yes   
  No
Complete for each site if Duke is the Primary grant awardee or coordinating center:
       Entry 1       
Site Name:
City:
State/Province:
Country:
Site Contact Information
Primary Contact Name:
Primary Contact Phone:
Primary Contact Email:
Site Details
Does the site have an IRB?
  Yes   
  No
Site IRB approval expiration 
date:
If date not provided, 
explanation of why:
Has the site granted 
permission for the research 
to be conducted?
  Yes   
  No
Does the site plan to rely on 
the DUHS IRB for review?
  Yes   
  No
What is the status of the 
study at this site?
Open 
Closed 
Site approval letters or site 


personnel lists:
Attach site approval letters, site closure letterS (if applicable), or site 
personnel lists in the Initial Submission Packet.
 
Research Abstract
Please type your Research Abstract here:
The Research Abstract should summarize the main points of your study in one paragraph. The following 
guidelines may help you:
 
1. Purpose and objective (1-2 sentences)
2. Study activities and population group (2-4 sentences)
3. Data analysis and risk/safety issues (1-2 sentences)
We propose to assess the relative role of nicotine dose and route of delivery in affecting successful 
switching from combustible cigarettes to e-cigarettes, as well as concomitant reductions in ad libitum 
cigarette smoking and exposure to harmful and potentially harmful constituents of combustion. The 
strategy will be to assess adoption of e-cigarette use and concomitant reduction in ad libitum smoking of 
subjects’ usual brands of cigarettes over an 8-week period, during which they will receive nicotine or non-
nicotine e-cigarettes, and nicotine skin patches. The nicotine patches will not be used as a therapeutic 
treatment in this study, but rather as a way to manipulate the nicotine dose, while varying the rate and 
route of nicotine delivery. Behavioral or “habit” aspects of e-cigarette use will be controlled for by the 
groups receiving non-nicotine e-cigarettes. One hundred thirty daily cigarette smokers will be randomly 
assigned to receive 8 weeks of exposure to the following conditions (65/group):
1. Nicotine containing e-cigarettes + 21 mg nicotine skin patches
2. Zero-nicotine e-cigarettes + 21 mg nicotine skin patches
The time commitment for subjects is 8 weeks once their participation begins, plus one follow-up session at 
four weeks. Subjects will return every two weeks to obtain e-cigarette and patch supplies, and for outcome 
measures of e-cigarette and combustible cigarette use to be collected; alternatively, remote partipants will 
be sent supplies in two shipments and will complete study questionnaires online. Ad libitum smoking will 
be assessed weekly using daily diary recordings of cigarettes smoked per day as well as the objective 
index of expired air carbon monoxide (CO) levels measured at the study visits.
The primary outcome measures will be the amount of combustible cigarette use and e-cigarette use in the 
last week of the 8-week exposure period. The main index of combustible cigarette use will be expired air 
CO. Self-reported cigarettes/day recorded on diaries will be a secondary index of cigarette consumption. 
The main index of e-cigarette use will be the number of cartridges consumed, based on self-report and 
counts of the number of unused e-cigarette tanks returned. 
Continuing to smoke carries significant health risks. Subjects enrolling in this study are not being asked to 
quit smoking over the course of the study, but will be exposed to no additional risk from their usual 
smoking behavior. Their exposure to harmfully and potentially harmful constituents in combustible 
cigarettes may decrease to the extent they use e-cigarettes as an alternative to combustible cigarettes.
 
Research Summary
State your primary study objectives
We propose to assess the relative role of nicotine dose and route of delivery in affecting successful 
switching from combustible cigarettes to e-cigarettes, as well as concomitant reductions in 
 
ad libitum
cigarette smoking and exposure to harmful and potentially harmful constituents of combustion.
 
The strategy will be to assess adoption of e-cigarette use and concomitant reduction in 
 smoking 
ad libitum
of subjects’ usual brands of cigarettes over an 8-week period, during which they will receive nicotine or 
non-nicotine e-cigarettes, and nicotine skin patches. The nicotine patches will 
 be used as a therapeutic 
not
treatment in this study, but rather as a way to manipulate the nicotine dose, while varying the rate and 
route of nicotine delivery.  Behavioral or “habit” aspects of e-cigarette use will be controlled for by the 
groups receiving non-nicotine e-cigarettes.
State your secondary study objectives


Please select your research summary form:
Standard Research Summary Template
This is the regular (generic) research summary template which is required  for all regular applications (unless 
your protocol fits under the other research summary templates in this category).  Use of these instructions is 
helpful for ensuring that the research summary contains all necessary elements.
 
Standard Research Summary
Purpose of the Study
 
Objectives & hypotheses to be tested
We propose to assess the relative role of nicotine dose and route of delivery in affecting successful 
switching from combustible cigarettes to e-cigarettes, as well as concomitant reductions in 
 
ad libitum
cigarette smoking and exposure to harmful and potentially harmful constituents of combustion.
The strategy will be to assess adoption of e-cigarette use and concomitant reduction in 
 smoking 
ad libitum
of subjects’ usual brands of cigarettes over an 8-week period, during which they will receive nicotine or 
non-nicotine e-cigarettes, and nicotine or non-nicotine skin patches. The nicotine patches will 
 be used 
not
as a therapeutic treatment in this study, but rather as a way to manipulate the nicotine dose, while 
varying the rate and route of nicotine delivery.  Behavioral or “habit” aspects of e-cigarette use will be 
controlled for by the groups receiving non-nicotine e-cigarettes.
We hypothesize that e-cigarette use will be higher, and concomitantly, combustible cigarette use will be 
lower, in the nicotine e-cigarette condition compared to the zero-nicotine e-cigarette condition (i.e., 
comparing Group 1 vs. Group 2).
Background & Significance
Should support the scientific aims of the research
Cigarette smoking remains the leading cause of preventable disease and death in developed countries, due 
principally to its contributions to heart disease, chronic obstructive pulmonary disease (COPD), and cancer 
(Lando & Wilson, 2010).  The annual death toll in the U.S. from diseases caused by smoking has been 
increasing steadily and is estimated to be the highest ever, 540,000/year (Carter et al., 2015).
The U.S. Surgeon General’s Report of 2010 (USDHHS, 2010) concluded that the combustion products of 
smoke, rather than nicotine, were responsible for most smoking related diseases. E-cigarettes, which 
deliver nicotine in the absence of combustion, have been advanced as a tobacco harm reduction strategy. 
Thus far, however, only a minority of smokers have adopted e-cigarettes to satisfy their nicotine 
dependency without concurrent use of combustible cigarettes. A number of factors may serve as barriers 
to the adoption of e-cigarettes, including insufficient dose of nicotine and lack of familiar sensory/habit 
components (e.g., aroma, “throat hit”) associated with smokers’ usual brands of cigarettes. The present 
study will examine the relative roles of nicotine dose and route of administration in affecting the ability of 
smokers to transfer their dependency from combustible cigarettes (CC) to e-cigarettes.
There are several reasons why administration of a given dose of nicotine by inhalation (via e-cigarettes), 
vs. transdermal administration (via nicotine patches) would be more reinforcing and lead to greater 
switching from combustible cigarettes to e-cigarettes.  First, inhaled nicotine reaches the bloodstream and 
brain much faster than transdermal administration (Rose et al., 2010), producing immediate reinforcing 


effects.  Also, inhaled nicotine produces familiar respiratory tract cues that smokers find rewarding (Rose, 
2006). Indeed studies have reported a greater suppression of combustible cigarette use when smokers 
used e-cigarettes as an alternative compared with nicotine patch (McRobbie et al., 2014).
Although subjects receiving nicotine from e-cigarettes will no doubt receive a range of nicotine doses, 
depending on the extent of use, data from previous studies (Shahab et al., 2017) suggests that the mean 
dose is expected on average to be similar to that provided by a 21 mg/day patch (and actual mg/day, as 
estimated from the number of e-liquid cartridges consumed, will be a covariate in the statistical analyses.).
Design & Procedures
Describe the study, providing detail regarding the study intervention (drug, device, physical 
procedures, manipulation of the subject or the subject’s environment, etc.). Discuss justifications for 
placebo control, discontinuation or delay of standard therapies, and washout periods if applicable. 
Identify procedures, tests and interventions performed exclusively for research purposes or more 
frequently than standard of care. Include alternative therapies, concurrent therapies discontinued per 
protocol, risk benefit ratio, and use of tissue/specimens. Discuss monitoring during washout periods if 
applicable. Include brief description of follow-up, if any.
Design Overview
The study will comprise a randomized, double-blind parallel-arm study to ascertain the role of nicotine 
dose and route of administration in reducing use of combustible cigarettes and in facilitating adoption of e-
cigarettes. One hundred thirty daily cigarette smokers will be randomly assigned to receive 8 weeks of 
exposure to the following conditions (65/group):
1.  Nicotine containing e-cigarettes + 21 mg nicotine skin patches
2.  Zero-nicotine e-cigarettes + 21 mg nicotine skin patches
Nicotine and non-nicotine e-cigarettes will be purchased from JUUL Labs.  The JUUL is a rectangular closed-
system e-cigarette. This e-cigarette was commercially available as of August 8, 2016 and does not contain 
any alterations to the chemistry or physical characteristics. Each JUUL Pod pack contains 4 pods. Each 
JUUL Pod contains 0.7mL with 5% nicotine by weight, approximately equivalent to one pack of cigarettes 
or 200 puffs.  Multiple flavors will be used in this study in order to more accurately mimic real world 
conditions. Subjects will receive packs containing tobacco-flavored and mint-flavored or menthol-flavored 
 
pods. Subjects will be provided with enough additional packs of pods to use during the smoking period.
JUUL Pods are sealed system cartridges for use in the JUUL e-cigarette. Each pod is contained in tamper 
resistant blister packs. The nicotine patches will be purchased from Duke Outpatient Pharmacy.
 smoking will be assessed weekly using daily diary recordings of cigarettes smoked per day as 
Ad libitum
well as the objective index of expired air carbon monoxide (CO) levels measured at the study visits.
 
Screening and Session Procedures
Interested potential subjects will respond to advertisements by contacting our Center to be phone 
screened.  Potential subjects also will have the option to complete a REDCap screening survey on the Duke 
Center for Smoking Cessation website.  Potential subjects will be given a brief description of the study and 
will be asked questions to assess eligibility and interest.  Eligible subjects interested in participating will be 
scheduled for the screening visit.
After granting their informed consent, potential subjects will complete a smoking history form and will 
have their expired air CO measured.  Subjects will provide a urine sample for testing of illicit drug use (all 
participants) and for pregnancy (women of child bearing potential only).  Potential subjects will fill out the 
Medical History Form and Review of Systems Form on REDCap, as well as asked about any other medical 
issues they are aware of, on the revised Preliminary Contact Form. A Physician Assistant will review this 
information with the potential participant either during the screening visit or during a brief (approx. 15 
minute) phone call. The screening visit will last approximately 1.5 hours.
The time commitment for subjects is 12 weeks once their participation begins. Subjects will return every 
two weeks (for eight weeks -- i.e., 5 visits) to obtain e-cigarette and patch supplies, and for outcome 
measures of e-cigarette and combustible cigarette use to be collected. Four weeks after Study Visit 5, 
subjects will return for one follow-up session.
 


