Addressing Rural Cancer Disparities Via Proactive Smoking Cessation Treatment Within Primary Care: A Hybrid Type 1 Effectiveness-Implementation Trial of a Scalable Smoking Cessation Electronic Visit
Phase: NA
Conditions: Smoking Cessation
Sponsor: Medical University of South Carolina

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PROTOCOL TITLE: Addressing Rural Cancer Disparities via Proactive Smoking Cessation 
Treatment within Primary Care: A Hybrid Type 1 Effectiveness-Implementation Trial of a Scalable 
Smoking Cessation Electronic Visit 
 
PRINCIPAL INVESTIGATOR: Jennifer Dahne, Ph.D. 
 
 
 

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1.0 
Objectives / Specific Aims 
We will conduct a Hybrid Type I effectiveness-implementation trial to comprehensively assess 
effectiveness of a proactive electronic visit (e-visit) for smoking cessation relative to treatment as usual 
(TAU) while simultaneously evaluating implementation when delivered across rural primary care settings. 
In Aim 1, we will conduct a stepped-wedge, cluster-randomized clinical trial (N=288) to examine the 
effectiveness of the smoking cessation e-visit vs. TAU for smoking cessation across seven rural (Rural-
Urban Commuting Area codes 4-10) primary care practices in South Carolina. In Aim 2, we will evaluate 
e-visit implementation outcomes across rural South Carolina primary care settings at patient, provider, 
and organizational levels. Main outcomes include: 1) biochemically verified 7-day PPA (point prevalence 
of abstinence) at six-month follow-up, 2) reduction in cigarettes per day, and 3) evidence-based smoking 
cessation treatment utilization (medication, psychosocial cessation counseling). We hypothesize that rural 
smokers randomized to the e-visit condition will have significantly better cessation outcomes relative to 
TAU. 
 
2.0 
Background 
Rural residents are both more likely to smoke cigarettes and less likely to quit than their urban 
counterparts. Consequently, individuals in rural areas have a 7% higher incidence of tobacco-associated 
cancers. Comprehensive smoking cessation treatment dissemination strategies are needed to increase 
utilization of evidence-based treatment, improve cessation outcomes, and ultimately decrease cancer 
incidence among rural smokers. Primary care providers (PCPs) see 70% of smokers annually, and rural 
residents are more likely than urban residents to have a usual source of health care. As such, primary care 
offers a ripe opportunity to deliver cessation treatment to rural smokers. All primary care practices that 
qualify for Centers for Medicare and Medicaid Services reimbursement are required to maintain 
electronic health records (EHRs) with coded smoking status data for adult patients. These data can be 
utilized to proactively identify smokers and deliver remote treatment. Our team recently completed a pilot 
study to develop, refine, and preliminarily evaluate a proactive asynchronous smoking cessation 
electronic visit (e-visit) delivered via the EHR. The goal of the e-visit is to automate best practice 
guidelines for cessation treatment via primary care to ensure that all smokers receive an evidence-based 
intervention. An initial baseline e-visit gathers information about smoking history and motivation to quit, 
followed by an algorithm to determine the best FDA-approved cessation medication to prescribe. A one-
month follow-up e-visit assesses progress toward cessation. Clinical outcomes of our pilot (N=51 
followed for three months) were promising. Among rural participants who received the e-visit (n=6), 17% 
reported 7-day point prevalence abstinence (PPA), 67% reduced their cigarettes per day (CPD) by >50%, 
and 50% used a cessation medication. E-visit participants, relative to treatment as usual (TAU), were 4.2 
times more likely to report 7-day PPA, 4.1 times more likely to have reduced their CPD by >50%, and 4.7 
times more likely to have used a cessation medication. Acceptability outcomes were strong, with 100% of 
rural e-visit participants reporting that they would use an e-visit again in the future. These data suggest 
that the e-visit may be a feasible, efficacious approach to extend the reach of evidence-based cessation 
treatment via rural primary care. We now propose a Hybrid Type I effectiveness-implementation trial to 
comprehensively assess e-visit effectiveness relative to TAU while simultaneously evaluating 
implementation when delivered across rural primary care settings. Effectiveness outcomes will be 
assessed through 6-months of follow-up and include: 1) biochemically verified 7-day PPA, 2) reduction in 
CPD, and 3) evidence-based cessation treatment utilization. Implementation outcomes will be assessed at 
patient, provider, and organizational levels. This trial has the potential to expand cessation treatment 
access in a manner scalable across rural healthcare systems and ultimately reduce rural cancer disparities. 
 
