Clinical trial NCT03722966
Conditions: Smoking Cessation
Keywords: smoking cessation varenicline nicotine gum nicotine lozenges nicotine replacement therapy adherence mHealth
Sponsor: University of Oklahoma
Start date: 2020-01-07; Completion date: 2022-02-07
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
Varenicline is considered to be a first-line tobacco cessation treatment. Previous studies have evaluated the impact of the combination of varenicline and nicotine patches (versus varenicline alone) on smoking cessation, though findings have been equivocal. No studies to date have evaluated the combination of varenicline and oral nicotine replacement therapy (NRT; i.e., nicotine lozenges or gum). Nicotine lozenges and gum can provide acute relief during cravings and high risk situations, which offers individuals the flexibility to deliver nicotine when they need it most (in contrast with the continuous and passive delivery of nicotine offered via the patch). Prospective clinical trials are needed in real-world settings to determine whether the combination of varenicline and oral nicotine replacement therapy (i.e., lozenges, gum) is superior to varenicline alone for smoking cessation. The proposed pilot randomized trial would enroll 100 participants over 1 year (≈8 participants per month) utilizing a 2x2 factorial design. Twelve weeks of a pharmacological intervention \[varenicline + oral NRT (VAR+N) vs. varenicline alone (VAR)\] will be crossed with automated medication reminders (reminder messages vs. no reminder messages). All participants will receive an adapted version of the standard counseling offered through the Tobacco Treatment Research Program (TTRP).

The primary outcomes will be biochemically-verified smoking cessation at 12 and 26 weeks following a scheduled quit attempt (1 week after enrollment). Smartphone-based ecological momentary assessment (EMA) will be employed to measure withdrawal symptoms, medication adherence, side effects, and adverse events using the Insight™ platform developed by the Stephenson Cancer Center (SCC) mHealth Shared Resource. This pilot study will provide information regarding the feasibility, acceptability, and preliminary efficacy of combination varenicline and oral NRT for smoking cessation, which will support an NIH funding application for a larger, adequately powered study.

Detailed description:
Tobacco Treatment Research Program (TTRP).The TTRP led by Dr. Darla Kendzor and located at the University of Oklahoma Health Science Center (OUHSC), offers free tobacco cessation treatment to adults from campus or the community who would like to quit using tobacco. The proposed study would take place within the context of the TTRP. Individuals are linked with the TTRP via the electronic medical record and 1-click referrals from clinical departments at the OUHSC or SCC; or from the community by phone \[(405) 271-QUIT (7848)\], email (ttrp@ouhsc.edu), or fax referrals. Treatment includes counseling with a Tobacco Treatment Specialist either in-person or over the telephone and pharmacological treatment.

Baseline (1-Week Pre-quit; Visit 1):

Informed Consent/Screening. Informed consent will be obtained from all participants in a private room in the TTRP. Individuals will be included in the study if they: 1) are ≥ 18 years of age, 2) demonstrate \> 6th grade English literacy level, 3) agree to install the study smartphone application onto their personal phone (or agree to carry a study-provided phone with the app), 4) agree to complete phone-based or in-person surveys through 26 weeks post-quit date, 5) have an expired CO level \> 7 ppm at the baseline screening visit suggestive of current smoking, 6) currently smoke ≥ 5 cigarettes per day, 7) are willing to initiate a quit attempt 7 days after the baseline visit (enrollment). Individuals will be excluded from the study if they 1) have a history of seizures or allergic reaction to varenicline, 2) report current suicidality, 3) are taking anti-depressant or anti-psychotic medications, or 4) are pregnant, planning to become pregnant, or currently breastfeeding. Please note that the smartphone application used in this pilot study is only available in English.

Smartphones. Participants will be guided through the process of downloading the InsightTM smartphone application onto their personal smartphone and they will be asked to complete daily EMAs during the 12 week period when they are taking their study medication(s). Those who do not possess a phone that meets the minimum requirements to download the Insight™ app, will be provided with a study phone. The smartphone app home screen will include: 1) a "Call Staff" function/button that automatically calls study staff when participants have problems with the app, and 2) a "Payment" function/button that enables participants to track their current level of compliance with phone-based surveys and level of compensation. At the baseline visit, all participants will receive training about how to use the smartphone app to complete EMA and how to use the "Call Staff" and "Payment" button/options. Participants will be instructed to quit smoking at bedtime or 10:00 pm (whichever occurs first), 6 days following their Baseline session. The app will remind participants about their approaching quit date during each day of the pre-cessation period.

Questionnaires and Other Measures. Participants will complete self-report questionnaires on a tablet computer; and expired CO, weight, and height will be measured in a private room to ensure confidentiality.

Varenicline. All participants will be evaluated by the study physician, and prescribed varenicline (if eligible). Individuals with a history of seizures, allergic reaction to varenicline, and/or those who are pregnant, planning to become pregnant, or breastfeeding will be excluded from the proposed study. As a precaution, individuals who report current cardiovascular disease will require clearance from the study physician or their personal physician to use varenicline. Notably, recent research has indicated that neither varenicline nor NRT increases the risk of serious cardiovascular events. In December 2016, the FDA lifted the boxed warning for varenicline after findings were published from a large clinical trial showing that the risk of neuropsychiatric adverse events associated with varenicline did not differ from the nicotine patch or placebo, and that varenicline was more effective for smoking cessation than the nicotine patch, bupropion, and placebo (the nicotine patch and bupropion were more effective than placebo). Participants will be excluded for current suicidality and current use of anti-depressant and anti-psychotic medications, which are suggestive of severe and/or unstable mental illness. As a precaution, female participants will be advised to avoid pregnancy while taking varenicline and to discontinue the medication should they become pregnant. However, the findings of observational research suggests that taking varenicline does not appear to be harmful during pregnancy. During the first (pre-quit) week of the study, participants will continue smoking and begin taking varenicline. Doses are titrated during the first week of medication (days 1-3: 0.5 mg once daily; days 4-7: 0.5 mg twice daily).

Oral NRT. Participants randomized to VAR+N will be provided with a supply of 4 mg nicotine lozenges or 4 mg gum (depending on participant preference) and instructed to use a piece every 1-2 hours (12-24 per day) after they quit smoking, and especially when they have the urge to smoke.

Developing a Quit Plan. Eligible participants will meet with a tobacco cessation counselor who will provide an overview of the tobacco cessation program, and help participants to set and prepare for their quit date. Participants will be asked to quit smoking the evening prior to their next weekly appointment.

Randomization. At the conclusion of the first visit, participants will be randomized to one of the four cells within the 2x2 factorial design: pharmacological treatment (VAR+N vs. VAR) and medication reminders (reminders vs. no reminders) at the baseline visit. Adaptive randomization will be used to assign participants to groups based upon race, sex, cigarettes smoked per day, and education.

Quit Day (Visit 2; 1-Week Post-Enrollment):

Questionnaires and Other Measures. Participants will complete self-report questionnaires on a tablet computer; and expired CO and weight will be measured in a private room to ensure confidentiality.

Oral NRT. Participants randomized to VAR+N will be instructed to use a piece of gum or lozenge at least every 1-2 hours (12-24 per day), and especially when they have the urge to smoke. Participants assigned to VAR+N with medication reminders will receive smartphone prompts (through the Insight™ app) every 2 hours (during waking hours) reminding them to use a piece of gum or a lozenge when they have cravings and at least every 1-2 hours.