Sessions
The first study visit (V1) will take place approximately one week after the screening visit.  Subjects will 
complete baseline questionnaires and will be randomized to one of the two groups. Subjects will be tested 
for exhaled air carbon monoxide, and saliva samples will be collected for analysis of smoking related 
chemicals (e.g., cotinine).  Subjects will also complete questionnaires assessing their dependence on 
cigarettes (Fagerström Test for Nicotine Dependence (FTND) (Heatherton et al., 1991)), and rewarding 
effects of cigarettes (modified Cigarette Evaluation Questionnaire (Cappelleri et al., 2007)).
Subsequent study visits will occur approximately two weeks apart (with a five-day window on either side of 
the scheduled visit).  If a participant does not attend a visit and it cannot be rescheduled within the 
allowable window, the visit will be considered a missed visit; if participants miss two consecutive visits 
they will be withdrawn from the study.  Participants will be tested for exhaled air carbon monoxide, and 
will also complete questionnaires assessing their dependence on cigarettes (Fagerström Test for Nicotine 
Dependence (FTND) (Heatherton et al., 1991)), and rewarding effects of cigarettes (modified Cigarette 
Evaluation Questionnaire (Cappelleri et al., 2007)).
Questionnaires will be completed within REDCap on a desktop computer in the Center office.  The 
technician will log on to the REDCap site and will open the questionnaires for the subjects.  Subjects will 
only have access to their questionnaires.  Access to any other websites will be blocked by Duke Psychiatry 
Information Technology.
At the first (V1) and final (V5) sessions, participants will provide saliva and urine samples.  The saliva 
sample will be used for analysis of smoking related chemicals (e.g., cotinine).  The urine sample will be 
used to assess total urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of the 
tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The half-life of NNAL 
is 10 days (Goniewicz et al., 2009), yielding a valuable index of sustained reductions in cigarette smoking. 
The half-life of expired air CO, in contrast, is 4.5 h (Sandberg et al., 2011).  Total urinary nicotine 
equivalents (a measure of total nicotine intake) will also be assessed.
Subjects will also be given diaries to record the number of cigarettes smoked each day and e-cigarette 
cartridges used, and will be instructed to return the diaries at the next visit.  At Sessions V1-V4, 
participants will be dispensed a sufficient supply of skin patches and e-cigarette refill tanks (pods) to last 
until the next session.  Participants will be given pods with both flavors (Virginia tobacco and cool mint or 
menthol) of e-liquid. They will be asked to return all used and unused pods and used patches at their 
subsequent visit for proper disposal and compliance monitoring.
 
Four-week Follow-up
Study participants will return to the laboratory for a brief follow-up session four weeks after Session 
V5.  This session will include an expired air CO reading, collection of saliva and urine samples, and 
completion of several questionnaires on REDCap.
 
Remote Study Participation
Potential subjects who live in North Carolina but do not live close enough to travel to our Center will be 
able to participate in the study remotely.  Interested individuals will complete the online REDCap initial 
screening survey and provide contact information.  The responses of potential participants who agree to be 
in the study will be reviewed by study staff who will then contact eligible respondents by phone to answer 
any questions and explain how to electronically sign and date the e-consent form.  A PDF copy of the 
signed consent form will be emailed to participants.  Participants will then report to a LabCorp facility close 
to them to provide a urine sample to test for illegal drugs and pregnancy (for females of child bearing 
potential). If the urine tests are negative, participants will be sent a CO monitor for measuring carbon 
monoxide (CO), and study e-cigarettes and nicotine patches.  Participants will record daily diary entries 
about their cigarette and e-cigarette use on paper diaries.  Participants will complete surveys (asking 
about potential side effects, mood, and experiences with the e-cigarettes, patches and their usual brand 
cigarettes) at five time points, once every 2 weeks, and at follow-up 4 weeks after stopping the use of 
study e-cigarettes and patches. CO readings will be obtained at screening and evisit 5. 
Interested individuals will respond to various advertisement strategies 
Electronic Screening Survey:  
(television, social media advertisement, etc.) by completing a public online REDCap screening 
survey.  After reading a brief description of the study in the survey, interested potential participants will 
complete questions regarding smoking and medical history in order to assess safety and eligibility for 
participation in the study.  Potential participants will be deemed ineligible if they decline to complete the 
initial online screening survey, fail to leave their contact information, or do not meet eligibility criteria 
based on survey responses.  Eligible individuals interested in participating will be contacted via phone by 
study personnel to discuss the process of remote e-consent.


eConsent:  Because of the nature of this study and the number of questionnaires that participants are 
expected to complete, we will not recruit potential participants who do not read, are blind or who do not 
read/understand English.  We are not equipped to validate alternate versions of our questionnaires, most 
of which are not published.  Questionnaires cannot be administered orally by a translator or by Technicians 
to illiterate or blind individuals because the data obtained would not be comparable to self-administered 
questionnaires.
Over the phone, potential participants who passed the initial screening survey will be given instructions on 
how to view the electronic REDCap Informed Consent Form (ICF).  If eligibility could not be determined 
based on survey responses, study staff will follow-up concerning any additional information needed to 
determine eligibility, such as information about medical conditions.  Potential participants who are eligible 
will then be sent a link to the eConsent form via email and will be given an adequate amount of time to 
thoroughly read the consent form and have any questions answered by study staff.  The final section of 
the consent form will ask participants to make a selection between three choices:  1) I have read the 
consent document and I wish to participate in the study, 2) I have read the consent document and have 
questions that I would like answered before I decide whether to participate in the study, or 3) I have read 
the consent document and I DO NOT wish to participate in the study.  If participants have questions about 
the information contained in the consent form, they will be prompted to contact study staff and NOT sign 
the consent form.  If participants have no questions and select “I have read the consent document and I 
wish to participant in the study,” an additional form will open and participants will provide First Name, Last 
Name, an electronic signature (with their finger on a touchscreen device or a stylus/mouse on a 
computer), the date of the signature, and an email address.  Participants will also be provided a PDF copy 
of the electronically signed consent form for their records.
Participants will be contacted via Zoom in order to verify their identity and age by 
Identity Confirmation:  
viewing their picture ID.  The Zoom session will not be recorded.  Identity and age of the participant will 
be cross-verified with the contact information provided at LabCorp for the initial drug screen/pregnancy 
test as recorded on results sent by LabCorp to the Duke Center for Smoking Cessation (CSC).
Potential participants who pass the initial screening survey will be asked to 
LabCorp Drug/Pregnancy Test:  
go to a local LabCorp facility (information on locations provided to them by research staff) to provide a 
urine sample for testing of illicit drug use (all participants) and for pregnancy (women of child bearing 
potential only).  Participants will complete this test at no cost to them.  Participants will be asked to 
provide a copy of their driver’s licenses/photo ID upon check-in.  Results of the test(s) will be sent directly 
to the study medical providers via the LabCorp Beacon online system. Drug screens and pregnancy tests 
must be negative in order for participants to continue in the study. 
Participants who are still eligible after drug and pregnancy screens will be sent a carbon 
CO Monitor:  
monoxide (CO) monitor (Covita micro basic Smokerlyzer, valued at $620). Study staff will also provide 
troubleshooting recommendations for possible problems that may arise.  Participants will be asked to use 
the CO monitor to obtain a CO reading during a Zoom meeting with research staff.  The research staff will 
write the CO reading displayed on the monitor on a study visit form.  The Zoom meeting will not be 
recorded.  The initial CO measurement, evaluated by study staff, will be used to determine whether 
participants meet the minimum CO inclusion requirement.  Participants will also complete preliminary 
questionnaires on REDCap, including smoking history and demographic information.
After the 1-week training/baseline period is complete and any 
Randomization and E-cigarette Distribution:  
concerns or questions about the CO monitoring have been addressed, the participants will be assigned a 
participant number that will determine their randomly assigned study condition, and will be sent by study 
staff the first shipment of study patches and e-cigarette devices and cartridges containing e-liquid 
corresponding to their group assignment (nicotine containing e-cigarettes vs. zero-nicotine e-
cigarettes).  Packages containing nicotine patches and e-cigarettes and liquids require signature by 
someone who is 21 years of age or older for delivery; the packages will not be delivered if no one 
appropriate is available to sign for them.  This supply will be designed to last through the first 4 weeks of 
the study; if participants remain in the study, they will be sent a second shipment to use for the final 4 
weeks.
  Remote participants will complete study milestones (“e-visits”) that correspond to the 
Study Milestones:
study visits attended by local participants:  baseline, week 2, week 4, week 6 and week 8, plus 4-week 
follow-up; they will take approximately one hour each to complete and include the same questionnaires 
that are completed at the in-person study visits, as well as a CO measurement at e-visit 5.  The first 
(baseline) study milestone (V1) will take place after the participants receive their first shipment of e-
cigarettes but before they start using them.  At this time, participants will be called by study staff and 
given instructions on how to use the e-cigarettes.  They will be asked to switch from cigarette use to use 
of e-cigarettes during the study. They will then be instructed on the use of daily self-report diaries to be 
completed on paper.  In these diary entries, participants will record the number of conventional cigarettes 
smoked each day and the number of occasions of e-cigarette use (an occasion defined as taking at least 
one puff). Participants will be emailed a survey link to complete the questionnaires online via REDCap. 
Participants will have 72 hours to complete the survey until it expires and it is considered a “missed 
milestone”; if participants miss two consecutive milestones they will be withdrawn from the study. The 


diary entries will be reported to the research staff by phone after e-visit online surveys have been 
 
completed.
Each subsequent study milestone (V2-V5) will occur 2 weeks after the previous one, with the follow-up 
milestone occurring 4 weeks after milestone 5.  Participants will be sent a link by email on each study 
milestone date with instructions to complete the REDCap questionnaires. After the second milestone is 
completed, participants will be sent a second shipment of e-cigarette cartridges to use until the end of 
study.  At the time of the baseline and final milestones (V1 and V5) and follow-up, participants will be 
asked to collect a urine sample for NNAL analysis and a saliva sample for analysis of smoking related 
chemicals (e.g., cotinine), and send these samples to the Duke CSC via UPS.
Participants will be called within 3 days after the first day of study intervention to make sure the study 
products are being used as directed as well as to ask about any study related side effects. Any reports of 
 
side effects, in addition to responses to the Side Effects Form completed online at the study milestones, 
will be reviewed by the study medical provider.  The provider will call the participant if any of the side 
effects require follow up.
Return and Re-use of the CO monitor:  Participants will be asked to return the CO monitor after the CO 
reading has been obtained during the screening process.  If they are accepted into the study and complete 
e-visits 1-4, then a CO monitor will be sent to them to obtain the CO reading at e-visit 5.  The participant 
will be asked to return the CO monitor after e-visit 5.  Upon return of the CO monitor, research staff will 
disinfect the monitor before sending it to another participant.
Selection of Subjects
 
List inclusion/exclusion criteria and how subjects will be identified.
We propose to enroll up to 1600 smokers in order to identify 130 participants who meet all criteria to be 
accepted into the study and to be randomized into one of four experimental conditions.
Inclusion Criteria
• Are 21-65 years old;
• Smoke an average of at least 10 cigarettes per day;
• Have smoked for the past year;
• Have an expired air CO reading of at least 10ppm;
• Have a self-reported body weight of < 350 lbs.;
• Are able to read and understand English.
Potential subjects of child bearing potential must agree to use two forms of contraception during their 
participation in this study.  Women are considered past the age of child-bearing potential if:
• They are greater than 55 years of age;
• They are at least 50 years of age AND have not menstruated for at least 12 months, OR have a 
documented Follicle Stimulating Hormone (FSH) level of greater than 40 mIU/mL;
• They are at least 45 years of age AND have not menstruated for at least 18 months, OR have a 
documented Follicle Stimulating Hormone (FSH) level of greater than 40 mIU/mL.
Medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal ligation or 
hysterectomy), (2) approved hormonal contraceptives (such as birth control pills, patches, implants or 
injections), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an 
intrauterine device (IUD). Contraceptive measures such as Plan B (TM), sold for emergency use after 
unprotected sex, are not acceptable methods for routine use.
Potential subjects must agree to avoid the following during their participation in this study:
• Participation in any other nicotine-related treatment study protocol outside of this protocol;
• Use of tobacco products other than cigarettes, including pipe tobacco, cigars, e-cigarettes (other than 
those provided during the study), snuff, and chewing tobacco;
• Use of experimental (investigational) drugs or devices;
• Use of illegal drugs;
• Use of exclusionary medications.
 


