Development and Testing of a Depression-Specific Behavioral Activation Mobile App Paired With Nicotine Replacement Therapy Sampling for Smoking Cessation Treatment Via Primary Care
Phase: NA
Conditions: Cigarette Smoking, Smoking Cessation, Depression
Sponsor: Medical University of South Carolina

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PROTOCOL TITLE: Development and Testing of a Depression-Specific Behavioral Activation Mobile 
App Paired with Nicotine Replacement Therapy Sampling for Smoking Cessation Treatment Via Primary 
Care 
 
PRINCIPAL INVESTIGATOR: Jennifer Dahne, Ph.D. 
 
 

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1.0 
Objectives / Specific Aims 
 
The goal of this work is to develop, systematically evaluate, and clinically test an integrated cessation 
intervention comprised of a depression-specific Behavioral Activation (BA) for cessation mobile app 
(“Goal2Quit”) packaged with nicotine replacement therapy (NRT) sampling. This integrated intervention 
will address the need for an easily disseminable, evidence-based, depression-specific cessation intervention 
for delivery via primary care.  
Aim 1: We will first develop Goal2Quit consistent with the BA for smoking cessation manual(1) 
and will complete usability testing of the app with depressed smokers (N=10) engaged with primary 
care. 
 
Aim 2: We will then refine the app and preliminarily test the integrated intervention via a single-
arm feasibility test (N=10) followed by individual interviews to address potential pitfalls. Goals of 
feasibility testing include assessment of: 1) access, 2) user feasibility/acceptability, 3) engagement 
and retention, 4) adherence, and 5) NRT utilization.  
 
Aim 3: Upon further refinement, we will then conduct an RCT (N=150, followed for 12 weeks) of 
Goal2Quit+NRT Sampling as compared to treatment as usual (TAU) among primary care engaged 
adults with primary objective to provide effect size estimates for a larger RCT.  
Hypotheses: Participants randomized to Goal2Quit+NRT Sampling, compared to TAU, will 
have greater (numerically, if not statistically) decreases in depressive symptoms as well as 
superior cessation-related outcomes (motivation to quit, confidence in quitting, quit 
attempts/quit duration). Secondary outcomes include all those listed in Aim 2.  
 
2.0 
Background 
 
Cigarette Smoking is a Major Public Health Problem, Highly Prevalent Among those with Depressive 
Symptoms. Over the last 50 years, the United States has seen substantial declines in cigarette smoking 
among the general population, with smoking prevalence dropping from 43% in 1965 to 18% today(2). 
Despite these general population declines, smoking prevalence remains astonishingly high among certain 
vulnerable subgroups. One such subgroup is the 20 million adults in the US with depressive 
symptomatology(3-5). Nearly half of all adults with elevated depressive symptoms are smokers(6-9), and 
these symptoms are a robust risk factor for the etiology of tobacco use across the lifespan(10-12).  
Despite similar levels of motivation to quit(13, 14) and incidence of quit attempts(15) as their non-
depressed counterparts, depressed smokers are 30-50% less likely to be abstinent one-month post-quit(15), 
regardless of depression severity(16). These disproportionate smoking and cessation rates in turn confer 
heightened risk for tobacco-related mortality(17). Consistent with the transdiagnostic emotional 
vulnerability framework for smoking(18), the relationship between depressive symptomatology and 
cigarette smoking is bidirectional, as depressive symptoms confer risk across stages of smoking and 
continued smoking in turn leads to worsening of depression over time. To significantly reduce the continued 
public health burden of cigarette smoking, it is necessary to address tobacco use among those with 
depressive symptoms(19). 
 
Integrated Treatments that Target Smoking Cessation and Depressive Symptoms Improve Outcomes. 
Numerous intervention studies have integrated psychosocial depression components into cessation 
treatment. A recent Cochrane review identified 33 randomized clinical trials (RCTs) comparing cessation 
interventions with specific psychological components targeting depression to standard evidence-based 
cessation programs and found that the addition of depression-specific psychological treatment increased 
long-term quit rates 50% among those with current depressive symptoms(20). Thus, off-the-shelf 
interventions are insufficient to meet the needs of this population and tailored cessation treatments 

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incorporating depression-specific psychological treatment are necessary for smokers with depressive 
symptoms to quit. 
 
Available Depression-Specific Cessation Treatments Have Limited Reach and are Unlikely to 
Significantly Impact Cigarette Smoking. The predominant delivery method for depression-specific 
psychological cessation treatments is in-person individual or group psychotherapy(20). In-person 
psychotherapy has been widely criticized as unlikely to reach the majority in need(21-24) and a recent 
nationally representative study from our group found that only 4.0% of smokers who attempted to quit in 
the last year utilized individual or group psychotherapy to quit(25). There is clear need to reach depressed 
smokers through other outlets. 
Primary care is the most important point of healthcare contact for current smokers as there are 
established procedures for depression and smoking screening within primary care(26, 27) and at least 70% 
of smokers visit a primary care physician (PCP) annually(27). US Public Health Service clinical practice 
guidelines advise PCPs to utilize the 5As/AAR model (Ask, Advise, Assess, Assist, Arrange/Ask, Advise, 
Refer) for cessation treatment(28). Beyond documented problems with compliance(29-32), this model lacks 
depression-specific treatment and is unlikely to help depressed smokers quit. Barriers to adding depression-
specific treatment to the 5As/AAR include: 1) lack of training among PCPs in the delivery of evidence-
based depression-specific cessation treatment, 2) lack of time to acquire such training and to deliver such 
interventions, and 3) lack of confidence among PCPs in their ability to deliver psychological 
interventions(33). Thus, there is a need to improve dissemination of depression-specific cessation treatment 
from the point of contact with a PCP. 
 
Mobile Health Technologies Can Be Leveraged to Disseminate Depression-Specific Cessation 
Treatment. Mobile health (mHealth) technologies offer an ideal strategy to disseminate evidence-based 
depression-specific cessation treatment while eliminating the above barriers(34). Smartphones and mobile 
applications (apps) are ubiquitous, with recent estimates suggesting more than 75% of U.S. adults own a 
smartphone(35), 77% of smartphone owners download apps(36), and 56% of physicians already utilize 
apps in their practices(37). Hundreds of apps marketed for cessation are available for iOS and Android, 
many with downloads exceeding 1 million per month(38-40). Recent content analyses of these apps reveal 
that the majority do not adhere to clinical practice guidelines, and none incorporate evidence-based 
depression-specific treatment(38-40). Further, having an app and using an app are not synonymous as apps 
lose, on average, 70% of their users within the first week(41). By leveraging the trusted patient-physician 
relationship to reach depressed smokers, we can both broadly disseminate treatment and promote continued 
utilization(34, 42, 43). Taken together, despite clear interest among smokers in utilizing mobile apps to 
quit, extant cessation apps are insufficient to address the need for an evidence-based depression-specific 
cessation app. An ideal depression-specific cessation treatment to adapt for mHealth delivery must be: 1) 
evidence-based, to promote PCP buy-in and 2) simple/straightforward, so that the treatment can be easily 
recommended to and understood by patients. A logical next step is to tailor an evidence-based depression-
specific cessation treatment for delivery via mHealth and primary care. 
 