Counseling. Participants will complete an in-person counseling session with a Tobacco Treatment Specialist. Since participants were scheduled to quit smoking the evening prior, the counselor will check in with participants about the difficulties and successes they have experienced, and plan for any challenging situations that are anticipated. Advice and support will be provided as needed.

Weekly Telephone Counseling Sessions (1, 2, and, 3 weeks post-quit) Following the quit day, 3 additional weekly telephone counseling sessions will be scheduled. Topics will include 1) the impact of tobacco on health/benefits of quitting, 2) stress management strategies, 3) making positive lifestyle changes, 4) developing coping skills, and 5) relapse prevention. The counselor will check in with participants each week about the difficulties and successes they have experienced, and plan for any challenging situations that are anticipated. Advice and support will be provided as needed. Participants will be reminded to take their varenicline dose twice daily (VAR+N and VAR), and to use a piece of gum or a lozenge at least every 1-2 hours (VAR+N only) and especially when they have the urge to smoke.

4-Weeks Post-Quit Day (Visit 3):

Questionnaires and Other Measures. Participants will complete self-report questionnaires on a tablet computer; and expired CO and weight will be measured in a private room to ensure confidentiality.

Oral NRT. Participants randomized to VAR+N will be instructed to continue using a piece of gum or lozenge every 1-2 hours (12-24 per day), and to begin reducing to at least every 2-4 hours (6-12 per day). Additional supply of gum or lozenges will be provided at this visit. VAR+N participants will receive a smartphone reminder prompt to use a piece of gum or lozenge every 2 hours during waking hours through 6 weeks post-quit, and every 4 hours during post-quit weeks 7-12.

Counseling. Participants will complete an in-person counseling session with a Tobacco Treatment Specialist. The counselor will check in with participants each week about the difficulties and successes they have experienced, and plan for any challenging situations that are anticipated. Advice and support will be provided as needed.

8-Weeks Post-Quit Day (Visit 4):

Questionnaires and Other Measures. Participants will complete self-report questionnaires on a tablet computer; and expired CO and weight will be measured in a private room to ensure confidentiality.

Oral NRT. Participants randomized to VAR+N will be instructed to continue using a piece of gum or lozenge every 2-4 hours (6-12 per day), and to begin reducing to at least every 4-8 hours (3-6 per day). Additional supply of gum or lozenges will be provided at this visit. VAR+N participants will receive a smartphone prompt every 4 hours (during waking hours) through 12 weeks post-quit reminding them to use a piece of gum or a lozenge as directed.

12-Weeks Post-Quit Day (Visit 5):

Questionnaires and Other Measures. Participants will complete self-report questionnaires on a tablet computer; and expired CO and weight will be measured in a private room to ensure confidentiality. Participants will be asked to return their study-provided smartphones after they have completed their 12 week course of varenicline.

Oral NRT. Participants randomized to VAR+N will be asked to discontinue using oral NRT.

26-Weeks Post-Quit Day (Visit 6):

Questionnaires and Other Measures. Participants will complete self-report questionnaires on a tablet computer; and expired CO and weight will be measured in a private room to ensure confidentiality.

Arms: arm 1: Participants will receive behavioral tobacco cessation counseling, a 13-week course of varenicline, and automated medication reminders via their smartphones. arm 2: Participants will receive behavioral tobacco cessation counseling, a 13-week course of varenicline, and no automated medication reminders. arm 3: Participants will receive behavioral tobacco cessation counseling, a 13-week course of varenicline, 12 weeks of oral nicotine replacement therapy (NRT; gum or lozenge), and no automated medication reminders. arm 4: Participants will receive behavioral tobacco cessation counseling, a 13-week course of varenicline, 12 weeks of oral nicotine replacement therapy (NRT; gum or lozenge), and automated medication reminders via their smartphones.
Interventions: intervention 1: Varenicline intervention 2: Oral Nicotine Replacement Therapy (NRT) intervention 3: Medication Reminders intervention 4: Tobacco Cessation Counseling
Intervention descriptions: intervention 1: All participants will be offered a 13-week course of varenicline (including a 1 week titration period). Dosage and administration per manufacturer: 0.5mg once daily for days 1-3 and 0.5mg twice daily for days 4-7 encompass the titration period, then 1mg twice daily for 12 weeks. An additional 12 weeks of treatment is recommended for long-term abstinence. intervention 2: Half of study participants will be randomly assigned to receive oral nicotine replacement therapy (4mg gum or 4mg lozenge, depending on preference; to be used every 1-2 hours as urges occur) in addition to varenicline. intervention 3: Half of study participants will be randomly assigned to receive automated medication reminders via their smartphones. intervention 4: All participants will be offered 6 weekly tobacco cessation counseling sessions with a Tobacco Treatment Specialist.

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: 10184
IRB APPROVAL DATE: 08/03/2021
Page 1 of 18
The University of Oklahoma Health Sciences Center
Study Protocol
Institutional Review Board
Title of Project: A comparison of the effectiveness of combination varenicline and oral nicotine 
replacement therapy versus varenicline alone for smoking cessation: A pilot study
Principal Investigators:
Darla E. Kendzor, Ph.D.; Department of Family and Preventive 
Medicine, Stephenson Cancer Center, OUHSC
Emily T. Hébert, DrPH; University of Texas Health Sciences 
Center at Houston, School of Public Health Austin 
Co-Investigators: 
Jasjit S. Ahluwalia, MD, MPH, MS; Department of Behavioral and 
Social Sciences and Center for Alcohol and Addiction Studies, 
Brown University School of Public Health
Michael S. Businelle, Ph.D.; Department of Family and Preventive 
Medicine, Stephenson Cancer Center, OUHSC
Summer G. Frank-Pearce, Ph.D., Department of Biostatistics and 
Epidemiology, OUHSC
Lourdes Planas, Ph.D.; Department of Pharmacy: Clinical and 
Administrative Sciences; OU College of Pharmacy, OUHSC
Abstract: Varenicline is considered to be a first-line tobacco cessation treatment.1 Previous 
studies have evaluated the impact of the combination of varenicline and nicotine patches 
(versus varenicline alone) on smoking cessation, though findings have been equivocal.2-5 No 
studies to date have evaluated the combination of varenicline and oral nicotine 
replacement therapy (NRT; i.e., nicotine lozenges or gum). Nicotine lozenges and gum can 
provide acute relief during cravings and high risk situations, which offers individuals the flexibility 
to deliver nicotine when they need it most (in contrast with the continuous and passive delivery 
of nicotine offered via the patch). Prospective clinical trials are needed in real-world settings to 
determine whether the combination of varenicline and oral nicotine replacement therapy (i.e., 
lozenges, gum) is superior to varenicline alone for smoking cessation. The proposed pilot 
randomized trial would enroll 100 participants over 1 year (≈8 participants per month) utilizing a 
2x2 factorial design. Twelve weeks of a pharmacological intervention [varenicline + oral NRT 
(VAR+N) vs. varenicline alone (VAR)] will be crossed with automated medication reminders 
(reminder messages vs. no reminder messages). All participants will receive an adapted version 
of the standard counseling offered through the Tobacco Treatment Research Program (TTRP). 
The primary outcomes will be biochemically-verified smoking cessation at 12 and 26 weeks 
following a scheduled quit attempt (1 week after enrollment). Smartphone-based ecological 
momentary assessment (EMA) will be employed to measure withdrawal symptoms, medication 
adherence, side effects, and adverse events using the Insight™ platform developed by the 
Stephenson Cancer Center (SCC) mHealth Shared Resource.6 This pilot study will provide 
information regarding the feasibility, acceptability, and preliminary efficacy of combination 
varenicline and oral NRT for smoking cessation, which will support an NIH funding application 