3.0 
Intervention to be studied  

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Smoking Cessation E-Visit. The goal of the e-visit is to automate the 5As (Ask, Advise, Assess, Assist, Arrange) to 
ensure that all smokers receive treatment. After completing screening and consent, adult smokers recruited from 
clinics assigned to the e-visit condition will be automatically linked to initiate an asynchronous cessation e-visit via 
MyChart. The baseline e-visit will gather information about smoking history and motivation to quit, followed by an 
algorithm to determine the best FDA-approved cessation medication (i.e., NRT, varenicline, bupropion). This 
algorithm is based on our team’s prior research1-3 and evidence-based guidelines4. It uses branching logic to prioritize 
the most efficacious medications (varenicline and combination NRT), while tailoring recommendations based on 
contraindications and patient preference. The outcome is a medication recommendation displayed to the patient with 
a personalized rationale. All medication recommendations are provided in conjunction with a referral to the quitline 
for psychosocial counseling. The patient can agree with the recommendation or request a different treatment. E-visit 
results are automatically sent to the PCP’s in-basket, who will have 48 business hours to respond. If the e-visit is not 
responded to within this timeframe, it will be routed to MUSC’s e-visit care team for review and response. Providers 
will open the e-visit from their in-basket, review the e-visit and its algorithm outcome (e.g., medication 
recommendation), review the chart for contraindications to that outcome, agree or disagree with the recommendation, 
respond to the patient via MyChart with instructions, and e-prescribe (if indicated) medication. Varenicline, a class 
C medication, may be provided as a result of the e-visit. Because risks during pregnancy related to Varenicline are 
unknown, all females of childbearing potential will subsequently be asked if they would be willing to complete a 
pregnancy test that will be mailed to them. Females of childbearing potential who report a positive pregnancy test 
will not be prescribed Varenicline. All medications will be prescribed on label to the patient’s pharmacy of record, 
consistent with procedures from our pilot, and will be billed as in usual practice (i.e., to the patient’s insurance if 
insured). Participants are not required to obtain their prescribed medication from their pharmacy or to take the 
medication as part of their participation in this study. In addition to the quitline referral for psychosocial counseling, 
all responses from providers to patients will also include a digital copy of NCI’s Clearing the Air: Quit Smoking 
Today5. In a recent trial, smokers who were provided with Clearing the Air had a 12% abstinence rate at 6 months6. 
There will be direct contact between the PCP and patient prior to prescription, either via secure MyChart 
messaging or telephone, depending on the provider’s preference and need for information. If contraindications 
are present (e.g., a contraindicated medication is noted in the EHR) or if the patient reports untreated health concerns 
requiring attention (e.g., cough with blood), electronic contact will be supplemented with phone and/or in person 
contact.  
All participants will be scheduled for a follow-up e-visit one month later. The purpose of the 1-month e-visit 
is to assess progress toward cessation and troubleshoot barriers consistent with 5As guidelines to Arrange follow-up. 
This e-visit will begin by assessing current smoking status, quit attempts in the last month, and quit duration. 
Subsequently, the participant will report: 1) whether they received a cessation medication following baseline, 2) 
whether they are currently taking the medication, and 3) whether they have any questions/concerns. Participants will 
be asked if they are interested in any other treatment options, including a medication refill. Results will be sent to 
providers and reviewed and responded to in the same manner as the baseline e-visit.  
IRB approved investigators (e.g., Drs. Dahne, Diaz, and Player) will provide training on the smoking 
cessation e-visit to all PCPs at the beginning of each division’s e-visit period. All MUSC Regional Health Network 
(RHN) providers already respond to e-visits. Within the last year alone, MUSC PCPs have responded to 3,412 e-
visits. Thus, additional training herein will focus on the specific use of the smoking cessation e-visit and its decision-
support algorithm. All RHN clinics have monthly all-staff meetings, during which training will occur. Trainings will 
be recorded and distributed following meetings. Drs. Dahne, Diaz, and Player will also develop a brief video 
describing the workflow and tip sheets with overviews of e-visit functionality. These tip sheets will include 
information on smartphrases developed to improve the ease with which e-visits can be responded to (e.g., with 
information regarding dosing and links to additional information). These procedures are consistent with MUSC’s 
current training approaches which have been successful in promoting new workflow adoption. For example, this 
approach was used to train providers in the use of virtual check-ins and video visits during the COVID-19 pandemic 
and resulted in primary care providing 75.1% of historical in-person volume virtually within two weeks of 
implementation. Training recordings and tip sheets will be provided to new hires in clinics active within the e-visit 
condition upon onboarding. Similar training will be provided at study start to MUSC’s e-visit care team, which will 
be responsible for responding to e-visits not responded to within 48-hours by a patient’s PCP. It is important to note 
that this same training approach has been taken by Drs. Diaz and Player to train MUSC’s PCPs and the e-visit care 
team in delivery of all other e-visits currently available in MUSC’s e-visit primary care menu (e.g., for back pain, 
nosebleed, etc.). Because the workflow for this e-visit mirrors that of other e-visits, we believe it can likely be adopted 
with minimal training.  
 
TAU. TAU mimics existing standard care and follows procedures from our pilot trial. Participants recruited 
during TAU steps will be linked to a screen that includes information on the state quitline, education about quitting, 

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and a recommendation to contact their PCP to discuss cessation. TAU enrollment will precede e-visit enrollment for 
all divisions, which will prevent treatment contamination. Participants enrolled during a division’s TAU step will not 
be eligible for re-enrollment after the division transitions to the e-visit.   
 
4.0 
Study Endpoints (if applicable) 
Primary outcome variables include: 
• 
Experience using technology and internet access (home broadband, access via mobile device) will be 
assessed via questions from Pew Research Center’s technology adoption survey7. 
• 
Digital literacy will be assessed at baseline  via the Mobile Device Proficiency Questionnaire (MDPQ-16)8 
and the Computer Proficiency Questionnaire (CPQ-12)9. Both questionnaires are valid, reliable measures of 
device (mobile, computer) proficiency and have been used to facilitate digital literacy training within 
research contexts.8,9 
• 
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 assessment10,11. Nicotine dependence will be assessed at baseline via the 
Fagerström Test of Nicotine Dependence12. Participants will report motivation to quit and confidence in 
quitting using a modified Contemplation Ladder13. Self-reported smoking will be biochemically verified 
via breath CO, with abstinence defined as CO of ≤ 4ppm14. Self-report and CO data will be utilized 
together to determine 7-day PPA. 
• 
Treatment utilization will be assessed via self-report and EHR data. At each follow-up, all participants 
regardless of intervention will be queried for: 1) use of a cessation treatment (medication or psychosocial 
counseling) since the last assessment, 2) how the medication was obtained, and 3) receipt of the 5As from 
their PCP15. Self-report data will be supplemented with treatment utilization data pulled from the EHR 
coinciding with each follow-up. Specifically, we will capture: 1) cessation medication prescriptions, 2) if 
prescribed, whether cessation medications were filled, 3) whether the participant was referred to 
counseling, and 4) whether the participant attended a counseling session. 
• 
Confounders of CO including combustible cannabis use, secondhand smoke exposure, and environmental 
CO exposure within the last 24 hours will be assessed at all timepoints to account for factors that may 
falsely inflate CO. 
• 
Additional data from the EHR will be captured to describe the sample including information on: 1) 
medical and psychiatric comorbidities, 2) medications, 3) tobacco-related billing codes, and 4) insurance 
type. 
 
 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
Participants will complete a REDCap survey to be screened for eligibility and we will use cold-contact 
recruitment approaches herein.  
 