Behavioral Activation is an Ideal Depression-Specific Cessation Treatment for mHealth in Primary 
Care. Behavioral Activation (BA) is an evidence-based depression intervention that focuses on regular self-
monitoring to 1) examine already occurring activities and 2) facilitate the incorporation of new activities 
consistent with individualized values/goals across life areas. BA specifically targets the anhedonic 
component of depression, identified by the transdiagnostic emotional vulnerability framework as central to 
the comorbidity of depression and smoking(18). BA has an extensive literature-base for the treatment of 
depression (including both Major Depressive Disorder and sub-threshold elevated depressive 
symptoms)(44-52) as well as demonstrated promise for cessation(53, 54). In one seminal study, 
MacPherson and colleagues(53) developed a modified version of BA for cessation and conducted an RCT 
comparing BA for cessation to standard cessation counseling among smokers with elevated depressive 
symptoms. Smokers attended weekly in-person group therapy for 8-weeks and completed measures of 
smoking cessation outcomes (7-day verified point prevalence abstinence) and depressive symptoms at 1, 4, 

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16, and 26 weeks post quit date. Across 26 weeks of follow-up, BA participants were 3.6 times more likely 
to maintain abstinence and had significantly greater reductions in depressive symptoms than those 
randomized to standard treatment. While this study demonstrates treatment efficacy, effectiveness remains 
unknown. There is clear interest in BA for cessation, with four currently NIH-funded studies 
(R01CA206058, R43CA206682, R01CA184211, R34DA037391) and two recently completed, but not yet 
published studies (K23HL10739, I01CX000560) to examine BA for cessation. None of these studies are 
examining BA for smoking cessation with depressed smokers based within the real-world (e.g., primary 
care), delivered using mobile technologies. The present study fills this gap.  
 
A Mobile App Alone is Insufficient to Promote Quitting; Pairing with Pharmacotherapy is Needed. In 
light of physiological withdrawal associated with quitting smoking(55), an app would likely have maximum 
benefit when integrated with pharmacotherapy for quitting. Provision of pharmacotherapy for smoking 
cessation is a first line treatment recommendation for all smokers treated in primary care(28). Thus, another 
feature of the current study is to integrate BA with pharmacotherapy (specifically nicotine replacement 
therapy; NRT). NRT products, both alone and in combination, have significant benefits on quitting 
smoking(56, 57) (see C.2. for additional rationale). Medication sampling (i.e., provision of a two-week 
NRT starter kit including nicotine patch and lozenge) is a highly disseminable and translatable medication 
delivery strategy, well-suited to primary care. NRT sampling is inexpensive, can be delivered briefly (i.e., 
1-2 minutes), and is an immediately actionable cessation catalyst, regardless of motivation to quit. Longer 
duration of NRT might be better, but this would require smokers to return for frequent visits for re-supply, 
which has limited feasibility. NRT sampling is disseminable in ways that both a full NRT course and a 
prescription treatment are not. Most importantly, sampling is associated with significantly higher incidence 
of 24-hour quit attempts relative to control (43% vs. 34%)(58), while also increasing motivation to quit(59) 
and self-efficacy(60), which in turn are predictive of sustained cessation(61, 62).  
 
Summary of Scientific Premise. Cigarette smoking remains a public health priority and is highly prevalent 
among those with depressive symptoms. Depression-specific cessation interventions, particularly 
disseminable treatments that can be applied within primary care, are necessary but currently lacking. 
Tailoring a simple, straightforward evidence-based depression-specific cessation intervention, such as BA, 
for delivery via a mobile app holds the potential to overcome treatment barriers and reach large numbers of 
depressed smokers who are not currently receiving necessary treatment. The integration of such an app with 
pharmacologic treatment with similar translational potential, such as NRT sampling, offers a dual-pronged 
approach targeting both psychological and physical dependence risk factors for relapse. Herein, we propose 
to develop, systematically evaluate, and clinically test an integrated cessation intervention comprised of a 
depression-specific BA for cessation smartphone mobile app (Goal2Quit) and NRT sampling that will meet 
this unmet need for an easily disseminable, evidence-based, depression-specific cessation intervention for 
delivery via primary care.  
 
3.0 
Intervention to be studied  
 
The intervention to be studied herein is an integrated cessation intervention comprised of Goal2Quit 
paired with NRT sampling (Goal2Quit+NRT Sampling), which will be compared to a TAU condition. 
Each component of the integrated intervention is described below, as is the TAU condition. 
 
Goal2Quit. Goal2Quit treatment content (outlined below) will follow treatment content from the BA for 
cessation manual(1), including integrated BA and standard smoking cessation components. Interactive 
functionality (e.g., videos, quizzes, animations) will be incorporated throughout. Goal2Quit will prioritize 
user autonomy (i.e., how to use the app/what to use in the app, tracked as study outcomes), which is key to 
retention and engagement(63).  
BA components will include: 1) Psychoeducation highlighting the connection between mood and 
smoking, the BA model for cessation, and description of Goal2Quit treatment components, 2) Activity 

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monitoring including rating of enjoyment and importance associated with each activity and number of 
cigarettes smoked (or craving after quitting) during each activity, 3) Identification of values and activities 
within six life areas including relationships, daily responsibilities, recreation, career/education, health, and 
being smoke-free, 4) Activity planning, consisting of scheduling in and monitoring new, value-driven, 
smoke-free activities, and 5) Enlisting social support to obtain help completing difficult activities and 
remaining smoke-free.  
Standard smoking cessation components will include: 1) Reinforcement and support for quitting, 
including education about the benefits of quitting and suggested lifestyle changes, 2) Guided and interactive 
questions to identify past quit experiences in order to determine what hindered past quit attempts and how 
to avoid pitfalls, 3) Setting a quit date, suggested to be no later than three weeks after treatment initiation, 
4) Identification of triggers and high risk situations and development of coping strategies (i.e., avoid, alter, 
substitute) to target these situations and limit the abstinence violation effect, 5) Information about alcohol 
use and suggestion to refrain from or limit alcohol use while trying to quit, and 6) Education about 
medications for quitting smoking including guidance on NRT use, potential side effects, tracking of NRT 
use, and suggestions for obtaining additional NRT.  
 
NRT Sampling. We will provide a 2-week supply of combination nicotine patch and lozenge in uniform 
doses (14mg patch and 4mg lozenge; the standard minimum dose for this population). We considered a 
tailored dosing (e.g., with 21mg patch), but believe this diminishes the translational potential of the 
intervention and is not clinically indicated given adjunctive lozenge use. Goal2Quit will educate 
participants about nicotine withdrawal/intoxication, with suggested dosage alterations and guidance on 
where to obtain NRT. Participants will be instructed to use the NRT however they wish (e.g., to get started 
quitting, to reduce, to practice quitting).  
 
TAU Condition. Participants randomized to the TAU condition will receive NCI’s “Clearing the Air” 
booklet, which includes information on quitting smoking. 
 
4.0 
Study Endpoints 
Outcome variables include:  
• Cigarette smoking, use of other tobacco products (e.g., e-cigarettes), and quit attempts/quit 
duration 
• Nicotine dependence 
• Motivation to quit and confidence in quitting 
• Depressive symptoms 
• Activation 
• Environmental reward 
• Treatment adherence 
• Feasibility 
• Acceptability 
 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
 
Participants will complete a REDCap survey to be screened for eligibility. Inclusion criteria for usability 
testing (Aim 1), feasibility testing (Aim 2), and the subsequent pilot RCT (Aim 3) include: 1) current 
elevated depressive symptoms defined as a score of > 10 (at least mild depression) on the Patient Health 
Questionnaire-8 (PHQ-8); if a participant reports a Beck Depression Inventory-II (BDI- II) score < 10 
during baseline the PHQ from screening will be repeated with the particicpant over the phone (64), 2) 
current smoking, defined as smoking 5+ cigarettes/day, for 25+ days out of the last 30, for the last 6+ 
months, 3) ownership of an Android or iOS smartphone compatible with Goal2Quit, 4) age 18+, 5) a 

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valid e-mail address that is checked daily to access follow-up assessments, 6) English fluency, and 7) has 
been seen by a primary care physician within the last year. Exclusion criteria include: 1) contraindications 
for NRT (pregnancy/intention to become pregnant/breastfeeding, recent cardiovascular 
trauma/uncontrolled hypertension), 2) severe visual impairment, which may limit ability to utilize an app, 
and 3) household member currently enrolled in the study.   
 