IRB NUMBER: 10184
IRB APPROVAL DATE: 08/03/2021
Page 2 of 18
for a larger, adequately powered study.
Specific Aims: 
Aim 1: To determine whether the combination of varenicline and oral NRT (gum or lozenges 
based on participant preference) increases the likelihood of biochemically-verified smoking 
cessation relative to varenicline alone at 12 and 26 weeks following a scheduled quit attempt. It 
is hypothesized that there will be a trend towards higher cessation rates in the VAR+N  
compared with the VAR group, with a p-value of ≤ 0.2 supporting further investigation in a larger 
trial.
Aim 2: To determine the effect of medication reminders on pharmacotherapy adherence 
and cessation. Participants will be randomly assigned to receive either reminder messages or 
no reminder messages to take their varenicline as prescribed each day. In addition, those 
assigned to VAR+N with medication reminders will receive smartphone reminder prompts to use 
oral NRT at regular intervals. It is hypothesized that those who are randomized to medication 
reminders will be more adherent to the medication regimen and more likely to quit smoking than 
those who do not receive reminders.
Aim 3: To characterize and compare the course of withdrawal symptoms and side effects 
within the VAR+N and VAR groups measured in real time via EMA, and to determine their 
influence on the likelihood of cessation. It is hypothesized that those in the VAR+N group, who 
are using two pharmacotherapies to address nicotine dependence, may experience less severe 
withdrawal symptoms than those in the VAR group. However, those in the VAR+N group may 
also report more medication side effects because two pharmacotherapies are employed. It is 
expected that withdrawal symptom severity and the presence and severity of medication side 
effects may mediate the relations between treatment type and cessation outcomes.  
A. Background and Significance
Smoking is the leading preventable cause of death and disease in the United States7 
resulting in over 480,000 premature deaths each year.8 Although the prevalence of smoking has 
declined over the past 5 decades, approximately 15.1% of adults continue to smoke in the U.S.9 
Nearly 70% of smokers report that they want to quit smoking, and 55% of all smokers try to quit 
each year,10 but only 20% of smokers report that they are planning to quit within the next 30 
days.11 Effective pharmacotherapies to aid cessation are available, and the combination of 
behavioral support with pharmacotherapy provides optimal cessation outcomes.12 Most recently, 
research has focused on evaluating combination pharmacotherapies in an effort to refine 
current evidence-based treatment approaches. Varenicline alone is currently considered a first-
line tobacco cessation treatment.1 A few studies have evaluated the combination of varenicline 
and nicotine patches (versus varenicline alone), though the findings have been equivocal.2-5 No 
studies to date have evaluated the combination of varenicline and oral NRT (i.e., nicotine 
lozenges or gum). Nicotine lozenges and gum can provide acute relief during cravings and high 
risk situations, which offers individuals the flexibility to deliver nicotine when they need it most, 
in contrast with the continuous and passive delivery of nicotine offered via the patch. Little is 
known about the utility of using smartphone apps to provide automated medication 
reminders.14,15 Notably, in clinical trials of combination bupropion and nicotine gum, participants’ 
use of the gum was infrequent,16,17 making it difficult to determine whether there might be an 
added benefit of oral NRT beyond the impact of bupropion alone. Plausibly, scheduled 
medication reminders might increase adherence to both varenicline and oral NRT. Prospective 
clinical trials are needed in real-world settings to determine whether the combination of 
varenicline and oral NRT is superior to varenicline alone, and to evaluate the impact of 
medication reminders on varenicline and oral NRT adherence.


IRB NUMBER: 10184
IRB APPROVAL DATE: 08/03/2021
Page 3 of 18
B. Preliminary Studies/Study Team
Tobacco Treatment Research Program (TTRP).The TTRP18 led by Dr. Darla Kendzor19 and 
located at the University of Oklahoma Health Science Center (OUHSC), offers free tobacco 
cessation treatment to adults from campus or the community who would like to quit using 
tobacco. The proposed study would take place within the context of the TTRP. Individuals are 
linked with the TTRP via the electronic medical record and 1-click referrals from clinical 
departments at the OUHSC or SCC; or from the community by phone [(405) 271-QUIT (7848)], 
email (ttrp@ouhsc.edu), or fax referrals. Treatment includes counseling with a Tobacco 
Treatment Specialist either in-person or over the telephone and pharmacological treatment. 
Participants pick up their prescribed medication from the Family Medicine Center (FMC) 
pharmacy on campus, and the cost of the medication is charged to the TTRP. The TTRP is an 
Institutional Review Board (IRB)-approved observational research study (OUHSC protocol 
#6951) where participants complete relevant questionnaires via tablet computers as they 
receive tobacco dependence treatment. Participants are followed for 27 weeks and 
compensated for providing smoking status information at key visits (including biochemical 
verification). Appointments are the TTRP are scheduled by a Tobacco Treatment Navigator, 
who also manages appointments with counselors for individual treatment. An appointment letter 
with directions to the TTRP and a map is mailed or emailed to participants after they are 
scheduled for their first appointment. Participants are reminded of all future appointments via 
telephone, mail, email, and/or text. Participants with transportation difficulties living in the 
Oklahoma City metro area may be scheduled for pick-up and drop-off for key visits with 
SendaRide (https://sendaride.com) through their secure dashboard. The TTRP also serves as a 
recruitment resource for ongoing research studies, and offers a strong resource and structure 
through which to facilitate the delivery of both empirically-supported and experimental 
treatments.  
Since inception in Oct. 2016, the TTRP has enrolled ≈ 500 participants into standard 
treatment or clinical trials. Enrollment numbers will continue to increase as new OUHSC clinical 
departments are linked via the electronic medical record, as evidenced by the ≈ 300 participants 
enrolled in the TTRP over the past 12 months. In addition, advertising will be employed to 
increase enrollment specifically in the proposed research study. TTRP participants are primarily 
White (55.4%), Black (27.7%), and American Indian (5.6%), and the majority are female 
(62.1%). Participants report smoking an average of 17.0 (SD=9.7) cigarettes per day prior to 
quitting, for an average of 29.7 (SD=13.1) years. Participants are socioeconomically 
disadvantaged with 21.1% reporting less than a high school education, 44.1% reporting an 
annual household income of < $20,000, and 54.4% reporting that they are uninsured or 
receiving Medicaid benefits. 
Study Investigators. Overall, the study team has an impressive track record of tobacco-
related research, and the investigators have varied and complementary expertise, with 
significant strengths in tobacco cessation intervention and mobile health research. Dr. 
Kendzor21 is an Associate Professor in the Department of Family and Preventive Medicine in 
the University of Oklahoma College of Medicine. Her research focuses largely on tobacco 
cessation intervention among socioeconomically disadvantaged adults, and she is currently 
conducting two NIH-funded studies within the TTRP that focus on using small financial 
incentives as an adjunct to standard treatment to improve smoking cessation rates (both studies 
utilize smartphone-based EMA).22,23 Dr. Hébert24 is an Assistant Professor at the School of 
Public Health Austin and, and her research interests include the use of technology for health 
promotion, tobacco prevention and cessation, EMA, and the role of social media in tobacco 
marketing and health communication. Dr. Businelle25 is an Associate Professor in the 
Department of Family and Preventive Medicine in the University of Oklahoma College of 