Exclusion Criteria
• Actively seeking treatment for nicotine dependence;
• Uncontrolled high blood pressure (self-report);
• Coronary heart disease with symptoms (e.g., chest pain);
• Heart attack in the past year;
• Cardiac rhythm disorder (irregular heart rhythm with symptoms);
• Chest pain in the last month (unless history indicates a non-cardiac source);
• Symptomatic heart disorder such as heart failure;
• Advanced liver or kidney disease that requires medication or dialysis, paracentesis;
• Bleeding stomach ulcers in the past 30 days;
• Lung disease that requires oxygen;
• Major brain disorder (including stroke with residual deficit, brain tumor, and seizure disorder);
• Migraine headaches that occur more frequently than once per week;
• Recent, unexplained fainting spells;
• Diabetes with insulin use;
• Current cancer or treatment for cancer in the past six months (except basal or squamous cell skin 
cancer);
• Other major medical condition (as determined by study medical provider);
• Diagnosis of thought disorder; such as bipolar disorder or schizophrenia;
• Psychiatric hospitalization within the past 12 months;
• Pregnant or nursing mothers;
• Use (within the past 7 days) of illegal drugs (or if the urine drug screen is positive for THC, Cocaine, 
Amphetamine, Opiates, Methamphetamines, PCP, Benzodiazepines, or Barbiturates), unless recent use of 
prescription opiates or benzodiazepines were taken for management of acute symptoms (e.g., tooth 
extraction, recent surgery, or sleep);
• Use of experimental (investigational) drugs within the past 7 days;
• Use of psychiatric medications including antidepressants and anti-psychotics may be permitted if the 
condition is stable (study medical provider discretion).
• Use of opiates, benzodiazepines, and muscle relaxants (unless taken for sleep or acute symptoms such 
as tooth extraction or recent surgery) within the past 7 days (study medical provider discretion);
• Use of Wellbutrin, bupropion, Zyban, Chantix, varenicline, nicotine patch, nicotine replacement therapy, 
clonidine or any other smoking cessation aid within the past 30 days;
• Use of cigars, cigarillos, pipes, Hookah, dissolvable nicotine, snuff, chewing tobacco, or e-cigarettes 
within the past 7 days;
• Diagnosis of alcohol abuse or dependence or self-report of consuming more than 6 drinks on one 
occasion more than one day per week;
• Significant adverse reaction to nicotine patch in the past;
• Current or recent participation (in the past 30 days) in another smoking treatment study at our Center or 
another research facility;
 
Assessment of Eligibility
Potential subjects who do not have a self-reported diagnosis of the above listed conditions may be 
excluded if the study physician or physician assistant determines that the history reveals information that 
may jeopardize the subjects’ safe study participation.  For medical conditions that do not appear above, 
the study physician will be consulted, and if the medical condition does not jeopardize safe study 
participation, then the subject may be enrolled.
Subject Recruitment and Compensation
Describe recruitment procedures, including who will introduce the study to potential subjects. Describe 
how you will ensure that subject selection is equitable and all relevant demographic groups have access 
to study participation (per 45 CFR 46.111(a) (3)). Include information about approximately how many 
DUHS subjects will be recruited. If subjects are to be compensated, provide specific prorated amounts 
to be provided for expenses such as travel and/or lost wages, and/or for inducement to participate.
Subject Recruitment
Smokers with no major health problems will be recruited from communities in and around Durham, North 
Carolina, and, for remote participation, across the state of North Carolina.  Recruitment will occur through 
television, newspaper and internet advertisements, flyers, Facebook, Duke List, and by word-of-
mouth.  We will also recruit via the Duke Primary Care Research Consortium. This consortium oversees all 


research within Duke Primary Care, a network of over 30 clinics primarily around the Research Triangle 
Area. The consortium is primarily interested in whether studies offered to patients would provide safe and 
effective means for supporting or improving health outcomes. Duke Primary Care clinics serve a broad 
cross section of the community. Patients from the Duke Primary Care Research Consortium will be 
recruited from 1 of the 30 clinics. A study team member will conduct a query into the electronic health 
record through DEDUCE (Duke Enterprise Data Unified Content Explorer) to identify potentially eligible 
patients. DEDUCE is an electronic technology system designed to enable access to specific patient data 
fields across the Duke Health System for approved research purposes. After identifying individuals who fall 
within our recruitment categories, we will directly contact these patients by MyChart message and/or 
telephone to offer them additional information about the research study (Duke’s Cold Call Policy).  Any 
potential subjects who have opted out of contact for research studies will not be contacted for this study.
Potential subjects will be pre-screened on the phone by a member of the Duke CSC.  If potential subjects 
meet the pre-screening study requirements and are still interested in participation, they will attend a 
physical screening session at the Duke CSC, located at 2424 Erwin Road, Suite 201, Durham, NC  27705, 
or complete screening procedures online and by visiting a local LabCorp facility.  If after the screening 
process it is determined that they qualify for participation, participants will attend subsequent study visits 
at the Duke Center for Smoking Cessation located at 2424 Erwin Road, Suite 201, Durham, NC  27705, or 
online via REDCap and phone contact.
 
Subject Compensation
Local (in-person) participants will be paid $25 for completing the Screening procedures. Subjects will be 
reimbursed $25 per visit for completing the five study visits, plus $60 for completing the follow-up 
visit.  In addition, subjects will receive a payment of $10 for each of the 5 visits attended in which they 
return their completed take-home diaries with questions in which they record smoking behavior and patch 
and e-cigarette use, as well as their used and unused e-cigarettes and patches. Subjects who do not 
complete each visit will still receive payment for the ones completed.  Thus, subjects who complete the 
screening and five visits and hand in their completed take-home diaries and study investigational product 
(IP) each time and also attend the follow-up visit will receive a total payment of $335.
Remote participants will be paid $35 for completing the Screening procedures ($10 for completing online 
surveys and CO readings, and $25 for visiting a LabCorp facility and providing a urine sample). Subjects 
will be reimbursed $25 per milestone for completing the five study e-visits, with an additional $15 for e-
visit 1 and an additional $5 for e-visit 5. Those milestones involve collecting and sending urine and saliva 
samples.  In addition, participants will receive $30 for completing the follow-up e-visit.  In addition, 
subjects will receive a payment of $5 at the time of milestones 1-5 for completing 75% of the daily diary 
entries. Subjects who do not complete each e-visit will still receive payment for the ones 
completed.  Subjects will also receive $50 for returning the CO monitor after screening and an additional 
$50 for returning the CO monitor at the end of the study. Thus, subjects who complete the screening and 
five e-visits and complete 75% of the daily diaries and also complete the follow-up e-visit will receive a 
total payment of $335.
Consent Process
 
Complete the consent section in the iRIS Submission Form.
Subject’s Capacity to Give Legally Effective Consent
If subjects who do not have the capacity to give legally effective consent are included, describe how 
diminished capacity will be assessed. Will a periodic reassessment occur? If so, when? Will the subject 
be consented if the decisional capacity improves?
We will not include subjects who do not have the capacity to give legally effective consent.


Study Interventions
If not already presented in #4 above, describe study-related treatment or use of an investigational 
drug or biologic (with dosages), or device, or use of another form of intervention (i.e., either physical 
procedures or manipulation of the subject or the subject’s environment) for research purposes.
Risk/Benefit Assessment
Include a thorough description of how risks and discomforts will be minimized (per 45 CFR 46.111(a) (1 
and 2)). Consider physical, psychological, legal, economic and social risks as applicable. If vulnerable 
populations are to be included (such as children, pregnant women, prisoners or cognitively impaired 
adults), what special precautions will be used to minimize risks to these subjects? Also identify what 
available alternatives the person has if he/she chooses not to participate in the study. Describe the 
possible benefits to the subject. What is the importance of the knowledge expected to result from the 
research?
  Continuing to smoke carries significant health risks.  Subjects 
Conventional (combustible) cigarettes:
enrolling in this study are not being asked to quit smoking over the course of the study, but will be 
exposed to no additional risk from their usual smoking behavior. Their exposure to harmfully and 
potentially harmful constituents in combustible cigarettes may decrease to the extent they use e-cigarettes 
as an alternative to combustible cigarettes.
  The nicotine patch poses very little risk and is approved for over-
Potential side effects of Nicotine patch:
the-counter sales as a smoking cessation treatment. It is not being used as a treatment for nicotine 
dependence in this protocol but the risks will be minimal.  Insomnia and abnormal dreams are common 
and expected side effects associated with 24-hour nicotine patches.  If a subject complains of disturbed 
sleep, he or she will be instructed to remove the patch at bedtime and apply a new one the next day at the 
usual time. Skin irritation may occur, although this will be minimized by changing the site of patch 
application daily.  If a subject develops itching or a rash at the patch site, he or she will be advised to use 
1% hydrocortisone cream on the affected area.  Symptoms associated with nicotine toxicity include 
lightheadedness, dizziness, nausea, fainting and vomiting. A less likely side effect of nicotine patches is 
somnambulism.  If a subject reports significant side effects, the dose of the nicotine patch may be reduced 
if necessary.
  ENDS, or “e-cigarettes,” have been marketed in the U.S. 
Electronic Nicotine Delivery Systems (ENDS):
since 2007 and have been used worldwide by millions of smokers. While the potential risks of long-term 
use of e-cigarettes are unknown, most experts agree that the constituents of e-cigarettes are less harmful 
than those of combustible cigarettes (Grana et al., 2014).  Although it is conceivable that participants 
could receive an overdose of nicotine, this is extremely unlikely inasmuch as smokers can control the dose 
according to how they puff and inhale from the devices, as they do with conventional cigarettes.  The main 
side effect that is anticipated with the relatively short 8-week duration of exposure to ENDS in the 
proposed project is mild irritation of the respiratory tract from inhalation of the propylene glycol and 
nicotine contained in the product.  Should any clinically significant changes occur, the study physician will 
recommend discontinuation of ENDS use if it is indicated.
The Centers for Disease Control and Prevention (CDC), the U.S. Food and Drug Administration (FDA), state 
and local health departments are investigating a respiratory syndrome associated with the use of e-
cigarettes. People with this syndrome have reported a wide variety of symptoms including cough, 
shortness of breath, chest pain, nausea, vomiting, diarrhea, fatigue, fever, and abdominal pain.
In a New England Journal of Medicine article entitled "Vaping-Induced Lung Injury" (September 6, 2019), 
Dr. Christiani stated that "[a]bout 80% of the persons who vaped and became ill reported having used 
both nicotine products and tetrahydrocannabinol (THC) or cannabidiol (CBD) products". Thus far, 
investigators have not found a single product linked to all reports of this respiratory syndrome. Most cases 
have been linked to "street" products or substances added to e-cigarettes -- changes not intended by e-
cigarette manufacturers.  The e-cigarettes used in this study will be obtained directly from JUUL, a 
manufacturer registered with the FDA, and will not be altered in any way.  Overall, the respiratory 
syndrome associated with e-cigarette use has been reported in less than 1 in 1,000 people who use e-
cigarettes.
Subjects will be monitored throughout the duration of the study for side effects and severe adverse effects 
(SAEs). They will be instructed to report any side effects to the study technicians, who will communicate 
these reports immediately to the medical staff.  The most appropriate course of action will be determined, 


which may include options for dose reduction or termination of study intervention.  Participants will be 
reminded that they have the option to withdraw from the study at any time.  Subjects will also be given 
the 24-hour emergency contact numbers in the event that side effects or adverse events occur between 
sessions.  SAEs will be reported to the IRB and will be monitored until resolution or stabilization.
The sponsor for this study will ensure the investigational tobacco product is distributed only to qualified 
members of key personnel in accordance with this protocol.
Costs to the Subject
Describe and justify any costs that the subject will incur as a result of participation; ordinarily, subjects 
should not be expected to pay for research without receiving direct benefit.
There are no costs to participants for taking part in this study.  All the study costs, including any study 
supplies and procedures related directly to the study, will be paid for by the research grant awarded to 
Duke University. 
Data Analysis & Statistical Considerations
Describe endpoints and power calculations. Provide a detailed description of how study data will be 
analyzed, including statistical methods used, and how ineligible subjects will be handled and which 
subjects will be included for analysis. Include planned sample size justification. Provide estimated time 
to target accrual and accrual rate. Describe interim analysis including plans to stop accrual during 
monitoring. Phase I studies, include dose escalation schema and criteria for dose escalation with 
definition of MTD and DLT.
The primary outcome measures will be the amount of combustible cigarette use and e-cigarette use in the 
last week of the 8-week exposure period. The main index of combustible cigarette use will be expired air 
CO, a highly sensitive and specific measure of smoke inhalation. As a secondary measure (at the first (V1) 
and final (V5) sessions), we will assess total urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
(NNAL), a metabolite of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 
(NNK). The half-life of NNAL is 10 days (Goniewicz et al., 2009), yielding a valuable index of sustained 
reductions in cigarette smoking. The half-life of expired air CO, in contrast, is 4.5 h (Sandberg et al., 
2011).
Self-reported cigarettes/day recorded on diaries will also be a secondary index of cigarette 
consumption.  The main index of e-cigarette use will be the number of cartridges consumed, based on self-
report and counts of the number of unused e-cigarette tanks returned. We hypothesize that e-cigarette 
use will be higher, and concomitantly, combustible cigarette use will be lower, in the nicotine e-cigarette 
condition compared to the zero-nicotine e-cigarette condition (i.e., comparing Group 1 vs. Group 2). This 
hypotheses will be evaluated using General Linear Modeling (GLM) techniques to assess the significance of 
the nicotine factor, using a 1-tailed alpha=0.05. A one-tailed comparison is justified given that a higher 
dose of nicotine in the e-cigarette would only be expected to decrease use of conventional cigarettes. 
Moreover, there would be no interest in pursuing the nicotine e-cigarette plus nicotine patch combination if 
it led to greater smoking than the placebo e-cigarette plus nicotine patch. Thus, the 5% Type I error rate 
can reasonably be assigned to the 1-tailed comparison. Covariates in the analysis of combustible cigarette 
use will include the amount of e-cigarette use, since that will affect the overall dose of nicotine received by 
subjects, as well as baseline combustible cigarette use, and baseline demographic and smoking history 
variables (the latter will also serve as covariates in the analysis of e-cigarette use as a dependent 
measure). We predict at least a moderate effect size (0.5) for each of the main effects, nicotine and route 
of administration, so that a sample size of 50 per group will yield at least 80% power to detect the 
hypothesized effects.
Data & Safety Monitoring


