Development and Evaluation of a Brief Behavioral Activation Mobile Application for Nicotine Vaping Cessation Among Adolescent Primary Care Patients
Phase: NA
Conditions: Depressive Symptoms, Depression, Adolescent Behavior
Sponsor: Medical University of South Carolina

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PROTOCOL TITLE: Development and Evaluation of a Brief Behavioral Activation Mobile 
Application for Nicotine Vaping Cessation Among Adolescent Primary Care Patients 
 
PRINCIPAL INVESTIGATOR: Jennifer Dahne, Ph.D. 
 
 
 

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1.0 
Objectives / Specific Aims 
The goal of this Stage 1 treatment study is to develop, systematically refine, and clinically evaluate a 
depression-specific Brief Behavioral Activation (BA) for adolescent vaping cessation mobile app 
(“VapeX”). 
 
Aim 1: Develop and refine VapeX. Individual interviews with end-users (n=10) will inform the design 
of VapeX.  
 
Aim 2: Via a two-arm pilot randomized controlled trial (N=106, randomized 1:1), examine the 
feasibility and efficacy of 1) VapeX vs. 2) treatment as usual. Subsequent iterative usability testing 
(n=5, or until saturation) will guide app refinements. Main outcomes, which will be assessed across 4-
weeks of follow-up, include: 1) treatment feasibility, 2) treatment acceptability, 3) change in depression 
over time as a function of treatment, and 4) changes in vaping behavior (e-cigarette use episodes per day, 
days using an e-cigarette per week, number/duration of quit attempts, 7-day point prevalence abstinence at 
Week 4, use of other tobacco products) as a function of treatment.   
 
2.0 
Background 
Nicotine Vaping is an Epidemic among Adolescents. The prevalence of vaping nicotine (i.e., e-cigarette 
use) has skyrocketed among adolescents in recent years1-3, rising from near zero in 2011 to 27.8% in 20194. 
These rapid increases in adolescent vaping led the Surgeon General in 2018 to declare adolescent e-cigarette 
use an epidemic5. High rates of vaping among adolescents are concerning because: 1) vaping carries a 
variety of short-term health risks6-8, with largely unknown long-term risks, 2) nicotine is highly addictive9, 
and 3) adolescents who vape are three times more likely to initiate combustible cigarette use10-14. 
 
Adolescents who Vape are Interested in Quitting, but Interventions are Limited. Nearly half of all 
adolescents who vape are seriously interested in quitting, as our group reported in JAMA Pediatrics15. Yet, 
vaping quit attempts are often unsuccessful: one quarter of current vapers have made a quit attempt in the 
past year that resulted in relapse15. Despite high interest in quitting, extant cessation interventions have 
received little empirical investigation and no NIH-funded trials have examined the efficacy of interventions 
for adolescent vaping cessation. FDA-approved medications for adult nicotine dependence are not approved 
for adolescent use16. Instead, clinical guidelines17 and systematic reviews18,19 conclude that 
behavioral/psychosocial counseling is the first-line treatment approach for adolescent nicotine dependence. 
As such, there is clear need to develop, evaluate, and disseminate evidence-based psychosocial 
interventions for adolescent vaping cessation. 
 
An Appropriate Intervention Must Target Established Vaping Risk Factors. Depressive symptoms, which 
are common among adolescent vapers (36%)20, have recently been identified as a predominant vaping-
related risk factor. Similar to the general population of adolescents who vape, 46.8% of adolescent vapers 
with depressive symptoms report seriously thinking about quitting15. Consistent with the transdiagnostic 
emotional vulnerability framework21, the relationship between depression and vaping is bidirectional such 
that depressive symptoms prospectively predict vaping initiation, and sustained e-cigarette use exacerbates 
depression22. This aligns with decades of research documenting depression as a robust risk factor for 
initiation of combustible tobacco use among adolescents21,23,24, transition to regular smoking25,26, 
difficulties quitting27-29, and relapse30-33.  
 
Among cigarette smokers with depressive symptoms, tailored interventions that target both depression and 
tobacco use are necessary for cessation34,35. Thus, an ideal candidate treatment for adolescent vapers with 
depressive symptoms likely must also target depressed mood. Brief Behavioral Activation (BA) is a well-
established, evidence-based treatment for depression36-39 that has demonstrated promise for smoking 
cessation among adults40 and adolescents41. Brief BA focuses on regular self-monitoring to 1) examine 

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already occurring activities and 2) facilitate the incorporation of new activities consistent with 
individualized values/goals across life areas. Completing enjoyable, important activities improves mood, 
making it easier to initiate and sustain cessation40. An adapted version of Brief BA for adolescent vaping 
cessation could offer a promising approach to simultaneously target depressive symptoms in the service of 
promoting vaping cessation.  
 
Summary of Scientific Premise. Nicotine vaping among adolescents is an epidemic. Adolescents want to 
quit vaping, but available treatment approaches within primary care, where youth are likely to receive 
treatment, are limited both in scope and in evidence base. To maximize efficacy and reach, a product that 
will fill this gap must: 1) directly target established risk factors for adolescent vaping and 2) be accessible 
via platforms already utilized by adolescents. The goal of this Stage 1 treatment study is to develop, 
systematically refine, and preliminarily evaluate a depression-specific Brief BA for adolescent vaping 
cessation mobile app (“VapeX”). This will build upon our team’s prior and ongoing research developing 
mobile app adaptations of Brief BA for depression and smoking cessation treatment within primary care42-
45.  
 
3.0 
Intervention to be studied  
VapeX. Features identified via individual interviews will form the basis of VapeX development. 
VapeX will be developed for iOS and Android, will be HIPAA-compliant, and will retain all key 
elements of Brief BA and standard cessation treatment in Goal2Quit (our team’s Brief BA for 
smoking cessation app), though these features will be modified based on individual interviews. 
Brief BA components include: 1) Psychoeducation highlighting the connection between mood and 
vaping, 2) Identification of values and activities across life areas including relationships, 
responsibilities, recreation, education/career, health, and being vape-free, 3) Activity planning, and 
4) Tracking mood and vaping. Standard cessation components include: 1) Reinforcement and 
support for quitting, 2) Interactive questions to identify past quit attempts and contributors to 
relapse, 3) Setting a quit date, suggested to be no later than two weeks after treatment initiation, 
and 4) Identification of triggers and development of coping strategies. 
 