6.0 
Number of Subjects 
 
We will recruit 10 participants for usability testing, 10 participants for feasibility testing, and 150 
participants for the pilot RCT (Total number of participants = 170, up to 240 assuming 20% attrition).  
 
7.0 
Setting 
 
Research will be conducted remotely via REDCap as well as in clinics affiliated with MUSC’s 
Department of Family Medicine (DFM) and MUSC Health Primary Care. The DFM operates three family 
medicine clinics across the Charleston County area: 1) MUSC Family Medicine located on James Island, 
2) East Cooper Family Medicine located in Mount Pleasant, and 3) Rutledge Tower Family Medicine 
located downtown on the Charleston peninsula. The DFM also has a community residency site at the 
Trident Regional Medical Center in North Charleston. 
 
8.0 
Recruitment Methods 
 
Participants will be recruited in the following ways: 
1) Via MyChart: MUSC DFM and MUSC Health Primary Care patients who have previously been 
identified as smokers will be sent a secure message via MyChart informing them of this research 
study. These patients will have either agreed to research contact within MyChart or their attending 
physician will have agreed to contact their patients who smoke cigarettes via MyChart. Within the 
message, potential participants will be invited to click a link to complete an eligibility screening 
via REDCap. 
2) In Clinic: Participants may be recruited in clinic after being identified as a smoker by research 
personnel listed on this application. 
3) Via advertisements (e.g., flyers) and online postings such as Craigslist. 
 
9.0 
Consent Process 
 
For all components of this project, signed informed consent will be obtained from study participants. The 
consent process may take place either in person (e.g., in clinic) or remotely utilizing electronic consent or 
mailed consent paired with a video/telephone connection to an IRB-approved member of the study team. 
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. Our study team has laptops and tablets that may be used for the eConsent and all eligible 
participants will own a smartphone on which eConsent may also be obtained. No information will be 
stored locally on study team laptops or tablets; all information will be stored securely in REDCap if 
captured electronically. 
 

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10.0 Study Design / Methods 
 
Study Overview. We will develop, refine, and iteratively test Goal2Quit+NRT Sampling. Through an 
established partnership with MountainPass Technology LLC (MPT; developer of prior app interventions 
to be expanded and refined herein), we will develop Goal2Quit consistent with the BA for smoking 
cessation manual(1). Usability testing will guide app refinements prior to a small, single arm feasibility 
trial of Goal2Quit+NRT Sampling. Following participant interviews, the intervention will be further 
refined. We will then conduct a 2-group RCT of 1) Goal2Quit+NRT Sampling vs. 2) TAU.   
 
Goal2Quit Development. We have an established partnership with MPT and will expand on this 
relationship to develop Goal2Quit. MPT has expertise in developing HIPAA-compliant mobile apps. We 
will develop Goal2Quit for both iOS and Android. In order to customize BA for smoking cessation for 
mHealth delivery, we will utilize an iterative, patient-centered, agile software development approach(65). 
See above for Goal2Quit functionality. 
 
Usability Testing and Refinements. We will recruit 10 participants (up to 12 assuming 20% attrition, the 
standard number for usability testing(66)) for usability testing. Smoking status is assessed for every Family 
Medicine/Primary Care patient, consistent with MUSC’s best practice guidelines. Patients identified as 
smokers will be asked either in person or remotely (e.g., via MyChart or REDCap) if they are interested in 
participating in a study examining a mobile app for the treatment of depressive symptoms and smoking. If 
interested, the participant will subsequently complete an eligibility screening via MUSC’s REDCap system, 
a secure, HIPAA-compliant data management system.  
 
All patients, whether study eligible or not, will continue with standard care as provided by their 
PCP. Eligible participants will be contacted by Dr. Dahne’s research team to schedule a usability testing 
visit. At the beginning of the usability visit, participants will be provided with a copy of the consent form 
and the consent document will be described to them by a member of the research team. Upon informed 
consent, we will follow the Concurrent Think Aloud (CTA) method(67), which elicits real-time feedback. 
Participants will be videotaped while completing user-specific tasks (e.g., create a new value, schedule a 
new activity, set a quit date, learn about NRT). During the CTA process, research staff will take notes to 
report emotional reactions, task time, errors, and if the participant successfully completes the assigned tasks. 
Participants will be compensated $40 for participation.  
 
Feasibility Testing.  We will recruit 10 participants (up to 12, assuming 20% attrition) for a single-arm 
feasibility test of the integrated Goal2Quit+NRT Sampling intervention. The goal of feasibility testing is to 
preliminarily test the integrated Goal2Quit+NRT Sampling intervention to target any potential pitfalls prior 
to larger-scale testing. Interested participants will be recruited either via MUSC’s primary care/family 
medicine clinics or online and will first complete an eligibility screening via REDCap. If eligible, 
participants will review study procedures and proceed with completing informed consent, detailed above. 
Participants will be provided with a code to download Goal2Quit by a member of the reserch team and the 
staff member will ensure the participant successfully downloads the app and will allow them to use the app 
for ~10 minutes and ask questions regarding functionality. Subsequently, participants will be mailed: 1) A 
two-week “starter kit” sample of NRT (14mg patch and 4mg lozenge, both in original packaging; the 
standard minimum dose for daily smokers smoking at least 5 cigarettes per day), 2) Educational material 
suggesting that participants utilize Goal2Quit regularly, at least daily, and the provided NRT in an attempt 
to quit smoking, 3) A handout detailing subsequent assessments and payment schedule for assessments, and 
4) NCI’s “Clearing the Air” booklet, which includes information on quitting smoking. The follow-up 
assessment schedule and compensation will be the same for feasibility testing participants as for participants 
enrolled in the RCT (see below).   
 
We will utilize app analytics to examine indicators of user engagement and retention including: 1) 
Access, defined as the number of users who download Goal2Quit divided by the number provided with a 
download code, 2) User feasibility and acceptability, assessed both during and following treatment 

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utilization, 3) App engagement and retention (i.e., “stickiness”), with engagement defined as the percentage 
of participants with > 10 app sessions during a month and retention defined as the percentage returning to 
the app within 2 weeks of their first session, and 4) Treatment adherence, measured via Goal2Quit’s activity 
selection and scheduling component (score calculated by dividing number of activities completed/number 
scheduled). We will assess NRT sampling utilization weekly including use of NRT products, additional 
NRT purchase, and perception of NRT products.  
 
Small-Scale RCT. A two-arm RCT (N=150) will test the efficacy of Goal2Quit+NRT Sampling vs. TAU. 
See above for inclusion/exclusion criteria. After completing determination of eligibility, reviewing study 
procedures, completing informed consent, and completing baseline assessments, if eligible, the participant 
will be randomized 2:1 to either Goal2Quit + NRT sampling or TAU. Participants randomized to Goal2Quit 
+ NRT sampling will be provided with their intervention in the same manner as feasibility testing 
participants. TAU participants will be mailed a package that includes only 1) NCI’s “Clearing the Air” 
booklet, which includes information on quitting smoking, and 2) Information on study participation, 
including the schedule of follow-up assessments and compensation. Participants will subsequently be e-
mailed a REDCap link (accessible via smartphone, tablet, or computer) to complete follow-ups weekly for 
8 weeks, with an additional follow-up at Week 12.  
 