Inclusion criteria: 
a) 
Current cigarette smoking, defined as smoking 5+ cigarettes per day, for 20+ days out of the last 30, for the 
last 6+ months 
b) 
Age 18+ 
c) 
Enrolled in Epic’s MyChart program or willing to enroll 
d) 
Possess a valid e-mail address that is checked daily to access study assessments and MyChart messages  
e) 
Owner of an iOS or Android compatible smartphone to provide remote CO readings 
f) 
Have a valid address at which mail can be received (for mailing iCO™) 
g) English fluency 
Exclusion criteria: 
a) 
Current engagement in cessation treatment, defined as use of an FDA-approved cessation medication within 
the last 30 days 
 

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6.0 
Number of Subjects 
We will recruit up to 288 subjects. 
 
7.0 
Setting 
Research will be conducted remotely via REDCap and MyChart. Study participants will be recruited from 
rural South Carolina primary care clinics affiliated with MUSC’s Regional Health Network (RHN). The 
RHN is divided into four divisions: 1) Florence, 2) Marion, 3) Lancaster, and 4) Chester. At the time of 
this submission, 7 MUSC RHN primary care clinics are located in federally designated rural areas,  
defined as RUCA codes of 4-10. Among these seven clinics, three are affiliated with the Florence 
division, three with Marion, and one with Lancaster (no rural clinics are affiliated with Chester). 
 
8.0 
Recruitment Methods 
Participants will be recruited in the following ways: 
1) Cold-contact Recruitment: We will submit a research data request to obtain a recruitment report of 
MUSC patients who potentially meet eligibility criteria. We 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. We will use the following methods to 
contact participants: 1)  e-mail , 2) phone, 3) text messaging, 4) MyChart. 
2) Via  advertisements (e.g. flyers) and online postings 
3) Participants for key informant interviews will be recruited for interviews via targeted e-mail and 
phone messages. 
 
Note, that while we include the options to recruit via advertisements, these will be used as backup options 
should cold-contact recruitment be slow and /or result in an insufficient number of participants recruited.  
 
 
Recruitment of Minority Smokers 
Minorities will be included in the R01 trial. All participants will be recruited from rural MUSC Regional Health 
Network (RHN) primary care practices, which primarily serve residents of Florence, Marion, and Lancaster, South 
Carolina. Data from the 2019 American Community Survey reveal that the population within these areas is 67.2% 
White, 26.8% Black, 2.1% American Indian/Alaskan Native, Asian, or Pacific Islander, 2.3% reporting two or more 
races, and 5.7% are Hispanic or Latinx. Compared to overall area demographics, members of racial and/or ethnic 
minority groups tend to be overrepresented among adult smokers treated via MUSC’s rural RHN primary care 
practices. Roughly half of adult smokers treated via these clinics are members of a racial or ethnic minority group 
and 49.8% of participants enrolled in our e-visit pilot study identified as Black. We will monitor closely our minority 
recruitment goals on an ongoing basis. If the recruitment of minorities is lower than expected (less than 80% projected 
enrollment for each minority group), efforts will be made to improve recruitment of minorities into the study through 
oversampling. 
 
9.0 Consent Process 
After determination of eligibility, a study team member will complete remote electronic informed consent 
(e-consent) with the participant via REDCap. Participants will receive a link to an electronic consent 
form, available via REDCap, that they can review and sign. Review of the consent form will be paired 
with a phone call with a member of the research team to ensure that all questions are answered prior to 
enrollment. This remote consent procedure is currently utilized by Dr. Dahne in both her K23 and R21 
awards and has been used with success with smokers residing in rural areas. As smartphone ownership is 
an inclusion criterion (to provide remote CO), all participants will have internet access and thus access to 
the electronic consent form.    
 

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be assigned to treatment based on their divisional affiliation. Participants will be recruited within clinics. After 
completing consent, participants will complete baseline assessments and receive the intervention currently assigned 
to their clinic/division (based on their last primary care visit). Women who indicate during the e-visit that they are 
currently pregnant or are planning to become pregnant within the next 6 months will not receive a medication 
recommendation/prescription as a result of the e-visit. These women will receive NRT, Bupropion, and/or a 
counseling referral. Any female of childbearing potential will be asked to complete a pregnancy test. Females of 
childbearing potential will be mailed a pregnancy test by study staff and will receive a REDCap form within 3 days 
to verify (with signature) that they completed the test and their pregnancy test results. If the participant reports a 
positive pregnancy test to the study team, they will not receive varenicline as a result of the e-visit. These women 
instead will either receive NRT, bupropion and/or counseling based on other contraindications and medication 
preferences indicated throughout the e-visit. All participants will complete follow-up research assessments at 1-, 3-, 
and 6-months post-enrollment. 
 