IRB NUMBER: 10184
IRB APPROVAL DATE: 08/03/2021
Page 4 of 18
Medicine He is also the scientific director of the mHealth Shared Resource26 at the NCI-
designated Stephenson Cancer Center, which has developed the Insight™ Platform, to be used 
in the proposed study, which empowers researchers to build, test, and launch technology-based 
assessment and intervention tools. Dr. Jasjit S. Ahluwalia27 is a Professor of Social and 
Behavioral Sciences and Professor of Medicine at Brown University and an internationally 
recognized scientist. His research has primarily focused on nicotine addiction and smoking 
cessation in African-American smokers, has led or co-led nine large single site cessation clinical 
trials, worked on three treatment trials with varenicline, and has previously led a NIH-funded 
R01 2x2 factorial RCT.13,28-31 Dr. Summer Frank-Pearce32 is an Assistant Professor of 
Research in Biostatistics at the University of Oklahoma Health Sciences Center. She has 
developed numerous collaborations with investigators at the OTRC, including Drs. Kendzor, 
Businelle. Dr. Lourdes Planas33 is an Associate Professor in the Dept. of Pharmacy: Clinical 
and Administrative Sciences at the University of Oklahoma College of Pharmacy. Her research 
focuses on medication optimization intervention in community and primary care settings. 
C. Research Design and Methods
Study Design. The study will utilize a 2x2 factorial design in which participants are 
randomized to pharmacological treatment (VAR+N or VAR) and medication reminders 
(reminders or no reminders) at baseline (see Table 1). All participants will receive 12 weeks of 
varenicline after the standard 1-week titration period, with half of participants additionally 
receiving oral NRT (gum or lozenges, based on participant preference). Those assigned to 
VAR+N with medication reminders will receive smartphone prompts at scheduled intervals 
(during waking hours) with a reminder to use oral NRT regularly and as directed. The primary 
study outcomes will be carbon monoxide (CO)-confirmed 7-day point prevalence abstinence at 
12 and 26 weeks post-quit date. 
Table 1. 2 x 2 Factorial Design
Pharmacological Intervention 
(VAR+N or VAR)
VAR+N
+
Reminders
VAR
+
Reminders
Medication 
Reminders 
(Reminders vs. 
No Reminders)
VAR+N
+
No Reminders
VAR
+
No Reminders


IRB NUMBER: 10184
IRB APPROVAL DATE: 08/03/2021
Page 5 of 18
Study Procedures.
Recruitment and Screening (Telephone). Adults who are referred to the OTRC Tobacco 
Treatment Research Program (TTRP), those who respond to study advertisements, and those 
who have previously enrolled in treatment at the TTRP but remain non-abstinent six months 
after enrollment will be eligible to be screened for this study (this will allow us to help 
participants who have failed to quit smoking after receiving treatment). Research staff will 
contact individuals who may be eligible for this study. Those who are interested in participating 
will complete a phone- or web-based REDCap screener. Those who meet the initial study 
inclusion criteria will be scheduled to complete a baseline visit where final screening for study 
inclusion criteria will be conducted. 
Informed Consent/Screening. Informed consent will be obtained from all participants either in-
person at the TTRP or remotely using REDCaps electronic signature feature. Individuals will be 
included in the study if they: 1) are ≥ 18 years of age, 2) demonstrate > 6th grade English 
literacy level, 3) agree to install the study smartphone application onto their personal phone (or 
agree to carry a study-provided phone with the app), 4) agree to complete phone-based or in-
person surveys through 26 weeks post-quit date, 5) currently smoke ≥ 5 cigarettes per day, 6) 
are willing to initiate a quit attempt 7 days after the baseline visit (enrollment), 7) are willing to 
use nicotine gum/lozenges, 8) are eligible to receive Chantix after a consult with the study 
physician. Individuals will be excluded from the study if they 1) have a history of seizures, 2) 
have had an allergic reaction to varenicline, 3) report current suicidality (screen with the MINI 
Suicidal Scale64), or 4) are pregnant, planning to become pregnant, or currently breastfeeding. 
Please note that the smartphone application for this pilot study is only available in English. 
Remote Enrollment. Remote baseline appointments will take place in 2-parts and participants 
will required to download a video conferencing smartphone app and/or provide photo 
identification. Participants will be excluded from the study if they cannot download a video 
conferencing smartphone app and/or provide photo identification. Part 1 will follow same 
procedure as an in-person visit (informed consent/screening, randomization, questionnaires, 
and counseling). At the end of part 1, the participant will be mailed Varenicline and if applicable 
any additional materials (smartphone, Bedfont iCO smokerlyzer, oral NRT). Part 2 will take 
place once the participant receives the Varenicline and additional materials. During part 2, the 
participant will be provided with Varenicline instructions and assisted with InsightTM smartphone 
application set up. The participant will receive the baseline compensation once they complete 
part 2. 
Study Timeline. Enrolled Participants will be followed for a total of 27 weeks. For an overview of 
study participation, please see figure 1.
Randomization. At the conclusion of the first visit, participants will be randomized to one of the 
four cells within the 2x2 factorial design (see Table 1): pharmacological treatment (VAR+N vs. 
VAR) and medication reminders (VAR+N+reminders vs. VAR+reminders only) at the baseline 
visit. Adaptive randomization will be used to assign participants to groups based upon race, sex, 
cigarettes smoked per day, and education.
 
Questionnaires, Equipment, and Other Measures. 
Participants will be asked to complete questionnaires at baseline (1-Week Pre-quit), Quit Day 
(1-Week Post-Enrollment), 1-Week Post-Quit Day, 2-Weeks Post-Quit Day, 3-Weeks Post-Quit 
Day, 4-Weeks Post-Quit Day, 8-Weeks Post-Quit Day, 12-Weeks Post-Quit Day, and 26-Weeks 
Post-Quit Day. At in-person visits, participants will complete self-report questionnaires on a 