 
TAU. TAU is designed to mimic existing vaping cessation standard treatment. Participants in both 
conditions will be provided educational material about depression and vaping available via the 
National Cancer Institute’s Smokefree Teen website with a suggestion to discuss questions with 
their PCP. Across conditions, participants will not be precluded from obtaining additional 
treatment, which will be tracked as an outcome. 
 
4.0 
Study Endpoints (if applicable) 
Primary outcome variables include: 
Depression. The PHQ-8 will be used for preliminary screening and the PHQ-9 will be 
administered at final screening. Across all timepoints depressive symptoms will also be assessed via the 
Beck Depression Inventory-II (BDI-II). The BDI-II is a validated assessment of depressive symptoms 
among adolescents and is our primary depression outcome. Self-report and Electronic Health Record 
(EHR) data will be used to categorize concurrent depression treatment (therapy, medications) at baseline 
and across the trial. 
Vaping. Nicotine vaping and quit outcomes will be assessed at each follow-up using a Timeline 
Followback for the last 6-months at baseline and since prior follow-up for each subsequent assessment. 
Frequency of vaping will be assessed in multiple ways including number of vaping episodes per day and 
number of days per week vaping. Use of other tobacco products and frequency of use will also be 
assessed. Cessation outcomes include: 1) number of quit attempts since last assessment, 2) duration of 
each quit attempt, 3) point-prevalence abstinence, and 4) continuous abstinence. E-cigarette dependence 

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will be assessed at baseline via the 10-item Penn State Electronic Cigarette Dependence Index (ECDI). 
Participants will report motivation to quit and confidence in quitting using a modified Contemplation 
Ladder. 
 
Treatment Utilization. VapeX utilization will be tracked via analytics data. Specifically, we will 
examine 1) number of app sessions, 2) average time per session, and 3) total time using the app. 
Additionally, we will assess engagement with each individual component of the app. Analytics will be 
examined within each week and across the entire trial duration. 
 
VapeX Feasibility and Acceptability. VapeX participants will self-report feasibility and 
acceptability at all follow-ups. As in our prior trials, participants will report: 1) ease of app use, 2) 
continued desire to use the app, 3) perceived benefits of using the app, and 4) suggested improvements.  
 
Assessment Grid 
 
Screening 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Screening Questionnaire 
x 
 
 
 
 
 
PHQ-8 
x 
 
 
 
 
 
Demographics 
 
x 
 
 
 
 
PHQ-9 
 
x 
 
 
 
 
BDI-II 
 
x 
x 
x 
x 
x 
Current use of Psych 
Meds 
 
x 
x 
x 
x 
x 
TLFB 
 
x 
x 
x 
x 
x 
Cessation outcomes 
 
x 
x 
x 
x 
x 
ECDI 
 
x 
x 
x 
x 
x 
Contemplation Ladder 
 
x 
x 
x 
x 
x 
Tech Comfort 
 
x 
 
 
 
 
Feasibility/Acceptability 
 
 
x 
x 
x 
x 
VapeX Usability Scale 
 
 
x 
x 
x 
x 
VapeX Utilization  
 
 
x 
x 
x 
x 
 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
Inclusion criteria: 
a) age 16-20 
b) vaped nicotine on ≥20 days out of the last 3046 
c) elevated depressive symptoms, defined as a score of ≥10 on Patient Health Questionnaire-8 (PHQ-
8) during preliminary screening and the Patient Health Questionnaire-9 (PHQ-9)47 at final eligibility 
during baseline  
d) currently own an iOS or Android smartphone 
e) report willingness to utilize an app for quitting vaping nicotine (response of “yes” on yes/no item) 
f) have a valid e-mail address that is checked regularly or regular access to text messages (for follow-
up assessments) 
g) has been seen (in person or remotely) by a primary care physician within the last year 
Exclusion criteria: 
a) smoked cigarettes or used other tobacco products on ≥9 days out of the last 3048-50  
b) severe visual impairment 
c) currently receiving treatment for vaping or tobacco use 
d) current suicidal ideation, defined as a response ≥2 on item 9 of the BDI-II at baseline (See Protection 
of Human Subjects for comprehensive plans to address suicidality and clinical deterioration) 
e) household member currently enrolled in the study 
f) inability to read the consent form 
 
6.0 
Number of Subjects 
We will recruit up to 10 participants for individual interviews and 106 for the RCT, the first 5 of the RCT 
will be for usability testing.  

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7.0 
Setting 
Study participants will be recruited from primary care/family medicine practices affiliated with MUSC’s 
Primary Care Integrated Center of Clinical Excellence (ICCE). Participants may also be recruited 
remotely via advertisements (e.g., online ads).  
 
8.0 
Recruitment Methods 
Recruitment will occur proactively and remotely leveraging data available within the EHR. As part of 
routine clinical care, adolescents are screened at each visit for nicotine/tobacco use, including e-cigarette 
use, and for depressive symptoms via the Patient Health Questionnaire-2 (PHQ-2). To recruit our targeted 
population, we will utilize cold contact methods by submitting a Research Data Request to obtain a EHR 
recruitment report created for all patients treated within the Primary Care ICCE during the past 12 months 
who: 1) are age 16-20, 2) vape, and 3) had depressive symptoms during their last visit. Depressive 
symptoms will be defined as either: 1) a score of ≥3 on their last PHQ-2 (the optimal cut-point to identify 
those symptomatic), 2) depression on their problem list, or 3) a depression-related billing code. The study 
team will not cold-contact any patients who have chosen to opt-out of receiving contact about research or 
who have met the maximum number of contact attempts at the time of recruitment. 
 