Summarize safety concerns, and describe the methods to monitor research subjects and their data to 
ensure their safety, including who will monitor the data, and the frequency of such monitoring. If a 
data monitoring committee will be used, describe its operation, including stopping rules and frequency 
of review, and if it is independent of the sponsor (per 45 CFR 46.111(a) (6)).
Data Safety Monitoring Plan (DSMP)
To address potential safety issues in addition to collection of the primary study outcomes, severe side 
effects and adverse events potentially associated with the study will be examined, recorded and then 
reported to the IRB in a manner consistent with Duke HRPP policies. The principal investigator will be 
responsible for monitoring data collection and safety of this study.
Data collection for this study will be carried out at the Durham clinical site of the Duke Center for Smoking 
Cessation (CSC) or remotely via REDCap and phone contact. All members of the study team will complete 
research integrity (“code of conduct”) and CITI (Collaborative Institutional Training Initiative) Human 
Research Curriculum and clinical laboratory safety training as required by Duke University Medical Center. 
All study staff who are involved in data collection, management, and processing will be thoroughly trained 
following standards of procedures prior to working on this project.
Study staff responsible for data collection will use a checklist for completion for each study visit of each 
participant.  Missing Data Forms, along with explanations should missing data occur, will be completed by 
the study staff for each study visit/e-visit.
Microsoft Access will be used for logging subject information (Enrollment Log, Visit Log, etc.). Data will be 
entered by the study staff.  The key study personnel will further examine the computerized data entries 
and original records for accuracy and completion.
 
Emergency Unblinding
This is a blinded protocol such that all participants and all study personnel except for the Clinical Research 
Coordinator and the Research Program Leader are blinded to group allocation.  During specific 
circumstances it will be necessary to unblind other study personnel, such as study team medical 
personnel.  Emergency unblinding will occur under the discretion of the study physician (or one of the 
study physician assistants) in any situation in which unblinding is deemed necessary to ensure or promote 
the safety of a study participant.  The decision to unblind for safety reasons may occur for a number of 
reasons and it is not possible to enumerate all potential circumstances.  Examples of reasons for 
unblinding to ensure participant safety include situations in which it is necessary to know which study 
drugs the subject was taking in order to manage the side effect(s), advise the subject on the risk of future 
negative drug reactions, uncover potential safety information about the drug, and/or determine whether 
the adverse event is study related.  In those situations, the Clinical Research Coordinator or Research 
Program Leader will inform the study physician (or physician assistant handling the event) of that subject’s 
study condition.  If unblinding occurs, that subject’s data will be censored and will not be included in final 
data analyses.
Privacy, Data Storage & Confidentiality
 
Complete the Privacy and Confidentiality section of the iRIS submission form.
Describe Role of External Personnel:
External key personnel will assist in data collection, data entry, data analysis, and recruitment under the 
supervision of our staff.  They will also shadow all aspects of the research process, including consent, but 
will not be conducting consent independently. They will not be accessing Maestro or OnCore but will have 
access to our paper and electronic PHI in REDCap (name, address, phone, DOB, medical history, SSN for 
payment). Onsite training on research practices, confidentiality/privacy, and HIPAA will be conducted 
during their first week.
 
Study Scope


Does the subject population contain >50% malignant hematology or oncology patients, or their caregivers?
  Yes   
  No
Are you using a drug, biologic, food, or dietary supplement in this study?
 Yes   
 No
Are you using a medical device, an algorithm (whether computer based or not), an in vitro diagnostic test, or 
using samples to look for biomarkers in this study?
 Yes   
 No
Does this study involve a Humanitarian Use Device (HUD)?
  Yes   
  No
Does this study employ magnetic resonance, including imaging (MRI), spectroscopy (MRS), angiography 
(MRA) or elastography (MRE) beyond the standard of care?
  Yes   
  No
Does this study specify or require the performance of diagnostic procedures using ionizing radiation (x-rays, 
DEXA, CT scans, nuclear medicine scans, etc.) that are beyond the standard of care?
  Yes   
  No
Does this study specify or require the performance of therapeutic procedures using ionizing radiation 
(accelerator, brachytherapy or systemic radionuclide therapy) that are beyond the standard of care?
  Yes   
  No
Will the participant be subjected to increased or decreased ambient pressure?
  Yes   
  No
Do you plan to recruit subjects from Duke Regional Hospital (DRH)?
  Yes   
  No
Do you plan to recruit subjects from Duke Raleigh Hospital (DRAH)?
  Yes   
  No
Does this study utilize the Duke Early Phase Clinical Research Unit (DEPCRU)?
  Yes   
  No
Are you using the Duke logo in any advertisements?


 Yes   
 No
Is this study retrospective, prospective, or both?
"Retrospective" means that data or samples already in existence (collected prior to the study submission) will 
be used.
"Prospective" means there will be data or samples collected in this study for research purposes.
Retrospective 
Prospective 
Retrospective and Prospective 
If the study is both retrospective and prospective: Is this a review soley of information collected for non-
research purposes (i.e. a review of medical records)?
  Yes   
  No
Does this protocol include any research using botulinum toxin, including the FDA-approved clinical product 
(Botox)?
  Yes   
  No
Does this protocol involve the administration of any of the following materials to humans?
   •Any viral vector or plasmid
   •Any cells that have been modified by a viral vector
   •Any other genetically-modified cells
   •Any genetically-modified virus, bacterium, or other agent
   •Any other recombinant or synthetic nucleic acid
  Yes   
  No
 
Subject Population Groups and Enrollment
Population Groups (Select 
 population groups only):
targeted
Note:
If Minors are included, the study will be routed to the Department of Pediatrics for Pediatric Risk 
Assessment. 
Students and Employees over whom Key Personnel have a supervisory role may not be enrolled in this 
study
Adults
Minors who are Wards of State
Minors
Duke Patients
Pregnant Women
Fetuses
Prisoners
Adults incapable of giving consent
Adults with diminished capacity
Handicapped subjects
Students
Employees
Healthy Controls
Deceased subjects


Blanket Protocol
Students and Employees over whom Key Personnel have a supervisory role may not be enrolled in this study.
Please select any population groups excluded from participation in this study:
Pregnant women
Will you administer a pregnancy test to eligible female subjects prior to the start of study activities?
 Yes   
 No
Maximum number of subjects to be consented at Duke:    
Enter a single number. If you anticipate consenting a range of subjects, enter the 
 limit of the range. 
upper
The number should represent the maximum number of subjects for the life of the study.
1600
Maximum number of subjects to be consented at all sites:
Enter a single number. If you anticipate consenting a range of subjects, enter the 
 limit of the range. 
upper
The number should represent the maximum number of subjects for the life of the study.
1600
 
Subject Procedures and Costs
Biobank - Does this study involve the collection, use, tracking, banking (storage) or distribution of human 
biological specimens?
Human biological specimens include blood or its components, healthy or diseased tissue, bodily fluids, DNA
/RNA or human stem cells.
 Yes   
 No
Procedures
Check all the apply:
Genetic Testing
Gene Transfer
DNA Banking
Testing for Reportable Infectious Diseases
Human Cell Banking
*Use of Human Embryonic Stem Cells
*Use of Human-induced Pluripotent Stem Cells
*Use of Other Cells Derived from Human Embryos
*Use of Human/Animal Chimeric Cells
*Specialized Cell Populations for Cell Therapy
Use of Human Tissue
Use of Bodily Fluids
Use of Blood (or its components)
Not Applicable
Will blood be drawn in this study for research purposes?


  Yes   
  No
Will the Operating Room be used in this study?
Include only research time, not clinical care time.
  Yes   
  No
Will there be extra costs to subjects or insurance as a result of the research (e.g. tests, hospitalization)?
  Yes   
  No
Will there be Subject Compensation?
 Yes   
 No
Compensation for Travel / Lost Income (in USD):
335
Other Subject Compensation:
None
 
Subject Recruitment Materials
For each document to be reviewed, use the table below to provide the following information:
Attach a copy of each advertisement that you will be using with this study in the Initial 
Submission Packet. If any Ad will have multiple wording variations, attach a copy of each version 
of the Ad.
All materials that will be used to advertise the study in order to recruit subjects must be approved by the IRB.
Types of subject recruitment materials include, but are not limited to, the following:
Direct Advertising
Posters 
Billboards 
Flyers 
Brochures
Media Advertising
Newspaper Ads 
Magazine Ads 
Radio Ads 
TV commericals / Video 
Internet website
Social Media
Other Types of Advertising
Newsletter 
Email 
Postcards / Letters
(Note: Doctor-to-Doctor letters do not require IRB approval)


Document name
Material category
Location material 
displayed
Has this material 
previously been 
approved by the 
IRB?
Final_DukeCSC_ECig_Study_062018
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
Spectrum cable 
channels
  Yes   
  No
Final_DukeCSC_ECig_Study_062018
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
Facebook
  Yes   
  No
ENDS-Switch Facebook Ad
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
Facebook
  Yes   
  No
Billboard / 
Flyer / Poster 
Brochure 
Internet 
Please be 
specific. For 
example, "Duke" 
would not be an 


ENDS Switch BannerAd
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
To be placed on 
various 
websites by 
Spectrum/Time 
Warner
  Yes   
  No
ENDS Switch Craigslist Ad
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
Craigslist
 Yes   
 No
ENDS Switch Poster
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
These posters 
will be 
displayed in the 
Triangle area.
 Yes   
 No
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
Durham


ENDS Switch Print Ad
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
/Raleigh: News 
& Observer 
(http://www.
newsobserver.
com/), and 
Herald Sun 
(www.
heraldsun.com 
) & The 
Independent 
Weekly (www.
indyweek.com). 
a. Local 
papers: 
Southside 
Shopper, 
Carolina 
Weekly, 
Raleigh Coffee 
News and the 
Triangle 
JobFinder.
b. College 
newspapers: 
UNC Daily 
Tarheel, Duke 
Chronicle, 
NCSU 
Technician & 
NCCU Campus 
Echo.
www.
dukesmoking.
com
www.
clinicalconnectio
n.com
www.
centerwatch.
com
www.
dukehealth.org 
http://psychiatr
y.duke.edu
Google Adwords
Facebook
Craigslist
  Yes   
  No
ENDS Switch Print Web Ad
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
www.
dukesmoking.
com
www.
clinicalconnectio
 Yes   
 No


Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
n.com
www.
centerwatch.
com
www.
dukehealth.org 
http://psychiatr
y.duke.edu
Google Adwords
Facebook
Craigslist
Duke List
Electronic Job 
Finder
Other websites
ENDS Switch Web Ad
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
www.
dukesmoking.
com
www.
clinicalconnectio
n.com
www.
centerwatch.
com
www.
dukehealth.org 
http://psychiatr
y.duke.edu
Google Adwords
Facebook
Craigslist
Duke List
Electronic Job 
Finder
Other websites
 Yes   
 No
ENDS-Switch Facebook Ad-2
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
Facebook
  Yes   
  No


ENDS-Switch Facebook Ad-3
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
Facebook
  Yes   
  No
ENDS-Switch Reminder Letter
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
NA
  Yes   
  No
ENDS-Switch Reminder Email
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
NA
  Yes   
  No
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 