IRB NUMBER: 10184
IRB APPROVAL DATE: 08/03/2021
Page 6 of 18
tablet computer; and have their expired CO, weight, and height measured in a private room to 
ensure confidentiality. At remote visits, participants will complete self-report questionnaires on 
their own device via REDCap or complete them over the phone. Participants completing remote 
appointments will also be provided with a Bedfont iCO smokerlyzer to measure expired CO. 
The questionnaire appendix will come from the TTRP IRB 6951. 
Smartphones. Participants will be guided through the process of downloading the InsightTM 
smartphone application onto their personal smartphone and will be asked to complete daily 
EMAs during the 13 week period when they are taking their study medication(s). Those who do 
not possess a phone that meets the minimum requirements to download the Insight™ app, will 
be provided with a study phone. The smartphone app home screen will include: 1) a “Call Staff” 
function/button that automatically calls study staff when participants have problems with the 
app, and 2) a “Payment” function/button that enables participants to track their current level of 
compliance with phone-based surveys and level of compensation. At the baseline visit, all 
participants will receive training about how to use the smartphone app to complete EMAs (i.e., 
they will watch a “How to Use This App” video) and how to use the “Call Staff” and “Payment” 
button/options. Participants will be instructed to quit smoking at bedtime or 10:00 pm (whichever 
occurs first), the night before their scheduled quit day. The app will remind participants about 
their approaching quit date during each day of the pre-cessation period. 
Varenicline. All participants will be evaluated by the study physician, and prescribed varenicline 
(if eligible). Individuals with a history of seizures, allergic reaction to varenicline, endorse current 
suicidality, and/or those who are pregnant, planning to become pregnant, or breastfeeding will 
be excluded from the proposed study. As a precaution, individuals who report current 
cardiovascular disease will require clearance from the study physician or their personal 
physician to use varenicline. Notably, recent research has indicated that neither varenicline nor 
NRT increases the risk of serious cardiovascular events.37,38 In December 2016, the FDA lifted 
the boxed warning for varenicline after findings were published from a large clinical trial39 
showing that the risk of neuropsychiatric adverse events associated with varenicline did not 
differ from the nicotine patch or placebo, and that varenicline was more effective for smoking 
cessation than the nicotine patch, bupropion, and placebo (the nicotine patch and bupropion 
were more effective than placebo). As a precaution, female participants will be advised to avoid 
pregnancy while taking varenicline and to discontinue the medication should they become 
pregnant. However, the findings of observational research suggests that taking varenicline does 
not appear to be harmful during pregnancy.40 During the first (pre-quit) week of the study, 
participants will continue smoking and begin taking varenicline. Doses are titrated during the 
first week of medication (days 1-3: 0.5 mg once daily; days 4-7: 0.5 mg twice daily).
Oral NRT. Participants randomized to a VAR+N group will be provided with a supply of 
2mg/4mg nicotine lozenges or 2mg/4mg gum (depending on participant preference) and 
instructed to use a piece as directed after they quit smoking, especially when they have the urge 
to smoke. Participants will be instructed to chew a piece of gum as follows:
Baseline: every 1-2 hours (12-24 per day)
4-Weeks Post-Quit: every 1-2 hours (12-24 per day), and to begin reducing to at least 
every 2-4 hours (6-12 per day)
8-Weeks Post-Quit: every 2-4 hours (6-12 per day), and to begin reducing to at least 
every 4-8 hours (3-6 per day)
Additional supply of gum or lozenges will be provided during in-person visits or through the mail. 
Participants assigned to VAR+N with medication reminders will receive smartphone prompts 
(through the Insight™ app) (during waking hours) reminding them to use a piece of gum or a 


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Page 7 of 18
lozenge every 3 hours through 4 weeks post-quit,  every 4 hours during post-quit weeks 5-8, 
and every 6 hours during post-quit weeks 12.
Reminders. Participants assigned to the reminder groups will receive reminders to take 
varenicline and/or oral NRT as follows:
Varenicline Reminders. Participants will receive varenicline reminders that correspond with the 
medication schedule. The reminders will provide a message and then ask the participant if they 
have taken medication. Reminder 2 will only appear if the participant has reported “no” to 
reminder 1. Reminder 3 will only appear if the participant has reported “no” to reminder 2. On 
the 3rd reminder the participant will be asked why they did not take their medication. 
Pre-Quit Day 1: Only PM reminder (1 white pill (0.5 mg) daily)
Pre-Quit Days 2-3: Only AM reminder (1 white pill (0.5 mg) daily)
Pre-Quit Days 4-7: AM and PM reminders (1 white pill (0.5 mg) in the morning and 1 in the 
evening)
Day 8 to end of treatment: AM and PM Reminders (1 blue pill (1 mg) in the morning and 1 in the 
evening)
Table 2. Varenicline reminders
Pre-Quit Day 
1 Message
Don’t forget to take your Chantix pill tonight! 
Pre-Quit Days 
2-3 Message
Don’t forget to take your Chantix pill this morning! 
Pre-Quit Day 
4-7 
Don’t forget to take your Chantix pill twice daily (morning and night)! 
Day 8 to end 
of treatment
Don’t forget to take your Chantix pill twice daily (morning and night)!
AM
PM
Reminder 1
(30 minutes 
after Daily 
Diary)
You were scheduled to take your 
morning Chantix pill at [INSERT 
TIME] AM. Have you taken your 
Chantix pill this morning? 
(Yes/No)
Reminder 1
(2 hours and 
30 minutes 
after before 
sleep time)
You were scheduled to take 
your evening Chantix pill at 
[INSERT TIME] PM. Have 
you taken your Chantix pill 
this morning? (Yes/No)
Reminder 2
(1 hour after 
Reminder 1)
You were scheduled to take your 
morning Chantix pill at [INSERT 
TIME] AM. Have you taken your 
Chantix pill this morning? 
(Yes/No)
Reminder 2
(1 hour after 
Reminder 1)
You were scheduled to take 
your evening Chantix pill at 
[INSERT TIME] PM. Have 
you taken your Chantix pill 
this morning? (Yes/No)
Reminder 3
(1 hour after 
Reminder 2)
You were scheduled to take your 
morning Chantix pill at [INSERT 
TIME] AM. Have you taken your 
Chantix pill this morning? 
(Yes/No)
Reminder 3
(1 hour after 
Reminder 2)
You were scheduled to take 
your evening Chantix pill at 
[INSERT TIME] PM. Have 
you taken your Chantix pill 
this morning? (Yes/No)


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If no: What are the main reasons 
that you did not take your 
Chantix pill this morning? 
(Check all that apply)
1.
I forgot to take it.
2.
I was away from home.
3.
I experienced side effects.
4.
I didn't feel like I needed it.
5.
I didn't think it is working.
6.
I have decided not to quit 
smoking.
7.
Other
 
If no: What are the main 
reasons that you did not take 
your Chantix pill this evening? 
(Check all that apply)
1.
I forgot to take it.
2.
I was away from home.
3.
I experienced side 
effects.
4.
I didn't feel like I needed 
it.
5.
I didn't think it is 
working.
6.
I have decided not to 
quit smoking.
7.
Other 
NRT Reminder. Participant will receive a message and then be asked if they have used NRT in 
the past 2, 4, or 8 hours. 
Quit Day – 4 Weeks Post-Quit: Reminder every 3 hours 
5 Weeks Post-Quit – 8 Weeks Post-Quit: Reminder every 4 hours 
9 Weeks Post-Quit – 12 Weeks Post-Quit: Reminder every 6 hours 
Table 3. NRT reminders
1.
T
a
Don't forget to use nicotine gum/lozenges regularly throughout the day! It 
is recommenced that you use a piece of gum/lozenge every 1-2 hour.  
After you have been smoke free for 6 weeks, taper down to using a piece of 
gum/lozenge every 2-4 hours and then after being smoke free for 8 weeks, taper 
down to a piece every 4-8 hours. 
2.
Have you used a piece of gum/lozenge within the past 
2 hours?
No
Yes
3.
(If 2 = No) Have you used a piece of gum/lozenge 
within the past 4 hours?
No
Yes
4.
(If 3 = No) Have you used a piece of gum/lozenge 
within the past 8 hours?
No
Yes
Table 4. Study compensation schedule (all groups)