Identified patients will be sent an electronic communication (e-mail or message via the EHR patient 
portal, based on patient preferences) from a member of the study team inviting them to participate in a 
study. This electronic communication will include a link to complete study screening via REDCap. 
Within South Carolina, the legal age to consent to medical treatment is 16. At age 16, all MUSC patients 
can receive their own patient portal account and parents/guardians can be appointed as proxies. If 
participants do not respond to this invitation within 72-hours, we will contact them via phone, e-mail, 
and/or text-message (based on preferences within the EHR) to ensure they received the message. If 
interested, participants will complete an eligibility screening via MyChart/REDCap. This eligibility 
screening will assess: age, sex, e-mail access, English fluency, smartphone ownership, nicotine vaping 
status, willingness to use a mobile app for nicotine vaping cessation, and depressive symptoms via the 
PHQ-8. This eligibility screening will be used solely for screening purposes, not for research purposes. 
Within our informed consent documents, if a participant provides informed consent to participate in the 
study, they will agree that their screening information can be used for research purposes. After completing 
determination of eligibility, a member of the research team will complete remote electronic informed 
consent with the participant (see details below).  
 
 
Recruitment may also occur in the following ways: 
1) In Clinic: Participants may be recruited in clinic after being identified as a nicotine vaper by 
research personnel listed on this application. 
2) Via advertisements (e.g., flyers) and online postings such as Craigslist. 
3) Snowball recruitment: Enrolled participants can refer others to the study. If they refer someone 
that enrolls, they will receive additional compensation. 
4) Recruiting parents with children who vape directly using IRB approved advertisements on online 
platforms.  
 
9.0 Consent Process 
Signed informed consent will be obtained from study participants. The consent process will take place via 
one of the following modalities: 1) Remote or in person electronic consent (e-consent) via REDCap (if 
remote, e-consent will be facilitated with a discussion over the phone or via video), 2) Remote consent via 
doxy.me facilitated with either a discussion over the phone or video connection via doxy.me, 3) Mailed 

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(paper) consent facilitated with a discussion over the phone, or 4) in person consent (e.g., in clinic, in the 
investigator’s lab space).  
 
All participants will be provided with a hard copy and/or an electronic copy of the consent form. 
Participants will be informed that participation in this research is strictly voluntary. Informed consent will 
include a detailed description of the purpose and the procedure of the study emphasizing our policy 
regarding privacy and confidentiality and an opportunity for the individual to ask any questions or voice 
concerns. Signatures on the consent form may be obtained with paper and pen OR electronically via 
REDCap/doxy.me. Participants who do not have access to the required technology to complete consent 
remotely via REDCap or doxy.me will be given the option to complete consent via mail facilitated with a 
discussion over the phone.  
 
Parents/guardians of participants under 18 years old will be required to attend the informed consent/assent 
procedure. Participants 18 years and older will be able to provide their own informed consent. Particular 
caution will be exercised in obtaining informed adolescent assent separately and independently from 
parental consent to limit potential for coercion. To this end, an initial step in participant recruitment 
involves obtaining parental/legal guardian permission for participation by the adolescent. Once parental 
consent is secured, youth will be asked separately and independently for informed consent (i.e., parental 
consent will not be used to persuade teens to participate). This approach is considered very effective in 
minimizing coercion to participate. In the case of adolescents in South Carolina Department of Social 
Services custody, state guidelines regarding consent for clinical research participation will be followed. 
 
10.0 Study Design / Methods 
 
Aim 1: Develop and Refine VapeX. 
VapeX Development Testing 
VapeX development will take place in three 
steps: 
1) 
semi-structured 
individual 
interviews with end-users (n=10) and 2) 
software 
development. 
Individual 
interviews 
will 
follow 
standard 
procedures51. Individual interviews (1hr 
each, $40 compensation in electronic gift 
card codes (e.g., Amazon) emailed to 
participants) will be divided into four parts: 
1) discussion of apps for positive health 
behavior change and participants’ experiences with such apps, 2) narrowed focus on mobile apps for 
quitting vaping and managing low mood, 3) even narrower focus on an initial version of the VapeX app, 
which will be previewed for the participant during the interview, and 4) discussion of features that 
participants would like included in VapeX that are not currently included This discussion will begin with 
facilitators presenting participants with a list of features that have been included in other mobile app 
interventions for adolescent substance use treatment (Table 1)52,53. Individual interviews may occur either 
remotely using an MUSC-approved HIPAA compliant video conferencing platform (e.g., Microsoft Teams) 
or in person, depending on the status of the COVID-19 pandemic. 
 
Features identified via individual interviews will form the basis of VapeX development. VapeX will 
be developed for iOS and Android, will be HIPAA-compliant, and will retain all key elements of Brief BA 
and standard cessation treatment in Goal2Quit, though these features will be modified based on individual 
interviews. Brief BA components include: 1) Psychoeducation highlighting the connection between mood 
and vaping, 2) Identification of values and activities across life areas including relationships, 
responsibilities, recreation, education/career, health, and being vape-free, 3) Activity planning, and 4) 
Tracking mood and vaping. Standard cessation components include: 1) Reinforcement and support for 
Table 1: App Features to Consider for VapeX 
Domain 
Specific Potential Features 
Gamification 
Rewards earned for continued app use or 
decreased vaping; Competitions within the app  
Social 
Interaction 
In-app communication with peers; Ability to help 
others quit vaping/provide peer support 
Family 
Involvement 
Resources for discussing depressed mood and/or 
substance use with parents 
Dual Use 
Psychoeducation about dual use and strategies to 
quit smoking while quitting vaping 

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quitting, 2) Interactive questions to identify past quit attempts and contributors to relapse, 3) Setting a quit 
date, suggested to be no later than two weeks after treatment initiation, and 4) Identification of triggers and 
development of coping strategies. As in prior projects, to develop VapeX, we will follow an agile software 
development approach54. Key phases of development will include whiteboard design, wireframing of user 
stories, graphic design, programming, and deployment. Development will be led by MoutainPass 
Technology LLC, with iterative testing completed by the PI and co-Is. 
 