Assessments: Assessments are estimated at 20 minutes each and will be administered remotely via 
REDCap through our established procedures. Participants will be sent an email and/or SMS text each week 
with a link to access their REDCap surveys. 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 surveys are not completed via texting, just prompted via text with 
link to RedCap.  Participants can choose to receive their weekly surveys via email if they wish, again with 
a link to a secure RedCap survey. Participants will be compensated $10 in cash and/or electronic gift codes 
(e.g., Amazon) for completion of each and will receive a $20 bonus if at least 2/3 are complete. Participants 
will also receive a second bonus of $20 for completing all follow up surveys. To help with retention, the 
last 20-25 participants enrolled will receive a signed letter from the study team and a few small items with 
the study’s logo (e.g., pen, flash drive, coaster, t-shirt) from the study team at random time points throughout 
their participation as a thank you for joining. Cigarette smoking, use of other tobacco products (e.g., e-
cigarettes), and quit attempts/quit duration 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(71, 72). Nicotine 
dependence will be assessed at baseline via the Fagerstrom Test of Nicotine Dependence(73). Participants 
will report motivation to quit and confidence in quitting using a modified Contemplation Ladder(74). 
Depressive symptomatology will be assessed via both the PHQ-8(64) and the Beck Depression Inventory-
II (BDI-II)(75). The PHQ-8 is briefer than the BDI-II, and thus will determine study eligibility. The BDI-
II will be administered at all time points to determine change in symptoms. We will assess and track 
psychiatric medication use over time and will stratify randomization based on medication use. Adequate 
procedures are in place to assess for and protect against the potential for suicidal ideation (see Protection of 
Human Subjects). Process-related variables including activation, assessed via the activation subscale of the 
Behavioral Activation for Depression Scale(76), and environmental reward, assessed via the Reward 
Probability Index(77) will be assessed at baseline and all follow-ups to examine potential treatment 
mechanisms. Treatment adherence will reflect both Goal2Quit and NRT utilization. Regarding Goal2Quit, 
adherence will be measured based on 1) download of Goal2Quit (yes/no) and 2) analytic data including: 
number of logins, duration of sessions (average per session and cumulative), rolling retention, number of 
activities scheduled, and percent completed activities. Regarding NRT utilization, participants in both 
groups will be queried at all follow-ups for: 1) use of NRT since the last assessment, 2) purchase of NRT 
since the last assessment, and 3) perception of NRT products via the Attitudes Toward NRT Scale(78). 
Engagement in other cessation (other medications, behavioral treatment, quitlines) and mental health 
(medications, therapy) treatments will also be assessed. Feasibility and acceptability will be assessed for 
those in the Goal2Quit+NRT Sampling condition during each assessment. Participants will be prompted to 

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respond to questions querying their experiences with the intervention including: 1) ease of use, 2) barriers 
to utilization, and 3) suggested improvements to the treatment. 
 
Measure 
Screening 
Baseli
ne 
1 
2 
3 
4 
5 
6 
7 
8 
12 
PHQ-8 
x 
 
 
 
 
 
 
 
 
 
 
BDI-II 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Current use 
of 
Psychotropi
c Meds 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Demographi
cs 
x 
x 
 
 
 
 
 
 
 
 
 
Smoking 
History, 
Including 
History of 
Previous 
Quit 
Attempts 
and NRT 
Use 
 
x 
 
 
 
 
 
 
 
 
 
BADS 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
RPI 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SHAPS 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SF-12 
 
x 
 
 
 
x 
 
 
 
 
x 
Tech 
Comfort 
 
x 
 
 
 
 
 
 
 
 
 
Utilization 
of 
Goal2Quit 
/Other 
smoking 
cessation 
apps in the 
last week 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Cigarettes 
per smoking 
day 
x 
 
 
 
 
 
 
 
 
 
 
 
Fagerstrom 
Test of 
Nicotine 
Dependence 
 
x 
 
 
 
 
 
 
 
 
 
TLFB 
(cigarettes, 
quit 
attempts, 
NRT) 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Contemplati
on Ladder 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
MTQ 
Saliency 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
NRT Use 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
App 
Feedback 
(only for 
those who 
receive 
Goal2Quit) 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 

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Goal2Quit 
Usability 
Scale 
 
 
 
 
 
x 
 
 
 
 
 
Attitudes 
Toward 
NRT  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
NRT AEs 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Payment 
 
$10 
$10 
$10 
$10 
$10 
$10 
$10 +$20 
bonus 
(completing 6 
out of 9 
surveys 
$10 
$10 
$10 + $20 
bonus (all 
surveys 
completed) 
 
 
11.0 Data Management  
 
As this is a pilot trial, our primary goal is to determine feasibility/acceptability and estimate an 
intervention effect size. To estimate an effect size for the Goal2Quit+NRT Sampling intervention, we will 
randomize participants 2:1 (active:control), with 100 participants in the active condition and 50 in the 
control condition. Assuming a quit attempt rate (point prevalence) of 40% in the active condition and 15% 
in the control(59), with 2:1 randomization we will have 60% power to detect an effect; again our intent is 
not a fully powered trial. To further account for attrition (assumed to be 20% across groups), we will recruit 
180 participants total. For this pilot RCT, with a 22-month enrollment period, subtracting three months for 
final study participants, we fully expect to feasibly recruit 9-10 participants per month (180 participants/19 
months).  
Data analysis will focus on descriptive analysis of changes over time in depressive symptoms and 
cigarette smoking by condition. Considering the relatively small sample, possible missing data, and 
repeated measures, we will fit the longitudinal data with Hierarchical Linear Modeling (HLM) to fully use 
available data(80). With HLM, we can estimate and model the degree of relatedness of our observations 
within the same treatment condition and within the same individual, thereby correctly estimating standard 
errors and eliminating the problem of inflated Type I error(81). First, we will assess patterns of missing 
data, research dropout, and distributional properties of all measures. Then, effects of the Goal2Quit+NRT 
Sampling intervention as compared to TAU on cigarette smoking (motivation to quit, confidence in quitting, 
and quit attempts/quit duration) and depressive symptoms over time will be examined using HLM. Planned 
covariates will include sex and baseline levels of depression and nicotine dependence as well as the main 
effect of time.  
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 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 

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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 application consists of a 3-aim proposal. In Aim 1, participants (N=10) will complete usability testing 
of a depression-specific smoking cessation mobile app, Goal2Quit. Usability testing data will subsequently 
be utilized to refine Goal2Quit. In Aim 2, the refined Goal2Quit app will be integrated with NRT Sampling 
(14mg patch and 4mg lozenge, both in original packaging; the standard minimum dose for daily smokers 
smoking at least 5 cigarettes per day) and examined via a single-arm feasibility test of the integrated 
intervention (N=10). The goal of feasibility testing is to preliminarily test the integrated Goal2Quit+NRT 
Sampling intervention to target any potential pitfalls prior to larger-scale testing. In Aim 3, we will conduct 
a small-sale RCT (N=180) of Goal2Quit + NRT Sampling vs. TAU to provide effect size estimates for a 
larger RCT.  
 
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. 
 
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 
data). The data analysis plan is 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 assistants 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 3) 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 IND from the FDA. All 
serious AEs will be reported to the MUSC Committee on Human Research within 48 hrs. 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 5% or less. Potential conflicts of interest (COI) 
will be reported using the SRNT rules for disclosure as well as the rules of MUSC’s COI committee. 
 