Generic Flyer
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
Television" would 
be an appropriate 
response.
These flyers 
will be posted 
in the Triangle 
and 
surrounding 
areas including 
college 
campuses.
  Yes   
  No
Generic Bus Ad
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
This ad will be 
posted on 
buses in the 
Triangle and 
surrounding 
area.
  Yes   
  No
TV Ad
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Newsletter / 
Newspaper / 
Magazine 
Other 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
Spectrum On 
Demand 
markets in NC
  Yes   
  No
ENDS-Switch Facebook Ad-Remote
Billboard / 
Flyer / Poster 
Brochure 
Internet 
website / 
Email  
Letter / 
Postcard 
Phonescript 
Radio 
Television / 
Video 
Please be 
specific. For 
example, "Duke" 
would not be an 
appropriate 
location. "Duke 
Hospital 
Television" would 
be an appropriate 
response.
  Yes   
  No


Newsletter / 
Newspaper / 
Magazine 
Other 
Facebook
 
Consent Process
Attach draft consent forms in the Initial Review Submission Packet.
Consent forms must be MS Word documents and follow the specific format outlined by the IRB. 
 to 
Click here
download a copy of the consent form template.
 Please do not edit the section of the footer that contains the Protocol ID, Continuing Review 
Note:
and Reference Date fields. Those fields will be used to stamp the final consent form when it is approved by the 
IRB. If you want to add an internal version date, please put it in the header.
Who will conduct the consent process with prospective participants? 
Give the person's role in this study (PI, Study Coordinator, etc.):
The consent process will be conducted by Clinical Research Coordinators, Clinical Research Specialists 
(Clinical Trials Assistants), Physician and Physician Assistants. Dr. Rose will not be involved in the 
consenting process.
Who will provide consent or permission?
(Select all that apply):
Participant
Parent(s) or Legal Guardian(s)
Legally Authorized Representative (LAR)
How much time will the prospective participant (or legally authorized representative) have between being 
 
approached about participating in the study and needing to decide whether or not to participate?  
If you are not giving the person overnight to consider whether or not to participate, please justify.
Potential subjects are given as much time as they need to make an informed decision.
Where will the consent process occur?
The consenting process will occur at the Duke Center for Smoking Cessation in a private office/room.  For 
remote participants, the consenting process will occur via REDCap e-consent and phone conversations with 
study staff.
What steps will be taken in that location to protect the privacy of the prospective participant?
Only the potential subject and the person obtaining consent will be present.   For remote participants, 
phone conversations will take place in private staff areas.
How much time will be allocated for conducting the initial consent discussion, including presenting the 
information in the consent document and answering questions, with each prospective participant?


There is no set amount of time devoted to conducting the initial consent discussion. Each potential subject 
is allowed as much time as necessary to ask questions.
What arrangements will be in place for answering participant questions before and after the consent is 
signed?
The consenter will go through the consent form page-by-page with the potential subject before the 
consent form is signed. They will discuss the study procedures, length of time involved in the study, risks, 
benefits, alternatives to study participation, confidentiality, costs and compensation, research related 
injuries, their right to decline participation at anytime and the contact information for both the principal 
investigator and the IRB. The potential subject will be given the opportunity and encouraged to ask 
questions then and throughout their study participation.
 
For remote participants, the REDCap e-consent survey will offer the alternative "I have read the consent 
document and have questions that I would like answered before I decide whether to participate in the 
study".  Potential participants will be encouraged in the introduction to the consent form to ask any 
questions prior to signing: "If you have any questions or if there is information that you do not clearly 
understand, please call the study staff at 919-668-1327 or 919-668-5055 to clarify 
 signing this 
before
consent form."  Study staff will also talk with participants on the phone and make sure they understand 
the study before beginning study procedures.
Describe the steps taken to minimize the possibility of coercion or undue influence.
It is made clear to the subjects both in the ICF and by the person obtaining consent that they may 
withdraw from the study at any time. We are also careful that our compensation is sufficient to reimburse 
for time and travel expenses but is not coercive.
What provisions will be in place to obtain consent from participants who do not read, are blind or who do not 
read/understand English?
Because of the nature of this study and the amount of questionnaires that subjects are expected to 
complete we do not recruit potential subject who do not read, are blind or who do not read/understand 
English. We are not equipped to validate alternate versions of our questionnaires, most of which are not 
published. Questionnaires cannot be administered orally by a translator or by key personnel to illiterate or 
blind subjects because the data obtained would not be comparable to self-administered questionnaires.
Do you plan to obtain written consent for the conduct of research?
 Yes   
 No
 
Protected Health Information (PHI)
Indicate how you intend to use potential subjects' Protected Health Information (PHI):
I will review, but not record, PHI prior to consent. 
I will record PHI prior to consent. 
I do not intend to use PHI prior to consent. 
I will record PHI without consent. (decedent research, database repository, chart review) 
 
Request for Waiver or Alteration of Consent and/or HIPAA Authorization
Will the population include deceased individuals?
  Yes   
  No
This waiver request applies to the following research activity or activities:


Scheduling of research activities in MaestroCare and/or the recording of PHI via telephone for 
screening purposes prior to obtaining written consent for the research. Scheduling of research 
activities in MaestroCare and/or the recording of PHI via telephone for screening purposes prior to 
obtaining written consent for the research. (If you check this box, please complete all sections below.)
Ascertainment (identification, selection) and/or recruitment of potential subjects while recording 
identifiable private information, such as protected health information (PHI), prior to obtaining the 
subject’s consent. (If you check this box, please complete sections B and C below.)
Conduct of the research project without obtaining verbal or written consent and authorization. (If you 
check this box, please complete sections B and C below.)
Note: Answer the questions below as they pertain solely to PHI collected prior to consent.
Provide the following information:
List the elements of informed consent and/or HIPAA authorization for which waiver or alteration 
is requested:
Provide the rationale for each.
All elements of consent and HIPAA authorization are being requested for waiver.  It is not possible to 
ascertain whether someone is a suitable study candidate without asking about protected health 
information.
List the specific protected health information (PHI) to be collected and its source(s):
(Note: PHI = health information + identifiers)
Name, phone number, e-mail address and a history of medical conditions and smoking behavior and 
tobacco use will be collected verbally and electronically from the potential subjects.
Criteria for Waiver: The DUHS IRB may waive the requirement for informed consent and authorization if all 
of the following criteria are met:
Please respond to each item in the space below using protocol-specific language to provide justification:
a) The research or clinical investigation involves no more than minimal risk to subjects:
The PHI collected during the initial screening will be used solely for recruitment review.  The PHI is 
necessary for the purposes of this review only.  The pre-enrollment PHI will not leave this office
b) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects.  Include a description of any measures to be taken to ensure that the rights and welfare 
of subjects will be protected:
There is no adverse effect on the rights and welfare of potential subjects because all PHI that is to be 
collected prior to informed consent will be de-identified if the subject does not qualify for the study.  After 
obtaining informed consent, the information will be protected according to the usual standards of 
confidentiality applicable to research studies.  The identifiers will be kept in the Data Manager’s office and 
the office will be locked when unoccupied.  Only those individuals listed as key personnel will have access 
to this information.  For subjects who choose not to enroll in this study and do not provide consent, their 
pre-enrollment PHI will be de-identified.
c) Whenever appropriate, the subjects will be provided with additional pertinent information 
after participation:
Potential subjects will be given a description of study procedures and requirements prior to any questions 
being asked about their health status.
d) If this research activity relates to research involving deception, explain how subjects will be 
provided with additional pertinent information after study participation and what information will 
be provided. Otherwise indicate “not applicable”:
This research will not involve deception.


e) The use or disclosure of protected health information involves no more than minimal risk to 
the privacy of individuals, based on, at least, the presence of the following elements (e1. and e2.)
 
Demonstrate that the use or disclosure of PHI involves no more than minimal risk to the privacy 
of subjects by describing the plans requested below:
e1) An adequate plan to protect the identifiers from improper use and disclosure.
Describe the plan (how protection will be accomplished) and indicate where the PHI will be 
stored and who will have access:       
The identifiers will be stored in a secure database on a server hosted by Duke Health Technology Services 
or on a paper form which will be kept in a locked office within our locked Center, and only those individuals 
listed as key personnel will have access to this information.  Identifiers will only be kept for individuals who 
complete the survey and are eligible for study participation.  If an individual answers “yes” to the question 
about illegal drug use the survey will end and no identifiers will be collected (including IP address).
e2) An adequate plan to destroy the identifiers at the earliest opportunity consistent with 
conduct of the research, unless there is a health or research justification for retaining the 
identifiers or such retention is otherwise required by law.
 
Describe the plan (how and when identifiers will be destroyed and by whom). If there is a health 
or research justification for retaining the identifiers or such retention is otherwise required by 
law, provide the reason to retain identifiers:
For potential subjects who choose not to enroll in this study and do not provide consent, their pre-
enrollment PHI will be de-identified.
e3) Adequate written assurances that the protected health information will not be reused or 
disclosed to any other person or entity except (i) as required by law, (ii) for authorized oversight 
of the research study, or (iii) for other research for which the use or disclosure of PHI would be 
permitted by the HIPAA Privacy Rule.  By electronically signing this submission, the PI provides 
this written assurance:
The protected health information will not be reused or disclosed to any other person or entity except (i) as 
required by law, (ii) for authorized oversight of the research study, or (iii) for other research for which the 
use or disclosure of PHI would be permitted by the HIPAA Privacy Rule. 
f) The research could not practicably be conducted or carried out without the waiver or alteration:
Explain why informed consent/authorization can not be obtained from subjects.   
This waiver is necessary to allow us to collect and record contact information from potential subjects who 
are interested in participating in this study on the phone prior to seeing the potential subject in person (in 
order to decide whether they should be seen in person) and therefore prior to an opportunity to obtain 
written consent.
g) The research could not practicably be conducted or carried out without access to and use of 
the protected health information:
It is not possible to ascertain whether someone is a suitable study candidate without asking about 
protected health information.
h) For research using biospecimens or identifiable information, the research could not practicably 
be carried out without access to and use of the protected health information:
Biospecimens will not be collected until written consent is obtained.  It is not possible to ascertain whether 
someone is a suitable study candidate without asking about protected health information, and it must be 
identifiable so that we'll know which information goes with which potential subject.  For potential subjects 
who choose not to enroll in this study and do not provide consent, the pre-enrollment PHI will be de-
identified.
Waiver of Documentation of Consent and HIPAA Authorization for Scheduling in MaestroCare and/or the 
recording of PHI via telephone for screening purposes:
These research activities prior to obtaining written consent for the study presents no more than 
minimal risk of harm to subjects:


True 
False 
These are procedures for which written consent is normally not required outside of the research 
context:
True 
False 
An IRB-approved phone script will be used to obtain verbal consent from subjects for scheduling 
and/or screening prior to obtaining written consent for the study:
True 
False 
 
Drugs, Biologics, and Other Substances
Select Protocol Phase (for studies with FDA regulated drugs or biologics only). Choose only one:
Phase 0 
Phase I 
Phase I/II 
Phase II 
Phase II/III 
Phase III 
Phase IV 
N/A 
Pilot 
Drugs, biologics, or other substances being evaluated as a part of this research study:
Add all drugs, biologics, or other substances being evaluated as a part of this research study for which an IND 
is provided for the indication used in this study.
Also add any other drugs, biologics or other substances here that are being used as a part of this research 
study, for which an 
.
IND is not provided
 
List every other drug, biologic or other substance for which side effects are described in the consent form.
View 
Details
Drug Name
FDA Approved
A new drug or a 
new use of 
approved drug:
IND Number
Drug/Biologic
/Substance 
Generic Name:
Nicotine 
patches
Generic Drug 
Name:
Investigational 
Drug Name:
No 
No 
 
Drug/Biologic/Substance Generic 
Name:
Nicotine patches 
Generic Drug Name:
 
Investigational Drug Name:
 
Drug/Biologic/Substance Source:
 
Is the drug/substance being 
provided to the subject free-of-
charge?
No  
Is the Drug FDA Approved?:
No  


Is this drug/biologic or other 
chemical, metabolite, nutritional 
substance or other substance to 
be used in this research subject to 
the provisions of the Controlled 
Substances Act?
No  
Does this Drug have an IND 
Number?
No  
IND Number
 
IND Holder:
 
IND details:
 
If FDA Approved and an IND is 
not required, Please provide a 
rationale for exemption:
 
Will drug/substance be shipped 
from Duke to external locations
 
Dose Range:
 
Frequency:
 
Will this drug, biologic, chemical, 
metabolite, nutritional substance 
or other substance be 
manufactured or compounded at 
Duke?
 