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Developing a Quit Plan. At baseline, eligible participants will meet with a tobacco cessation 
counselor who will provide an overview of the tobacco cessation program, and help participants 
to set and prepare for their quit date. Participants will be asked to quit smoking the evening prior 
to their next weekly appointment (Visit 2).
Counseling. Participants will complete counseling session in-person or remotely with a Tobacco 
Treatment Specialist at the baseline visit and each visit through 4 Weeks Post-Quit . The 
counselor will check in with participants about the difficulties and successes they have 
experienced, and plan for any challenging situations that are anticipated. Advice and support 
will be provided as needed. Topics will include 1) the impact of tobacco on health/benefits of 
quitting, 2) stress management strategies, 3) making positive lifestyle changes, 4) developing 
Visit
Weeks 
Post-Quit
QuestionnairesQuesti
onnaires
Smartphone 
Assessments
Total 
Per Week
1
-1
$20
$20
2
0
$20
up to $10
$30
-
1
-
up to $10
$10
-
2
-
up to $10
$10
-
3
-
up to $10
$10
3
4
$20
up to $10
$30
5
-
up to $10
$10
6
-
up to $10
$10
7
-
up to $10
$10
4
8
$20
up to $10
$30
9
-
up to $10
$10
10
-
up to $10
$10
11
-
up to $10
$10
5
12
$20
up to $10
$30
6
26
$20
-
$20
Total Possible
up to $250
Daily Smartphone Assessments
Varenicline
Oral NRT (for VAR + N groups)
Medication reminders (for reminder groups)
Visit 1:
Baseline
Visit 2: 
Quit Day
Visit 3: 
1 Week 
Post-Quit
Visit 4: 
2 Weeks 
Post-Quit
Visit 5: 
3 Weeks 
Post-Quit
Visit 6: 
4 Weeks 
Post-Quit
Visit 7: 
8 Weeks 
Post-Quit
Visit 8: 
12 Weeks 
Post-Quit
Visit 9:
 26 
Weeks 
Post-Quit
Figure 1: Study Timeline


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coping skills, and 5) relapse prevention. The counselor will check in with participants each week 
about the difficulties and successes they have experienced, and plan for any challenging 
situations that are anticipated.
Compensation. Participants will receive a $20 payment for completion of the Baseline visit, Quit 
Day, 4 Weeks Post-Quit, 8 Weeks Post-Quit, 12 Weeks Post-Quit, and 26 Weeks Post-Quit. 
(see Table 4 for study compensation schedule). In addition, participants will receive up to $10 
weekly for completing the daily smartphone assessments. Specifically, they will receive $10 for 
completing at least 6 out of 7 EMAs, and $5 for completing at least 4 out of 7 EMAs each week. 
Participants who complete 3 or fewer EMAs will not receive additional compensation. 
Participants may earn up to $250 for participation in the study. 
Discontinuing Reminders, Varenicline, or NRT. Using the following guidelines a participant may 
continue in the study if: 1) they no longer wants to receive reminders via the app, we will disable 
app reminders, 2) they no longer wants to take varenicline, we will have them delete the app, 
but will still ask that they come in to the clinic for in-person visits for follow-up, 3) they no longer 
wants to take NRT, they will be asked to answer that they didn’t chew gum on the EMAs.
Remote Treatment Follow-up Visits.  Due to the evolving circumstances regarding COVID-19, 
participants may complete any follow-up visits remotely. The requirements and compensation 
for remote visits will be identical to in-person visits. Participants will remotely complete web-
based questionnaires and provide a smartphone-based CO measurement using a Bedfont iCO 
smokerlyzer. Participants may also keep the study smartphone until the 26 Weeks Post-Quit 
visit if necessary. 
Study Measures.
Screening Measures (online or over the phone). Screening data will be collected using the 
secure web-based REDCap platform, which provides an intuitive user interface that streamlines 
project development and improves data entry through real-time validation rules. The initial 
online screening will include assessment of demographics, smoking history, readiness to quit, 
and other eligibility criteria. 
Traditional Questionnaire Measures. Questionnaire data, including measures of tobacco/health 
history, sociodemographic characteristics, nicotine dependence,41 withdrawal symptom 
severity,42 depression,43 perceived stress,44 mental health,45 beliefs about medications,46 
medication adherence,47 and self-efficacy48 will be collected via REDcap on tablet computers. 
The amount of time needed for participants to complete the computer-administered 
questionnaires varies by study visit. It is estimated that the longest visit (baseline) will require 
one hour to complete. We have found that even individuals with no experience using computers 
have had few problems completing study assessments. The questionnaire appendix will come 
from the TTRP IRB 6951.
Biological/Anthropometric Measures. Expired CO levels will be measured at each visit either in-
person using the portable Vitalograph ecolyzer or remotely using the Bedfont iCO smokerlyzer 
which will interface the InsightTM smartphone application. Please note that the InsightTM 
smartphone application has integrated automated and secure (i.e., encrypted) facial recognition 
software to ensure that only the participant provides a CO breath sample. Self-reported 
abstinence from smoking will be verified with a CO level of ≤ 6 ppm at all subsequent post-quit 
visits. Body Mass Index (BMI) will be calculated (kg/m²) based on height and weight 
measurements collected at the baseline visit. 


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Ecological Momentary Assessment (EMA). EMA can accurately measure phenomena in real-
time, natural settings.50,51 EMA items will identify fluctuations in key variables that predict study 
outcomes with less bias than traditional in-person assessments. 
Scheduled EMAs. The EMA methodology used in this study will be similar to what was used in 
our previous studies, and by other researchers.52-60 All participants will download the study app 
onto their personal or study-provided phone and will be asked to complete scheduled EMAs 
once a day for 13 weeks. The scheduled EMAs will be prompted by the smartphone app, 30 
minutes after the participant’s scheduled wake time. The phone will ring and vibrate to cue 
these EMAs for 30 seconds. If the participant has not responded after 5 prompts, the 
assessment will be rescheduled and will be prompted again (e.g., 15 minutes later). This 
process will continue until the participant acknowledges the prompt, or the assessment is 
recorded as missed (i.e., 4 prompts spaced 15 minutes apart). These EMAs will ask questions 
about current and past 24-hour thoughts, feelings, experiences, behaviors (e.g., smoking 
lapses), physical symptoms, and medication adherence.
Programming. The mHealth Shared Resource at the OUHSC and Stephenson Cancer Center 
(SCC) offers resources that empower researchers to build, test, and launch technology-based 
assessment and intervention tools. The mHealth resource employs a program manager and 3 
senior programmers who develop and maintain web and mobile applications and relational 
databases. Applications are developed using state-of-the-art cross-platform design tools. The 
Insight™ platform has already been developed and is being used by the OTRC investigators in 
other studies. The platform will allow the project investigators to quickly set up scheduled EMAs 
and messaging that are unique to the proposed study. 
Smartphone application training. As in all of our studies, participants will watch a brief step-
by-step video tutorial (created by the researchers) at the baseline visit that demonstrates use of 
all app features and participants will receive hands-on training. This training approach has 
minimized participant difficulties in our past research.
Data loss prevention. In order to overcome potential loss of data, phones will be programmed 
to connect to our secure server to upload encrypted data every 1.5 hours. This will ensure that 
no collected EMA data are lost. This tactic will also allow the researchers to remotely monitor 
each participant’s EMA completion rate and intervene (e.g., call the participant) when this rate is 
low. Importantly, EMA data are password protected and encrypted on the phone and only 
encrypted data are transmitted to our secure server. Thus, study data are ONLY accessible by 
the research team. In addition, all study data can be remotely wiped from phones once the 
study is completed.
EMA alert settings. At the baseline visit, a phone set-up wizard is used to set participant sleep 
and wake times for each day of the week. This practice reduces the likelihood that the phone 
will ring when participants are sleeping. In addition, participants may delay EMAs by up to 20 
minutes (i.e., by clicking the snooze assessment option when an EMA is pushed).  
D. Statistical Methods 
All questionnaires will be scored using methodology described in the published literature.
Sociodemographic information will be summarized using frequencies with associated 
percentages (categorical/binary outcomes) or means with standard deviations (continuous 
outcomes). The 2x2 factorial design will be evaluated using logistic regression models, where 