 
 
HIPAA Compliance 
 
Regarding user privacy while using VapeX, users will create a username and password in order to 
login to their account without storing their true identity. In VapeX, we will store a one-way hashed 
version of the patient’s email address to support password reset and unique identification, but that 
identification will not be traceable back to the user’s true identity. We will not store any personally 
identifiable information (e.g., first name, last name, email address, phone number) of users in our app 
database. VapeX will be HIPAA compliant. We will use a HIPAA-compliant server protected by 
industry-standard safeguards to prevent unauthorized access. Since we are not associating patient health 
information with personally identifiable information there will not be a risk of unauthorized release of 
patient medical data in the event of a security breach. User personal information will be contained behind 
secured networks and will only be accessible by the investigators, who will have special access rights to 
such systems. In addition, all sensitive information users supply will be encrypted via Secure Socket 
Layer (SSL) technology. We will not sell, trade, or otherwise transfer personally identifiable information 
to outside parties. Our privacy policy will be available within the app for users to view at any time. This 
plan is consistent with that used by our partnering app development company, MountainPass Technology 
LLC, in several other previous products with similar protection requirements. Mr. Kustanowitz from 
MountainPass Technology has expertise in HIPAA-compliant software development and will oversee all 
aspects of HIPAA compliance within this project.  
 
Aim 2: Pilot Feasibility RCT (N=106) of VapeX vs. TAU. 
Procedures 
 
After completing determination of eligibility and consent, usability testing will commence. 
Recruitment will continue until we reach data saturation (planned n=5)56. The first 5 participants enrolled 
will be assigned to the VapeX group to assess to capture any app refinements necessary at the start of the 
trial. All other procedures while remain the same across participants. The remaining participants (n=98) 
will be randomized via REDCap 1:1 to VapeX or TAU. Participants will be randomized via a mixed 
block design stratified by age, baseline depressive symptoms, and concurrent depression treatment. All 
participants will complete baseline assessments remotely and if randomized to VapeX, study staff will 
remotely provide participants with app download codes and will ensure successful downloads. Study staff 
will then give participants brief overviews regarding app utilization and will provide the participants 10 
minutes to use the app and ask questions. 
 
Assessments 
Participants will be text messaged or emailed a REDCap link to complete follow-up assessments 
weekly for 4 weeks. Assessments are estimated at 20 minutes each. Participants will be compensated in 
electronic gift card codes (e.g., Amazon) emailed to participants in the amount of $20 for completion of 
each assessment with a $50 bonus if all are completed. If a participant does not meet final eligibility at 
baseline, they will be compensated $20 for the visit but will not be enrolled. Enrolled participants may also 
refer others to this study. If they refer someone that is eligible and enrolls they will receive an additional 
$40 (Total possible compensation = $190). If fraud is detected within the surveys, the Principal Investigator 
may decide to withdraw a participant from the study. Fraud may include 1) a research assessment being 
completed in an unusually short period of time, 2) straightlining (i.e., responding with the same answer to 

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all items on a survey), 3) inaccurate responses to a validity check question. If fraud is suspected, the study 
team may request additional verification of identity such as a photo ID prior to trial enrollment.  
Vaping. Nicotine vaping and quit outcomes will be assessed at each follow-up using a Timeline 
Followback for the last 6-months at baseline and since prior follow-up for each subsequent assessment59. 
Frequency of vaping will be assessed in multiple ways including number of vaping episodes per day and 
number of days per week vaping. Use of other tobacco products and frequency of use will also be assessed. 
Cessation outcomes include: 1) number of quit attempts since last assessment, 2) duration of each quit 
attempt, 3) point-prevalence abstinence, and 4) continuous abstinence. E-cigarette dependence will be 
assessed at baseline via the 10-item Penn State Electronic Cigarette Dependence Index (ECDI)60,61. 
Participants will report motivation to quit and confidence in quitting using a modified Contemplation 
Ladder62. Depression. The clinic-administered PHQ-263 will be used for preliminary her screening and the 
PHQ-8 will be completed during initial screening. As the PHQ-8 does not assess suicidality, the full PHQ-
947 will be administered at final screening. Across all timepoints depressive symptoms will also be assessed 
via the Beck Depression Inventory-II (BDI-II)64,65. The BDI-II is a validated assessment of depressive 
symptoms among adolescents65 and is our primary depression outcome. Self-report EHR data will be used 
to categorize concurrent depression treatment (therapy, medications) at baseline and across the trial. 
Treatment Utilization. VapeX utilization will be tracked via analytics data. Specifically, we will examine 
1) number of app sessions, 2) average time per session, and 3) total time using the app. Additionally, we 
will assess engagement with each individual component of the app. Components will be finalized based on 
feedback from individual interviews but are likely to include identification of activities, scheduling of 
activities, mood tracking, monitoring frequency of vaping, and standard vaping cessation treatment content 
(e.g., setting a quit date, education about the benefits of quitting vaping). Participants will be asked to use 
the app at least once per day for at least 5-10 minutes at a time. Analytics will be examined within each 
week and across the entire trial duration. VapeX Feasibility and Acceptability. VapeX participants will self-
report feasibility and acceptability at all follow-ups. As in our prior trials, participants will report: 1) ease 
of app use, 2) continued desire to use the app, 3) perceived benefits of using the app, and 4) suggested 
improvements. 
 
11.0 Data Analysis and Data Management  
 
Data Analytic Plan for Aim 1 Qualitative Data 
 
Qualitative data from interviews, quantitative data from questionnaires, and video and audio recordings will 
be incorporated for mixed methods data analysis66. This approach was chosen because, while quantitative 
data can identify usability errors and areas of dissatisfaction, qualitative data provides guidance on the root 
of errors and methods for optimization. Qualitative data will be analyzed using NVivo software67 and a 
deductive/inductive template analysis approach68,69 using iterative codes to identify core concepts70. From 
these core concepts, we will determine the needs, concerns, and impressions of our prototypes. Two coders 
will independently review and code data using an iterative, team-based process with discrepancies resolved 
by the study team. Qualitative themes will be supplemented by patterns identified in quantitative results. 
After completing qualitative and quantitative data analysis independently, data from each source will be 
synthesized using graphical matrix configurations for data triangulation71. This analytic approach was 
selected due to the expectation that participants will raise unanticipated needs. Mean ratings of VapeX 
components from the After-Scenario Questionnaires (ASQs) will be calculated and components with lowest 
satisfaction will be flagged for refinement. Video and audio recordings be coded for navigation errors 
(difficulty locating a function), content errors (difficulty due to information labeling), and usage errors 
(improper tool use). Problems will be grouped according to severity (critical/serious/minor).  
 