Drug Storage Restrictions 
(including temperature, etc.):
 
As indicated in the Investigator's 
Brochure or other available 
documentation, what is the 
highest FDA Use-in-Pregnancy 
Rating for drug used for research 
purposes in this study?:
 
Are you using an investigational pharmacy at Duke?
Please be aware that inpatient administration of an investigational drug requires the use of the Duke IDS or 
Oncology ICS, as per Department of Pharmacy policy.
  Yes   
  No
Who will be responsible for the storage, inventory and control of the drug/biologic or other chemical, 
metabolite, nutritional substance or other substance to be evaluated in this research?
The IDS is available to assist any investigator (upon request) with storage and control of investigational drugs 
in the outpatient setting
The Medical Director of the Duke Center for Smoking Cessation (CSC) will be responsible for the ordering 
of the study drugs and will ensure storage of these drugs in the CSC laboratory. Dispensing logs will be 
maintained to monitor and track the inventory.
Where will the drug/biologic or other chemical, metabolite, nutritional substance, or other substance to be 
evaluated in this research be stored?
Once the drugs are received they will be stored in a temperature maintained locked room. Only authorized 
key personnel have access to this room.
From where will the drug/biologic or other chemical, metabolite, nutritional substance or other substance to 


be evaluated in this research be dispensed?
Dispensing of the drugs will occur at the Duke CSC office located in Durham, NC.
At the completion of this research study, what will be done with the unused or returned investigational drug
/biologic or other chemical, metabolite, nutritional substance or other substance?
The unused e-cigarettes will be kept in inventory until all subjects have completed the final study 
visit.  Subjects will be permitted to keep the e-cigarettes that have been given to them.  E-cigarettes that 
are returned will be disposed of in biohazard containers.
 
Devices
Include all devices being evaluated in this study:
Include all devices being evaluated in this study to determine their safety or effectiveness, and include 
information about a humanitarian use device where requested.Also dd devices without an IDE here, including 
any Humanitarian Use Device that does not require an IDE because it is to be used according to its FDA 
approved product labeling and its safety or effectiveness is not being evaluated.
 
Complete an 
 as applicable. This can be attached with the Brochure in the Initial Submission 
IDE Billing Notice
Packet.
View 
Details
Device Name
Is the Device FDA 
Approved
Will the device to 
be evaluated or 
the Humanitarian 
Use Device be 
manufactured at 
Duke?
IDE
/Compassionate 
Use Request 
Number
JUUL electronic cigarette 
Yes 
No 
 
Device Source
Juul labs 
CMS Category
A
B
Is the device provided to subject 
free of charge?
Yes 
Is this a HUD (HDE)?
No 
HDE Number
 
Is the Device FDA Approved
Yes 
Will the device to be evaluated or 
the Humanitarian Use Device be 
manufactured at Duke?
No  
Do you have an IDE number for 
this device?
No  
IDE/Compassionate Use Request 
Number
 
IDE Holder
N/A  
IDE Details
 
In the opinion of the sponsor, 
select the level of risk associated 
with this device
No Significant Risk  
Micro + Basic Smokerlyzer 
Yes 
No 
 
Device Source
Covita 


CMS Category
A
B
Is the device provided to subject 
free of charge?
Yes 
Is this a HUD (HDE)?
No 
HDE Number
 
Is the Device FDA Approved
Yes 
Will the device to be evaluated or 
the Humanitarian Use Device be 
manufactured at Duke?
No  
Do you have an IDE number for 
this device?
No  
IDE/Compassionate Use Request 
Number
 
IDE Holder
N/A  
IDE Details
 
In the opinion of the sponsor, 
select the level of risk associated 
with this device
No Significant Risk  
Who will be responsible for the storage, inventory and control of the device to be evaluated or the 
Humanitarian Use Device?
The Medical Director of the Duke Center for Smoking Cessation (CSC) will be responsible for the ordering 
of the e-cigarettes and will ensure storage of these e-cigarettes in the CSC laboratory. Dispensing logs will 
be maintained to monitor and track the inventory.
Where will the device to be evaluated or the Humanitarian Use Device be stored?
Once the e-cigarettes are received they will be stored in a temperature maintained locked room. Only 
authorized key personnel have access to this room.
Who will be responsible for giving or administering the device to be evaluated or the Humanitarian Use 
Device to the research subject?
The Duke CSC research staff will be responsible for giving the device to be evaluated. 
From where will the device to be evaluated or the Humanitarian Use Device be dispensed?
The device will be dispensed from the Duke Center for Smoking Cessation
At the completion of this research study, what will be done with the unused or returned device or the 
Humanitarian Use Device? 
The unused e-cigarettes will be kept in inventory until all subjects have completed the final study 
visit.  Subjects will be permitted to keep the e-cigarettes that have been given to them.  E-cigarettes that 
are returned will be disposed of in biohazard containers.
 
Privacy and Confidentiality
Explain how you will ensure that the subject's privacy will be protected:
Consider privacy interests regarding time and place where subjects provide information, the nature of the 
information they provide, and the type of experience they will be asked to participate in during the research.


Subjects who participate in person will be consented and complete all study questionnaires in a private 
location. Subjects will be given a unique identifier to protect their confidentiality.
Describe how research data will be stored and secured to ensure confidentiality:
How will the research records and data be protected against inappropriate use or disclosure, or malicious or 
accidental loss or destruction? Records and data include, for example, informed consent documents, case 
report forms or study flow sheets, survey instruments, database or spreadsheets, screening logs or telephone 
eligibility sheets, web based information gathering tools, audio/video/photo recordings of subjects, labeled 
specimens, data about subjects, and subject identifiers such as social security number.
All data collected on paper will be stored in locked cabinets within the Center for Smoking Cessation. 
Except when required by law, subjects will not be identified by name, social security number, address, 
telephone number, or any other direct personal identifier in study records disclosed outside of Duke 
University Health System (DUHS). For records disclosed outside of DUHS, a unique code number will be 
assigned. The key to the code will be kept in a locked file in the PI’s office.
 
Application Questions Complete
Please click Save & Continue to proceed to the Initial Submission Packet.
The Initial Submission Packet is a short form filled out after the protocol application has been completed.  This 
is an area to attach protocol-related documents, consent forms, and review the application.
 

Prot_SAP_000.pdf: 
Version 5/14/2018 
 
Page 1 of 15 
The Role of Nicotine Dose and Route of Delivery in Affecting Adoption of E-ciga-
rettes and Reducing Exposure to Toxic Combustion Products 
 
PI:  Jed E. Rose, Ph.D. 
Sub Investigator:  James Davis, M.D. 
 
NCT03492463 
 
 
PURPOSE OF THE STUDY: 
 
We propose to assess the relative role of nicotine dose and route of delivery in affecting 
successful switching from combustible cigarettes to e-cigarettes, as well as concomitant 
reductions in ad libitum cigarette smoking and exposure to harmful and potentially harm-
ful constituents of combustion. 
 
The strategy will be to assess adoption of e-cigarette use and concomitant reduction in ad 
libitum smoking of subjects’ usual brands of cigarettes over an 8-week period, during 
which they will receive nicotine or non-nicotine e-cigarettes, and nicotine or non-nicotine 
skin patches. The nicotine patches will not be used as a therapeutic treatment in this 
study, but rather as a way to manipulate the nicotine dose, while varying the rate and 
route of nicotine delivery.  Behavioral or “habit” aspects of e-cigarette use will be con-
trolled for by the groups receiving non-nicotine e-cigarettes.  
 
 
BACKGROUND & SIGNIFICANCE: 
 
Cigarette smoking remains the leading cause of preventable disease and death in devel-
oped countries, due principally to its contributions to heart disease, chronic obstructive 
pulmonary disease (COPD), and cancer (Lando & Wilson, 2010).  The annual death toll 
in the U.S. from diseases caused by smoking has been increasing steadily and is esti-
mated to be the highest ever, 540,000/year (Carter et al., 2015).   
 
The U.S. Surgeon General’s Report of 2010 (USDHHS, 2010) concluded that the com-
bustion products of smoke, rather than nicotine, were responsible for most smoking re-
lated diseases. E-cigarettes, which deliver nicotine in the absence of combustion, have 
been advanced as a tobacco harm reduction strategy. Thus far, however, only a minority 
of smokers have adopted e-cigarettes to satisfy their nicotine dependency without concur-
rent use of combustible cigarettes. A number of factors may serve as barriers to the adop-
tion of e-cigarettes, including insufficient dose of nicotine and lack of familiar sen-
sory/habit components (e.g., aroma, “throat hit”) associated with smokers’ usual brands 
of cigarettes. The present study will examine the relative roles of nicotine dose and route 
of administration in affecting the ability of smokers to transfer their dependency from 
combustible cigarettes (CC) to e-cigarettes. 
 


Version 5/14/2018 
 
Page 2 of 15 
There are several reasons why administration of a given dose of nicotine by inhalation 
(via e-cigarettes), vs. transdermal administration (via nicotine patches) would be more re-
inforcing and lead to greater switching from combustible cigarettes to e-cigarettes. First, 
inhaled nicotine reaches the bloodstream and brain much faster than transdermal admin-
istration (Rose et al., 2010), producing immediate reinforcing effects.  Also, inhaled nico-
tine produces familiar respiratory tract cues that smokers find rewarding (Rose, 2006). In-
deed studies have reported a greater suppression of combustible cigarette use when smok-
ers used e-cigarettes as an alternative compared with nicotine patch (McRobbie et al., 
2014). 
 
Although subjects receiving nicotine from e-cigarettes will no doubt receive a range of 
nicotine doses, depending on the extent of use, data from previous studies (Shahab et al., 
2017) suggests that the mean dose is expected on average to be similar to that provided 
by a 21 mg/day patch (and actual mg/day, as estimated from the number of e-liquid car-
tridges consumed, will be a covariate in the statistical analyses described below).   
 
 
DESIGN & PROCEDURE: 
 
Design Overview 
 
The study will comprise a randomized, double-blind parallel-arm study to ascertain the 
role of nicotine dose and route of administration in reducing use of combustible cigarettes 
and in facilitating adoption of e-cigarettes. Two hundred sixty daily cigarette smokers 
will be randomly assigned to receive 8 weeks of exposure to the following conditions 
(65/group): 
 
1. Nicotine containing e-cigarettes + 21 mg nicotine skin patches 
2. Zero-nicotine e-cigarettes + 21 mg nicotine skin patches 
3. Nicotine containing e-cigarettes + 0 mg skin patches 
4. Zero-nicotine e-cigarettes + 0 mg skin patch patches 
Nicotine and non-nicotine e-cigarettes will be purchased from JUUL Labs.  The JUUL is 
a rectangular closed-system e-cigarette. This e-cigarette was commercially available as of 
August 8, 2016 and does not contain any alterations to the chemistry or physical charac-
teristics. Each JUUL Pod pack contains 4 pods. Each JUUL Pod contains 0.7mL with 5% 
nicotine by weight, approximately equivalent to one pack of cigarettes or 200 puffs. Mul-
tiple flavors will be used in this study in order to more accurately mimic real world con-
ditions. Each pack contains four of either tobacco-flavored or mint-flavored pods. Sub-
jects will be provided with enough additional packs of pods to use during the smoking 
period. JUUL Pods are sealed system cartridges for use in the JUUL e-cigarette. Each 
pod is contained in tamper resistant blister packs. The nicotine patches will be purchased 
from Duke Outpatient Pharmacy and non-nicotine patches will be obtained from Rejuve-
nation Laboratories. 


Version 5/14/2018 
 
Page 3 of 15 
Ad libitum smoking will be assessed weekly using daily diary recordings of cigarettes 
smoked per day as well as the objective index of expired air carbon monoxide (CO) lev-
els measured at the study visits.   
 


Version 5/14/2018 
 
Page 4 of 15 
The Study timeline is shown below: 
 
 
 
Screening and Session Procedures 
 
Interested potential subjects will respond to advertisements by contacting our Center to 
be phone screened.  Potential subjects will be given a brief description of the study and 
will be asked questions to assess eligibility and interest.  Eligible subjects interested in 
participating will be scheduled for the medical history and physical examination screen-
ing visit. 
  