Trial Safety 

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The potential risks and benefits and methods to minimize these risks are outlined in the “Risks to Subjects” 
section. AEs will be tracked and rated as mild, moderate or severe and as related to NRT by the participant. 
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. Since a maximum two-week supply of OTC NRT will be 
provided, AEs will be rare. Nonetheless, they will be coded on a weekly basis using the FDA’s COSTART 
rules(82) and entered into a database. For each weekly study meeting, the research assistant(s) will prepare 
a summary of all AEs, including their severity, whether they caused a dropout, required treatment and 
presumed relation to drug intake. The PI will review this at the weekly study meeting (or before if more 
urgent). At the weekly meeting (or before if urgent), research assistants will report any premonitory 
symptoms to suggest emergence of a serious psychiatric condition (e.g., major depression, suicidality). See 
“Risks to Subjects” for procedures in place for handling significant clinical deterioration/suicidality. Dr. 
Diaz, a board-certified Family Medicine physician, will be available on ad-hoc basis for on-site medical 
supervision for any issues that cannot be resolved by Drs. Dahne and Carpenter.  
 
Study procedures will follow as much as possible the FDA’s Good Clinical Practice Guidelines and our 
research team has found Spilker’s comprehensive text on conducting clinical trials to be useful(83). We 
will encourage, but not require, participants to notify their physicians that a) they are in a randomized 
controlled research study examining a treatment for mood and smoking cessation, 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.  
 
Data and Safety Monitoring Plan Administration 
The PI will be responsible for monitoring the trial, with oversight provided by the primary mentor, Dr. 
Carpenter. 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(s) 
immediately prior to the lab meeting a) to see if any particular COSTART categories are being endorsed 
more frequently than normal and b) to determine if any side-effect symptom checklist scores are higher 
than expected. 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. 
 
13.0 Risks to Subjects 
 
This is considered a minimal risk study. Minimal risk means the probability and magnitude of harm or 
discomfort anticipated in the research are not greater in and of themselves other than those ordinarily 
encountered in daily life or during performance of routine physical or psychological examinations or tests. 
The potential risks in this study include those related to: a) clinical deterioration, b) suicidality, c) NRT, d) 
confidentiality, e) potential data breach from the app database, and f) frustration.  
a) Clinical deterioration: Depressive symptoms will be monitored via the BDI-II. All participants will 
complete the BDI-II weekly online and at 12 weeks via a REDCap survey that is accessible via mobile 
phone, computer, and tablet web browsers. All participants will own an iOS- or Android-compatible 
smartphone. Thus, all participants will have access to the online BDI-II assessments. Dr. Dahne and her 
research team will monitor participant BDI-II scores for possible clinical deterioration (i.e., increasing 

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depressive symptoms) throughout the course of the study as participants complete the BDI-II. Clinical 
deterioration will be defined as an increase of 10 or more points on the BDI-II from the baseline BDI-
II assessment. 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 and/or instruction to 
go to the ED or call 911 for immediate depression treatment. Dr. Dahne 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 evidences clinical deterioration, the participant will be allowed to continue in the trial, but 
we will recruit an additional participant for data collection purposes.  
 
b) Suicidality: Dr. Dahne and her research team will monitor participant BDI-II scores for suicidality, 
defined as 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 at any point during the study, including at baseline. In 
the event that a participant reports suicidal ideation, Dr. Dahne, a licensed clinical psychologist with 8 
years of experience conducting risk assessments with high risk populations (e.g., adults in residential 
and outpatient substance use treatment, patients in a mood disorders clinic), will complete a risk 
assessment with the participant via phone. Dr. Dahne 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, Dr. Dahne will call emergency services and will remain on the phone with the 
participant until emergency services arrives. In the event that Dr. Dahne makes contact with the 
participant (e.g., via phone), the participant expresses an imminent likelihood of harming him/herself, 
and the connection is lost, Dr. Dahne will contact emergency services and will provide emergency 
services with the participant’s contact information, including address. In the event that the participant 
is not in imminent danger, Dr. Dahne will provide referrals for local mental health resources and/or 
instruction to go to the ED or call 911 should suicidal ideation worsen. Dr. Dahne 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 Dr. Dahne’s phone call within 
48 hours, Dr. Dahne will e-mail the participant a list of local mental health resources and will suggest 
that the participant seek additional treatment. Dr. Dahne will also ask that the participant respond to Dr. 
Dahne either via phone or e-mail within 24 hours to confirm receipt of the treatment referrals. Should 
the participant not respond to Dr. Dahne’s email within an additional 48 hours (4 days from completion 
of the assessment) and endorse “I would kill myself if I had the chance” on the BDI-II (score = 3 on 
BDI-II Item 9) Dr. Dahne will call emergency services and provide emergency services with the 
participant’s name and address. In the event that a participant endorses suicidal ideation, the participant 
will be allowed to continue in the trial, but an additional participant will be recruited for data collection 
purposes.  
 
c) NRT: Through brochures delivered as part of the sampling intervention, participants will be educated 
about lozenge/patch adverse events (AEs) and nicotine intoxication symptoms. We will clearly advise 
against use of NRT during pregnancy and breast-feeding but we will not require pregnancy tests to be 
in the study. Female participants will be required to sign a waiver endorsing that: 1) they are not 
pregnant, 2) they do not plan on becoming pregnant during the study period, and 3) they are using an 
accepted birth control method. We will not explicitly encourage or discourage use of combined 
medication (patch+lozenge), though accompanying brochures will advise smokers not to smoke while 
using NRT product (even though most studies have demonstrated no significant events for combined 
use). The sampling experience is meant to provide smokers with a real-world opportunity to “test drive” 
different medications. Our accompanying brochures will discuss the anticipated negative consequences 
of dual use (nausea, headache) and advise participants to discontinue one or both products should they 
arise. Participants will be provided with our study phone number and instructed to call our study 
personnel should they experience such AEs or if they have questions/concerns about NRT use. Given 

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the 2-week sampling experience, we expect AEs, which will be assessed across follow-up timepoints 
via REDCap, to be rare and mild. In a prior trial, our group found that 9% of participants who utilized 
NRT samples in an attempt to quit reported an AE(84). None of these AEs were unexpected, nor did 
any study participants drop out as a result of an NRT-related AE. Participants will be encouraged to 
contact Dr. Dahne as soon as possible for serious AEs and for those conditions that OTC labeling 
suggests seeing a provider. We will withdraw participants who have a serious AE. For other AEs, if the 
participant wishes it, the participant will be withdrawn from the study. 
 
This study allows smokers to sample individual or combined NRT products, with a suggestion, though 
not a requirement, to utilize those products in an attempt to quit smoking. Thus, smokers could be using 
NRT products concurrently (same day) with smoking. This could result in nicotine intoxication; i.e. 
nausea, dizziness, headache, stomachache, etc.(85). In a prior study conducted by Dr. Carpenter, 
participants completed a nicotine intoxication scale, and no evidence was found of nicotine intoxication 
when gum and cigarettes were used concurrently(84). In addition, a review of prior smoking reduction 
studies indicates that most participants do not have higher than normal cotinine levels with concurrent 
use of cigarettes and NRT, and few AEs are reported across studies(86). 
 
d) Confidentiality: Participants will be made aware of limits to confidentiality at the beginning of 
screening and when reviewing study procedures/during informed consent which include report of 
suicidal or homicidal intent or report of abuse or neglect. If the participant reports suicidal or homicidal 
intent or abuse/neglect, Dr. Dahne will take appropriate action as outlined by the MUSC IRB, NIH, and 
the State of South Carolina, which may include 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 and instructed to 
contact their physician.  
 
e) Data breach from app database: Although health information will be collected within Goal2Quit 
(e.g., daily mood ratings, activities, values, use of NRT, etc.), personally identifiable information will 
not be collected within the app (e.g., name, phone number, email address, etc.), and thus we will neither 
collect nor retain protected health information (PHI) within Goal2Quit. Upon app download, all 
participants will be assigned an anonymous username that does not contain personally identifiable 
information. 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 collection of 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.  
 
f) Frustration: Participants may become frustrated while completing questionnaires or while using 
Goal2Quit. 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 Goal2Quit at any time (which will be tracked 
as a study outcome). 
 