Sample Size Estimation 
 

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As a pilot, our goal is to determine VapeX feasibility/acceptability and estimate effect sizes for a larger 
Phase II project. We can obtain more robust estimates in the VapeX group via 1:1 randomization with the 
first 5 being assigned to the VapeX group for usability testing. Toward these ends, we will randomize 49 
to VapeX and 49 to TAU. To account for 20% attrition, we will enroll a maximum of 108 participants.  
 
Data Analytic Plan for Aim 2 
  
Feasibility and Acceptability. Within the VapeX group, retention will be defined as the proportion of 
participants who use the app at least once within each week following enrollment. Retention point estimates 
and 95% CIs will be calculated, and a one-sided, one-sample proportion test will be used to determine 
whether retention is at least 70% (or higher) within each group. Other metrics of feasibility/acceptability 
(ease of use, continued desire to use, etc.) will be summarized within group via summary statistics and 95% 
CIs, as appropriate. 
 
Vaping Behavior and Vaping Cessation Outcomes. Descriptive statistics will be calculated and compared 
for overall group differences via Fisher’s exact tests, chi-square tests, or nonparametric equivalents, as 
necessary, for baseline variables. Pairwise differences will be explored for categorical variables that show 
a significant overall group difference to see where differences may exist. Significant baseline demographic 
differences between groups will be included as covariates in vaping and depression outcomes analyses. 
Descriptive statistics (e.g., means, frequencies, percentages) will be calculated for the primary vaping-
related outcomes including frequency of vaping and other tobacco product use (number of e-cigarette use 
episodes per day, number of days using an e-cigarette per week, number of days using other tobacco 
products including cigarettes) and vaping cessation outcomes (number and duration of e-cigarette quit 
attempts, 7-day point prevalence abstinence at Week 4) overall and by treatment group. To examine group 
differences adjusted for relevant covariates based on baseline differences between groups, generalized 
linear mixed models with logit links for binary outcomes will be used, including a random component for 
participant and/or clinic. These mixed models will account for any clustering effects within participant and 
clinics. 
 
Depression. Similar generalized linear mixed models will be used to examine group differences (VapeX vs. 
TAU) in depression (BDI-II) over time along with an interaction between group and time adjusting for 
baseline differences and baseline depression. All models will include a random component to account for 
any clustering effects from the clinic from which the participant was recruited along with a random effect 
for repeated measures within an individual. Sex will be examined for inclusion as a covariate in all models. 
These generalized linear models allow for examination of overall main effects of group, time, and the 
interaction between group and time, while also accounting for repeated measures within participants and 
clustering with clinics72,73. 
 
Missing Data. All randomized participants will be included in primary analyses, and imputation methods 
will be used to accommodate missing data if missing data is >10%. Sensitivity analyses will be done using 
only those with complete data, with results compared to primary analyses. Attrition will be assessed to 
determine whether there is differential dropout by group. 
 
Adverse Events (AEs). AEs will be defined as a clinically significant (i.e., 10-point64) increase in depression 
on the BDI-II from baseline or any incidence of suicidality (response of “I would like to kill myself” or “I 
would kill myself if I had the chance” on the BDI-II suicidality item). We will determine the incidence of 
AEs and associated 95% CIs. A chi-square test will determine if the rate of AEs is greater than 5% in any 
group. 
 
Data Management 
 

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Regarding questionnaire data, data will be obtained for research purposes only. The recruitment project is 
stored in REDCap and only study team members will have access to the recruitment project database. The 
research team will only have access to the REDCap recruitment project while actively enrolling for the 
study. The recruitment project will be stored separately from the project containing research data. The 
recruitment REDCap project will potentially contain both identifiers and health information in the same 
project. All data will be collected, stored, and managed via REDCap, which is a secure, web-based 
application designed exclusively to support data capture for research studies. REDCap provides secure, 
web-based flexible applications, including real time validation rules with automated data type and range 
checks at the time of entry. The underlying database is hosted in a secure data center at MUSC, a secure 
environment for data systems and servers on campus, and includes redundancy, failover capability, backups 
and extensive security checks. The system has several layers of protection including user/group account 
management, "Data Access Groups" which allow data to be entered by multiple groups in one database 
with segmented user rights for entered data, audit trails for all changes, queries and reports, and Secure 
Sockets Layer (SSL) encryption. Name and relevant contact information will be obtained to provide 
compensation and every effort will be made to maintain subject confidentiality, in accordance with HIPAA. 
All data will be identified only by code numbers (participant IDs). Participant IDs will be linked to 
participants’ names in a password-protected file that is accessible only to the PI and trained research staff.  
 
12.0 Provisions to Monitor the Data to Ensure the Safety of Subjects (if applicable) 
 
This section is based on the recommendations in NIDA’s “Guidelines for developing a Data and Safety 
Monitoring Plan” as well as NCI’s “Essential Elements of a Data and Safety Monitoring Plan for Clinical 
Trials Funded by the National Cancer Institute”.  
 
Summary of the Protocol 
This R41 application consists of a 2-Aim proposal. In Aim 1, targeted end-users, defined as adolescent 
(ages 16-20) regular nicotine vapers (vaped on ≥20 days out of the last 3046) with elevated depressive 
symptoms (score of ≥10 on the PHQ-947) who have been seen at least once in the last year by a PCP, will 
be recruited for individual interviews (n=10) that will inform the development of VapeX. In Aim 2, we will 
conduct a two-arm pilot feasibility randomized controlled trial (N=106; 1:1 randomization) with the first 5 
participants recruited for usability testing and randomized to receive the VapeX app, to examine the 
feasibility and acceptability of VapeX as well as treatment efficacy for depression and nicotine vaping 
cessation relative to TAU.  
 
Trial Management 
The study will be managed from the Addiction Sciences Division within the Department of Psychiatry and 
Behavioral Sciences at the Medical University of South Carolina (MUSC). Recruitment, data collection, 
data management, and treatment provision will be coordinated and centrally managed at our research lab at 
MUSC and will be implemented within local Family Medicine/Primary Care clinics that are part of MUSC’s 
Primary Care ICCE.  
 