After granting their informed consent, potential subjects will be given the HIPAA Notice 
of Privacy Practices.  They will also complete a medical history form and will have their 
blood pressure, pulse, weight, height, temperature and expired air CO measured.  Sub-
jects will provide smoking history information, a saliva sample, blood (maximum of 
50mL) for tests to measure general health, nicotine metabolite ratio (NMR), and for ge-
netic evaluation, and urine for urinalysis and illicit drug testing. Women of child bearing 
potential will also have a serum pregnancy test.  The study physician or one of his assis-
tants will perform a physical examination and an ECG.  The ECG will be used to screen 
for the presence of major arrhythmias such as atrial fibrillation, SVT, and bradycardia.  It 
will also be used to confirm positive physical exam findings.The screening visit will last 
approximately 2.5 hours. 
 
Blood and urine specimens will be sent to LabCorp for processing.  The results of labora-
tory blood and urine tests will not routinely be given to participants to send or be sent to 
their physician to include in their medical record.  However, if the subject’s lab results 
are outside the acceptable range for participation in the study the Physician/P.A. will send 
the subject a medical exclusion letter and a copy of the lab results.  Participants who are 
accepted into the study but need medical follow up due to minor abnormalities in lab re-
sults will also be informed by letter from the Physician/P.A.  A copy of the laboratory re-
sults will be included with the letter, which will also indicate that the condition does not 
interfere with his/her participation in the study.   
 
The blood samples for genetic evaluation and NMR will be stored at the Center for 
Smoking Cessation.  If they are sent to an external lab for analysis (to be determined), 
there will be no identifiers except for a code number on the samples. 
 
V2
V3
V4
V5
Zero-nicotine e-Cigarettes + 0mg Nicotine Patches
WK2
WK4
WK6
WK8
     Group 4
     Group 1
     Group 2
     Group 3
Nicotine e-Cigarettes + 21mg Nicotine Patches
Zero-nicotine e-Cigarettes + 21mg Nicotine Patches
Nicotine e-Cigarettes + 0mg Nicotine Patches
FU
WK1
WK3
WK5
WK7
Scr
V1
4 wk.


Version 5/14/2018 
 
Page 5 of 15 
The time commitment for subjects is 8 weeks once their participation begins, plus one 
follow-up session at four weeks. Subjects will return every two weeks to obtain e-ciga-
rette and patch supplies, and for outcome measures of e-cigarette and combustible ciga-
rette use to be collected.   
 
Questionnaires will be completed within REDCap on a desktop computer in the Center 
office.  The technician will log on to the REDCap site and will open the questionnaires 
for the subjects.  Subjects will only have access to their questionnaires.  Access to any 
other websites will be blocked by Duke Psychiatry Information Technology. 
 
Sessions 
 
The first study visit (V1) will take place approximately one week after the screening visit.  
Subjects will complete baseline questionnaires and will be randomized to one of the four 
groups. Subjects will be tested for exhaled air carbon monoxide, and saliva samples will 
be collected for analysis of smoking related chemicals (e.g., cotinine).  They will also 
have their blood pressure, heart rate and weight measured.  Subjects will also complete 
questionnaires assessing their dependence on cigarettes (FagerstrÖm Test for Nicotine 
Dependence (FTND)  (Heatherton et al., 1991)), and rewarding effects of cigarettes 
(modified Cigarette Evaluation Questionnaire (Cappelleri et al., 2007)).  
 
Subsequent study visits will occur approximately two weeks apart (with a five-day win-
dow on either side of the scheduled visit).  Subjects will complete questionnaires and be 
tested for exhaled air carbon monoxide, provide a saliva sample for analysis of smoking 
related chemicals (e.g., cotinine), and have their blood pressure, heart rate and weight 
measured.  Subjects will also complete questionnaires assessing their dependence on cig-
arettes (FagerstrÖm Test for Nicotine Dependence (FTND) (Heatherton et al., 1991)), and 
rewarding effects of cigarettes (modified Cigarette Evaluation Questionnaire (Cappelleri 
et al., 2007)).  
 
At the first (V1) and final (V5) sessions, we will assess total urinary 4-(methylnitrosa-
mino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of the tobacco-specific carcinogen 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The half-life of NNAL is 10 
days (Goniewicz et al., 2009), yielding a valuable index of sustained reductions in ciga-
rette smoking, The half-life of expired air CO, in contrast, is 4.5 h (Sandberg et al., 
2011).  Also at these two visits subjects will use one of the e-cigarettes for ten minutes.  
By weighing the device before and after puffing, an estimate of mouth nicotine intake or 
placebo aerosol intake will be obtained.  Subjects will refrain from smoking for one hour 
prior to using the e-cigarette. 
 
Subjects will also be given diaries to record the number of cigarettes smoked each day 
and e-cigarette cartridges used, and will be instructed to return the diaries at the next 
visit.  At Sessions V1-V4, participants will be dispensed a sufficient supply of skin 
patches and e-cigarette refill tanks (pods) to last until the next session.  Participants will 
be given pods with both flavors (Virginia tobacco and cool mint) of e-liquid. They will be 


Version 5/14/2018 
 
Page 6 of 15 
asked to return all used and unused pods and used patches at their subsequent visit for 
proper disposal and compliance monitoring. 
 
Four-week Follow-up 
 
Study participants will return to the laboratory for a brief follow-up session four weeks 
after Session V5.  This session will include an expired air CO reading, blood pressure, 
heart rate and weight measurements, collection of saliva and urine samples, and comple-
tion of several questionnaires. 
 
 
SUBJECT IDENTIFICATION: 
 
We propose to enroll up to 1600 smokers in order to identify 260 participants who meet all crite-
ria to be accepted into the study and to be randomized into one of four experimental conditions. 
 
Inclusion Criteria 
 
• Are 18-65 years old; 
• Smoke an average of at least 10 cigarettes per day; 
• Have smoked at least one cumulative year; 
• Have an expired air CO reading of at least 10ppm; 
• Have a body weight of > 110 lbs. (50 kg) and ≤ 300 lbs. (136 kg); 
• Are able to read and understand English. 
 
Potential subjects of child bearing potential must agree to use two acceptable forms of 
contraception during their participation in this study.  Women are considered past the age 
of child-bearing potential if: 
 
• they are greater than 55 years of age, OR  
• they are at least 50 years of age AND have not menstruated for at least  
• 12 months, OR  
• have a documented Follicule Stimulating Hormone (FSH) level of greater than  
• 40 mIU/mL.  
• they are at least 45 years of age AND have not menstruated for at least 18 
• months, OR have a documented Follicule Stimulating Hormone (FSH) level of 
greater than 40 mIU/mL.  
 
Medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal li-
gation or hysterectomy), (2) approved hormonal contraceptives (such as birth control 
pills, patches, implants or injections), (3) barrier methods (such as a condom or dia-
phragm) used with a spermicide, or (4) an intrauterine device (IUD). Contraceptive 
measures such as Plan B (TM), sold for emergency use after unprotected sex, are not ac-
ceptable methods for routine use.  
 


Version 5/14/2018 
 
Page 7 of 15 
Potential subjects must agree to avoid the following during their participation in this 
study:  
• participation in any other nicotine-related study protocol outside of this protocol; 
• use of tobacco products other than cigarettes, including pipe tobacco, cigars, e-ciga-
rettes, snuff, and chewing tobacco;  
• use of experimental (investigational) drugs or devices;  
• use of illegal drugs; 
• use of exclusionary medications. 
 
 
Exclusion Criteria 
 
• Hypertension – systolic BP > 160 mm Hg, diastolic BP > 100 mm Hg.  Individuals 
with a history of hypertension may be allowed to participate in the study if the study 
physician or medical provider determines that the condition is stable and will 
not jeopardize the individual’s safety. 
• Hypotension (with symptoms) – systolic BP < 90 mm Hg, diastolic BP < 60 mm Hg. 
• Coronary heart disease with symptoms (e.g., chest pain) 
• Heart attack in the past year  
• Cardiac rhythm disorder (irregular heart rhythm with symptoms) 
• Chest pain in the last month (unless history indicates a non-cardiac source)  
• Symptomatic heart disorder such as heart failure  
• Advanced liver or kidney disease that requires medication or dialysis, paracentesis 
• Major gastrointestinal illness (e.g. Celiac disease, Crohn’s dx Ulcerative Colitis) 
• Bleeding stomach ulcers in the past 30 days 
• Lung disease that requires oxygen 
• Major brain disorder (including stroke with residual deficit, brain tumor, and seizure 
disorder) 
• Migraine headaches that occur more frequently than once per week  
• Recent, unexplained fainting spells  
• Problems giving blood samples  
• Diabetes with insulin use or with HbA1C over 7%  
• Current cancer or treatment for cancer in the past six months (except basal or squa-
mous cell skin cancer)  
• HIV, Hepatitis B, or Hepatitis C 
• History of Tuberculosis or recent positive PPD  
• Other major medical condition (as determined by study physician)  
• Currently symptomatic psychiatric disease  (as determined by study physician)  
• Psychosis, bipolar disorder, or psychiatric hospitalization within the past 12 months  
• Suicidal ideation (thinking about ways to commit suicide) (within the past 12 months) 
or a lifetime occurrence of attempted suicide;  
• Current depression – The Patient Health Questionnaire PHQ-9 for Depression will be 
used to screen for current (within 2 weeks) depression.  Potential subjects  who score 
>9 (or who score >0 on item #9 (“Thoughts that you would be better off dead, or of 


Version 5/14/2018 
 
Page 8 of 15 
hurting yourself in some way”) will be excluded from study participation, and, at the 
discretion of the study physician, referred to appropriate psychiatric treatment; 
• Pregnant or nursing mothers 
• Use (within the past 30 days) of: 
➢ 
Illegal drugs (or if the urine drug screen is positive for THC, Cocaine, Ampheta-
mine, Opiates, Methamphetamines, PCP, Benzodiazepines, or Barbiturates), un-
less recent use of prescription Opiates or Benzodiazepines were taken for man-
agement of acute symptoms (e.g., tooth extraction, recent surgery); 
➢ 
Experimental (investigational) drugs;  
➢ 
Psychiatric medications including antidepressants (SSRIs, SNRIs, TCAs, MAOIs, 
St. John’s Wort), lithium, anti-psychotics or any other medications that are known 
to affect smoking cessation (e.g. clonidine); 
➢ 
Phentermine, triptans, tryptophan, linezolid, dextromethorphan, opiates (unless 
taken for management of acute symptoms), tramadol, or dopamine agonists; 
➢ 
Any agents that have documented correlation with increased incidence of val-
vulopathy and/or pulmonary hypertension (e.g., cyproheptadine, trazodone, ne-
fazodone, amoxapine, tricyclic antidepressants, mirtazapine, pergolide, ergota-
mine, methysergide) (or anticipated use during the study);  
➢ 
Wellbutrin, bupropion, Zyban, Chantix, varenicline, nicotine patch, nicotine re-
placement therapy or any other smoking cessation aid. Use of cigars, cigarillos, 
pipes, Hookah, dissolvable nicotine, snuff, chewing tobacco, or e-cigarettes 
within the past 30 days 
• Concurrent use of a serotonergic agent/combination associated with severe serotonin 
syndrome (within the past 30 days) 
• Use of cigars, cigarillos, pipes, Hookah, dissolvable nicotine, snuff, chewing tobacco, 
or e-cigarettes within the past 30 days 
• Self-report of consuming more than 6 alcoholic drinks on 1 or more days per week 
• Significant adverse reaction to nicotine patch in the past 
• Current participation or recent participation (in the past 30 days) in another smoking 
study at our Center or another research facility  
• Current participation in another research study 
 
Assessment of Eligibility 
 
Potential subjects who do not have a self-reported diagnosis of the above listed condi-
tions may be excluded if the study physician or physician assistant determines that the 
history, physical findings, ECG, or laboratory studies reveal information that may jeop-
ardize the subjects’ safe study participation.  For medical conditions that do not appear 
above, the study physician will be consulted, and if the medical condition does not jeop-
ardize safe study participation, then the subject may be enrolled. 
 
