Clinical trial NCT05541497
Conditions: Smoking Cessation
Keywords: e-cigarette
Sponsor: Yale University
Start date: 2022-11-04; Completion date: 2023-09-01
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Varenicline is used to treat tobacco use dependence. It helps reduce cravings for tobacco use and decreases the pleasurable effects of cigarettes and other tobacco products. Varenicline has been proven to reduce the desire to smoke cigarettes. This study aims to test whether it shows a similar benefit for individuals who vape and are interested in quitting.

Detailed description:
Varenicline is a highly efficacious FDA-approved smoking cessation pharmacotherapy. The aim of this study is to examine the effectiveness of varenicline for e-cigarette cessation medication for mono- e-cigarette use in combination with a minimal, self-guided behavior change booklet. This booklet will include general tips for e-cigarettes cessation and information about the free web-based e-cigarette cessation program sponsored by The Truth Initiative and Mayo called "This is Quitting". This study will have an 8-week treatment period and a 4-week follow-up phase. Participants will be randomized to receive an 8-week supply of varenicline or matching placebo (gel capsule filled with cellulose powder) in combination with the self-change booklet. The investigators hypothesize that participants who receive varenicline will have higher rates of e-cigarette cessation.

Arms: arm 1: * Days 1-3: 0.5mg study pill once per day
* Days 4-7: 0.5mg study pill twice per day
* Weeks 2-8: 1mg study pill twice per day in combination with a minimal, self-guided behavior change booklet. This booklet includes general tips for e-cigarettes cessation and information about the free web-based e-cigarette cessation program sponsored by The Truth Initiative and Mayo called "This is Quitting". This study will have an 8-week treatment period and a 4-week follow-up. arm 2: * Days 1-3: 0.5mg placebo pill once per day
* Days 4-7: 0.5mg placebo pill twice per day
* Weeks 2-8: 1mg placebo pill twice per day in combination with a minimal, self-guided behavior change booklet. This booklet includes general tips for e-cigarettes cessation and information about the free web-based e-cigarette cessation program sponsored by The Truth Initiative and Mayo called "This is Quitting". This study will have an 8-week treatment period and a 4-week follow-up.
Interventions: intervention 1: Varenicline Tartrate intervention 2: Placebo
Intervention descriptions: intervention 1: Days 1-3: 0.5mg study pill once per day, Days 4-7: 0.5mg study pill twice per day, Weeks 2-8: 1mg study pill twice per day intervention 2: Days 1-3: 0.5mg pill once per day, Days 4-7: 0.5mg pill twice per day, Weeks 2-8: 1mg pill twice per day

Protocol documents:
Prot_SAP_000.pdf: 
APPROVED BY THE YALE UNIVERSITY IRB 3/23/2023
CLINICAL STUDY PROTOCOL
Interventional Drug or Biologic
 