Data Management and Analysis 
Participants will enter data in REDCap, a secure, web-based application designed exclusively to support 
data capture for research studies. REDCap provides: 1) an intuitive interface for data entry (with data 
validation); 2) audit trails for tracking data manipulation and export procedures; 3) automated export 
procedures for seamless data downloads to common statistical packages (SPSS, SAS, Stata, R); 4) 
procedures for importing data from external sources; and 5) advanced features, such as branching logic and 
calculated fields. These procedures are effective in minimizing data entry errors (e.g., missing or errant 

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data). All data from VapeX will be stored on a HIPAA-compliant server. Data analytic plans are outlined 
above. 
 
Quality Assurance 
Accuracy and completeness of the data collected will be ensured by weekly review. The REDCap system 
does not accept outliers, illogical response patterns, etc. The PI and research assistant will have weekly 
meetings to discuss any qualitative comments received during data collection and any problems in data 
collection. The PI will examine the database for potential irregularities monthly. Initial data analyses will 
examine distributions of variable scores and comparability of baseline characteristics across conditions (for 
Aim 2) in case analyses need to be adjusted for these. Confidentiality procedures are outlined above.  
 
Regulatory Issues 
This study will be registered on ClinicalTrials.gov. The study does not require an Investigational Device 
Exemption (IDE) from the FDA. All serious AEs will be reported to the MUSC Committee on Human 
Research within 48-hours. Follow-up of all unexpected and serious AEs will also be reported. All AEs will 
be reviewed weekly by the PI and yearly by the IRB. Any significant actions taken by the local IRB and 
protocol changes will be relayed to the funding agency. We estimate the significant AE rate to be very low 
(<5%). If monthly monitoring indicates the rate is above this, we will convene a meeting of the DSMB. 
Potential conflicts of interest (COI) will be reported using the rules of MUSC’s COI committee. 
 
Trial Safety 
The potential risks and benefits and methods to minimize these risks are outlined in the “Risks to Subjects” 
section. We will determine if any AEs result in dropouts or are serious according to FDA guidelines. The 
PI (Dr. Dahne) will serve as the Program Manager for AEs. All unexpected AEs will be monitored while 
they are active to determine if treatment is needed. We anticipate that AEs will be rare given that the VapeX 
app is non-invasive and that all participants will be engaged with current healthcare. Nonetheless, any AEs 
will be coded on a weekly basis using the FDA’s COSTART rules74 and entered into a database. For each 
weekly study meeting, the research assistant will prepare a summary of all AEs, including their severity, 
whether they caused a dropout, required treatment, and presumed relation to app utilization. The PI will 
review this at the weekly study meeting (or before if more urgent). At the weekly meeting (or before if 
urgent), the research assistant will report any premonitory symptoms to suggest emergence of a serious 
psychiatric condition (e.g., suicidality). Dr. Diaz, a board-certified Family Medicine physician, will be 
available on an ad-hoc basis for on-site medical supervision for any issues that cannot be resolved by Dr. 
Dahne.  
 
Study procedures will follow the FDA’s Good Clinical Practice Guidelines and our research team has found 
Spilker’s comprehensive text on conducting clinical trials to be useful75. We will encourage participants to 
notify their physicians that a) they are in a randomized controlled research study examining a treatment for 
depressed mood and nicotine vaping, and b) the physician should contact the PI directly if the physician 
has any questions. 
  
The research assistants will be instructed not to reveal whether a person is a participant in the study and 
will report to the PI any outside requests for information about a participant or any breaches in 
confidentiality. All requests by participant’s physicians and other medical providers will be referred directly 
to the PI.  
 
Trial Efficacy 
The Data and Safety Monitoring Board (see below) may request a blinded interim efficacy report (blinded 
to the PI and research team) for review while the trial is ongoing. Final (fully unblinded) efficacy analysis 
will occur after all participants have completed all follow-ups. 

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Data and Safety Monitoring Plan Administration 
The PI will be responsible for monitoring the trial, with additional oversight provided by study co-
Investigators. The PI will examine monthly the outcomes database for missing data, unexpected 
distributions or responses, and outliers. The PI will check weekly the AE database prepared by the research 
assistant immediately prior to the lab meeting. A DSM report will be filed with the IRB and funding agency 
on a yearly basis, unless greater than expected problems occur. The report will include participant 
characteristics, retention and disposition of study participants, quality assurance issues and reports of AEs, 
significant/unexpected AEs and serious AEs. We will report efficacy at the end of the trial. 
 
Data and Safety Monitoring Board Plan 
We will create a Data and Safety Monitoring Board (DSMB), comprised of 3 clinicians with expertise in 
adolescent depression and substance use treatment, primary care, and clinical trials, as well as a 
statistician. The DSMB will meet once prior to beginning Aim 2 enrollment, once during Aim 2 
enrollment, and once following study completion to review any AEs related to the study, as well as 
review any data management related errors. The board may be called at any point if needed for 
unexpected, serious AEs, etc. Modification will be made in the procedures and/or the protocol if 
necessary based on the findings of the board. 
 
13.0 Risks to Subjects 
 
The potential risks in this study include those related to: a) depressive symptoms, b) clinical deterioration, 
c) confidentiality, d) potential data breach from the app database, and e) frustration. Risk mitigation 
strategies are outlined below and have previously been implemented with success in Dr. Dahne’s prior 
trials.  
a) Depressive symptoms: Depressive symptoms will be monitored via the BDI-II. All participants will 
complete the BDI-II weekly online via a REDCap survey that is accessible via mobile phone web 
browsers. All participants will own smartphones. Thus, all participants should have access to the online 
BDI-II assessments. 
 
b) Clinical deterioration: Dr. Dahne and her research team will monitor participant BDI-II scores for 
possible clinical deterioration (i.e., increasing depressive symptoms and/or the development of suicidal 
ideation) throughout the course of the study as participants complete the BDI-II weekly. Clinical 
deterioration will be defined as an increase of 10 or more points on the BDI-II from the baseline BDI-
II assessment or a response of “I would like to kill myself” or “I would kill myself if I had the chance” 
on the suicidal thoughts or wishes item of the BDI-II. Our team has developed real-time alerts within 
REDCap which alert the investigative team if a participant completes a BDI-II assessment and 
evidences clinical deterioration. In the event that a participant evidences clinical deterioration, Dr. 
Dahne will contact the participant via phone and will provide referrals for local mental health resources 
for depression treatment. Dr. Dahne will suggest that the participant seek treatment and then will follow-
up with the participant via phone one week later. If the participant is under the age of 18, this discussion 
will occur both with the participant and with the parent/legal guardian. If Dr. Dahne is unavailable, Drs. 
Carpenter, Squeglia, and/or Diaz, all licensed clinicians, will serve as clinical back-ups. 
 