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smoking status (12 or 26 weeks post-quit date) is included as the dependent variable. The 
dichotomous variables, medication type (NVAR vs. VAR) and message reminder type 
(medication reminders vs. no reminders), will be included as independent variables, as well as 
the interaction term. Sociodemographic covariates and nicotine dependence will be included in 
the model as covariates. Generalized Linear Mixed Models (GLMM) will be used to examine the 
influence of EMA variables that are measured repeatedly and are therefore correlated within 
subjects. The PROCESS macro for SPSS/SAS (described in Hayes, 201361 and available 
online62) will be used to conduct mediation analyses with the goal of identifying variables (e.g., 
withdrawal symptom severity) that mediate the relation between treatment condition and 
smoking cessation outcomes. This method uses an ordinary least squares path analytic 
framework to estimate direct and indirect effects in single and multiple mediation models, and 
bootstrapping methods are incorporated to generate confidence intervals. The data collected in 
the proposed study will provide preliminary information for future external funding applications. 
E. Gender/Minority/Pediatric Inclusion for Research
The study has no inclusion/exclusion criteria based on gender or race/ethnicity. Individuals >18 
years of age will be eligible for participation in this study. Children < 18 years of age will be 
excluded from the study. 
F. Human Participants 
1. Subject Population. Individuals will be included in the study if they: 1) are ≥ 18 years of 
age, 2) demonstrate > 6th grade English literacy level, 3) agree to install the study smartphone 
application onto their personal phone (or agree to carry a study-provided phone with the app), 4) 
agree to complete phone-based or in-person surveys through 26 weeks post-quit date, 5) 
currently smoke ≥ 5 cigarettes per day,5) are willing to initiate a quit attempt 7 days after the 
baseline visit (enrollment), 7) are willing to use nicotine gum/lozenges, 8) are eligible to receive 
Chantix based on the study physicians discretion. Please note that participants who enroll 
remotely will be required to download a video conferencing smartphone application and/or 
provide a photo identification. Individuals will be excluded from the study if they 1) have a 
history of seizures, 2) have had an allergic reaction to varenicline, 3) report current suicidality 
(screen with the MINI Suicidal Scale64), or 3) are pregnant, planning to become pregnant, or 
currently breastfeeding. Please note that the smartphone application for this pilot study is only 
available in English. 
2. Sources of Research Material. Demographic, psychosocial, environmental, and 
behavioral data will be collected via: 1) REDCap (online or over the phone), 2) traditional 
REDcap self-report questionnaires completed in-person on a laptop/tablet computer and 
completed via secure online web portal, 3) EMAs completed via secure smartphone application, 
4) smoking status based on expired CO and self-report, and 6) anthropometric information 
including height and weight.
3. Recruitment and Informed Consent. Individuals who complete the initial online/phone 
screener and meet the initial study inclusion criteria will be invited to complete the in-person 
screening visit. Upon arrival to the TTRP, participants will be provided with detailed information 
about the study and given the opportunity to have their questions answered within a private 
room to ensure confidentiality. Written informed consent will be obtained from those who are 
interested in participating. 
4. Risks. Participation in this study poses risk to participants. However, one potential, 
although unlikely, risk is loss of confidentiality. The severity of harm in the case of loss of 
confidentially may range from mild to severe depending upon the individual and the specific 
circumstances. However, the risks of participation in the study are similar to that of participation 
in standard clinic care, as loss of confidentially may be experienced in either case. The 


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Page 13 of 18
investigators are unaware of any risks associated with the use of the Vitalograph BreathCO 
monitor for the measurement of expired CO levels.
Medication Risks. All tobacco cessation medications offered or prescribed as part of this 
research protocol are FDA-approved for tobacco cessation. Nicotine replacement therapy is 
available over-the-counter, while varenicline requires a prescription. Possible risks of nicotine 
gum include: increased heart rate and blood pressure; mouth, teeth, and jaw problems; irregular 
heartbeat or palpitations; symptoms of nicotine overdose including nausea, vomiting, dizziness, 
weakness, and rapid heartbeat; or allergic reaction such as difficulty breathing or rash. Possible 
risks of nicotine lozenges include: increased heart rate and blood pressure; mouth, teeth, and 
jaw problems; indigestion or sore throat; irregular heartbeat or palpitations; symptoms of 
nicotine overdose including nausea, vomiting, dizziness, weakness, and rapid heartbeat; or 
allergic reaction such as difficulty breathing or rash. Nicotine replacement medications may 
have enough medication to make children and pets sick. The most common adverse reactions 
to varenicline include nausea, abnormal dreams, constipation, flatulence, and vomiting. Serious 
risks include new or worsening seizures, cardiovascular events (particularly among those with 
known cardiovascular disease), angioedema and hypersensitivity reactions, and serious skin 
reactions. Increased effects of alcohol and accidental injuries (e.g., traffic accidents) have been 
reported while taking varenicline. Serious neuropsychiatric symptoms have been reported 
including changes in mood (depression and mania), psychosis, hallucinations, paranoia, 
delusions, homicidal ideation, hostility, agitation, anxiety, panic, suicidal ideation, suicide 
attempts, and completed suicide. The study physician working in the clinic will prescribe these 
medications, monitor treatment response and medication side effects, and make adjustments as 
needed. Varenicline prescribing information is available at: 
https://www.pfizermedicalinformation.com/en-us/chantix
5. Protections against Risk. 
General Procedures. Each participant will be assigned an identification number that will be 
utilized in place of names in all electronic and print data files. The file containing the links 
between participant names and identifiers will be kept in a file that will be stored in a locked 
filing cabinet when not in use and will be destroyed 12 months after the completion of the study. 
All print information including informed consent, screening questionnaires, and smoking status 
questionnaires will be stored in locked filing cabinets at the OTRC. Electronic data (with names 
omitted) will be maintained on the investigators’ computers, and all computers and electronic 
files will be password protected. Participants will complete questionnaire data on a laptop/tablet 
computer through RedCAP. Participants will complete smartphone assessments through an 
encrypted mobile application, and all data will be automatically saved and sent to study servers. 
Baseline anthropometric measures and CO will be collected at the TTRP. All project staff will 
receive training focused on each of the following topics: 1) project rationale and objectives, 2) 
the informed consent process, 3) general data collection procedures (e.g., computer data 
collection, privacy), 4) measurement of anthropometric data, and 5) use of the CO 
measurement devices.
EMA Confidentiality Procedures. The following features are designed to address 
smartphone/EMA data security issues: 1) the data stored on the smart phone device are in a 
SQLite database in a sandbox environment, where read/write operations are only available 
through the programming application (i.e., no file or output is readable to end users); 2) a > 8 
character password (only known to researchers) is required to authenticate the current user 
before data can be manually accessed or manually downloaded from the smart phone to the 
server; 3) the web browser application linking the investigator’s computer to the database is on 
HTTPS protocol (SSL certificate with encryption), which will guarantee the data transfer from 
web browser to the backend database is well protected; and, 4) the backend databases are 