Following enrollment, participants will be mailed an iCO™ Smokerlyzer. Prior to mailing, all iCO™ devices 
will be tested against a fixed concentration CO cannister and only devices that test within the manufacturer’s stated 
accuracy range (+15%) will be sent to participants. All participants will receive their iCO™ prior to their 1-month 
follow-up, and we anticipate having CO readings for all follow-ups.  
In addition to CO readings, participants will be text messaged and/or emailed (based on preference) a 
REDCap link to complete follow-up assessments at 1-, 3-, and 6-months post-enrollment. The 1-month research 
assessments and 1-month e-visit invitations will be sent at the same time, as baseline research assessments and the 
baseline e-visit are both completed at the same time. All participants (e-visit and TAU) will complete research 
assessments via REDCap (i.e., assessments are not embedded in the MyChart e-visit). We will require that 
participants complete follow-ups via their smartphone so that CO collection is seamlessly integrated with 
assessments.  
Assessments are estimated at 20 minutes. All compensation for this study will be provided with electronic 
gift card codes (e.g., Amazon). Participants will be compensated $20 in electronic gift codes for completion of each 
assessment, $20 for submission of CO at each follow-up timepoint, and will receive a $100 bonus if all follow-up 
assessments are completed. Procedures for remote remuneration are well-established through our prior trials22. At 
baseline, participants will self-report basic demographics including home address which will be used to determine 
degree of rurality. Experience using technology and internet access (home broadband, access via mobile device) will 
be assessed via questions from Pew Research Center’s technology adoption survey7. Digital literacy will be assessed 
at baseline  via the Mobile Device Proficiency Questionnaire (MDPQ-16)8 and the Computer Proficiency 
Questionnaire (CPQ-12)9. Both questionnaires are valid, reliable measures of device (mobile, computer) proficiency 
and have been used to facilitate digital literacy training within research contexts.8,9 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 assessment10,11. 
Nicotine dependence will be assessed at baseline via the Fagerström Test of Nicotine Dependence12. Participants will 
report motivation to quit and confidence in quitting using a modified Contemplation Ladder13. Self-reported smoking 
will be biochemically verified via breath CO, with abstinence defined as CO of ≤ 4ppm14. Self-report and CO data 
will be utilized together to determine 7-day PPA. Treatment utilization will be assessed via self-report and EHR data. 
At each follow-up, all participants regardless of intervention will be queried for: 1) use of a cessation treatment 
(medication or psychosocial counseling) since the last assessment, 2) how the medication was obtained, and 3) receipt 
of the 5As from their PCP15. Self-report data will be supplemented with treatment utilization data pulled from the 
EHR coinciding with each follow-up. Specifically, we will capture: 1) cessation medication prescriptions, 2) if 
prescribed, whether cessation medications were filled, 3) whether the participant was referred to counseling, and 4) 
whether the participant attended a counseling session. Confounders of CO including combustible cannabis use, 
secondhand smoke exposure, and environmental CO exposure within the last 24 hours will be assessed at all 
timepoints to account for factors that may falsely inflate CO. Additional data from the EHR will be captured to 
describe the sample including information on: 1) medical and psychiatric comorbidities, 2) medications, 3) tobacco-
related billing codes, and 4) insurance type. 
Interviews with key informants are estimated at 30-45 minutes and will be audio and video recorded. 
Participants will be compensated $20 in electronic gift card codes to Amazon upon completion of the interview. 
Interviews will be held with patients (n = 30), PCPs (n = 10), and stakeholders (n = 5). Drs. Dahne and Sterba will 
guide these interviews using the Consolidated Framework for Implementation Research (CFIR). 
 
 
Assessments: 
 

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Measure 
Screening 
Baseline 
1-month 
3-month 
6-month 
Screening 
x 
 
 
 
 
Demographics 
 
x 
 
 
 
PRC Technology Survey 
 
x 
 
 
 
MDPQ-16 
 
x 
 
 
 
CPQ-12 
 
x 
 
 
 
TLFB 
 
x 
x 
x 
x 
FTND 
 
x 
 
 
 
Contemplation Ladder 
 
x 
x 
x 
x 
MTQ Saliency 
 
x 
x 
x 
x 
Use of Other Tobacco Products 
 
 
x 
x 
x 
Use of Cessation Treatment 
 
 
x 
x 
x 
Brief Physician Advice 
 
 
x 
x 
x 
EHR data (e-visit group) 
 
 
 
x 
 
AIM (e-visit group) 
 
 
 
x 
 
E-Visit Feedback (e-visit group) 
 
 
x 
x 
x 
Confounders/Validity of CO  
 
 
x 
x 
x 
Adverse Events 
 
 
 
x 
x 
x 
 
 
Aim 2: Implementation Evaluation 
 
We will use mixed methods to assess implementation during our 
effectiveness trial at patient, provider, and organizational levels. Our 
framework is guided by the Consolidated Framework for Implementation 
Research (CFIR), which provides a comprehensive, pragmatic approach to 
understand implementation barriers, facilitators and processes23. The goal is 
to provide an in-depth understanding of implementation acceptability, 
adoption, and capacity for sustainability. Specific implementation outcomes 
will be assessed according to Proctor’s guidance17, which has recently been 
adapted by Hermes et al. for digital intervention evaluation18. These models suggest the evaluation of key 
implementation factors including: acceptability, adoption, fidelity, cost, penetration, and sustainability. All self-report 
Implementation Evaluation 
IMPLEMENTATION
OUTCOMES
Patient
Acceptability
Adoption
Fidelity
Organization
Cost
Penetration
Sustainability
Provider
Acceptability
Adoption
Fidelity

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assessments will be administered to patients in the e-visit condition during the 3-month research assessment,  
following completion of baseline and 1-month e-visits. Provider questionnaires will be administered via REDCap to 
MUSC RHN PCPs affiliated with the rural clinics involved in the trial who have at least one patient enrolled in the 
e-visit condition. Provider questionnaires will be sent at 6 weeks following each site’s start in the e-visit arm and 
again at the end of Year 4. Systems-level evaluation will utilize aggregate analytics supplemented with qualitative 
data. We will conduct key informant interviews with patients, PCPs, and stakeholders to enhance quantitative data. 
No studies to our knowledge have specifically examined implementation outcomes of proactive EHR-facilitated 
cessation treatments. As such, for each implementation factor, we have identified benchmarks that would be 
indicative of meaningful uptake. These benchmarks have been selected based on prior documented rates of cessation 
treatment acceptance and medication receipt within primary care24, Healthy People 2020’s goals for cessation 
treatment in ambulatory settings25, and prior uptake rates in response to proactive, automated cessation intervention 
delivery in primary care26,27. 
 
Acceptability 
 
Acceptability refers to the extent to which an innovation is agreeable, palatable, or satisfactory to a 
stakeholder. We will measure acceptability at patient and provider levels via the 4-item Acceptability of Intervention 
Measure (AIM)28. Items are scored on a 5-point Likert scale, and the resulting scale score is the mean of responses. 
The e-visit will be considered acceptable if the average score within each group across respondents is greater than or 
equal to 4 (scale range = 1-5). 
 