Varenicline for treatment of e-cigarette 
dependence
 Protocol Number
2000032740
Protocol Version
9/20/2022
Version 5
PRINCIPAL INVESTIGATOR:
Name Lisa Fucito, Ph.D.
Department Psychiatry
Telephone Number 201-341-8865
Email Address: lisa.fucito@yale.edu
IND Number: N/A
IND Holder: N/A
NCT Number: Pilot study, not applicable
Study Phase (1, 2, 3, or 4-postmarketing): 1
Confidentiality Statement:
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REVISION HISTORY:
Revision #
Version Date
Ver1
4.20.2022
Ver 2
5.2.2022-minor changes
Ver 3
5.23.2022
Ver 4
8.11.2022
Ver 5
9.20.2022
Ver 6
3/17/23
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Synopsis
Primary Objective
The primary objective of this Phase 1 study is to determine whether varenicline reduces e-
cigarette use in adults who regularly use e-cigarettes.
Secondary Objective (if applicable)
The secondary objective[s] of this study is] to determine whether varenicline promotes vaping 
cessation at week 12.
Study Duration
Participant duration in this study is 12 weeks. The entire study is expected to take about 2 year.
Study Design 
Randomized, Placebo-controlled, double blind pilot study
Number of Study Sites
This is a dual site study that will be carried out at Yale and Medical University of South Carolina 
The study will use remote/telehealth procedures, as much as possible, as detailed below
Study Population
This study will use various media outlets to recruit adults who report current e-cigarette use in 
South Carolina (for MUSC) and in Connecticut (for Yale). Advertising will target e-cigarette 
users who have a desire to quit and are willing to undergo treatment, set a quit date, and 
attempt to maintain e-cigarette abstinence. Mono-vapers will click the link in our Craigslist and 
social media ads which will open a screening survey through REDCap on their mobile devices. 
If the individual meets pre-screening eligibility, the research staff will call the participant to 
schedule an intake to confirm final eligibility for the study.
Number of Participants
We plan to enroll 40 participants across two sites. As with previous studies, we will 
make every effort to maximize participant retention via a thorough informed consent 
process, careful screening, and other practices.
Primary Outcome Variables
The primary outcome will be abstinence from vaping at week 8. Abstinence is defined as no 
vaping, not even a puff, every day for the last 7 days via self-report (i.e., 7 day point prevalent 
abstinence). 
Secondary and Exploratory Outcome Variables (if applicable)
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The secondary outcome will be abstinence from vaping at week 12. Abstinence is defined as 
no vaping, not even a puff, every day for the last 7 days via self-report (i.e., 7 day point 
prevalent abstinence). 
Abbreviations
Abbreviation 
Explanation
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Glossary of Terms
Glossary
Explanation
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Table of Contents
Synopsis ..................................................................................................................................2
Primary Objective.................................................................................................................2
Secondary Objectives (if applicable)....................................................................................2
Study Duration......................................................................................................................2
Study Design........................................................................................................................2
Study Population ..................................................................................................................2
Number of Participants.........................................................................................................2
Number of Study Sites .........................................................................................................2
Primary Outcome Variables .................................................................................................2
Secondary and Exploratory Outcome Variables (if applicable)............................................2
Visit Schedule Table (Optional)............................................................................................2
Study Flow Chart (optional)..................................................................................................2
Abbreviations ...........................................................................................................................3
Glossary of Terms....................................................................................................................4
1
Introduction.......................................................................................................................6
1.1
Introductory Statement ..............................................................................................6
2
Background.......................................................................................................................7
2.1.1
Preclinical Experience........................................................................................7
2.1.2
Clinical Experience.............................................................................................7
2.2
Background/prevalence of research topic .................................................................7
3
Rationale/Significance ......................................................................................................8
3.1
Problem Statement....................................................................................................8
3.2
Purpose of Study/Potential Impact ............................................................................8
3.2.1
Potential Risks....................................................................................................8
3.2.2
Potential Benefits ...............................................................................................8
4
Study Objectives...............................................................................................................9
4.1
Hypothesis.................................................................................................................9
4.2
Primary Objective ......................................................................................................9
4.3
Secondary Objectives (if applicable) .........................................................................9
5
Study Design ..................................................................................................................10
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5.1
General Design Description.....................................................................................10
5.1.1
Study Date Range and Duration ......................................................................10
5.1.2
Number of Study Sites .....................................................................................10
5.2
Outcome Variables..................................................................................................10
5.2.1
Primary Outcome Variables .............................................................................10
5.2.2
Secondary and Exploratory Outcome Variables (if applicable)........................10
5.3
Study Population .....................................................................................................10
5.3.1
Number of Participants.....................................................................................10
5.3.2
Eligibility Criteria/Vulnerable Populations.........................................................10
6
Methods..........................................................................................................................12
6.1
Treatment - Drug .....................................................................................................12
6.1.1
Identity of Investigational Product/New Drug ...................................................12
6.1.2
Dosage, Admin, Schedule (if applicable) .........................................................12
6.1.3
Method of Assignment/Randomization (if applicable) ......................................12
6.1.4
Blinding and Procedures for Unblinding (if applicable).....................................12
6.1.5
Packaging/Labelling .........................................................................................12
6.1.6
Storage Conditions...........................................................................................12
6.1.7
Concomitant therapy ........................................................................................12
6.1.8
Restrictions.......................................................................................................12
6.2
Assessments ...........................................................................................................12
6.2.1
Efficacy.............................................................................................................12
6.2.2
Safety/Pregnancy-related policy.......................................................................13
6.2.3
Adverse Events Definition and Reporting.........................................................13
6.2.4
Pharmacokinetics (if applicable).......................................................................13
6.2.5
Biomarkers (if applicable).................................................................................13
6.3
Study Procedures....................................................................................................13
6.3.1
Study Schedule ................................................................................................14
6.3.2
Informed Consent.............................................................................................14
6.3.3
Screening .........................................................................................................14
6.3.4
Recruitment, Enrollment and Retention ...........................................................14
6.3.5
On Study Visits.................................................................................................14
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6.3.6
End of Study and Follow-up .............................................................................14
6.3.7
Removal of subjects.........................................................................................14
6.4
Statistical Method ....................................................................................................14
6.4.1
Statistical Design..............................................................................................14
6.4.2
Sample Size Considerations ............................................................................15
6.5
Planned Analyses....................................................................................................15
6.5.1
Primary Analyses .............................................................................................15
6.5.2
Secondary Objectives Analyses.......................................................................15
6.5.3
Safety/Pregnancy-related policy.......................................................................15
6.5.4
Analysis of Subject Characteristics ..................................................................15
6.5.5
Interim Analysis (if applicable)..........................................................................15
6.5.6
Health economic evaluation .............................................................................15
6.5.7
Other ................................................................................................................15
6.5.8
Subsets and Covariates ...................................................................................15
6.5.9
Handling of Missing Data .................................................................................15
7
Trial Administration.........................................................................................................16
7.1
Ethical Considerations: Informed Consent/Assent and HIPAA Authorization .........16
7.2
Institutional Review Board (IRB) Review.................................................................16
7.3
Subject Confidentiality.............................................................................................16
7.4
Deviations/Unanticipated Problems.........................................................................17
7.5
Data Collection ........................................................................................................17
7.6
Data Quality Assurance...........................................................................................17
7.7
Study Records.........................................................................................................17
7.8
Access to Source.....................................................................................................17
7.9
Data or Specimen Storage/Security ........................................................................17
7.10
Retention of Records...............................................................................................17
7.11
Study Monitoring......................................................................................................18
7.12
Data Safety Monitoring Plan....................................................................................18
7.13
Study Modification ...................................................................................................18
7.14
Study Discontinuation..............................................................................................18
7.15
Study Completion ....................................................................................................18
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7.16
Conflict of Interest Policy.........................................................................................18
7.17
Funding Source .......................................................................................................18
7.18
Publication Plan.......................................................................................................19
8
Appendices.....................................................................................................................20
9
List of Tables ..................................................................................................................21
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1 Introduction
1.1
Introductory Statement
This document is a protocol for a human research study. The purpose of this protocol is to 
ensure that this study is to be conducted according to ICH GCP guidelines, and according to 
CFR 21 Part 312, other applicable government regulations and Institutional research policies 
and procedures.
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2 Background
2.1.1
Preclinical Experience
Pharmacotherapy: Varenicline, an FDA-approved smoking cessation medication, functions 
as a partial agonist for the α4β2 nicotinic receptor and is the most effective monotherapy for 
smoking cessation.1-3 There is also persuasive evidence from a large clinical trial that 
varenicline is safe in a psychiatric population and does not increase the rate of suicidality or 
depression.1 The American Thoracic Society (ATS) Clinical Practice Guidelines, the most 
recent comprehensive tobacco treatment guideline released in July 2020, suggests that 
varenicline should be prescribed as first line pharmacotherapy even in smokers who are not 
ready to quit.21 Currently there is minimal literature that addresses pharmacotherapy as a 