 
 
 


Version 5/14/2018 
 
Page 9 of 15 
SUBJECT RECRUITMENT AND COMPENSATION 
 
Subject Recruitment 
 
Smokers with no major health problems will be recruited from communities in and 
around Durham, North Carolina.  Recruitment will occur through newspaper, flyers, and 
internet advertisements and by word-of-mouth.  Potential subjects will be pre-screened on 
the phone by a member of the Duke CSC.  If potential subjects meet the pre-screening 
study requirements and are still interested in participation, they will attend a physical 
screening session at the Duke CSC, located at 2424 Erwin Road, Suite 201, Durham, NC  
27705.  If after this visit it is determined that they qualify for participation, they will at-
tend subsequent study visits at the Duke Center for Smoking Cessation located at 2424 
Erwin Road, Suite 201, Durham, NC  27705.  
 
Subject Compensation 
 
Subjects will be reimbursed $40 per visit for attending the five study visits, plus $60 for 
attending the follow-up visit.  In addition, subjects will receive a payment of $10 for each 
of the 5 visits attended in which they return their completed take-home forms (brief ques-
tionnaires which describe subjective effects of product use and record smoking behavior 
and e-cigarette use) or (for visits 2-5) return unused supplies (patches and e-cigarette 
tanks). Subjects who do not complete each visit will still receive payment for the visits 
attended.  Thus, subjects who attend five visits and hand in their take-home forms each 
time and also attend the follow-up visit will receive a total payment of $310. Subjects 
will not be compensated for the screening session.   
 
 
CONSENT PROCESS 
 
Because of the nature of this study and the amount of questionnaires that subjects are ex-
pected to complete, we do not recruit potential subjects who do not read, are blind or who 
do not read/understand English.  We are not equipped to validate alternate versions of our 
questionnaires, most of which are not published.  Questionnaires cannot be administered 
orally by a translator or by Technicians to illiterate or blind subjects because the data ob-
tained would not be comparable to self-administered questionnaires. 
 
 
RISK/BENEFIT ASSESSMENT 
 
Conventional (combustible) cigarettes:  Continuing to smoke carries significant health 
risks.  Subjects enrolling in this study are not being asked to quit smoking over the course 
of the study, but will be exposed to no additional risk from their usual smoking behavior. 
Their exposure to harmfully and potentially harmful constituents in combustible ciga-
rettes may decrease to the extent they use e-cigarettes as an alternative to combustible 
cigarettes.  
 


Version 5/14/2018 
 
Page 10 of 15 
Potential side effects of Nicotine patch: The nicotine patch poses very little risk and is ap-
proved for over-the-counter sales as a smoking cessation treatment. It is not being used as 
a cessation treatment in this protocol but the risks will be minimal.  Insomnia and abnor-
mal dreams are common and expected side effects associated with 24-hour nicotine 
patches.  If a subject complains of disturbed sleep, he or she will be instructed to remove 
the patch at bedtime and apply a new one the next day at the usual time. Skin irritation 
may occur, although this will be minimized by changing the site of patch application 
daily.  If a subject develops itching or a rash at the patch site, he or she will be advised to 
use 1% hydrocortisone cream on the affected area.  Symptoms associated with nicotine 
toxicity include lightheadedness, dizziness, nausea, fainting and vomiting. A less likely 
side effect of nicotine patches is somnambulism. 
 
Electronic Nicotine Delivery Systems (ENDS):  ENDS, or “e-cigarettes,” have been mar-
keted in the U.S. since 2007 and have been used worldwide by millions of smokers. 
While the potential risks of long-term use of e-cigarettes are unknown, most experts 
agree that the constituents of e-cigarettes are less toxic than those of combustible ciga-
rettes (Grana et al., 2014).  Although it is conceivable that participants could receive an 
overdose of nicotine, this is extremely unlikely inasmuch as smokers can control the dose 
according to how they puff and inhale from the devices, as they do with conventional cig-
arettes.  The main side effect that is anticipated with the relatively short 8-week duration 
of exposure to ENDS in the proposed project is mild irritation of the respiratory tract 
from inhalation of the propylene glycol and nicotine contained in the product.  Should 
any clinically significant changes occur, the study physician will recommend discontinu-
ation of ENDS use if it is indicated. 
 
Needle stick / Blood drawing: The risks associated with venipuncture are minimal, and 
include momentary discomfort and/or bruising. Infection, excess bleeding, clotting, and 
fainting are also possible, although unlikely. 
 
Subjects will be monitored throughout the duration of the study for side effects and se-
vere adverse effects (SAEs). They will be instructed to report any side effects to the study 
technicians, who will communicate these reports immediately to the medical staff.  The 
most appropriate course of action will be determined, which may include options for dose 
reduction or termination of treatment.  Participants will be reminded that they have the 
option to withdraw from the study at any time.  Subjects will also be given the 24-hour 
emergency contact numbers in the event that side effects or adverse events occur between 
sessions.  SAEs will be reported to the IRB and will be monitored until resolution or sta-
bilization.   
 
The sponsor for this study will ensure the investigational tobacco product is distributed 
only to qualified members of key personnel in accordance with this protocol. 
 
 
 
 


Version 5/14/2018 
 
Page 11 of 15 
SERIOUS ADVERSE EVENT REPORTING PLAN 
 
The Principal Investigator will report all serious adverse events relating to the study in an 
expedited manner to the Duke University Health System (DUHS) Institutional Review 
Board (IRB) office, and all applicable regulatory authorities in accordance with the Cen-
ter’s standard operating procedures.  
 
If the Sponsor-Investigator is notified that a study subject has a serious and unexpected 
adverse experience associated with the use of the investigational tobacco product, we will 
inform the IRB, NIDA, FDA, and all participating clinical investigators within a few days 
after initial receipt of the notification. In addition, we will notify the IRB, NIDA, FDA, 
and all participating clinical investigators of any serious or unexpected adverse experi-
ence associated with the tobacco product within a few weeks after initial notification.  
Reporting to NIDA will be performed using the Serious Adverse Event Tracking and Re-
porting System (SAETRS) at https://saetrs.nida.nih.gov; reporting to FDA will be per-
formed using the Safety Reporting Portal (SRP) at https://www.safetyreporting.hhs.gov. 
 
 
COSTS TO PARTICIPANTS 
 
There are no costs to participants for taking part in this study.  All the study costs, includ-
ing any study medications and procedures related directly to the study, will be paid for by 
the research grant awarded to Duke University.   
 
 
DATA ANALYSIS & STATISTICAL CONSIDERATIONS 
 
The primary outcome measures will be the amount of combustible cigarette use and e-ciga-
rette use in the last week of the 8-week exposure period. The main index of combustible 
cigarette use will be expired air CO, a highly sensitive and specific measure of smoke inha-
lation. As a secondary measure (at the first (V1) and final (V5) sessions), we will assess 
total urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of the 
tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). 
The half-life of NNAL is 10 days (Goniewicz et al., 2009), yielding a valuable index of 
sustained reductions in cigarette smoking. The half-life of expired air CO, in contrast, is 
4.5 h (Sandberg et al., 2011).  Self-reported cigarettes/day recorded on diaries will be a 
secondary index of cigarette consumption.   The main index of e-cigarette use will be the 
number of cartridges consumed, based on self-report and counts of the number of unused e-
cigarette tanks returned. We hypothesize (H1) that e-cigarette use will be higher, and con-
comitantly, combustible cigarette use will be lower, in the nicotine e-cigarette conditions 
compared to the zero-nicotine e-cigarette conditions (i.e., comparing Group 1 and Group 3 
vs. Group 2 and Group 4) and also hypothesize (H2) that e-cigarette use will be higher, and 
concomitantly, combustible cigarette use will be lower, in the inhaled nicotine condition 
than the transdermal nicotine condition (i.e., comparing Group 3 with Group 2). These hy-
potheses will be evaluated using General Linear Modeling (GLM) techniques to assess the 


Version 5/14/2018 
 
Page 12 of 15 
significance of the nicotine factor and route-of-administration factor (and potential interac-
tive effects), using a 2-tailed alpha=0.05. Covariates in the analysis of combustible ciga-
rette use will include the amount of e-cigarette use, since that will affect the overall dose of 
nicotine received by subjects, as well as baseline combustible cigarette use, and baseline 
demographic and smoking history variables (the latter will also serve as covariates in the 
analysis of e-cigarette use as a dependent measure). We predict at least a moderate effect 
size (0.5) for each of the main effects, nicotine and route of administration, so that a sample 
size of 65 per group will yield at least 80% power to detect the hypothesized effects.     
  
  
DATA & SAFETY MONITORING 
 
Description of BP monitoring procedures after study enrollment 
 
After study enrollment, if blood pressure during return sessions is above 160/100, then 
the following actions will be taken to enhance subject safety: 
• If BP >210/100 with symptoms of malignant hypertension: stop experiment inter-
ventions and refer to appropriate medical treatment.  Resume participation and 
continue to be monitored if BP is no greater than 140/100. 
• If BP > 160/100 for 2 consecutive sessions, then CSC will provide either weekly 
BP checks or request that the participant have his/her BP checked weekly by PCP, 
local pharmacy, or home machine and call us with results.  The physician assis-
tant will discuss these results with the study physician. 
• A blood pressure memo to file form will be completed if BP>160/100 for 3 read-
ings per center approved procedure. 
 
Data Safety Monitoring Plan (DSMP) 
 
To address potential safety issues in addition to collection of the primary study outcomes, 
severe side effects and adverse events potentially associated with the study will be exam-
ined, recorded and then reported to the IRB in a manner consistent with Duke HRPP poli-
cies. The principal investigator will be responsible for monitoring data collection and 
safety of this study. 
 
Data collection for this study will be carried out at the Durham clinical site of the Duke 
Center for Smoking Cessation (CSC). All members of the study team will complete re-
search integrity (“code of conduct”) and CITI (Collaborative Institutional Training Initia-
tive) Human Research Curriculum and clinical laboratory safety training as required by 
Duke University Medical Center. All study staff who are involved in data collection, 
management, and processing will be thoroughly trained following standards of proce-
dures prior to working on this project. 
  
Study staff responsible for data collection will use a checklist for completion for each 
study visit of each participant.  Missing Data Forms, along with explanations should 
missing data occur, will be completed by the study staff for each study visit. 
 


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Microsoft Access will be used for logging subject information (Enrollment Log, Visit 
Log, etc.). Data will be entered by the study staff.  The key study personnel will further 
examine the computerized data entries and original records for accuracy and completion. 
 
Emergency Unblinding 
 
This is a blinded protocol such that all participants and all study personnel except for the 
Clinical Research Coordinator and the Research Program Leader are blinded to group allo-
cation.  During specific circumstances it will be necessary to unblind other study personnel, 
such as study team medical personnel.  Emergency unblinding will occur under the discre-
tion of the study physician (or one of the study physician assistants) in any situation in 
which unblinding is deemed necessary to ensure or promote the safety of a study partici-
pant.  The decision to unblind for safety reasons may occur for a number of reasons and it 
is not possible to enumerate all potential circumstances.  Examples of reasons for unblind-
ing to ensure participant safety include situations in which it is necessary to know which 
study drugs the subject was taking in order to manage the side effect(s), advise the subject 
on the risk of future negative drug reactions, uncover potential safety information about the 
drug, and/or determine whether the adverse event is study related.  In those situations, the 
Clinical Research Coordinator or Research Program Leader will inform the study physician 
(or physician assistant handling the event) of that subject’s treatment condition.  If unblind-
ing occurs, that subject’s data will be censored and will not be included in final data anal-
yses. 
 
 
DATA STORAGE & CONFIDENTIALITY 
 
Any PHI collected prior to documentation of informed consent will be de-identified if the 
potential subject does not qualify for this study.  Please refer to the “Request for Waiver 
of Documentation of Informed Consent”. 
 
Prior to any physical screening procedures, subjects will be informed, in their consent 
forms, of the data storage and confidentiality safeguards, which are practiced according 
to current HIPAA regulations.  Study records that identify subjects will be kept confiden-
tial as required by law. Blood and urine specimens will be sent to LabCorp for pro-
cessing.  Name, date of birth, and gender will be included with each specimen.  Except 
when required by law, subjects will not be identified by name, social security number, 
address, telephone number, or any other direct personal identifier in study records dis-
closed outside of Duke University Health System (DUHS) (except to LabCorp). For rec-
ords disclosed outside of DUHS, subjects will be assigned a unique code number. The 
key to the code will be kept in a locked file in the PI’s office separate from the locked file 
where the study records are stored. 
 
During data collection, data for active subjects are kept at our offices located in Durham, 
NC.  
 


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Carter BD, Abnet CC, Feskanich D, et al. (2015) Smoking and mortality -- beyond estab-
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