Adoption 
 
Adoption refers to the intention, decision, or initiation of use for an evidence-based practice and will be 
characterized at patient and provider levels via EHR data. At the patient level, we will capture the percent of: 1) e-
visits opened, 2) e-visits completed and forwarded to the PCP, and 3) prescribed medications obtained. Using EHR 
data, we will also compare demographics of patients who enroll in the trial vs. do not to determine whether a 
demographic-related adoption gap exists. At the provider level, we will assess the percent of e-visits: 1) opened by a 
patient’s PCP, 2) responded to by a patient’s PCP, and 3) that result in a prescription from a patient’s PCP. The same 
metrics will be captured for e-visits responded to by the ED e-visit team. The e-visit will be characterized as having 
high adoption potential among patients if >80% of e-visits are opened, completed, and forwarded to the PCP and 
>70% of patients prescribed a medication obtain their medication. The e-visit will be characterized as having high 
adoption potential among PCPs if >80% of completed e-visits are opened and responded to by a patient’s own PCP 
and if >80% of e-visits in which contraindications are not present result in medication prescription. Similar evaluation 
metrics will be applied to e-visits routed to the ED e-visit team. 
 
Fidelity 
 
Fidelity refers to the extent to which an intervention is used/delivered as intended. Fidelity evaluation herein 
will focus on protocol adherence, which will be assessed at patient and provider levels. We will utilize an 
implementation tracking checklist in REDCap to monitor completion of each step of the e-visit process for patients 
and providers. Research assistants will complete the checklist for each e-visit and we will evaluate the percentage of 
total steps completed. Across e-visits, we will assess which steps are most often skipped and why, which will be 
probed during key informant interviews and will guide refinements. For example, if across e-visits we find that PCPs 
are e-prescribing medications but are not responding to patients electronically with treatment plans, this would 
suggest needed intervention modifications to augment and facilitate this process. 
 
Cost Impact of Implementation 
 
Health systems may be more likely to implement the e-visit if it is established as either 1) cost-saving or 2) 
providing benefit cost-effectively. To examine cost-savings from the budgetary perspective, we will first calculate 
the net benefit of the e-visit: cost-savings = [(Expenditurespre – Expenditurespost)e-visit – (Expenditurespre-
Expenditurespost)TAU] – Coste-visit + Revenuese-visit. Healthcare utilization expenditures will be obtained from MUSC 
RHN billings. E-visit implementation cost will be provided by MUSC’s BMIC, who will provide ranges of e-visit 
development and distribution costs. Cessation medication costs will be based on actual billing data. We will conduct 
sensitivity analyses using medication cost ranges from the National Average Acquisition Cost data, and e-visit 
revenue ranges from $15.52 to $50.16 (current Medicare e-visit reimbursement rate). 
There is also a compelling case for adoption if the e-visit improves outcomes cost-effectively. We will follow 
gold standard procedures29 to calculate the incremental cost effectiveness ratio (ICER), or the additional cost per 
additional desired outcome. Here, ICER = (Coste-visit – CostTAU) / (7-day PPA Prevalencee-visit – 7-day PPA 
PrevalenceTAU). If differences in baseline patient characteristics between e-visit and TAU are evident, a generalized 

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linear model will be used to adjust outcomes and costs for these differences. We will conduct probabilistic sensitivity 
analyses to test results robustness across ranges of costs, revenues and treatment effectiveness30. Effectiveness ranges 
will be based on confidence intervals estimated in Aim 1. Ranges in cost and revenues will be captured as described 
above. All costs and revenues will be converted to net present value at standard discount rates of 3% and 5%. We 
will also construct an acceptability curve to demonstrate the probability of the e-visit being cost-effective under 
different levels of willingness to pay. 
 
Penetration 
 
Penetration refers to the integration of a practice within a service setting. Provider-level penetration will be 
assessed during the effectiveness trial. We will determine the total number of unique PCPs employed by MUSC’s 
rural RHN primary care clinics who reviewed a study e-visit and divide this number by the total number of PCPs 
employed by those clinics. High penetration will be indicated by >75% of providers reviewing an e-visit during the 
study. Patient-level penetration will be assessed during the sustainability evaluation period and will be defined as the 
total number of unique patients who complete a smoking cessation e-visit during Year 5 divided by the total number 
adult patients who are current smokers with MyChart access that have a primary care appointment in a rural RHN 
clinic during Year 5. High patient-level penetration will be defined as >20% of eligible patients completing a smoking 
cessation e-visit during the sustainability period. A 20% benchmark is similar31 or higher26,27 than other proactive 
cessation trials within the primary care setting. 
 
Sustainability 
 
Effectiveness trial enrollment will conclude by the end of Year 4, and e-visit sustainability will be evaluated 
in Year 5. During the final three months of Year 4, Dr. Dahne will work with MUSC’s BMIC team to ready the e-
visit for clinical implementation across rural RHN clinics. Drs. Dahne, Diaz, and Player will provide additional 
training to all providers and clinic staff regarding how to invite patients to complete the e-visit. MUSC’s BMIC will 
create patient lists, available to each provider, of patients that are e-visit eligible. Trainings will focus on accessing 
these lists, inviting patients to complete the e-visit, and review of procedures for responding to e-visits. As with 
trainings provided during the effectiveness trial, we will match as closely as possible training procedures that would 
occur in usual practice if a new e-visit were to be released. Billing procedures will be identical between the 
effectiveness trial and the sustainability evaluation (i.e., as in usual practice). At the beginning of Year 5, the e-visit 
will become available for clinical utilization. During this period, providers will be able to invite their own patients to 
complete the e-visit. During Year 5, we will track adoption, fidelity, and penetration via EHR analytics data. These 
metrics will be calculated and interpreted in the same manner as above.  
 