treatment option for vaping. This study will add to the literature on treatment options for 
adults who use e-cigarettes alone (mono-vapers). The participants will be given a dose 
titrated to 2mg daily which co aligns with the current FDA approved dose for smoking 
cessation. 
2.1.2
Clinical Experience
We are using the same dose of the oral medication for vapers as we would for cigarette 
smokers. The participants will be given a dose titrated to 2mg daily which co aligns with the 
current FDA approved dose for smoking cessation.
Black-box warnings were removed by the FDA in recent years following the large clinical 
EAGLES trial showing that this is a low risk medication.1 Additionally, meta-analyses have 
been conducted that show varenicline as a safe and useful medication. 17-20 Some side 
effects of varenicline include nausea, constipation, indigestion, abdominal pain, heartburn, 
increased or decreased appetite, trouble falling asleep or staying asleep, unusual dreams or 
nightmares, headache, lack of energy, back, joint, or muscle pain, and abnormal menstrual 
cycles.
2.2
Background/prevalence of research topic
The U.S. tobacco product landscape has changed dramatically within the last decade 
with the advent of new nicotine products, particularly electronic cigarettes (e-
cigarettes).1 While e-cigarettes were initially considered hopeful as a smoking 
alternative, they have shown to be less innocuous than previously believed. E-
cigarettes are highly addictive, 1, 3, 44 used commonly by youth,4,5 and are toxic to the 
lungs and circulatory system.6, 7, 47 In addition, most e-cigarette users commonly 
continue to smoke cigarettes, thus raising concerns about their ability to reduce 
tobacco-related harm. 8-10, 11, 45
Recent studies have shown that 20.7% of current combustible cigarette smokers that 
try e-cigarettes become dual users.49 An increasing number of individuals are 
interested in quitting e-cigarette use and open to treatment for this purpose.44-48 
Nevertheless, there is minimal literature on treatment options for e-cigarette 
addiction. There is a gap in research that does not address proper cessation 
methods for individuals who are mono e-cigarette users.
Varenicline is a highly efficacious FDA-approved smoking cessation 
pharmacotherapy. The aim of this study is to examine the effectiveness of varenicline 
for e-cigarette cessation medication for mono- e-cigarette use in combination with a 
minimal, self-guided behavior change booklet. This booklet will include general tips 
for e-cigarettes cessation and information about the free web-based e-cigarette 
cessation program sponsored by The Truth Initiative and Mayo called “This is 
Quitting”. This study will have an 8-week treatment period and a 4-week follow-up 
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phase. Participants will be randomized to receive an 8-week supply of varenicline or 
matching placebo (gel capsule filled with cellulose powder) in combination with the 
self-change booklet. We hypothesize that participants who receive varenicline will 
have higher rates of e-cigarette cessation.
Electronic cigarettes, also referred to as e-cigarettes, vaping devices, or vape pens, are 
battery-operated devices that heat and aerosolize a liquid solution that may contain nicotine 
and other additives such as flavors. Introduced to the U.S. in 2007, these devices were 
proposed as a potential harm reduction option for people who smoke combustible cigarettes. 
Indeed, there is some evidence that supports e-cigarettes for smoking cessation and 
tobacco-related harm reduction.9 Nevertheless, many smokers who try e-cigarettes to quit 
smoking are unsuccessful and become dual users of both products and among those who 
are successful quitting smoking, a number become dependent long-term e-cigarette users.10 
The highly addictive nature of e-cigarettes, the potential toxicity to the body, and the minimal 
research on the long-term health effects of e-cigarettes present much risk to individuals who 
use e-cigarettes for smoking cessation. 6, 7, 47 In the Tobacco Treatment Service at Smilow 
Cancer Hospital (for Yale) and in the Tobacco Treatment Program (at MUSC), we are now 
treating patients who quit smoking combustible cigarettes using e-cigarettes for their e-
cigarette dependence. These patients used e-cigarettes to quit smoking but reported that 
they became more dependent on e-cigarettes than combustible cigarettes and expressed a 
desire to stop for health reasons. Data from recent reports provide support for our clinical 
experience and that most adults who use e-cigarettes exclusively (60%) plan to quit use of 
these products.23
In the past decade, there has been a substantial increase in e-cigarette use in all adult age 
groups.17 A recent study52 shows that over 10% of the adult population in the US has tried e-
cigarettes.  At the same time, young people and never smokers also started using e-
cigarettes, cohorts for whom these products were not intended.11-12 Between 2011 and 2014, 
e-cigarette use increased by 900% among U.S. middle and high school students and e-
cigarettes have been the most commonly used tobacco product among U.S. youth since 
2014.12-13 Several factors contributed to e-cigarette initiation among young people and never 
smokers including the availability of flavor products that are appealing to youth (e.g., candy 
flavors) and new technology that made it easier to use and conceal use from others.11 
Although these new products have been created to market to youth, adults have also 
succumb to this enticing marketing. This new technology also improved the nicotine delivery 
of these products, increasing their addiction potential. Earlier e-cigarette models did not 
deliver high nicotine levels to users.14 However, newer devices such as nicotine salt-based 
e-cigarettes (e.g., JUUL) more closely mimic combustible cigarettes by quickly delivering 
high levels of nicotine.14-15 In fact, a single JUUL pod contains as much nicotine as a pack of 
cigarettes. 
Due to this rapidly evolving e-cigarette landscape, a new generation comprising never, 
former, and current smokers is now highly dependent on e-cigarettes and needs help. 
Tobacco product regulation and tobacco control policy cannot keep pace with this 
technology and are insufficient to address this new public health challenge. There has been 
minimal research on treatment for e-cigarette dependence; the limited focus has been on 
adolescents and young adults. 
To address this significant gap, we propose to conduct a preliminary test of a highly effective 
FDA-approved smoking cessation pharmacotherapy (varenicline tartrate) for the treatment of 
e-cigarette dependence among adult mono- e-cigarette users coupled with a brief behavioral 
intervention, adapted for e-cigarette dependence, and informed by evidence-based 
behavioral techniques for smoking cessation. A case report of varenicline for e-cigarette 
cessation provide evidence for its potential efficacy.53 Moreover, a clinical trial of varenicline 
for e-cigarette cessation is underway in adult dual users and adolescents.54-55 As more 
adults initiate vaping either for mono use or to quit smoking, e-cigarette dependence is 
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increasing. Yet, there is minimal scientific research on treatments for e-cigarette 
dependence. Our study aims to advance the science in this area.
3 Rationale/Significance
3.1
Problem Statement
As more adults initiate vaping either for mono use or to quit smoking, e-cigarette 
dependence is increasing. Yet, there is minimal scientific research on treatments for e-
cigarette dependence. Our study aims to advance the science in this area.
3.2
Purpose of Study/Potential Impact
The purpose of this study is to understand if varenicline tartrate can help people stop or 
reduce vaping. Varenicline has been proven to reduce the desire to smoke cigarettes. With 
this study, we aim to test whether it shows a similar benefit for individuals who vape and are 
interested in quitting.
3.2.1
Potential Risks
The main study procedures include completion of questionnaires (minimal risk), varenicline 
use (use will be tracked as well as any new or recurring symptoms), and Truth Initiative 
texting services. This is a low-risk medication study (see text below). There is also a risk that 
the treatment the study participant is randomized to may prove to be less effective than the 
other study treatment or other available treatments (i.e., participants who receive placebo). 
We will conduct scheduled assessment throughout the intervention to review participant 
symptoms, mood, and wellbeing.
Breach of confidentiality: Study investigators across both sites have experience as an 
investigator dealing with such sensitive information and has experience assuring that data is 
adequately protected. Safeguards to protect confidentiality include locked records and 
firewalls around password-protected electronic data, and all study data being coded, with the 
key linking the code with a subject’s identity being kept in a separate, locked file.
Assessments and Rating Scales: All assessments and rating scales are non-invasive and 
involve minimal risk to study participants.
Varenicline is an FDA approved smoking cessation medication. Black-box warnings were 
removed by the FDA in recent years following the large clinical EAGLES trial showing that 
this is a low risk medication.1 Additionally, meta-analyses have been conducted that show 
varenicline as a safe and useful medication. 17-20 Some side effects of varenicline include 
nausea, constipation, indigestion, abdominal pain, heartburn, increased or decreased 
appetite, trouble falling asleep or staying asleep, unusual dreams or nightmares, headache, 
lack of energy, back, joint, or muscle pain, and abnormal menstrual cycles.
Other contraindications for varenicline include suicidal ideation.21 Suicidality will be assessed 
at prior to randomization and during the follow-up assessments. If an individual endorses 
suicidality during the pre-randomization screening, they will be marked as ineligible for the 
study. This will be assessed using the PHQ9 toolkit for suicide ideation (refer to 
assessments section). An alert is programmed into the REDCap system that if an individual 
indicates an active plan to either physically harm or kill themselves, an alert will be sent to 
the study team. They will then be contacted by our clinical team to complete a risk 
assessment over via phone. A member of the clinical team will query the participant for 
details regarding the suicidal ideation, including a likelihood of harming oneself imminently 
and a plan for committing suicide. If the participant reports an imminent likelihood of harming 
him/herself or a plan for committing suicide, the clinical team member will call emergency 
services and will remain on the phone with the participant until emergency services arrive. In 
the event that the participant expresses an imminent likelihood of harming him/herself, and 
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the connection is lost, emergency services will be contacted to provide emergency services 
with the participant’s contact information, including address. If the participant is not in 
imminent danger, the clinical staff will provide referrals for local mental health resources 
and/or instruction to go to the ED or call 911 should suicidal ideation worsen. The clinical 
team member will suggest that the participant seek treatment and then will follow-up with the 
participant via phone one week later. 
In the event that a participant endorses suicidal ideation but is not responsive to clinical 
staff’s phone call within 48 hours, the participant will be emailed a list of local mental health 
resources and will suggest that the participant seek additional treatment. The email will also 
ask that the participant respond to the clinical staff either via phone or e-mail within 24 hours 
to confirm receipt of the treatment referrals. Should the participant not respond to the clinical 
staff’s email within an additional 48 hours (4 days from completion of the 
assessment) and endorse “Several days”, “More than half the days” or “nearly everyday” 
to “Thoughts that you would be better off dead or of hurting yourself in some way” on the 
PHQ9 suicidality toolkit at study screening, emergency services will be contacted and will be 
provided with the participant’s name and address. 
We will utilize the PHQ9 assessment to track depression and suicidal ideation during the 
baseline assessments. If suicidal ideation is endorsed, an automated “red flag” will be 
processed through our REDCap database. This red flag will indicate either a a) clinically 
significant increase in total PHQ scoring with an overall score of at least 15 (>5 point 
increase from baseline and resulting score >15), OR b) any value >0 for item 9/suicidal 
ideation). The red flag indicators will be monitored daily by our clinical team and will be met 
with the appropriate measures. These measures are based on prior MUSC-IRB approved 
protocols of varenicline (i.e., the STARS Pro00098479). 
3.2.2
Potential Benefits
The treatment the participant receives may prove to be more effective than other available 
treatments. In addition, participant participation will aid researchers in evaluating new 
methods of how varenicline, a medication approved for combustible smoking, affects e-
cigarette use behavior. Participants will also be compensated for their time.
4 Study Objectives
4.1
Hypothesis
We hypothesize that participants who receive varenicline will have higher rates of e-cigarette 
cessation
4.2
Primary Objective
The primary objective of this study is to determine whether varenicline increases cessation in 
e-cigarette users. 
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5 Study Design
5.1
General Design Description
For this preliminary, proof-of-concept study, we require smartphone ownership or email 
access to allow for receipt of weekly surveys (via text or email) during the sampling period, 
as well as weekly assessments (methods described below). According to the latest Pew 
survey, 77% of Americans own a smartphone; >73% among those under age 65. 
Requirement for smartphone ownership will not affect internal validity, but it could reduce 
external validity.2 
This is a randomized, placebo-controlled, double blind pilot study. This study aims to enroll 
20 adults who report daily mono- e-cigarette use at MUSC and 20 adults who report daily 
mono- e-cigarette use at Yale (N=40 total). This is a 12-week study with 8 weeks of study 
drug use (either varenicline or placebo) provided to the enrolled participants. 
Inclusion/exclusion criteria will be determined via initial online screening and then confirmed 
with tele-video/phone call final screening. Non-pregnancy verification will be ascertained via 
remote pregnancy test. If any of these exclusions are endorsed, then the potential 
participant will not be enrolled into the study. Once screening and informed consent are 
complete, eligible participants will be randomized to 1 of the following 2 groups: 
1) VRN + Self-Change Pamphlet
2) Placebo + Self-Change Pamphlet  
All participants will be asked to provide assessments (as described below) throughout the 
sampling process to assess vaping & smoking behavior (if the participant initiates smoking 
after enrolling in the trial), craving, varenicline/placebo use, use of web-based program, etc. 
Randomization: 20 participants per site (MUSC and Yale) will be stratified status of former or 
never smoker. Former smoker is defined as an individual who has smoked at least 100 
cigarettes in their lifetime but have not smoked in the past 6 months or longer.
Study Details
Guided Self-Change Booklet: This 3-page pamphlet includes information on how to 
reduce and quit e-cigarettes on their own (on Page 1), how to prevent relapse to 