Since patients will all currently be receiving medical care at MUSC, there are no additional risks associated 
with participation in this study. 
 
Adequacy of Protection Against Risks 
 
Recruitment and Informed Consent 
Study participants will be recruited from local MUSC Family Medicine/Primary Care clinics and/or online. 
Smoking status is assessed for every patient, consistent with MUSC’s best practice guidelines. Interested 
individuals will complete determination of eligibility via MUSC’s REDCap system, a secure, HIPAA-

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compliant data management system. All participants will 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. A copy of the informed consent will be kept centrally at our study office 
within locked filing cabinets, and a copy will be given to each study participant as well. Participants will 
be given a study phone number and e-mail address to contact for questions. 
 
Protections Against Risk 
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 3), will complete baseline assessments (Aims 2 and 3), and subsequently will receive their randomized 
intervention (or will complete usability testing for Aim 1). 
 
Upon completing eligibility screening, if study eligible, individuals will be provided with an overview of 
the study, asked to review study procedures via a consent form, and asked to provide informed consent. 
Participants will be informed of limitations of confidentiality (i.e., abuse or neglect, intention to harm self 
or someone else) both verbally and/or 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 Goal2Quit requires that participants are able to read, participants unable to read 
the consent form on their own will not be included. 
 
Regarding user privacy while using Goal2Quit, 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 and all participants who 
receive Goal2Quit will be assigned an anonymous username that does not include personally identifiable 
information. Our server is protected by industry-standard safeguards to prevent unauthorized access. Since 
we are not associating patient health information with personally identifiable information within Goal2Quit 
there would 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.   
 
Protection against risk resulting from depressive symptoms/suicidality include the following: Regarding 
suicidal ideation and broader mental health concerns, Dr. Dahne, a licensed psychologist, will take 
appropriate action as outlined by the MUSC IRB, NIH, and the State of South Carolina, which may include 
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. 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.  

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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 
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.  
 
Protection against risks associated with NRT (OTC products) include: 1) the short duration for which NRT 
will be provided—only a 2-week supply and 2) a Data and Safety Monitoring Plan that includes monitoring 
of AEs. We will exclude individuals based on standard FDA contraindications for NRT use (pregnancy, 
recent cardiac trauma). Through informational material provided with the NRT samples, participants will 
be educated about potential NRT AEs and nicotine intoxication symptoms. As an OTC product, given over 
short duration, we anticipate very few AEs. AE’s will be discussed with Dr. Carpenter and, if necessary, 
consultation with Dr. Diaz, a Family Medicine attending physician and co-investigator on this protocol.  
 
14.0 
Potential Benefits to Subjects or Others 
 
All smokers in this trial will receive at minimum standard smoking cessation care and evidence-based 
educational information about quitting smoking. The majority of participants in Aim 3 will receive a novel 
depression-specific smoking cessation mobile app (Goal2Quit) and a two-week sample of NRT, designed 
to target both affective and physical dependence risk factors for relapse. The major benefit to society will 
be whether Goal2Quit+NRT Sampling will improve cessation outcomes and depressive symptoms relative 
to TAU. Potential issues of clinical deterioration/suicidality, NRT risks, confidentiality, data breach, 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 enrollment and study outcomes will not be shared with medical staff, including the participant’s 
physician. 
 
 
REFERENCES 
 
1. 
MacPherson L, Collado A, Lejuez CW, Brown RA, Tull MT. Behavioral activation 
treatment for smoking (BATS) in smokers with depressive symptomatology. Advances in 
Dual Diagnosis 2016;9(2/3):85-96. 
2. 
Abuse S. Mental Health Services Administration.(2013) Results from the 2012 
National Survey on Drug Use and Health: Summary of National Findings (No. NSDUH 

Version 10; Version Date 12/2/2021 
 
Page 17 of 22 
 
Series H-46, HHS Publication No.(SMA) 13–4795). Rockville, MD: Substance Abuse and 
Mental Health Services Administration 2014. 
3. 
Kessler RC, Zhao S, Blazer DG, Swartz M. Prevalence, correlates, and course of 
minor depression and major depression in the National Comorbidity Survey. J Affect 
Disord 1997;45(1-2):19-30. 
4. 
Pietrzak R, Kinley J, Afifi T, Enns M, Fawcett J, Sareen J. Subsyndromal 
depression in the United States: prevalence, course, and risk for incident psychiatric 
outcomes. Psychol Med 2012;1(1):1-14. 
5. 
Centers for Disease Control and Prevention. Current depression among adults---
United States, 2006 and 2008. Morb Mortal Weekly Rep 2010;59(38):1229. 
6. 
Pratt LA, Brody DJ. Depression and smoking in the US household population aged 
20 and over, 2005-2008. NCHS data brief 2010(34):1-8. 
7. 
Trosclair A, Dube SR. Smoking among adults reporting lifetime depression, anxiety, 
anxiety with depression, and major depressive episode, United States, 2005-2006. Addict 
Behav 2010;35(5):438-443. 
8. 
Weinberger AH, Kashan RS, Shpigel DM, Esan H, Taha F, Lee CJ, et al. 
Depression and cigarette smoking behavior: a critical review of population-based studies. 
The American journal of drug and alcohol abuse 2016:1-16. 
9. 
Weinberger AH, Pilver CE, Desai RA, Mazure CM, McKee SA. The relationship of 
dysthymia, minor depression, and gender to changes in smoking for current and former 
smokers: Longitudinal evaluation in the US population. Drug Alcohol Depend 
2013;127(1):170-176. 
10. 
Leventhal AM, Ray LA, Rhee SH, Unger JB. Genetic and environmental influences 
on the association between depressive symptom dimensions and smoking initiation among 
Chinese adolescent twins. Nicotine Tobacco Res 2012;14(5):559-568. 
11. 
Audrain-McGovern J, Rodriguez D, Leventhal AM, Cuevas J, Rodgers K, Sass J. 
Where is the pleasure in that? Low hedonic capacity predicts smoking onset and 
escalation. Nicotine Tobacco Res 2012;14(10):1187-1196. 
12. 
Dierker L, Rose J, Selya A, Piasecki TM, Hedeker D, Mermelstein R. Depression 
and nicotine dependence from adolescence to young adulthood. Addict Behav 
2015;41:124-128. 
13. 
Prochaska JJ, Rossi JS, Redding CA, Rosen AB, Tsoh JY, Humfleet GL, et al. 
Depressed smokers and stage of change: implications for treatment interventions. Drug 
Alcohol Depend 2004;76(2):143-151. 
14. 
Buckner JD, Farris SG, Zvolensky MJ, Shah SM, Leventhal AM, Minnix JA, et al. 
Dysphoria and smoking among treatment seeking smokers: the role of smoking-related 
inflexibility/avoidance. The American journal of drug and alcohol abuse 2015;41(1):45-
51. 
15. 
Cooper J, Borland R, McKee SA, Yong HH, Dugué PA. Depression motivates quit 
attempts but predicts relapse: differential findings for gender from the International 
Tobacco Control Study. Addiction 2016. 