 
Qualitative Data Collection 
Quantitative data collection will be supplemented with key informant interviews with patients (n=30, or until 
saturation), PCPs (n=20, or until saturation), and organizational stakeholders (n=5). This mixed methods approach 
was chosen because, while quantitative data can identify implementation outcomes, qualitative data provide guidance 
regarding implementation barriers and facilitators faced and methods for optimization in rural practices and among 
rural patients. Diverse patients and PCPs in terms of clinic location, demographics, time in practice, and cessation 
outcomes will be recruited for interviews. For patient interviews, we will specifically recruit patients who were 
invited to enroll in the trial, but opted not to (n=10), patients who enrolled but did not complete either the baseline or 
1-month e-visit (n=10), and patients who enrolled and completed both the baseline and 1-month e-visits (n=10). A 
key focus of these interviews will be on the potential impact of the digital divide on trial/intervention access and 
uptake to determine which patients are most likely to access the e-visit, should it be scaled. Similarly, we will recruit 
PCPs with high e-visit adoption (i.e., responded to >80% of e-visits completed by their patients; n=10) and low e-
visit adoption (i.e., responded to <20%; n=10). Organizational stakeholders will include IT support staff from the 
RHN, the RHN’s Chief Quality Officer, practice managers and medical directors, clinical pharmacists, the co-
Director of MUSC’s BMIC, and the Chief Executive Officer of Palmetto Care Connections. PCPs and stakeholders 
will be recruited for interviews via targeted e-mail and phone messages. Interviews (~30-45 minutes) will be 
conducted by IRB approved members of the investigative team (e.g., Drs. Sterba and Dahne) in person or by telephone 
with a structured interview guide developed using the CFIR23. Interviews will focus on each implementation factor 
described above with the goal to enhance quantitative data within each domain and guide best practices for 
implementation in rural settings. Interviews will be conducted until theme saturation is achieved32,33 and will be audio-
taped and transcribed for analysis. All audio and video recordings will be destroyed within 12 months of completion 
of the entire study. Methods to ensure trustworthiness of qualitative data collection and analysis (e.g., audit trails, 
prolonged engagement with data) will be used34. 

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11.0 
Data Analysis and Data Management  
 
Aim 1 (Effectiveness RCT) Statistical Design 
 
Power. Our primary effectiveness outcome is cessation, defined as 7-day CO-verified PPA at 6-months. Preliminary 
data from our e-visit pilot demonstrated 7-day PPA rates at 3-months of 21.7% and 6.3% for e-visit and TAU groups, 
respectively. We expect similar group differences at 6-months and use these rates for power and sample size 
estimation. In addition, we expect some degree of intra-clinic/intra-division correlation (i.e., intraclass correlation 
(ICC)), where patients who attend the same clinic are not completely independent from each other and allow for the 
possibility that they are correlated with each other. We assume this to be relatively low and estimate it at 0.013, based 
on our prior site-randomized NRT sampling study35,36. A complete stepped-wedge cluster-randomized design with 
three clusters (divisions), four time periods (including a baseline period), three steps (one for each division to switch 
from TAU to e-visit), and an average of 72 patients per division (18 patients per division per time period), provides 
a total sample size of 216. Using a Wald Z-Test, with an ICC of 0.013 and a significance level of 0.05, N=216 has 
more than 80% power to detect a difference in 7-day CO-verified PPA at 6-months of 21.7% (e-visit) vs. 6.3% (TAU). 
To account for 25% possible attrition based on our previous studies35,37, the sample size is inflated to a total of 288 
participants (96 patients per division, with 24 patients per division per time period).   
 
Other outcomes for this trial include treatment utilization and reduction in CPD of >50%. In our e-visit pilot, treatment 
utilization rates at 3-months were higher in the e-visit group (60.9%) compared to the TAU group (25%); similarly, 
reduction in CPD of >50% was higher in the e-visit group (65.2%) compared to the TAU group (31.3%). Using a 
complete stepped-wedge cluster-randomized design (as above with three clusters, four time periods, and three steps 
with a total sample size of N=288), we will have more than sufficient power to see similar differences, and in fact 
smaller differences. For example, a stepped-wedge cluster-randomized trial (as defined herein) would have >80% 
power to see differences as small as 27% (Treatment Utilization: 52% e-visit, 25% TAU) and 29% (Reduction in 
CPD: 60% e-visit, 31% TAU). 
 
Cessation treatment utilization and cessation outcomes. Simple descriptive statistics will be summarized overall 
and within division and intervention group for baseline demographic variables, such as sex, age, race, ethnicity, 
digital literacy, insurance type, income, marital status, medical and psychiatric comorbidities (as indicated in the 
EHR), nicotine dependence, motivation to quit, and other household members who smoke. These baseline variables 
will also be summarized within division (between intervention groups) to evaluate balance within a division and 
between intervention groups and identify potential selection bias or time effects. Comparisons within clusters (i.e., 
TAU vs. e-visit within divisions) will be initially compared via paired testing such as paired-t-tests, Wilcoxon signed-
rank tests (continuous variables), or McNemar’s tests (categorical variables). To evaluate the possibility of time 
effects, generalized linear mixed models (GLMMs) will then be used including all patients from all divisions and all 
time periods. These models allow for examining baseline differences while accounting for random effects for division 
as well as fixed effects of time (for each step in the design). The fixed effect of time is important to include in order 
to verify that any potential intervention effects are not a function of a temporal trend outside of the intervention. This 
will allow for confidence in identifying any effects due to the intervention. A larger GLMM will then be used that 
incorporates all patients from all divisions to evaluate baseline differences between intervention groups (while 
accounting for division and time effects). 
 
Descriptive statistics (e.g., frequencies, percentages) will be calculated for the primary smoking-related outcomes 
(self-reported and biochemically verified 7-day PPA, reduction in CPD >50%, treatment utilization) overall, by 
division, by treatment group, and by treatment group within division. For analysis of these primary outcomes, 
GLMMs with logit links for binary outcomes will be used to examine between group (intervention) differences while 
accounting for division clustering effects and fixed time effects (for each step). To examine group differences adjusted 
for relevant covariates based on baseline differences, GLMMs will also be used by adding baseline effects to models 
in addition to a random effect for division and a fixed effect of time (for each step).    
 
Secondary subgroup analyses. While digital platforms have the potential to increase treatment access by decreasing 
barriers, they may be more readily accessed by more advantaged groups. Thus, it is critical to understand for which 
groups of rural smokers the e-visit is most/least beneficial. GLMMs including main effects of treatment group and 
specific subgroup variables of interest (e.g., education, race, income, degree of rurality, mental health comorbidities, 

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digital literacy, insurance type) along with an interaction term between treatment and the subgroup will be used to 
evaluate for which groups of smokers the e-visit is most beneficial. Each subgroup will be evaluated individually. 
All models will include a random division effect to account for clustering as well as a fixed effect for time. As this is 
an exploratory analysis, the focus will be on effect sizes rather than solely on statistical significance, with no 
adjustment for multiple comparisons. Statistical significance of interaction terms will be interpreted in conjunction 
with the effect size and will not solely define a significant, observed effect. 
 