combustible cigarettes (for mono vapers who quit combustible cigarettes by vaping; 
on Page 2), and how to enroll in the online This is Quitting services (described 
above; on Page 3).
All groups will receive this pamphlet as a brief behavioral component of the 
intervention. This 2-page pamphlet will include information on how to reduce and quit 
e-cigarettes on their own on one page, how to prevent relapse to combustible 
cigarettes (for mono vapers who quit combustible cigarettes by vaping) on the 
second page, and the third page will contain information about how to enroll in the 
Truth Initiative/Mayo “This is Quitting" online self-guided e-cigarette treatment 
program (described below). 
Truth Initiative/Mayo “This is Quitting” Program: All participants will be given 
information about how to enroll in treatment with the This is Quitting Program, which 
is a free online program that was created by the Truth Initiative in conjunction with 
Mayo Clinic as a tobacco cessation treatment tool. This program offers online and 
texting services that assist individuals with their quit attempts for general tobacco 
use, but they also have specific content/support for vaping. Upon enrolling in the 
program, the participant is prompted to select a quit date and give their contact 
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information (i.e., email and phone number). The participant is then granted access to 
the platform that gives them links with cessation tips such as how to deal with 
cravings, building a support system, dealing with relapse, using medication to help 
with cessation, etc. The This is Quitting Program also incorporates a text message 
option. This text message will send the participant 3-4 tobacco cessation related 
messages per day. If the participant texts “ECIG,” a new text thread will be created 
that will send vaping related messages directly to the participant. 
Pharmacotherapy: Twenty participants will be randomized to receive active 
varenicline. Prior to randomization, the study physician, Dr. Baldassarri or nurse 
practitioners from the Tobacco Treatment Service/PI Dr. Lisa Fucito will conduct a 
pre-randomization medical review to ensure that they qualify for varenicline based on 
study eligibility criteria collected during primary (e.g., smoking history, age, medical 
history, and comorbidities) and secondary screening (psychiatric history, suicidal 
history, pregnancy status). A summary report that we create within our REDCap 
screening database, will be delivered electronically to  study physician/nurse 
practitioners/PI Dr. Lisa Fucito. They will review each participant’s information and 
will determine whether to 1) accept the individual into the study, 2) reject the 
individual into the study (i.e., not eligible for varenicline), or 3) ascertain more 
information from the individual before either the decision to accept/reject the 
participant. The study physician/nurse practitioners may contact the individual to 
engage in further clinical interviewing of the potential participant. The disposition of 
each participant will be tracked within this screening database, allowing us to 
complete all CONSORT steps to study flow. The individual will not proceed to 
randomization and intake until we have signed, explicit documentation from the study 
physician/nurse practitioners/ PI Dr. Lisa Fucito to do so. Thus, these procedures 
ensure that we retain physician/APRN oversight and approval of varenicline 
disbursement at the study outset. Dr.Baldassarri/APRNs from the Tobacco 
Treatment Service retains their role in evaluation of adverse events as noted 
elsewhere within this application.  
Other contraindications for varenicline include suicidal ideation.21 Suicidality will be 
assessed at prior to randomization and during the follow-up assessments. If an 
individual endorses suicidality during the pre-randomization screening, they will be 
marked as ineligible for the study. This will be assessed using the PHQ9 toolkit for 
suicide ideation (refer to assessments section). An alert is programmed into the 
REDCap system that if an individual indicates an active plan to either physically harm 
or kill themselves, an alert will be sent to the study team. They will then be contacted 
by our clinical team to complete a risk assessment over via phone. A member of the 
clinical team will query the participant for details regarding the suicidal ideation, 
including a likelihood of harming oneself imminently and a plan for committing 
suicide. If the participant reports an imminent likelihood of harming him/herself or a 
plan for committing suicide, the clinical team member will call emergency services 
and will remain on the phone with the participant until emergency services arrive. In 
the event that the participant expresses an imminent likelihood of harming 
him/herself, and the connection is lost, emergency services will be contacted to 
provide emergency services with the participant’s contact information, including 
address. If the participant is not in imminent danger, the clinical staff will provide 
referrals for local mental health resources and/or instruction to go to the ED or call 
911 should suicidal ideation worsen. The clinical team member will suggest that the 
participant seek treatment and then will follow-up with the participant via phone one 
week later. 
In the event that a participant endorses suicidal ideation but is not responsive to 
clinical staff’s phone call within 48 hours, the participant will be emailed a list of local 
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mental health resources and will suggest that the participant seek additional 
treatment. The email will also ask that the participant respond to the clinical staff 
either via phone or e-mail within 24 hours to confirm receipt of the treatment referrals. 
Should the participant not respond to the clinical staff’s email within an additional 48 
hours (4 days from completion of the assessment)  
We will utilize the PHQ9 assessment to track depression and suicidal ideation during 
the baseline assessments. If suicidal ideation is endorsed, an automated “red flag” 
will be processed through our REDCap database. This red flag will indicate either a 
a) clinically significant increase in total PHQ scoring with an overall score of at least 
15 (>5 point increase from baseline and resulting score >15), OR b) any value >0 for 
item 9/suicidal ideation). The red flag indicators will be monitored daily by our clinical 
team and will be met with the appropriate measures. These measures are based on 
prior MUSC-IRB approved protocols of varenicline (i.e., the STARS Pro00098479). 
We will work with the Investigational Drug Service (IDS) pharmacy (MUSC) and Yale-
New Haven Pharmacy (Yale) to package and label varenicline. Both packaging and 
labelling will be done within the YNNH pharmacy, following all applicable laws. Under 
no circumstances will non-credentialed study staff package or label the medication. 
The IDS pharmacy (MUSC) and Yale-New Haven Pharmacy (Yale) will package and 
label the varenicline under our prescriber’s order.
Upon receipt of medication, the participant will receive a call from our team. This will 
be a brief orientation call during which they will have an overview of the medication. 
All participants will be encouraged to start their medication as soon as they receive it 
and to set a quit date 1-2 weeks from medication initiation. The varenicline 
prescription will follow the standard induction period: varenicline 0.5 mg once per day 
for Days 1-3, varenicline 0.5 mg twice per day for Days 4-7, then varenicline 1 mg 
twice per day (when varenicline reaches peak efficacy for tobacco cessation). 
Participants will remain on varenicline for 8 weeks total. Dose adjustments (e.g., 
reduction to 0.5 mg twice per day if 1 mg is not well tolerated) will be allowed at the 
discretion of the clinical pharmacist/APRN/physician. An 8-week supply of varenicline 
will be shipped. 
A novel alert system will be built into the Adverse Event surveys REDCap database 
such that any severe adverse events (e.g., severe nausea, severe sleep 
disturbances, severe changes in mood) that are endorsed along with self-report of 
cessation of pharmacotherapy use will be monitored by research staff, who will 
consult with the study physician/APRN from the Tobacco Treatment Service/PI Dr. 
Lisa Fucito when indicated for clinical assessment and management. We believe this 
alert system will improve varenicline medication adherence if the 
pharmacist/APRN/physician can quickly follow-up on any side effects that may be 
associated with pharmacotherapy use and call the patient with any recommended 
dose adjustments. All dose adjustments will be recorded in our REDCap database.
Guided Self-Change Pamphlet: All groups will receive this pamphlet as a brief 
behavioral component of the intervention. This 3-page pamphlet includes information 
on how to reduce and quit e-cigarettes on their own (on Page1), how to prevent 
relapse to combustible cigarettes (for mono vapers who quit combustible cigarettes by 
vaping; on Page 2), and how to enroll in the online This is Quitting services 
(described above; on Page 3).
5.1.1
Study Date Range and Duration
The duration of this study is 12 weeks.
5.1.2
Number of Study Sites
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This is a dual site study that will be carried out at Yale and Medical University of South 
Carolina. The study will use remote/telehealth procedures, as much as possible, as detailed 
below
5.2
Outcome Variables
5.2.1
Primary Outcome Variables
The primary outcome will be abstinence from vaping at week 8. Abstinence is defined as no 
vaping, not even a puff, every day for the last 7 days via self-report (i.e., 7 day point 
prevalent abstinence). 
5.2.2
Secondary Outcome Variables (if applicable)
5.2.3
The secondary outcome will be abstinence from vaping at week 12. Abstinence is 
defined as no vaping, not even a puff, every day for the last 7 days via self-report 
(i.e., 7 day point prevalent abstinence).
5.2.4
Exploratory Outcome Variables (if applicable)
N/a
5.3
Study Population
Participants: This study will use various media outlets to recruit adults who report current e-
cigarette use in South Carolina (for MUSC) and in Connecticut (for Yale). Advertising will 
target e-cigarette users who have a desire to quit and are willing to undergo treatment, set a 
quit date, and attempt to maintain e-cigarette abstinence. Mono-vapers will click the link in 
our Craigslist and social media ads which will open a screening survey through REDCap on 
their mobile devices. If the individual meets pre-screening eligibility, the research staff will 
call the participant to schedule an intake to confirm final eligibility for the study.
5.3.1
Number of Participants
We plan to enroll 40 participants across two sites. As with previous studies, we will 
make every effort to maximize participant retention via a thorough informed consent 
process, careful screening, and other practices.
5.3.2
Eligibility Criteria/Vulnerable Populations
Prospective participants will be screened on initial eligibility criteria.
Following completion of the screener, research staff will inform potential patients of their 
initial eligibility status. Those who meet initial criteria will be invited to attend an intake (via 
HIPPA compliant telehealth platform since this study is fully remote) to provide written 
informed consent and complete final screening for inclusion/exclusion criteria. Eligible 
individuals will be randomized to their condition to begin immediately after intake.
Inclusion criteria: 
1.
age 18+; 
2.
daily use of an e-cigarette containing nicotine (defined as use for at least 25 days out 
of the past month); 
3.
use of an e-cigarette containing nicotine> 6 months; 
4.
have desire to quit e-cigarettes, are willing to set a quit date and maintain e-cigarette 
abstinence; 
5.
have daily access to a smartphone or have regular (daily) access/use of email; and 
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6.
and live in South Carolina or Connecticut.
7.
No use of combustible tobacco in the past 30 days (including cigarettes, cigarillos, 
etc). 
a.
In the 2 months prior to the past 30 days, patients must not use combustible 
tobacco for >1 time per week.
8.
No use of non-combustible nicotine products (ie pouches, smokeless tobacco, etc.) 
in the past 30 days. 
a.
In the 2 months prior to the past 30 days, patients must not use non-
combustible nicotine products (ie pouches, smokeless tobacco, etc.) for >1 
time per week.
Exclusion criteria: 
1.
Vulnerable Populations: We will not be enrolling vulnerable populations, specifically 
pregnant women, children, prisoners, or institutionalized individuals. 
2.
 We also will not enroll participants incapable of providing their own consent. The 
rationale will be provided to the individual as well as his or her family members. 
Referrals for further evaluation, including urgent or emergent evaluation, will be made 
as needed and clinically warranted. 
3.
 We will exclude individuals with medical contraindications for varenicline use (i.e., 
severe renal impairment) 
4.
We will exclude anyone currently using smoking cessation medications. 
5.
 Individuals will also be excluded if another household member is currently enrolled in 
the study. 
6.
 Individuals will be excluded if not proficient in English. 
7.
Verification of Non-Pregnancy: Females ages <55 will be mailed a commercially 
available pregnancy test to verify non-pregnancy. Written confirmation of negative 
pregnancy test via REDCap will be required prior to enrollment in the trial. 
Participants are also informed that they should let us know if they become pregnant 
during the trial. Medications will not be sent until this verification is in place. These 
procedures are based on the MUSC IRB approved STARS protocol (MUSC IRB 
Pro00098479). 
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6 Methods
6.1
Treatment 
6.1.1
Identity of Investigational Product
Varenicline tartrate (sometimes called Chantix, Apo-Varenicline, or Par-Varenicline), is a 
prescription medication for smoking cessation. The oral supply we will use is approved by 
the US Food and Drug Administration (FDA), Par-varenicline. Many studies show that 
varenicline can help people who smoke quit smoking. Varenicline is a prescription 
medication, which usually means that you must see your doctor to get it. Varenicline is used 
to treat tobacco use dependence. It helps reduce cravings for tobacco use and decreases 
the pleasurable effects of cigarettes and other tobacco products.
6.1.2
We will be receiving the medication from the YNNH Investigational Drug 
Service. They will be the ones storing the medication. They will also do the 
encapsulation of the active drug and placebo. Written instructions will be 
attached to the medication from the pharmacy and the research staff will 
distribute the medication to the participant. 
6.1.3
Dosage, Administration, Schedule 
Dose and schedule: We are using the same dose of the oral medication for vapers as we 
would for cigarette smokers. The participants will be given a dose titrated to 2mg daily which 
co aligns with the current FDA approved dose for smoking cessation. The varenicline 
prescription will follow the standard induction period: varenicline 0.5 mg once per day for 
Days 1-3, varenicline 0.5 mg twice per day for Days 4-7, then varenicline 1 mg twice per day 
(when varenicline reaches peak efficacy for tobacco cessation). Participants will remain on 
varenicline for 8 weeks total. Dose adjustments (e.g., reduction to 0.5 mg twice per day if 1 
mg is not well tolerated) will be allowed at the discretion of the clinical 
pharmacist/APRN/physician. The entire 8-week supply of varenicline will be shipped at week 
1 according to the Pharmacy’s workflow..  
Medication Schedule: Both groups will follow the same medication schedule (listed below). 