In the event that a participant reports suicidal ideation either during study screening or during 
subsequent assessments, Dr. Dahne (or back-up clinician) will 1) page the participant’s attending 
primary care provider (if the participant is an MUSC patient) and 2) complete a risk assessment with 
the participant via phone. If the participant is under the age of 18, the participant’s parent/legal guardian 
will also be part of this discussion. Dr. Dahne will query the participant for details regarding the suicidal 

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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, Dr. 
Dahne will call emergency services and will remain on the phone with the participant until emergency 
services arrive. Contact information including home address will be collected during study screening 
and will be provided if necessary to emergency services personnel. Dr. Dahne is a licensed clinical 
psychologist and has more than 10 years of experience conducting suicide risk assessments. In the event 
that a participant evidences clinical deterioration, the participant will be allowed to continue in the trial, 
but we will recruit an additional participant for data collection purposes.  
 
c) Confidentiality: Participants will be made aware of limits to confidentiality at the beginning of 
screening and during informed consent which includes a report of suicidal or homicidal intent or report 
of abuse or neglect. If the participant is under the age of 18, they will also be notified that clinical 
information disclosed as part of the research study (e.g., clinical deterioration including significant 
increases in depressive symptoms and/or suicidality, vaping status) may be shared with their parent or 
legal guardian. If the participant reports suicidal or homicidal intent or abuse/neglect during screening 
or at any point during the trial, Dr. Dahne will take appropriate action as outlined by the MUSC IRB, 
NIH, and the State of South Carolina, which may include paging the participant’s physician, contacting 
the authorities and/or pursuing involuntary commitment at a mental health facility. If participants 
present no imminent danger but also need more extensive treatment of mental health concerns, they will 
be given appropriate referrals. All individual interviews will be recorded, transcribed, and destroyed 
within 12 months of completion of the entire study to protect confidentiality. 
 
d) Data breach: Although health information will be collected within VapeX (e.g., daily mood ratings, 
activities, values, vaping), personally identifiable information will intentionally not be collected within 
the app (e.g., name, phone number, email address, etc.), and thus we will not collect nor will we retain 
protected health information (PHI). In the event of a data breach, it is important to note that health 
information will not be able to be tracked back to specific individual users. By refraining from collecting 
PHI within the mobile app, we ensure HIPPA compliance while also protecting the identities of our 
users. In the event of a data breach, all app users will be notified via email.   
 
e) Frustration: Participants may become frustrated while completing questionnaires or while using 
VapeX. Participants will be informed that they may refuse to answer any question(s) that they do not 
wish to answer and that they may discontinue use of VapeX at any time. 
 
Adequacy of Protection Against Risks  
Recruitment and Informed Consent 
Study participants will primarily be recruited from local primary care/family medicine clinics associated 
with MUSC’s Primary Care Integrated Center of Clinical Excellence (ICCE). Study recruitment will occur 
proactively, and we will utilize cold contact procedures and available EHR data to identify ICCE patients 
between the ages of 16 and 20 with depressive symptoms who vape nicotine. As part of routine clinical 
care, all primary care patients (including adolescents between the ages of 16 and 20) complete the Patient 
Health Questionnaire-2 (PHQ-2) to screen for depressive symptoms during each primary care visit. 
Information on depression is also available via the EHR within each patient’s problem list and billing codes. 
Adolescent patients will be identified who have been seen within an ICCE clinic in the last year with: 1) a 
score of ≥3 on their last PHQ-2 assessment (i.e., the optimal cut-point for identifying those who are 
symptomatic63), 2) depression listed on their problem list, or 3) a depression-related billing code associated 
with their last visit. We will further narrow this list to only those patients who reported vaping nicotine 
during their last visit. Patients on the recruitment report will be contacted via the patient EHR portal 
(MyChart) or e-mail (based on patient preferences in the EHR) by a study team member inviting them to 
participate in the research study. Within South Carolina, the legal age to consent to medical treatment is 16. 

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At age 16, all MUSC patients are eligible to receive their own patient portal account and parents/guardians 
can be appointed as proxies. If participants do not respond to the initial invitation within 72-hours, we will 
contact them via phone, e-mail, and/or text-message (also based on patient communication preferences 
within the EHR) to ensure they received the initial study invitation message. If interested, participants will 
complete an eligibility screening via REDCap to determine study eligibility. After determination of 
eligibility, a member of the study team will complete remote electronic informed consent (e-consent) with 
the participant via REDCap76. Participants will receive a link to an electronic consent form that they can 
review and sign. Parents/guardians of participants under 18 years old will participate with the adolescent in 
the screening, evaluation, and informed consent/assent procedure. Participants 18 years and older will be 
able to provide their own informed consent. Review of the consent form will be paired with a phone call 
with an IRB-approved member of the research team to ensure that the consent form is read in full and that 
all questions are answered prior to trial enrollment. All participants will electronically sign informed 
consent forms that have been IRB-approved once the study is explained to them in full and they have stated 
that they understand what is being asked of them. Participants will be given the opportunity to ask questions 
about their participation throughout the course of the study. Participants will be given a study phone number 
and e-mail address to contact for questions. Particular caution will be exercised in obtaining informed 
adolescent assent separately and independently from parental consent to limit potential for coercion. To this 
end, an initial step in participant recruitment involves obtaining parental/legal guardian permission for 
participation by the adolescent. Once parental consent is secured, youth will be asked separately and 
independently for informed consent (i.e., parental consent will not be used to persuade teens to participate). 
This approach is considered very effective in minimizing coercion to participate. The complex issues of 
informed consent and assent, and related limitations of confidentiality, as they apply to adolescents and 
their parents/guardians, are understood by the investigative team and will be communicated clearly during 
screening and consent. In the case of adolescents in South Carolina Department of Social Services custody, 
state guidelines regarding consent for clinical research participation will be followed. 
 