Version 10; Version Date 12/2/2021 
 
Page 18 of 22 
 
16. 
Niaura R, Britt DM, Shadel WG, Goldstein M, Abrams D, Brown R. Symptoms of 
depression and survival experience among three samples of smokers trying to quit. 
Psychol Addict Behav 2001;15(1):13. 
17. 
Callaghan RC, Veldhuizen S, Jeysingh T, Orlan C, Graham C, Kakouris G, et al. 
Patterns of tobacco-related mortality among individuals diagnosed with schizophrenia, 
bipolar disorder, or depression. J Psychiatr Res 2014;48(1):102-110. 
18. 
Leventhal AM, Zvolensky MJ. Anxiety, depression, and cigarette smoking: A 
transdiagnostic vulnerability framework to understanding emotion–smoking comorbidity. 
Psychol Bull 2015;141(1):176. 
19. 
US Department of Health and Human Services. The health consequences of 
smoking—50 years of progress: a report of the Surgeon General. Atlanta, GA: US 
Department of Health and Human Services, Centers for Disease Control and Prevention, 
National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking 
and Health 2014;17. 
20. 
van der Meer RM, Willemsen MC, Smit F, Cuijpers P. Smoking cessation 
interventions for smokers with current or past depression. The Cochrane Library 2013. 
21. 
Kazdin AE. Evidence-based psychosocial treatment: Advances, surprises, and 
needed shifts in foci. Cogn Behav Pract 2016;23(4):426-430. 
22. 
Kazdin AE. Addressing the treatment gap: A key challenge for extending evidence-
based psychosocial interventions. Behav Res Ther 2017;88:7-18. 
23. 
Kazdin AE, Blase SL. Rebooting psychotherapy research and practice to reduce the 
burden of mental illness. Perspect Psychol Sci 2011;6(1):21-37. 
24. 
Clarke G, Yarborough BJ. Evaluating the promise of health IT to enhance/expand 
the reach of mental health services. Gen Hosp Psychiatry 2013;35(4):339-344. 
25. 
Dahne J, Wahlquist AE, Carpenter MJ. Prevalence of Evidence-Based Cessation 
Method Utilization by State and State-level Predictors of Cessation Method. In: Society 
for Research on Nicotine and Tobacco,. Chicago, Illinois; 2016. 
26. 
Siu AL, Bibbins-Domingo K, Grossman DC, Baumann LC, Davidson KW, Ebell M, 
et al. Screening for depression in adults: US Preventive Services Task Force 
recommendation statement. JAMA 2016;315(4):380-387. 
27. 
Jamal A, Dube SR, Malarcher AM, Shaw L, Engstrom MC, Control CfD, et al. 
Tobacco use screening and counseling during physician office visits among adults—
National ambulatory medical care survey and national health interview survey, United 
States, 2005–2009. Morb Mortal Weekly Rep 2012;61(Suppl):38-45. 
28. 
Fiore M, Jaén C, Baker T, Bailey W, Benowitz N, Curry S. Treating tobacco use 
and dependence: 2008 update. Washington, DC: US Department of Health and Human 
Services; 2008. In; 2012. 
29. 
Papadakis S, McDonald P, Mullen K-A, Reid R, Skulsky K, Pipe A. Strategies to 
increase the delivery of smoking cessation treatments in primary care settings: a systematic 
review and meta-analysis. Prev Med 2010;51(3):199-213. 

Version 10; Version Date 12/2/2021 
 
Page 19 of 22 
 
30. 
Kruger J, O’Halloran A, Rosenthal A. Assessment of compliance with US Public 
Health Service clinical practice guideline for tobacco by primary care physicians. Harm 
reduction journal 2015;12(1):7. 
31. 
Kruger J, O’Halloran A, Rosenthal AC, Babb SD, Fiore MC. Receipt of evidence-
based brief cessation interventions by health professionals and use of cessation assisted 
treatments among current adult cigarette-only smokers: National Adult Tobacco Survey, 
2009–2010. BMC Public Health 2016;16(1):141. 
32. 
Schnoll RA, Rukstalis M, Wileyto EP, Shields AE. Smoking cessation treatment by 
primary care physicians: an update and call for training. Am J Prev Med 2006;31(3):233-
239. 
33. 
Garg A, Serwint JR, Higman S, Kanof A, Schell D, Colon I, et al. Self-efficacy for 
smoking cessation counseling parents in primary care: an office-based intervention for 
pediatricians and family physicians. Clin Pediatr (Phila) 2007;46(3):252-257. 
34. 
Steinhubl SR, Muse ED, Topol EJ. Can mobile health technologies transform health 
care? JAMA 2013;310(22):2395-2396. 
35. 
Pew Research Center. (2017). Mobile Fact Sheet. Pew Internet & American Life 
Project.  Retrieved from http://www.pewinternet.org/fact-sheet/mobile/ 
36. 
Olmstead K, Atkinson M. Apps permissions in the Google Play store. Pew Research 
Center 2016. 
37. 
Franko OI, Tirrell TF. Smartphone app use among medical providers in ACGME 
training programs. J Med Syst 2012;36(5):3135-3139. 
38. 
Abroms LC, Padmanabhan N, Thaweethai L, Phillips T. iPhone apps for smoking 
cessation: a content analysis. Am J Prev Med 2011;40(3):279-285. 
39. 
Abroms LC, Westmaas JL, Bontemps-Jones J, Ramani R, Mellerson J. A content 
analysis of popular smartphone apps for smoking cessation. Am J Prev Med 
2013;45(6):732-736. 
40. 
McClure JB, Hartzler AL, Catz SL. Design considerations for smoking cessation 
apps: feedback from nicotine dependence treatment providers and smokers. JMIR mHealth 
and uHealth 2016;4(1). 
41. 
Sigg S, Lagerspetz E, Peltonen E, Nurmi P, Tarkoma S. Sovereignty of the Apps: 
There's more to Relevance than Downloads. arXiv preprint arXiv:161110161 2016. 
42. 
Thom DH, Hall MA, Pawlson LG. Measuring patients’ trust in physicians when 
assessing quality of care. Health Aff (Millwood) 2004;23(4):124-132. 
43. 
Luxton DD, McCann RA, Bush NE, Mishkind MC, Reger GM. mHealth for mental 
health: Integrating smartphone technology in behavioral healthcare. Professional 
Psychology: Research and Practice 2011;42(6):505. 
44. 
Collado A, Castillo SD, Maero F, Lejuez C, MacPherson L. Pilot of the brief 
behavioral activation treatment for depression in Latinos with limited English proficiency: 
preliminary evaluation of efficacy and acceptability. Behavior therapy 2014;45(1):102-
115. 
45. 
Cuijpers P, Van Straten A, Warmerdam L. Behavioral activation treatments of 
depression: A meta-analysis. Clin Psychol Rev 2007;27(3):318-326. 