Days 1-3: 0.5mg (or matching placebo) study pill once per day

Days 4-7: 0.5mg (or matching placebo) study pill twice per day

Weeks 2-8: 1mg or matching placebo) study pill twice per day
Adverse Events: Other contraindications for varenicline include suicidal ideation.21 Suicidality 
will be assessed at prior to randomization and during the follow-up assessments. If an 
individual endorses suicidality during the pre-randomization screening, they will be marked 
as ineligible for the study. This will be assessed using the PHQ9 toolkit for suicide ideation 
(refer to assessments section). An alert is programmed into the REDCap system that if an 
individual indicates an active plan to either physically harm or kill themselves, an alert will be 
sent to the study team. They will then be contacted by our clinical team to complete a risk 
assessment over via phone. A member of the clinical team will query the participant for 
details regarding the suicidal ideation, including a likelihood of harming oneself imminently 
and a plan for committing suicide. If the participant reports an imminent likelihood of harming 
him/herself or a plan for committing suicide, the clinical team member will call emergency 
services and will remain on the phone with the participant until emergency services arrive. In 
the event that the participant expresses an imminent likelihood of harming him/herself, and 
the connection is lost, emergency services will be contacted to provide emergency services 
with the participant’s contact information, including address. If the participant is not in 
imminent danger, the clinical staff will provide referrals for local mental health resources 
and/or instruction to go to the ED or call 911 should suicidal ideation worsen. The clinical 
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team member will suggest that the participant seek treatment and then will follow-up with the 
participant via phone one week later. 
In the event that a participant endorses suicidal ideation but is not responsive to clinical 
staff’s phone call within 48 hours, the participant will be emailed a list of local mental health 
resources and will suggest that the participant seek additional treatment. The email will also 
ask that the participant respond to the clinical staff either via phone or e-mail within 24 hours 
to confirm receipt of the treatment referrals. Should the participant not respond to the clinical 
staff’s email within an additional 48 hours (4 days from completion of the 
assessment) and endorse “several days” “More than half the days” or “nearly everyday” 
to “Thoughts that you would be better off dead or of hurting yourself in some way” on the 
PHQ9 suicidality toolkit at study screening, emergency services will be contacted and will be 
provided with the participant’s name and address. 
We will utilize the PHQ9 assessment to track depression and suicidal ideation during the 
baseline assessments. If suicidal ideation is endorsed, an automated “red flag” will be 
processed through our REDCap database. This red flag will indicate either a a) clinically 
significant increase in total PHQ scoring with an overall score of at least 15 (>5 point 
increase from baseline and resulting score >15), OR b) any value >0 for item 9/suicidal 
ideation). The red flag indicators will be monitored daily by our clinical team and will be met 
with the appropriate measures. These measures are based on prior MUSC-IRB approved 
protocols of varenicline (i.e., the STARS Pro00098479). 
Compliance: The weekly assessments will have questions built in ascertaining information 
about their medication adherence. We will prompt them through text if the assessments 
show that they are not compliant.
This study is under review for and Investigational New Drug Application exemption.
6.1.4
Method of Assignment/Randomization 
Randomization: 20 participants per site (MUSC and Yale) will be stratified by stratified by 
status of former or never smoker. Former smoker is defined as an individual who has 
smoked at least 100 cigarettes in their lifetime but have not smoked in the past 6 months or 
longer.
6.1.5
Blinding and Procedures for Unblinding 
Neither the participant nor research staff will know what medication condition to which the 
participant has been assigned. Only the study pharmacists who prepares and mails the 
participant’s medication will know their medication condition assignment. The study 
physician/APRNs will request a medication order for either Group A or B. They will not know 
the condition the participant is assigned since the designation of study group is only known 
by study statistician and pharmacist.
6.1.6
Packaging/Labelling
We will work with the Investigational Drug Service (IDS) pharmacy (MUSC) and Yale-New 
Haven Pharmacy (Yale) to package and label varenicline. Both packaging and labelling will 
be done within the IDS pharmacy, following all applicable laws. Under no circumstances will 
non-credentialed study staff package or label the medication. The IDS pharmacy (MUSC) 
and Yale-New Haven Pharmacy (YALE) will package and label the varenicline under our 
prescriber’s order. Once a participant is enrolled into the study, the medication, in original 
packaging, will be mailed or directly delivered distributed to the participant by research staff.
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This study is under review for an Investigational New Drug Application exemption.
6.1.7
Storage Conditions
We will use the YNHH Investigational Drug Service to prepare the study medication and store it...
6.1.8
Concomitant therapy
N/a
6.1.9
Restrictions
No restrictions
6.2
Assessments
6.2.1
Efficacy
Study Assessments
The following tools will be used for the assessments conducted at baseline (week 0) and 
end of follow-up (Week 0, 8 & 12). 
Demographics (Week 0): This questionnaire will collect basic demographic information for 
each subject including gender, ethnicity/race, employment status, etc. 
Smoking/Tobacco Use History (Week 0):  This will collect basic info about smoking and 
smoking cessation history, prior varenicline use, e-cigarette history, tobacco and nicotine 
product flavor preference, etc.
Modified Questionnaire on Smoking Urges (QSU) (Week 0, 8 & 12): This 3-item assessment 
is used to examine smoking related urges such as desire to smoke, anticipation of 
immediate positive outcome, etc.31E-cigarette Dependence (Week 0 & 8): The NIH Patient-
Reported Outcomes Measurement Information System (PROMIS) measure for daily 
smokers has also been adapted to measure for use of other tobacco products.30, 40 This is a 
4-item e-cigarette dependence questionnaire that measures withdrawal and craving.
E-cigarette Dependence Index (Week 0 & 8): This is a 10-item e-cigarette dependence 
questionnaire that measures difficulty quitting, withdrawal and cravings. 57 
Subjective Effects Cigarettes and E-cigarettes (Week 0, Week 4): Participants will report on 
subjective evaluation about cigarettes and e-cigarettes. Subjective evaluation includes items 
derived from the Modified E-Cigarette Evaluation Questionnaire (meCEQ)58 that have also 
been adapted for alternate tobacco products. It measures the degree to which participants 
experience reinforcing effects from smoking and e-cigarettes. The scale yields five clusters 
or domains: Smoking Satisfaction, Psychological Reward, Aversion, Enjoyment of 
Respiratory Tract Sensations, and Craving Reduction.56 
Patient Health Questionnaire-9 (PHQ9) (Week 0 and Bi-Weekly): which assesses for 
depression and includes an item on suicidal ideation.50 
Wisconsin Withdrawal Scale Brief (WSWS2-B): This 6-item scale assesses current 
symptoms of nicotine withdrawal including cravings and irritability.59 
Weekly Electronic Assessments: Participants will be asked to complete a brief compensated 
assessment to assess e-cigarette use, use of other tobacco products including cigarettes, 
and daily medication adherence. These Assessments be completed weekly throughout the 
entirety of the study. Assessments will assess vaping sessions/puffs per day, use of other 
tobacco products, medications/products used, purposes of that use (to reduce/quit), next-
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day e-cigarette use/other tobacco use/quit intentions, and mood/affect. The assessment will 
also assess e-cigarette brand, concentration, and habits surrounding e-cigarette use (i.e., 
location, type of device, and flavor choice). Weekly abstinence will be assessed in three 
different ways: “Have you quit today?”, “Have you used an e-cigarette in the past three 
days?”, and “Have you used an e-cigarette in the past 7 days?” To track medication 
adherence, the assessment will also ask how many varenicline pills that participant took per 
day. This will not replace traditional adverse event assessment (below) but complement (and 
enrich) them. We have established procedures to auto-send an email or SMS text (their 
choice) on a set schedule. SMS text messaging is possible via Twilio, embedded within our 
REDCap system, which allows participants to complete a survey directly from their phone, 
without having to access a webpage. Note that assessments are not completed via texting, 
just prompted via text with link to REDCap. Participants can choose to receive their 
assessment invitations via email if they wish, again with a link to a secure REDCap survey. 
Thus, per eligibility criteria above, we require participants to have smartphone or other 
device that has internet capacity. Assessments consist of a brief (<2 minutes) survey, 
directly enter an online protected database (REDCap) through secure encryption; all PHI is 
protected. Participants will be compensated for compliance based on % assessments 
completed (described below). 
Exit Survey: This survey, designed for the study, will be conducted for all participants. 
Questions to ascertain participants’ reactions to the different intervention conditions (i.e., 
varenicline, booklet) (e.g.,, overall satisfaction, perceived helpfulness, etc.), whether they 
utilized any of the external resources in the booklet (i.e., This is Quitting program)  and their 
reactions, as well as any other use of other medications (e.g., NRT), and  behavioral 
strategies that they used to reduce their e-cigarette use during  the study (e.g., titrate e-
cigarette nicotine dose, change flavors or switch to unflavored).
6.2.2
Safety and Pregnancy-related policy
Verification of Non-Pregnancy: Females ages <55 will be mailed a commercially available 
pregnancy test to verify non-pregnancy. Written confirmation of negative pregnancy test via 
REDCap will be required prior to enrollment in the trial. Participants are also informed that 
they should let us know if they become pregnant during the trial. Medications will not be sent 
until this verification is in place. These procedures are based on the MUSC IRB approved 
STARS protocol (MUSC IRB Pro00098479). 
6.2.3
Adverse Events Definition and Reporting
Adverse Events:
Participants will have the phone numbers of the Co-PIs, Dr. Lisa Fucito (201-341-8865) and 
Dr. Benjamin Toll (203-376-6113) and will be prompted to contact them if an adverse event 
occurs, along with the previously mentioned adverse event procedures. If a participant 
contacts the research team due to an adverse event, the event will be appropriately 
addressed, and the event will be reported per the criteria below. Adverse events will also be 
tracked via weekly assessments, where they will be able to rate the incident as mild, 
moderate, or severe. The research staff, with the guidance of Dr. Gray (for MUSC) and Dr. 
Baldassarri (for Yale), will track the relatedness of the incident to study medication. The 
variables that we will encourage the pharmacist/APRN to assess include severe renal 
impairment, history of serious hypersensitivity or skin reactions to varenicline, an immediate 
(within 2 weeks) post myocardial infarction period, serious arrhythmias, unstable angina 
pectoris, or hemodynamically or electrical instability. We will determine if any adverse events 
result in dropouts or are serious according to FDA guidelines.
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Serious adverse events, whether unanticipated or anticipated, will be reported immediately 
(within 24 hours) to the MUSC or Yale Institutional Review Board. The PIs will evaluate the 
adverse event and determine whether the adverse event affects the Risk/Benefit ratio of the 
study and whether modifications to the protocol or the consent procedures are required.
Plans for reviewing and reporting non-serious anticipated or unanticipated adverse events: 
Any participants' experiences of anticipated and unanticipated adverse events will be 
reported on an annual basis to the MUSC Institutional Review Board.
Plan for grading adverse events. Serious Adverse Events (SAE). The FDA’s definition of 
serious adverse events (21 CFR 312) will be used. Serious Adverse Events include any 
untoward medical occurrence that at any dose results in death or the immediate risk of 
death, hospitalization, or the prolonging of an existing hospitalization, persistent or 
significant disability/incapacity or a congenital anomaly/birth defect, new cancer, or 
medication overdose. Adverse events will be defined and graded for risk as follows:
Coding of Severity:
0 = No adverse event or within normal limits
1 = Mild adverse event
2 = Moderate adverse event
3 = Severe, resulting in psychiatric or medical hospitalization
4 = Life-threatening adverse event
5 = Fatal adverse event
Coding of Attribution will be made for adverse events grade 3 and above (i.e., serious 
adverse events):
1 = Unrelated to study interventions
2 = Unlikely relationship to study interventions
3 = Possible relationship to study interventions
4 = Probable relationship to study interventions
5 = Definite relationship to study intervention
6.2.4
Pharmacokinetics (if applicable)
N/A
6.2.5
Biomarkers (if applicable)
N/a
6.3
Study Procedures
This is study aims to enroll 20 adults who report daily mono- e-cigarette use at MUSC and 
20 adults who report daily mono- e-cigarette use at Yale (N=40 total). This is a 12-week 
study with 8 weeks of study drug use (either varenicline or placebo) provided to the enrolled 
participants. Inclusion/exclusion criteria will be determined via initial online screening and 
then confirmed with tele-video/phone call final screening. Non-pregnancy verification will be 
ascertained via remote pregnancy test. If any of these exclusions are endorsed, then the 
potential participant will not be enrolled into the study. Once screening and informed consent 