Missing data and dropout. All enrolled participants will be included in analyses (intent-to-treat approach). We will 
examine dropout as function of treatment group, division, and time to examine whether treatment is associated with 
differential study retention. A sensitivity analysis will be used to assess the potential effect of missing outcome data 
on parameter estimates. Parameters will be estimated using: 1) all available data, 2) missing outcome data imputed 
to baseline, and 3) methods of multiple imputations. Imputation of missing data in smoking cessation trials to the 
baseline condition is often used as it is conservative38, does not necessitate the missing and random assumption, and 
allows for correlation between missing status and smoking status39. 
 
Aim 2 Qualitative Data Analysis 
 
Qualitative data will be analyzed using NVivo software40 with a deductive/inductive template analysis approach41,42 
using an initial CFIR-derived codebook but also allowing additional codes to be generated directly from the data. 
Two coders will independently review and code data using an iterative, team-based process to refine the codebook 
with discrepancies resolved by the study team. After completing qualitative and quantitative data analysis 
independently, data from each source will be synthesized using graphical matrix configurations for data 
triangulation43. Qualitative themes will be supplemented by patterns identified in quantitative results. Findings will 
characterize needs, concerns, and impressions of our key informants and guide implementation strategies for 
disseminating the e-visit intervention widely in rural settings.  
 
Data Management 
 
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 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. Audio and video recordings from key informant interviews will 
be destroyed within 12 months of completion of the entire study. 
 
Recruitment projects are housed in REDCap. Only IRB-approved study personnel listed on this application 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. This recruitment project will be stored separately from the project containing 
research data.  
 
12.0 
Provisions to Monitor the Data to Ensure the Safety of Subjects (if applicable) 
 
This section is based on the recommendations in NCI’s “Essential Elements of a Data and Safety Monitoring Plan 
for Clinical Trials Funded by the National Cancer Institute” as well as NIDA’s “Guidelines for Developing a Data 
and Safety Monitoring Plan”.  
 
Summary of the Protocol 

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This R01 application consists of a 2-Aim proposal. In Aim 1, we will conduct a stepped-wedge, cluster-randomized 
clinical trial (N=288) to examine the effectiveness of the smoking cessation e-visit vs. TAU for smoking cessation 
across seven rural (Rural-Urban Commuting Area codes 4-10) primary care practices in South Carolina. In Aim 2, 
we will evaluate e-visit implementation outcomes across rural South Carolina primary care settings at patient, 
provider, and organizational levels. See “Protection of Human Subjects” for inclusion/exclusion criteria and C.4.g 
within the “Research Strategy” for sample size justification. 
 
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 rural primary care clinics that are part of MUSC’s Regional Health Network (RHN). The target population is 
described under “Protection of Human Subjects” and below in the adjoining Planned Enrollment Table. Participant 
enrollment for Aim 1 will occur during months 4-48 (months within total study duration). 
 
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). All data from the iCO™ Smokerlyzer (personal breath CO monitor) 
will also be entered and stored in REDCap. Data analytic plans are outlined in section C.4.h of the Research Strategy 
as well as in the Statistical Design and Power attachment. 
 
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 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-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 5% or less. 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 Society for Research on Nicotine and 
Tobacco’s rules for disclosure as well as the rules of MUSC’s COI committee. 
 
Trial Safety 
The potential risks and benefits and methods to minimize these risks are outlined in the “Protection of Human 
Subjects” section. AEs will be tracked and rated by the participant as mild, moderate or severe and as related or 
unrelated to cessation medications received as part of the e-visit. 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 as only FDA-approved medications for cessation will be used and all medications will be used on label. 
Nonetheless, any AEs will be coded on a weekly basis using the FDA’s COSTART rules44 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 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), the research assistant 
will report any premonitory symptoms to suggest emergence of a serious psychiatric condition (e.g., major 

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depression, suicidality). Drs. Diaz and Player, board-certified Family Medicine physicians, 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 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 useful45. We will encourage 
participants to notify their physicians that a) they are in a randomized controlled research study examining a treatment 
for 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.  
 
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. 
 
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 to 
a) see if any particular COSTART categories are being endorsed more frequently than normal and b) 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. 
 
Data and Safety Monitoring Board Plan 
We will create a Data and Safety Monitoring Board (DSMB), comprised of three clinicians with expertise in rural 
health, smoking cessation treatment, and smoking cessation clinical trials, and a statistician. The DSMB will meet 
annually (more frequently as needed for emergent situations) 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. 
If necessary, modifications will be made to the procedures and/or the protocol based on the findings of the board.  
 
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 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) 
smoking cessation medications, b) confidentiality, c) frustration, d) risks during pregnancy, e) randomization, and f) 
uknown risks. 
 
a) Smoking cessation medications: Participants assigned to the smoking cessation e-visit may receive an FDA-
approved smoking cessation medication recommendation and prescription as an outcome of the e-visit. 
Medication options include: nicotine replacement therapy (NRT; prescribed either as a single or combination 
therapy, e.g., patch+lozenge/gum), varenicline, and/or bupropion. Participants will be educated about their 
smoking cessation medication as part of the e-visit, which will include education about potential medication side 
effects. The e-visit will assess contraindications for each FDA-approved cessation medication and medication 
will only be prescribed if the participant does not have contraindications for that medication. Contraindications 
for NRT include: 1) recent (< 2 weeks) myocardial infarction, 2) serious underlying arrhythmias, and 3) 
serious/worsening angina pectoris. Contraindications for varenicline include: 1) severe renal impairment, 2) 
pregnancy, and 3) breastfeeding. Contraindications for bupropion include: 1) severe renal impairment, 2) 