Version 10; Version Date 12/2/2021 
 
Page 20 of 22 
 
46. 
Gros DF, Price M, Strachan M, Yuen EK, Milanak ME, Acierno R. Behavioral 
activation and therapeutic exposure: An investigation of relative symptom changes in 
PTSD and depression during the course of integrated behavioral activation, situational 
exposure, and imaginal exposure techniques. Behav Modif 2012:0145445512448097. 
47. 
Hopko DR, Lejuez C, Lepage JP, Hopko SD, McNeil DW. A Brief Behavioral 
Activation Treatment for Depression A Randomized Pilot Trial within an Inpatient 
Psychiatric Hospital. Behav Modif 2003;27(4):458-469. 
48. 
Lejuez C, Hopko DR, Acierno R, Daughters SB, Pagoto SL. Ten year revision of 
the brief behavioral activation treatment for depression: Revised treatment manual. Behav 
Modif 2011;35(2):111-161. 
49. 
Lejuez C, Hopko D, LePage J, Hopko S, McNeil D. A brief behavioral activation 
treatment for depression. Cogn Behav Pract 2001;8(2):164-175. 
50. 
Mazzucchelli T, Kane R, Rees C. Behavioral activation treatments for depression in 
adults: a meta-analysis and review. Clinical Psychology: Science and Practice 
2009;16(4):383-411. 
51. 
Reynolds EK, MacPherson L, Tull MT, Baruch DE, Lejuez C. Integration of the 
brief behavioral activation treatment for depression (BATD) into a college orientation 
program: Depression and alcohol outcomes. J Couns Psychol 2011;58(4):555. 
52. 
Sturmey P. Behavioral activation is an evidence-based treatment for depression. 
Behav Modif 2009;33(6):818-829. 
53. 
MacPherson L, Tull MT, Matusiewicz AK, Rodman S, Strong DR, Kahler CW, et 
al. Randomized controlled trial of behavioral activation smoking cessation treatment for 
smokers with elevated depressive symptoms. J Consult Clin Psychol 2010;78(1):55. 
54. 
MacPherson L, Collado A, Ninnemann A, Hoffman E. Development of a Behavioral 
Activation–Based Intervention for Cigarette-Smoking Young Adults. Cogn Behav Pract 
2017;24(1):101-114. 
55. 
Hughes JR, Hatsukami D. Signs and symptoms of tobacco withdrawal. Arch Gen 
Psychiatry 1986;43(3):289-294. 
56. 
Baker TB, Piper ME, Stein JH, Smith SS, Bolt DM, Fraser DL, et al. Effects of 
nicotine patch vs varenicline vs combination nicotine replacement therapy on smoking 
cessation at 26 weeks: A randomized clinical trial. JAMA 2016;315(4):371-379. 
57. 
Stead LF, Perera R, Bullen C, Mant D, Hartmann-Boyce J, Cahill K, et al. Nicotine 
replacement therapy for smoking cessation. The Cochrane Library 2012. 
58. 
Carpenter MJ, Hughes JR, Gray KM, Wahlquist AE, Saladin ME, Alberg AJ. 
Nicotine therapy sampling to induce quit attempts among smokers unmotivated to quit: a 
randomized clinical trial. Arch Intern Med 2011;171(21):1901-1907. 
59. 
Jardin BF, Cropsey KL, Wahlquist AE, Gray KM, Silvestri GA, Cummings KM, et 
al. Evaluating the effect of access to free medication to quit smoking: a clinical trial testing 
the role of motivation. Nicotine Tobacco Res 2014:ntu025. 
60. 
Burris JL, Heckman BW, Mathew AR, Carpenter MJ. A mechanistic test of nicotine 
replacement therapy sampling for smoking cessation induction. Psychol Addict Behav 
2015;29(2):392. 

Version 10; Version Date 12/2/2021 
 
Page 21 of 22 
 
61. 
Gwaltney CJ, Metrik J, Kahler CW, Shiffman S. Self-efficacy and smoking 
cessation: a meta-analysis. In: American Psychological Association; 2009. 
62. 
McCaul KD, Hockemeyer JR, Johnson RJ, Zetocha K, Quinlan K, Glasgow RE. 
Motivation to quit using cigarettes: A review. Addict Behav 2006;31(1):42-56. 
63. 
Mendiola MF, Kalnicki M, Lindenauer S. Valuable features in mobile health apps 
for patients and consumers: content analysis of apps and user ratings. JMIR mHealth and 
uHealth 2015;3(2). 
64. 
Kroenke K, Strine TW, Spitzer RL, Williams JB, Berry JT, Mokdad AH. The PHQ-
8 as a measure of current depression in the general population. J Affect Disord 
2009;114(1):163-173. 
65. 
Martin RC. Agile software development: principles, patterns, and practices: Prentice 
Hall PTR; 2003. 
66. 
Turner CW, Lewis JR, Nielsen J. Determining usability test sample size. 
International encyclopedia of ergonomics and human factors 2006;3(2):3084-3088. 
67. 
Van Den Haak M, De Jong M, Jan Schellens P. Retrospective vs. concurrent think-
aloud protocols: testing the usability of an online library catalogue. Behav Inf Technol 
2003;22(5):339-351. 
68. 
Krueger R. Doing qualitative research. Focus Groups: A Practical Guide for Applied 
Research California: Sage 1988. 
69. 
Krueger RA, Casey MA. Focus groups: A practical guide for applied research: Pine 
Forge Press; 2009. 
70. 
Strauss A, Corbin J. Basics of Qualitative Research. 1998. Thousand Oaks 1998. 
71. 
Sobell L, Sobell M. Timeline followback user’s guide: A calendar method for 
assessing alcohol and drug use. Toronto: Addiction Research Foundation 1996. 
72. 
Brown RA, Burgess ES, Sales SD, Whiteley JA, Evans DM, Miller IW. Reliability 
and validity of a smoking timeline follow-back interview. Psychol Addict Behav 
1998;12(2):101. 
73. 
Payne TJ, Smith PO, McCracken LM, McSherry WC, Antony MM. Assessing 
nicotine dependence: A comparison of the fagerström tolerance questionnaire (FTQ) with 
the fagerström test for nicotine dependence (FTND) in a clinical sample* 1. Addict Behav 
1994;19(3):307-317. 
74. 
Biener L, Abrams DB. The Contemplation Ladder: validation of a measure of 
readiness to consider smoking cessation. Health Psychol 1991;10(5):360. 
75. 
Beck AT, Steer RA, Brown GK. Beck Depression Inventory-II (BDI-II). San 
Antonio, TX: Psychological Corporation 1996. 
76. 
Kanter JW, Mulick PS, Busch AM, Berlin KS, Martell CR. The Behavioral 
Activation for Depression Scale (BADS): psychometric properties and factor structure. 
Journal of Psychopathology and Behavioral Assessment 2007;29(3):191-202. 
77. 
Carvalho JP, Gawrysiak MJ, Hellmuth JC, McNulty JK, Magidson JF, Lejuez C, et 
al. The reward probability index: design and validation of a scale measuring access to 
environmental reward. Behav Ther 2011;42(2):249-262. 

Version 10; Version Date 12/2/2021 
 
Page 22 of 22 
 
78. 
Etter JF, Perneger TV. Attitudes toward nicotine replacement therapy in smokers 
and ex-smokers in the general public. Clin Pharmacol Ther 2001;69(3):175-183. 
79. 
Sim J, Lewis M. The size of a pilot study for a clinical trial should be calculated in 
relation to considerations of precision and efficiency. J Clin Epidemiol 2012;65(3):301-
308. 
80. 
Raudenbush SW, Bryk AS. Hierarchical linear models: Applications and data 
analysis methods: Sage Publications, Incorporated; 2001. 
81. 
McCoach DB. Hierarchical linear modeling. The reviewer’s guide to quantitative 
methods in the social sciences 2010:123-140. 
82. 
Joseph MC, Schoeffler K, Doi PA, Yefko H, Engle C, Nissman EF. An automated 
COSTART coding scheme. Drug Inf J 1991;25(1):97-108. 
83. 
Spilker B. Guide To Clinical Trials. Philadelphia, PA: Lippincott Williams & 
Wilkins; 2000. 
84. 
Carpenter MJ, Hughes JR, Solomon LJ, Callas PW. Both Smoking Reduction With 
Nicotine Replacement Therapy and Motivational Advice Increase Future Cessation 
Among Smokers Unmotivated to Quit. J Consult Clin Psychol 2004;72(3):371. 
85. 
Benowitz NL. Nicotine Safety and Toxicity. New York: Oxford University Press; 
1998. 
86. 
Fagerström K-O, Hughes JR. Nicotine concentrations with concurrent use of 
cigarettes and nicotine replacement: A review. Nicotine Tob Res 2002;4:S73-S79.