are complete, eligible participants will be randomized to 1 of the following 2 groups: 
1) VRN + Self-Change Pamphlet
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2) Placebo + Self-Change Pamphlet  
All participants will be asked to provide assessments (as described below) throughout the 
sampling process to assess vaping & smoking behavior (if the participant initiates smoking 
after enrolling in the trial), craving, varenicline/placebo use, use of web-based program, etc. 
Randomization: 20 participants per site (MUSC and Yale) will be stratified by status of 
former or never smoker. Former smoker is defined as an individual who has smoked at least 
100 cigarettes in their lifetime but have not smoked in the past 6 months or longer.
Study Details
Guided Self-Change Booklet: This 3-page pamphlet includes information on how to 
reduce and quit e-cigarettes on their own (on Page 1), how to prevent relapse to 
combustible cigarettes (for mono vapers who quit combustible cigarettes by vaping; 
on Page 2), and how to enroll in the online This is Quitting services (described 
above; on Page 3).
All groups will receive this pamphlet as a brief behavioral component of the 
intervention. This 2-page pamphlet will include information on how to reduce and quit 
e-cigarettes on their own on one page, how to prevent relapse to combustible 
cigarettes (for mono vapers who quit combustible cigarettes by vaping) on the 
second page, and the third page will contain information about how to enroll in the 
Truth Initiative/Mayo “This is Quitting" online self-guided e-cigarette treatment 
program (described below). 
Truth Initiative/Mayo “This is Quitting” Program: All participants will be given 
information about how to enroll in treatment with the This is Quitting Program, which 
is a free online program that was created by the Truth Initiative in conjunction with 
Mayo Clinic as a tobacco cessation treatment tool. This program offers online and 
texting services that assist individuals with their quit attempts for general tobacco 
use, but they also have specific content/support for vaping. Upon enrolling in the 
program, the participant is prompted to select a quit date and give their contact 
information (i.e., email and phone number). The participant is then granted access to 
the platform that gives them links with cessation tips such as how to deal with 
cravings, building a support system, dealing with relapse, using medication to help 
with cessation, etc. The This is Quitting Program also incorporates a text message 
option. This text message will send the participant 3-4 tobacco cessation related 
messages per day. If the participant texts “ECIG,” a new text thread will be created 
that will send vaping related messages directly to the participant. 
Pharmacotherapy: Twenty participants will be randomized to receive active 
varenicline. Prior to randomization, the study physician/nurse practitioner/PI Dr. Lisa 
Fucito conduct a pre-randomization medical review to ensure that they qualify for 
varenicline based on study eligibility criteria collected during primary (e.g., smoking 
history, age, medical history, and comorbidities) and secondary screening 
(psychiatric history, suicidal history, pregnancy status). A summary report that we 
create within our REDCap screening database, will be delivered electronically to the 
study physician/nurse practitioners/ PI Dr. Lisa Fucito. They will review each 
participant’s information and will determine whether to 1) accept the individual into 
the study, 2) reject the individual into the study (i.e., not eligible for varenicline), or 3) 
ascertain more information from the individual before either the decision to 
accept/reject the participant.  The study physician/nurse practitioners/PI Dr. Lisa 
Fucito may contact the individual to engage in further clinical interviewing of the 
potential participant. The disposition of each participant will be tracked within this 
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screening database, allowing us to complete all CONSORT steps to study flow. The 
individual will not proceed to randomization and intake until we have signed, explicit 
documentation from the study physician/nurse practitioners/PI Dr. Lisa Fucito to do 
so. Thus, these procedures ensure that we retain physician/APRN oversight and 
approval of varenicline disbursement at the study outset. Dr. Baldassarri/APRNs from 
the Tobacco Treatment Service retains their role in evaluation of adverse events as 
noted elsewhere within this application.  
Upon receipt of medication, the participant will receive a call from our team. This will 
be a brief orientation call during which they will have an overview of the medication. 
All participants will be encouraged to start their medication as soon as they receive it 
and to set a quit date 1-2 weeks from medication initiation. The varenicline 
prescription will follow the standard induction period: varenicline 0.5 mg once per day 
for Days 1-3, varenicline 0.5 mg twice per day for Days 4-7, then varenicline 1 mg 
twice per day (when varenicline reaches peak efficacy for tobacco cessation). 
Participants will remain on varenicline for 8 weeks total. Dose adjustments (e.g., 
reduction to 0.5 mg twice per day if 1 mg is not well tolerated) will be allowed at the 
discretion of the clinical pharmacist/APRN/physician. The entire 8-week supply of 
varenicline will be shipped at week 1. .  
Guided Self-Change Pamphlet: All groups will receive this pamphlet as a brief 
behavioral component of the intervention. This 3-page pamphlet includes information 
on how to reduce and quit e-cigarettes on their own (on Page1), how to prevent 
relapse to combustible cigarettes (for mono vapers who quit combustible cigarettes by 
vaping; on Page 2), and how to enroll in the online This is Quitting services 
(described above; on Page 3).
Participant compensation: Participants in this study will have the opportunity to earn 
up to $185 for completing their assessments. After completing the randomization and 
intake during enrollment, they will be paid $20. Starting on week 1, they will be asked 
to complete a brief, weekly assessment. Payments for the weekly assessments will 
increase gradually throughout the treatment phase. You will be paid $5 for the 
completing weekly assessments during weeks 1-4, $10 per assessment for weeks 5-
8, $15 for weeks 9-10, and $25 for weekly assessment at week 12. End of treatment 
assessments will be completed at week 12 for a payment of $35. 
Study Week
0
1
2
3
4
5
6
7
8
9
10
11
12
Baseline 
Assessments
$20
Weekly 
Assessments
$5
$5
$5
$5
$10
$10
$10
$10
$15
$15
$15
$25
End of 
Follow-up 
Assessments
$35
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Week Total
$20
$5
$5
$5
$5
$10
$10
$10
$10
$15
$15
$15
$60
Maximum Total Compensation: $185
6.3.1
Study Schedule
1.
Intake Procedures (Week 0): Before joining the study, the patient will have first 
completed a screening visit using a telehealth platform (i.e., Doxy.me, Zoom, or other 
HIPAA compliant tele-video conferencing software) to obtain their consent using an 
electronic REDCap consent form) to confirm their eligibility. This research study will 
use exclusively remote/telehealth procedures as detailed below.
Once the informed consent has been signed, the research staff will ask a few additional 
questions to determine final eligibility. If they are a female of the age 55 or below, we 
will send them a pregnancy test in the mail. They will take the at home pregnancy test 
and complete a secure online survey to verify their test results. After final eligibility has 
been confirmed, they will be asked to complete some questions about their e-cigarette 
use.
Randomization (Week 0): They will be randomly assigned, like a flip of a coin, to either 
the (a) active varenicline medication group, or (b) the placebo group. Neither they nor 
research staff will know what medication condition to which they have been assigned; 
only the study pharmacists who prepare and mail their medication will know their 
medication condition assignment.
Treatment Phase (Week 0-Week 8): They will be sent an 8-week supply of the 
medication or placebo, along with a guided self-change booklet with information 
regarding quitting vaping. The study medication will be mailed to them free of charge. 
Neither they nor your doctor will decide which group they are in. Upon receipt of 
medication, they will receive a call from our tobacco treatment specialist. This will be 
a brief orientation call during which the specialist will go over medication use 
instructions with them. All participants will be encouraged to start their medication as 
soon as they receive it and to set a quit date 1-2 weeks after receiving the medication.
End of Follow up Phase (Week 12): End of treatment assessments will be completed 
at week 12.
6.3.2
Informed Consent
Participants will have 2 options to consent into this study: 1) remote consent via a virtual 
procedure (i.e., Doxy.me or other HIPAA compliant tele-video conferencing software), or 2) 
remote electronic consent (e-consent) via REDCap combined with a phone call. Informed 
consent will be maintained in each, allowing (requiring) discussion with study staff to ensure 
full understanding.
Remote consent via HIPAA compliant tele-video conferencing: This essentially is video, or 
telephone facilitated live discussion with study staff and potential study participants. After the 
initial determination of study eligibility, assessed online in our secure survey, participants will 
be asked about their capacity for virtual procedures (i.e., Doxy.meor other HIPAA compliant 
tele-video conferencing software), including access to a computer with a webcam and 
speakers, and compatible internet browser (Doxy.me is currently optimized for Google 
Chrome & Firefox, with planned expansion to additional browsers). For those who have the 
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required hardware and software for HIPAA compliant tele-video conferencing, we will offer 
this option and follow IRB-approved procedures as per precedent. All tele-conferencing 
signed consent forms will be saved as pdf files within our study records; the participant also 
receives an electronic copy. Research staff will then have the participant complete the 
baseline questionnaires. 
Remote e-consent via REDCap: This is similar to the above virtual procedures but without 
the video connection, replaced by live phone call. Participants will link to a REDCap-
delivered consent document and will have a concurrent phone discussion with study staff 
who will provide further details on the study and answer any questions. Like virtual 
procedures above, these will likely be scheduled with potential participants in advance, i.e., 
through a consent appointment. The individual would electronically sign the consent form, 
and this then becomes a part of the research record and like above the participant is given 
an electronic version of the consent to retain.
For all the above procedures, and throughout the study, the participants will have the 
research coordinators contact information for any additional support or necessary questions. 
Anyone who completes a consent form will comprise the consented sample. However, the 
sample is reduced further to those with whom we can establish phone contact (Day 0; 
weekly follow-up surveys will begin the following day); i.e., the enrolled sample. This enrolled 
sample is the intent-to-treat sample.
Although the mode of consent may differ across participants (i.e., Doxy.me vs. REDCap 
consent) we have taken steps to ensure that all participants will be fully informed of study 
procedures, including risks/benefits of participation, prior to providing signed consent. We 
ensure that all potential participants discuss the study with an IRB-approved consenter prior 
to providing signed consent. All participants, regardless of consenting modality, will be 
reminded with a study overview at the beginning of the Day 0 phone call and interest in 
continuing study participation will be confirmed at that point. We believe these methods will 
maximize opportunities for study participation.
6.3.3
Screening
This study will recruit using advertisements on various media platforms including, but not 
limited to, Craigslist ads, social media recruitment (e.g., Facebook and Instagram), print, 
radio, the Hollings and Smilow tobacco treatment services, etc. Since recruitment will also 
occur through referrals from TTS, medical records will be reviewed for the purposes of 
screening/recruitment, therefore a waiver of HIPAA authorization will be utilized in this study. 
Potential participants will complete a pre-screening survey that is linked in the ad. If the 
individual is deemed eligible, the research staff will conduct a screening appointment via the 
web/mobile phone with the participant to confirm eligibility. If the research staff deems the 
individual eligible, our study physician/nurse practitioner from the Tobacco Treatment 
Service/ PI Dr. Lisa Fucito will review their medical charts and approve their use of 
varenicline (described in more detail below). After confirming eligibility, the research staff will 
conduct a full consent and intake via the tele-consent platform (i.e., Doxy.me or other HIPAA 
compliant tele-video conferencing software)) or a link to a REDCap consent form. 
6.3.4
Enrollment 
Potential subjects will be identified through Tobacco Treatment Service at Yale New Haven 
Hospital as well as other clinics in Yale-New Haven Hospital. In addition, potential subjects 
will be identified by responses to community-based advertisements.
Individuals who contact investigators by phone or email or who respond to
mobile ads will be directed to complete a 5-minute, web-based pre-screening survey.
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Following completion of the pre-screener, research staff will contact potential subjects and 
inform them of their initial eligibility status. Those who meet initial criteria will attend an intake 
to provide written informed consent and complete final screening for inclusion/exclusion.
6.3.5
On Study Visits
Assessments
Week 0
Week 4
Week 8
Week 12
Weekly
Demographics
X
Smoking/Tobacco Use History
X
Modified Questionnaire on Smoking Urges (QSU)
X
X
X
E-Cigarette Dependence
X
X
E-Cigarette Dependence Index
X
X
Subjective Effects Cigarettes and E-cigarettes
X
X
X
Patient Health Questionnaire-9 (PHQ9)
X
X*
Wisconsin Withdrawal Scale Brief (WSWS2-B
Weekly Electronic Assessments
X
Exit Survey
X
*bi-weekly