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Page 14 of 18
hosted by Microsoft Azure and the University of Oklahoma Health Science Center. These steps 
will ensure the security of EMA data.
Medication Risk Management. Adverse events will be monitored in-person by research 
personnel at in-person visits or over the phone during counseling or follow-up calls. Qualified 
study staff will also follow-up with participants in person and via phone to monitor the use of 
NRTs and other tobacco cessation medications. The OTRC protocol for handling mental health 
emergencies will be followed as needed. All serious adverse events that meet reporting criteria 
will be promptly reported to the OUHSC IRB.
6. Potential Benefits. Potential benefits to participants include the possibility that the 
intervention will have a beneficial impact on smoking cessation outcomes. In addition, the 
knowledge gained from this study may be utilized to improve our understanding of the barriers 
to quitting and predictors of relapse. All study participants who are still smoking at the 
conclusion of the 26 week study period will be referred to the Oklahoma Tobacco Helpline to 
receive additional free smoking cessation resources.
7. Risks in relation to Benefits. The possible risks of participation in this study are minimal 
and reasonable in relation to benefits. The potential health benefits gained from tobacco 
cessation interventions far outweigh the risks of continued tobacco use.
G. Data and Safety Monitoring Plan 
The study poses risk to participants; therefore, continuous monitoring and reporting of 
events will be undertaken by OTRC investigators (Drs. Kendzor, Hébert, Businelle). 
Unanticipated problems will be promptly reported to the IRB. Possible (though unlikely) adverse 
events might include compromised data security and medication side effects. Procedures to 
minimize the risk of loss of confidentiality are described in section F under the heading 
Protections against Risk.
Data and Safety Monitoring Committee (DSMC). The DSMC is composed of individuals with 
the appropriate expertise in adult and pediatric hematology and medical oncology, radiation 
oncology, translational and correlative science, pharmacy, nursing and biostatistics. The DSMC 
operates under the rules of an approved data safety monitoring plan which complies with the 
National Cancer Institute (NCI) guidelines published as Essential Elements of a Data and Safety 
Monitoring Plan for Clinical Trials Funded by NCI as of January 2005 and the “NIH Policy for 
Data and Safety Monitoring,” NIH Guide for Grants and Contracts, 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html.
The Data Safety Monitoring Committee is charged with oversight of participant safety, study 
conduct and the validity and integrity of data for clinical trials at SCC. While the focus of the 
DSMC is to monitor interventional investigator-initiated trials (IITs) that are not subject to 
external monitoring, it has the authority to monitor any SCC protocol when potential concerns 
are identified. The DSMC also has the authority to suspend or close a study until the principal 
investigator addresses any issues that may cause harm or increase risks to subjects.  The 
DSMC reports all findings to the Institutional Review Board (IRB). 
DSMC Auditing
In addition to monitoring, the DSMC oversees an internal auditing process to ensure subject 
safety and data quality. All cancer-related clinical trials active at the SCC are eligible for audit; 
however, priority is placed on those clinical trials that are not monitored or audited by an outside 
entity. If an external entity conducts an audit of a clinical trial at the SCC, then the findings of 
that audit are reported to the DSMC, either through the formal audit report provided by the 


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Page 15 of 18
external auditing entity, if available, or from the PI, who will report any findings communicated 
during the audit process. 
H. Literature Cited 
 
1.
Hughes JR. An updated algorithm for choosing among smoking cessation treatments. 
Journal of Substance Abuse Treatment. 2013;45(2):215-221.
2.
Ramon JM, Morchon S, Baena A, Masuet-Aumatell C. Combining varenicline and 
nicotine patches: a randomized controlled trial study in smoking cessation. BMC 
Medicine. 2014;12(1):172.
3.
Koegelenberg CN, Noor F, Bateman ED, et al. Efficacy of varenicline combined with 
nicotine replacement therapy vs varenicline alone for smoking cessation: A randomized 
clinical trial. JAMA. 2014;312(2):155-161.
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Chang P-H, Chiang C-H, Ho W-C, Wu P-Z, Tsai J-S, Guo F-R. Combination therapy of 
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Hajek P, Smith KM, Dhanji AR, McRobbie H. Is a combination of varenicline and nicotine 
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OTRC. Mobile Health. 2016; http://otrc.stephensoncancercenter.org/MobileHealth.aspx. 
Accessed December 21, 2017.
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Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual causes of death in the United 
States, 2000. J. Am. Med. Assoc. 2004;291(10):1238-1245.
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US Department of Health and Human Services. The health consequences of smoking-
50 years of progress: a report of the Surgeon General. 2014; 
http://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf. 
Accessed June 22, 2016.
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Jamal A, King BA, Neff LJ, Whitmill J, Babb SD, Graffunder CM. Current Cigarette 
Smoking Among Adults - United States, 2005-2015. Morb. Mortal. Weekly Rep. 
2016(65):1205-1211.
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Babb S, Malarcher A, Schauer G, Asman K, Jamal A. Quitting Smoking Among Adults - 
United States, 2000-2015. MMWR Morb Mortal Wkly Rep. 2017;65(52):1457-1464.
11.
Harris KJ, Bradley-Ewing A, Goggin K, et al. Recruiting unmotivated smokers into a 
smoking induction trial. Health Educ. Res. 2016;31(3):363-374.
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Fiore MC, Jaen CR, Baker TB, Bailey WC, Benowitz NL, Curry SJ. Treating Tobacco 
Use and Dependence: 2008 Update. Clinical Practice Guideline 2008; 
https://www.ncbi.nlm.nih.gov/books/NBK63952/. Accessed October 26, 2017.


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13.
Buchanan TS, Berg CJ, Cox LS, et al. Adherence to Varenicline Among African 
American Smokers: An Exploratory Analysis Comparing Plasma Concentration, Pill 
Count, and Self-report. Nicotine Tob Res. 2012;14(9):1083-1091.
14.
Bruno M, Wright M, Baker CL, et al. Mobile App Usage Patterns of Patients Prescribed a 
Smoking Cessation Medicine: Prospective Observational Study. JMIR mHealth and 
uHealth. 2018;6(4).
15.
McClure JB, Anderson ML, Bradley K, An LC, Catz SL. Evaluating an adaptive and 
interactive mHealth smoking cessation and medication adherence program: a 
randomized pilot feasibility study. JMIR mHealth and uHealth. 2016;4(3).
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Piper ME, Federman EB, McCarthy DE, et al. Efficacy of Bupropion Alone and in 
Combination with Nicotine Gum. Nicotine Tob Res. 2007;9(9):947-954.
17.
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