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concomitant therapy with medications/conditions known to lower the seizure threshold, 3) hepatic impairment, 
4) seizure disorder, 5) current or prior diagnosis of bulimia or anorexia nervosa, 6) simultaneous abrupt 
discontinuation of alcohol or sedatives/benzodiazepines, 7) use of MAO inhibitors within the last 14 days or 
concurrent use of reversible MAO inhibitors, 8) pregnancy, and 9) breastfeeding. Participants will be provided 
with our study phone number and instructed to call our study personnel should they experience AEs or if they 
have questions/concerns about medication use. Given the relatively benign risk profiles of these medications, we 
expect AEs, which will be assessed across follow-up timepoints via REDCap, to be rare and mild. Participants 
will be encouraged to contact Dr. Dahne as soon as possible for serious AEs and for those conditions that 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. 
 
b) Confidentiality: There is a risk of a loss of confidentiality of the participant’s personal information when 
submitting online questionnaires or breath samples as a result of participation in this study. Participants will be 
made aware of limits to confidentiality at the beginning of screening and 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 during the phone screening or 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 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 primary care physician.  
 
c) Frustration: Participants may become frustrated while completing questionnaires or while using the smoking 
cessation e-visit. 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 the e-visit at any time (which will be tracked as a study outcome). 
 
d) Risks During Pregnancy: We do not know if medications that may be prescribed as part of this study will 
affect mother’s milk or an unborn fetus. If a participant is pregnant or becomes pregnant, there may be risks to 
the embryo or fetus that are unknown at this time. Participants will be made aware during consent that any woman 
of childbearing potential, as reported on the screening survey, must complete a pregnancy test before completing 
the e-visit. The pregnancy test will be mailed to her at no cost and the participant will receive a REDCap form 
within 3 days to verify (with signature) that they completed the test and their pregnancy test results. Once study 
staff receives this completed REDCap form from the participant, they will be scheduled for consent. Females of 
childbearing potential who report a positive pregnancy test will not receive varenicline as a result of the e-visit. 
These women instead will either receive NRT, bupropion and/or counseling based on other contraindications and 
medication preferences indicated throughout the e-visit.  
 
e) Randomization: Participants are made aware that one treatment method may prove to be more or less effective 
than the other treatment method provided via the study. Participants are free to discontinue study participation at 
any time, either prior to or following randomization in order to avoid this risk. 
 
f) Uknown Risks: The experimental treatments may have unknown side effects. The researchers will inform 
participants if they learn anything during the course of the study that might make participants change their mind 
about participating in the study. 
 
Since patients will all currently be receiving medical care within the MUSC Regional Health Network (RHN), 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 rural MUSC RHN primary care clinics. Smoking status is assessed for every 
patient, consistent with MUSC’s best practice guidelines. Patients will be idenfitied via cold contact for research 
recruitment methods and will be sent a message inviting them to participate in a research study.  These patients will 
be sent a message through MyChart to invite them to participate in a research study. Interested patients will complete 
determination of eligibility via MUSC’s REDCap system, a secure, HIPAA-compliant data management system. 

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Consent will take place remotely via REDCap e-consent paired with a phone call with a member of the research 
team19. This approach allows: 1) live audio contact with an IRB-approved consenter and 2) electronic signed consent. 
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. A copy of the 
informed consent will be kept centrally at our study office within locked filing cabinets and a copy will also be given 
to each study participant. 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 assigned to an intervention based on their clinic division’s current 
step, will complete baseline assessments, and subsequently will receive their randomized intervention. 
 
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. 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 the smoking cessation e-visit 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 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. Audio and video recordings from key informant interviews will 
be destroyed within 12 months of completion of the entire study. 
 
Protection against risks associated with FDA-approved smoking cessation medications that may be provided as a 
result of the e-visit includes: 1) review of all medication recommendations by physicians, 2) use of such medications 
strictly on label, and 3) a Data and Safety Monitoring Plan that includes monitoring of AEs. Participants will not be 
provided with a medication if they have FDA contraindications for that medication. There will be direct electronic 
contact between the participant and the PCP via MyChart prior to prescription. If contraindications are 
present (e.g., a contraindicated medication is noted in the EHR, but not reported in the e-visit) or if the patient 
reports untreated health concerns requiring attention (e.g., cough with blood), electronic contact will be 
supplemented with phone and/or in person contact. Thus, prescription-related safety concerns are no greater here 
than in other clinical scenarios. While this direct contact could be viewed as an impediment to scalability, we view it 
as necessary due to potential safety concerns related to prescription medications. Through informational material 
provided with the medications and through the e-visit, participants will be educated about potential AEs and nicotine 
intoxication symptoms. As FDA-approved medications with benign risk profiles, we anticipate very few AEs. AEs 
will be assessed in research follow-ups as well as in the 1-month follow-up e-visit. During consent and within the e-
visit, participants will be provided contact information to use should they experience an AE and need immediate 
clinical support. AEs will be discussed with Drs. Diaz and Player. We will also form a Data Safety and Monitoring 
Board (DSMB). If the percent of serious or severe AEs appears to be greater than 5% the DSMB will be notified to 
make a decision regarding early termination of the study.  
 

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14.0 
Potential Benefits to Subjects or Others 
 
All rural smokers in this trial will receive at minimum standard smoking cessation care via MUSC’s RHN primary 
care clinics and evidence-based educational information about quitting smoking. We will not augment standard 
smoking cessation care as provided by the RHN clinics. Participants may also receive an invitation to complete a 
smoking cessation e-visit. The major benefits to society will be whether this smoking cessation e-visit improves 
cessation treatment access and cessation outcomes relative to TAU for rural smokers and whether the approach has 
high implementation potential within rural primary care settings. Potential issues of medication risks, confidentiality, 
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. 
 
16.0 
Drugs or Devices  
This study involves the use of FDA-approved smoking cessation medications. Medications will 
not be stored or handled by any members of the research team. Medications recommended in the 
e-visit will be reviewed by the patient’s primary care physician before prescription. If no 
contraindications exist, the primary care physician will e-prescribe the medication to the patient’s 
preferred pharmacy. 
 
 

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