Baseline (Week 0):
o
Assessment
o
Randomization

Week 1:
o
Participant sent 1 week supply of 0.5mg and 3-week supply of 
1mgOrientation call about medication
o
Weekly assessments

Week 2
o
Weekly assessments

Week 3:
o
Weekly assessments

Week 4:
o
Participant sent second shipment of a 4-week supply of the 1 mg dose.
o
Weekly assessments 

Week 5:
o
Weekly assessments

Week 6
o
Weekly assessments

Week 7
o
Weekly assessments

Week 8
o
Weekly assessments
o
End of treatment phase

Week 9:
o
Weekly assessments

Week 10 
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o
Weekly assessments

Week 11
o
Weekly assessments

Week 12
o
Weekly assessments
o
Exit survey
6.3.6
End of Study and Follow-up
There will be an end of treatment assessment given at 12 weeks. This survey, designed for 
the study, will be conducted for all participants. Questions to ascertain participants’ reactions 
to the different intervention conditions (i.e., varenicline, booklet) (e.g.,, overall satisfaction, 
perceived helpfulness, etc.), whether they utilized any of the external resources in the 
booklet (i.e., This is Quitting program)  and their reactions, as well as any other use of other 
medications (e.g., NRT), and  behavioral strategies that they used to reduce their e-cigarette 
use during  the study (e.g., titrate e-cigarette nicotine dose, change flavors or switch to 
unflavored).
6.3.7
Removal of subjects
The Investigators have the right to withdraw a participant at any time. If participants do not 
follow study instructions, then they may be withdrawn from the study.
This is a voluntary study, in which participants have the right to withdraw at any time. If the 
participant decides to withdraw at any point, they can inform the research staff. No further 
data will be collected, and correspondents will stop. Any data collected up to that point will 
remain in study.
6.4
Statistical Method
6.4.1
Statistical Design
Baseline demographic and clinical characteristics will be tabulated for the overall study 
cohort as well as stratified by randomized treatment assignment.  Baseline characteristics 
will be assessed for association with the primary study abstinence outcomes using 
univariable logistic regression models and resulting effect sizes will be reported. The primary 
purpose to this pilot trial is to ascertain study efficacy and determine effect sizes of 
varenicline on vaping abstinence.  End of treatment and study follow up 7-day point 
prevalence abstinence rates will be tabulated and compared between varenicline, and 
placebo treated participants using a modified Poisson regression approach.  Proportion 
abstinent as well as risk ratios and associated 95% confidence intervals will be provided for 
the entire study time course as well as stratified by study time point (end of treatment, study 
follow-up).  Initial models will be adjusted for baseline vaping behavior as well as strata 
utilized in the randomization procedure. Sensitivity analysis will be employed to compare 
results from available study data to those with missing study data imputed to vaping (single 
imputation to worst case outcome).  Study results will be utilized to design and sufficiently 
power a follow up RCT. 
Secondary analysis of average reported vaping puffs per day and vaping days per week will 
be examined using generalized linear mixed effects models (GLMMs).  Vaping puffs will be 
summarized weekly and differences between randomized treatment groups will be assessed 
during the treatment and follow up time periods.  Model based means and standard errors 
will be used to determine pairwise comparisons and meaningful time points (weeks 8 and 
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12).  The number vaping days per week will be assessed using GLMMs with a negative 
binomial specified distribution for count data.  Median (inner quartile range) vaping days as 
well as risk ratios and associated 95% confidence intervals will be provided.  Longitudinal 
models will include study treatment, week, and the associated interaction when appropriate.
6.4.2
Safety 
Adverse events will be collected for all study emergent events throughout the treatment 
phase of the study.  The proportion of participants reporting study emergent adverse events 
will be compared between groups using a Chi-Square test (Fisher’s exact test when 
appropriate).
6.4.3
Analysis of Subject Characteristics
We will use descriptive statistics were used to summarize frequencies and
percentages of sociodemographic characteristics (age, race, ethnicity, gender, college
status) and clinical characteristics (medication use, e-cigarette use, etc.).
6.4.4
Interim Analysis (if applicable)
N/a
6.4.5
Health economic evaluation
N/a
6.4.6
Other
n/a 
6.4.7
Subsets and Covariates
n/a
6.4.8
Handling of Missing Data
N/a
7  Trial Administration
7.1
 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization
The information we are asking to use and share is called “Protected Health Information.” It is 
protected by a federal law called the Privacy Rule of the Health Insurance Portability and 
Accountability Act (HIPAA). In general, we cannot use or share patient’s health information 
for research without their permission. 
The specific information about them and their health that we will collect, use, and share 
includes:
• Research study records
• Medical and laboratory records of only those services provided in connection with this 
Study.  
• Records about phone calls made as part of this research
• Records about their study visits
• Information obtained during this research regarding