Protections Against Risk 
The recruitment project is stored in REDCap and only study team members will have access to the 
recruitment project database. The research team will only have access to the REDCap recruitment project 
while actively enrolling for the study. The recruitment project will be stored separately from the project 
containing research data. The recruitment REDCap project will potentially contain both identifiers and 
health information in the same project. All screening information will be kept in a password protected 
REDCap database. Only key study personnel will have access to the database. If an individual is not eligible 
to participate, his/her screener will include his/her first name and last initial and the reason for 
disqualification. Eligible participants’ full name, telephone number and e-mail address will be recorded in 
the database. This is the only place where participants’ names and subject identification numbers appear 
together. Eligible participants will be assigned a subject number, will complete informed consent (see 
procedures above), will be randomized (Aim 2), will complete baseline assessments, and subsequently will 
receive their randomized intervention (or will complete focus group Aim 1). 
 
Upon completing eligibility screening, if study eligible, individuals will be provided with a verbal overview 
of the study, asked to review a consent form, and asked to provide informed consent (or assent, if under the 
age of 18). Participants will be informed of limitations of confidentiality (i.e., abuse or neglect, intention to 
harm self or someone else) both verbally and in writing during the informed consent process. The consent 
form will include the participant’s name, but not his/her subject number. Consent forms will be provided in 
English. As utilization of VapeX requires that participants are able to read, participants unable to read the 
consent form on their own will not be included. 
 
Regarding questionnaire data, data will be obtained for research purposes only. All data will be collected, 
stored, and managed via REDCap, which is a secure, web-based application designed exclusively to support 

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data capture for research studies. REDCap includes real time validation rules with automated data type and 
range checks at the time of entry. The underlying database is hosted in a secure data center at MUSC and 
includes redundancy, failover capability, backups and extensive security checks. The system has several 
layers of protection including user/group account management, "Data Access Groups" which allow data to 
be entered by multiple groups in one database with segmented user rights for entered data, audit trails for 
all changes, queries and reports, and Secure Sockets Layer (SSL) encryption. Name and relevant contact 
information will be obtained to provide compensation and every effort will be made to maintain subject 
confidentiality, in accordance with HIPAA. All data will be identified only by code numbers (participant 
IDs). Participant IDs will be linked to participants’ names in a password-protected file that is accessible 
only to the PI and trained research staff.  
 
Regarding user privacy while using VapeX, users will create a username and password in order to login to 
their account without storing their true identity. In VapeX, we will store a one-way hashed version of the 
patient’s email address to support password reset and unique identification, but that identification will not 
be traceable back to the user’s true identity. We will not store any personally identifiable information (e.g., 
first name, last name, email address, phone number) of users in our app database. VapeX will be HIPAA 
compliant, which we believe will be critical not only for protecting patient information, but also for ensuring 
that VapeX will be a viable commercial treatment option. We will use a HIPAA-compliant server protected 
by industry-standard safeguards to prevent unauthorized access. Since we are not associating patient health 
information with personally identifiable information there will not be a risk of unauthorized release of 
patient medical data in the event of a security breach. User personal information will be contained behind 
secured networks and will only be accessible by the investigators, who will have special access rights to 
such systems. In addition, all sensitive information users supply will be encrypted via Secure Socket Layer 
(SSL) technology. We will not sell, trade, or otherwise transfer personally identifiable information to 
outside parties. Our privacy policy will be available within the app for users to view at any time. This plan 
is consistent with that used by our partnering app development company, MountainPass Technology LLC, 
in several other previous products with similar protection requirements. Mr. Kustanowitz from 
MountainPass has expertise in HIPAA-compliant software development and will oversee all aspects of 
HIPAA compliance.  
 
Protection against risk resulting from depressive symptoms includes the following: Regarding suicidal 
ideation and broader mental health concerns, Dr. Dahne (or back-up clinician), a licensed clinical 
psychologist, will take appropriate action as outlined by the MUSC IRB, NIH, and the State of South 
Carolina, which may include paging the participant’s referring physician, disclosing information to the 
participant’s parent/legal guardian, contacting the authorities and/or pursuing involuntary commitment at a 
mental health facility. If participants present no imminent danger but also need more extensive treatment 
of mental health concerns, they (and their parent/legal guardian, as appropriate) will be given appropriate 
referrals. As noted above, BDI-II data will be monitored over time in order to detect any possible clinical 
deterioration. BDI-II data will be monitored using only the participants’ subject numbers. Should a 
participant evidence clinical deterioration, Dr. Dahne will then use the participant database in order to obtain 
contact information for the participant based on their subject number. We will also form a Data Safety and 
Monitoring Board (DSMB) comprised of individuals with expertise in adolescent depression and substance 
use treatment, primary care, and clinical trials, as well as a statistician. If the percent of serious or severe 
AEs related to clinical deterioration appears to be greater than 5% the DSMB will be notified to make a 
decision on early termination of the study.  
 
Regarding recordings, all focus group sessions will be audio recorded and transcribed with recordings stored 
on an MUSC secure, password protected server. Recordings will be destroyed within one year of recording. 
Only IRB approved research staff will have access to recordings. Recordings will be destroyed within 12 
months of completion of the entire study. Only IRB approved research staff will have access to recordings. 

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14.0 Potential Benefits to Subjects or Others 
 
All participants in this trial will receive at minimum treatment as usual. There is the potential benefit to 
participants that the treatment they receive may prove to be more effective than other available treatments 
for quitting vaping, although this cannot be guaranteed. The majority of participants will also receive a 
mobile app developed to improve depressive symptoms in the service of quitting vaping. The major 
benefit to society will be whether VapeX is feasible, acceptable, and improves depression and vaping 
outcomes relative to TAU. Potential issues of clinical deterioration, confidentiality, data security, and 
frustration are a high priority and will be closely monitored throughout the study. Consequently, the risk 
to benefit ratio in the proposed study appears to be acceptable. 
 
15.0 Sharing of Results with Subjects 
 
Study outcomes will not be shared with subjects. 
 
 
 

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