Diaries and questionnaires

The diagnosis and treatment of a mental health condition

Use of illegal drugs or the study of illegal behavior

Records about any study drug you received
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All of their responses will be held in confidence. Only the researchers involved in this study 
and those responsible for research oversight (such as representatives of the Yale University 
Human Research Protection Program, the Yale University Institutional Review Boards, and 
others) will have access to any information that could identify them that is provided. We will 
share it with others if they agree to it or when we have to do it because U.S. or State law 
requires it. For example, we will tell somebody if we learn that they are hurting a child or an 
older person.
For the purposes of recruitment, a wavier of HIPPAA will be utilized in this study. 
We will use a Bank of America pre-paid debit card to provide the payment for taking part in 
the study. We will have to share the participant’s name, address, and telephone number with 
Bank of America for ePayments. the participant will receive a card in the mail with the first 
payment. They will then need to activate the card over the phone. Each additional payment 
will be automatically added to the same card.  
7.2
Institutional Review Board (IRB) Review
The protocol will be submitted to the IRB for review and approval. Approval of the protocol 
must be obtained before initiating any research activity. Any change to the protocol or study 
team will require an approved IRB amendment before implementation.  The IRB will 
determine whether informed consent and HIPAA authorization are required
The IRB will conduct continuing review at intervals appropriate to the degree of risk, but not 
less than once per year.
A study closure report will be submitted to the IRB after all research activities have been 
completed.  
 Other study events (e.g. data breaches, protocol deviations) will be submitted per Yale’s 
IRB's policies.
7.3
Subject Confidentiality
Participant confidentiality and privacy is strictly held in trust by the participating investigators,
their staff, and the sponsor(s) and their interventions. Therefore, the study protocol,
documentation, data, and all other information generated will be held in strict confidence. No
information concerning the study or the data will be released to any unauthorized third party
without prior written approval of the sponsor.
All research activities will be conducted in as private a setting as possible.
The study monitor, representatives of the Institutional Review Board (IRB), or regulatory
agencies may inspect all documents and records required to be maintained by the
investigator, including but not limited to, medical records (office, clinic, or hospital) for the
participants in this study. The clinical study site will permit access to such records.
At the end of the study, all records will continue to be kept in a secure location for 7 years.
Study participant research data, which is for purposes of statistical analysis and scientific
reporting, will be transmitted to and stored on Yale redcap servers and in locked cabinets in
locked office at CMHC. This will not include the participant's contact or identifying
information. Rather, individual participants and their research data will be identified by a
unique study identification number. The study data entry and study management systems
used will be secured and password protected. At the end of the study, all study databases
will be de-identified and archived on Yale servers and CMHC.
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Identifiable information including participant’s name, address, phone number, and date of
birth, will be collected and used to enroll and contact participants. It will only be used for
this purpose. This information will be stored in locked cabinet apart from the research
records.
Research data will be collected using interviews, self-reports, wearable devices, and
computer tasks. All identifiable information will be stored in a locked research cabinet. All
participants will be assigned a study participant number. Subsequently, participants will be
identified in the Case Report Forms (CRFs) only by that number and an encoded version of
their initials (i.e., John Doe = JDO). A list of numbers and the corresponding names will be
maintained by Dr. Fucito and stored in a locked research cabinet.
The data will be stored on secured server, laptop computer and desktop computer. The
data will be stored in a locked room for 7 years after the final data is collected. After this
point, the Data Manager and Principal Investigator, Dr. Fucito, will oversee the process in
which data is destroyed or de-identified.
Several steps will be taken to safeguard the confidentiality of subjects and their data. All
research data that is collected will be assigned a study participant number and that number
will only identify participants in digital databases. The names of participants will not be
associated with this data and assessments will be maintained according to participant study
number. A master list connecting participant study numbers to participant names will be kept
in a locked file cabinet where it can only be accessed by senior level project staff. Any
information published as a result of the study will be such that it will not permit identification
of any participant.
Right to privacy for participation in this research will be protected through alphanumeric
coding of data (in place of names) and proper storage of research records, including
treatment exit interviews. Collected materials will be maintained via an alphanumeric
reference system maintained by Dr. Fucito. Participants’ names will appear only on the
compound authorization form, and a master list maintained in a physically locked file that is
separate from research data. Our data collection and management procedures are fully
compliant with HIPAA. Access will be limited to personnel intimately involved in the study. A
Certificate of Confidentiality will also be obtained. However, participants will also be told that 
if they present with suicidal or homicidal ideation and/or report any form of child/elder abuse 
or report plans to damage property then we will have to report this to the appropriate 
authorities and/or provide them with referrals for immediate treatment. Electronic data will be 
de-identified, and password protected. Only members of the study team will have access to 
the physical or electronic data.
All investigators and key personnel have taken the required Yale University HIPAA
training. Right to privacy for participation in this research will be protected through coding
of data and proper storage of research records. A list of numbers and the corresponding
names will be maintained by the Principal Investigator in a locked research cabinet.
Individually identifiable health information will be protected in accordance with the Health
Insurance Portability and Accountability Act of 1996 and by additional protections of
substance abuse treatment records afforded under Code of Federal Regulations (CFR)
Part 2, Subpart E. All research personnel will be trained on human subjects’ protection and
HIPAA procedures.
We may share participant information with:
• The U.S. Department of Health and Human Services (DHHS) agencies
• Representatives from Yale University, the Yale Human Research Protection Program
and the Institutional Review Board (the committee that reviews, approves, and monitors
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research on human participants), who are responsible for ensuring research
compliance. These individuals are required to keep all information confidential.
• Those representatives at Yale who are responsible for the financial oversight of
research including billings and payments
• The Principal Investigator
• The study sponsor
• Laboratories and other individuals and organizations that analyze your health
information in connection with this study, according to the study plan
• Co-Investigators and other investigators
• Study Coordinator and Members of the Research TeamOther researchers through a 
shared data agreement through a required policy from
NIAAA
7.4
Deviations/Unanticipated Problems
A protocol deviation is any noncompliance with the study protocol. The noncompliance may
be either on the part of the participant, the investigator, or the study site staff. As a result of
deviations, corrective actions are to be developed by the site and implemented promptly.
It is the responsibility of the site investigator to identify and report deviations within 2 working
days of identification of the protocol deviation. All deviations must be addressed in study
source documents, reported to the study sponsor, and the reviewing Institutional Review
Board (IRB) per their policies.
Unanticipated problems involving risks to participants or others include, in general, any
incident, experience, or outcome that meets all of the following criteria:
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that
are described in the protocol-related documents, such as the Institutional Review Board
(IRB)-approved research protocol and informed consent document; and (b) the
characteristics of the participant population being studied;
Related or possibly related to participation in the research (“possibly related” means there is
a reasonable possibility that the incident, experience, or outcome may have been caused by
the procedures involved in the research); and
Suggests that the research places participants or others at a greater risk of harm (including
physical, psychological, economic, or social harm) than was previously known or recognized.
The investigator will report unanticipated problems (UPs) to the reviewing Institutional
Review Board (IRB) and to the study sponsor. The UP report will include the following
information: Protocol identifying information: protocol title and number, PI's name, and the 
IRB project number; A detailed description of the event, incident, experience, or outcome; 
An explanation of the basis for determining that the event, incident, experience, or outcome
represents an UP; A description of any changes to the protocol or other corrective actions 
that have been taken or are proposed in response to the UP. To satisfy the requirement for 
prompt reporting, UPs will be reported using the following timeline: UPs that are serious 
adverse events (SAEs) will be reported to the IRB and study sponsor, if applicable 
immediately (if possible) followed by a written report within 5 calendar days using the 
appropriate forms from NIH and Yale University IRB. Any other UP will be reported to the 
IRB and study sponsor within 14 calendar days of the investigator becoming aware of the 
problem. All UPs should be reported to appropriate institutional officials (as required by an 
institution's written reporting procedures), the supporting agency head (or designee), and the 
Office for Human Research Protections (OHRP) within 30 calendar days of the IRB's receipt 
of the report of the problem from the investigator.
7.5
Data Collection
The data will be stored in a locked room for 6 years after the final data is collected. The PI 
and the research staff will have access to PHI. Organizations that have a responsibility for 
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protecting human participants, including the MUSC/Yale IRB, may have access to subjects’ 
medical records containing PHI. Additionally, the funding source may have access to 
subjects’ medical records containing PHI.
Trained research staff will administer assessments and collect measurements. They will 
enter data directly into a secure electronic database, which will be backed up on a secure, 
password protected Yale University network drive. De-identified data will be stored in the 
database and only accessible by research staff using a password protected login. All data 
with identifiable information will be stored in locked file cabinets in locked offices and will 
only be accessible by research staff.
7.6
Data Quality Assurance
Multiple measures are in place to ensure the validity and integrity of the data. First, all
research staff receive Human Subjects Protection training, as well as training in Good
Clinical Practice. Second, Dr. Fucito will supervise and train the Research Coordinator and
key personnel on study procedures to ensure that all procedures are followed and are in
compliance with the approved Yale University IRB protocol. Dr. Fucito will also provide
training and oversight to study staff to ensure data are generated, documented, and reported
according to requirements by the Yale University IRB and NIH. She will then monitor
adherence to protocol procedures and use individual supervision to address any data quality
concerns. Third, weekly research meetings will be held for all research staff as a forum for
in-service training as well as to discuss questions regarding issues that arise in complex
clinical research protocols. Fourth, all research staff will be cross-trained to ‘cover’ for each
other; thus, review by multiple staff with oversight by the PI will facilitate early identification of
errors and oversight. Fifth, Dr. Fucito will also oversee quality assurance of data. The
Research Coordinator, in collaboration with Dr. Fucito, will review the study database on a
monthly basis to ensure data accuracy. Any data quality issues will be addressed
immediately. Last, the use of an electronic system for data capture will minimize data entry
errors.
7.7
Study Records
Protocol
Consent form 
weekly assessments
Subject medical records
7.8
Access to Source Documents
Source data will be maintained per Medical Records policy in a password protected, secure,
Health Insurance Portability and Accountability Act (HIPAA) compliant, web-based electronic
database with a built-in audit trail.
Only Institutional Review Board (IRB) approved research team members who have current
HIPAA and Collaborative Institutional Training Initiative (CITI) Good Clinical Practice (GCP)
and human subjects protection training will be authorized to access records.
7.9
Data or Specimen Storage/Security
Several steps will be taken to safeguard the confidentiality of subjects and their data. All 
research data that is collected will be assigned a study participant number and that number 
will only identify participants in digital databases. The names of participants will not be 
associated with this data and assessments will be maintained according to participant study 
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number. A master list connecting participant study numbers to participant names will be kept 
in a locked file cabinet where it can only be accessed by senior level project staff. Any 
information published because of the study will be such that it will not permit identification of 
any participant.
Research records are maintained under the person’s name, but the study number is not 
entered anywhere into a medical record. Right to privacy for participation in this research will 
be protected through coding of data and proper storage of research records. The Principal 
Investigators will maintain a list of IDs and the corresponding names in a locked research 
cabinet. Consistent with mandated reporting requirements for health providers, we advise 
participants that in the case of child abuse or neglect, threat of injury to self or others, or 
intention to destroy property, that we may need to intervene and report that information to 
the proper authorities. Subjects will be informed of this limit to confidentiality as it is stated in 
the informed consent document.
The data will be stored in a locked room for 6 years after the final data is collected. The PI 
and the research staff will have access to PHI. Organizations that have a responsibility for 
protecting human participants, including the MUSC/Yale IRB, may have access to subjects’ 
medical records containing PHI. Additionally, the funding source may have access to 
subjects’ medical records containing PHI.
Trained research staff will administer assessments and collect measurements. They will 
enter data directly into a secure electronic database, which will be backed up on a secure, 
password protected Yale University network drive. De-identified data will be stored in the 
database and only accessible by research staff using a password protected login. All data 
with identifiable information will be stored in locked file cabinets in locked offices and will 
only be accessible by research staff.
7.10 Retention of Records
The data will be stored in a locked room for 6 years after the final data is collected. The PI 
and the research staff will have access to PHI. Organizations that have a responsibility for 
protecting human participants, including the MUSC/Yale IRB, may have access to subjects’ 
medical records containing PHI. Additionally, the funding source may have access to 
subjects’ medical records containing PHI.
.
7.11 Study Monitoring
Dr. Fucito, the PI, will be responsible for monitoring the data, assuring protocol compliance,
and conducting the safety reviews at the specified frequency that must be conducted at a
minimum of every 6 months (including when reapproval of the protocol is sought), which is
appropriate for a study deemed to be of minimal risk. Dr. Fucito will review the frequency of
anticipated and unanticipated adverse events overall and by study arm with key personnel.
The focus of the evaluation will be to determine whether the study should continue
unchanged, require modification/amendment, continue or close to enrollment. Dr. Fucito, the
Yale University IRB, and the National Institutes of Health have the authority to stop or
suspend the study or require modifications.
Dr. Fucito will also lead a weekly research meeting with key personnel to review the status of
all enrolled participants and discuss the eligibility of potential participants. At this weekly
meeting, Dr. Fucito will review study progress (i.e., recruitment goals, retention, protocol
adherence). Any adverse events will be reviewed at this meeting including serious adverse
events that may have been attended to outside of this weekly meeting. An annual progress
report will be submitted to NIH and the Yale University IRB that lists and summarizes
adverse events; documents whether adverse event rates are consistent with pre-study
assumptions; summarizes recruitment and retention and reason for dropouts; and
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summarizes study progress related to the stated aims.
7.12 Data Safety Monitoring Plan
Other contraindications for varenicline include suicidal ideation.21 Suicidality will be assessed 
at prior to randomization and during the follow-up assessments. If an individual endorses 
suicidality during the pre-randomization screening, they will be marked as ineligible for the 
study. This will be assessed using the PH-Q toolkit for suicide ideation (refer to assessments 
section). An alert is programmed into the REDCap system that if an individual indicates an 
active plan to either physically harm or kill themselves, an alert will be sent to the study 
team. They will then be contacted by our clinical team to complete a risk assessment over 
via phone. A member of the clinical team will query the participant for details regarding 
the suicidal ideation, including a likelihood of harming oneself imminently and a plan for 
committing suicide. If the participant reports an imminent likelihood of harming him/herself or 
a plan for committing suicide, the clinical team member will call emergency services and will 
remain on the phone with the participant until emergency services arrive. In the event that 
the participant expresses an imminent likelihood of harming him/herself, and the connection 
is lost, emergency services will be contacted to provide emergency services with the 
participant’s contact information, including address. If the participant is not in imminent 
danger, the clinical staff will provide referrals for local mental health resources and/or 
instruction to go to the ED or call 911 should suicidal ideation worsen. The clinical team 
member will suggest that the participant seek treatment and then will follow-up with the 
participant via phone one week later. 
In the event that a participant endorses suicidal ideation but is not responsive to clinical 
staff’s phone call within 48 hours, the participant will be emailed a list of local mental health 
resources and will suggest that the participant seek additional treatment. The email will also 
ask that the participant respond to the clinical staff either via phone or e-mail within 24 hours 
to confirm receipt of the treatment referrals. Should the participant not respond to the clinical 
staff’s email within an additional 48 hours (4 days from completion of the 
assessment) and endorse “”Several days”, More than half the days” or “nearly everyday” 
to “Thoughts that you would be better off dead or of hurting yourself in some way” on the 
PH-Q suicidality toolkit at study screening, emergency services will be contacted and will be 
provided with the participant’s name and address. 
We will utilize the PHQ9 assessment to track depression and suicidal ideation during the 
baseline assessments. If suicidal ideation is endorsed, an automated “red flag” will be 
processed through our REDCap database. This red flag will indicate either a a) clinically 
significant increase in total PHQ scoring with an overall score of at least 15 (>5 point 
increase from baseline and resulting score >15), OR b) any value >0 for item 9/suicidal 
ideation). The red flag indicators will be monitored daily by our clinical team and will be met 
with the appropriate measures. These measures are based on prior MUSC-IRB approved 
protocols of varenicline (i.e., the STARS Pro00098479). 
7.13 Study Modification
Study modifications will be undertaken in response to ongoing study monitoring. Any
potential modifications that could have a major impact on the study objectives will be
discussed before submission to the IRB. More minor
modifications that do not impact study objectives but help with study recruitment and
implementation or allow for additional assessment of important questions will be submitted to
the IRB for approval.
7.14 Study Discontinuation
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If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, 
as applicable, and be informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:
Determination of unexpected, significant, or unacceptable risk to participants
Demonstration of efficacy that would warrant stopping   
Insufficient compliance to protocol requirements
Data that are not sufficiently complete and/or evaluable
Determination that the primary endpoint has been met
Determination of futility
7.15 Study Completion
Intended to complete in two years. The IRB will be notified in writing upon study completion
and the study will be archived with the IRB when all final analyses have been conducted on
identifiable information.
7.16 Conflict of Interest Policy
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 
be required to have such conflicts managed in a way that is appropriate to their participation 
in the trial. The study leadership in conjunction with the appropriate conflict of interest review 
committee has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest.
 All investigators will follow the applicable conflict of interest policies.
7.17 Funding Source
This research will be funded by Dr. Fucito’s department internal use funds.
7.18 Publication Plan
Study results will be made available via articles written for professional and layperson
publications; presentations at scientific and professional conferences; special lectures/talks
in academic and professional settings; collaborating agencies/research sites, and interest
groups. No identifiable information will be disclosed. Data will be presented and published
in aggregate. Dr. Fucito, as PI, has primary responsibility for publishing the study results.
Once all of the data have been cleaned and validated, and main findings
have been published, the data will be made available to the scientific community. Datasets
will be made available to any qualified individual who makes a direct request to the PI and
indicates the data will be used for the purposes of research (as defined in CFR Title 45
Part 46). Data will be provided to HIPPA-compliant, de-identified files. The following plan
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specifies the following conditions that need to be met before data are shared in the form of
a data sharing agreement.

A formal research question is specified a priori;

Names, affiliations, and roles of any other individuals who will access the shared

data;

The deliverable(s)—e.g., manuscript, conference presentation—are specified a priori;

Proper acknowledgement of the source of the data;

A statement indicating an understanding that the data cannot be further shared with

any additional individual(s) or parties without the PI’s permission;

IRB approval for use of the data (or documentation that the data are exempt);

Agreement to maintain the data in a physically and electronically secure location.

Data will be shared in electronic format and accessible to the software used by the 
Investigators; upon completion of the analyses, the requestor will be instructed to 
destroy all copies of the data.
The agreement to share data will be revisited annually to determine whether the current
policy should be modified based upon our prior experiences in sharing the data with other
investigators.
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8 Appendices
Appendix #
Title
Section
Topic
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9 List of Tables
APPROVED BY THE YALE UNIVERSITY IRB 3/23/2023