This study will offer both counseling and pharmacotherapy, consistent with current recommendations for optimal tobacco treatment [16]. All participants will receive 13 weeks of varenicline, beginning with the standard 1-week prequit titration (days 1‐3: 0.5 mg once daily; days 4‐7: 0.5 mg twice daily), followed by 1 mg twice daily for an additional 12 weeks. Additionally, all participants will have access to the study smartphone intervention app (with or without medication adherence components). Finally, all participants will receive 6 weekly telephone counseling sessions with a tobacco treatment specialist from the Tobacco Treatment Research Program [32] at the University of Oklahoma Health Campus. The initial counseling session will occur approximately 1 week prior to the scheduled quit date and will continue weekly through 4 weeks postquit (6 sessions total lasting 15‐30 min each). Consistent with clinical practice guidelines [7], counseling will focus on education, skill-building, and support, employing cognitive-behavioral and motivational strategies.

All participants will receive a 13-week supply of varenicline, which will be mailed prior to the scheduled quit date. Daily doses will be titrated during the week prior to the scheduled quit day (days 1‐7), as described above, and will continue at the full dose for 12 additional weeks (days 8‐91). Participants randomized to the combination therapy group will also be mailed a 12-week supply of nicotine lozenges (NRT). Participants will receive 5 boxes of nicotine lozenges (108 pieces per box; 540 pieces total) in a single mailing. This quantity provides a supply that supports flexible ad libitum dosing while also supporting optimal dosing based on package recommendations [33]. Participants may request additional lozenges during the first 12 weeks after the scheduled quit date if needed, and additional supply requests will be documented. Participants will be advised to begin using the lozenges on the quit day and continue through 12 weeks postquit (days 8‐91), following the standard nicotine lozenge dosing instructions printed on the package.

All participants will download the smartphone app, which will be configured via the Insight Mobile Health Platform [34]. For all participants, the app will provide access to core study features throughout participation, including study information, counseling appointment schedules, medication instructions, treatment topics, compensation tracking, troubleshooting resources, and the ability to contact study staff. Participants will also complete study assessments (eg, baseline, daily, weekly, interim, and follow-up surveys) and CO breath testing through the app at scheduled time points. For participants assigned to the COMBO-A intervention, additional medication adherence components will be activated, including automated medication reminders and graphical feedback on medication adherence. These features are designed to support consistent use of varenicline and nicotine lozenges. See Table 2 for a detailed description of intervention components by study group.

All participants will be required to specify a 13-hour wake period. During this period, participants assigned to the COMBO-A intervention will receive smartphone medication reminders aligned with the varenicline dosing schedule. Reminders will appear 30 minutes after participants’ self-reported wake time (AM reminder) and 2 hours before bedtime (PM reminder). Along with the reminder, participants will be asked whether they have taken their pill. Participants who indicate that they are going to take their pill or have already taken their pill will receive an affirmation message. If the participant has not yet taken the dose, follow-up prompts will appear at 30-minute intervals, for up to 3 follow-up prompts. Following the final prompt, participants who indicate that they have not taken their pill will be asked about the main reason for the missed dose and will receive an adherence-promotion message tailored to their response. See Table 3 for example messaging and assessments.

Participants randomized to VAR+NRT+COMBO-A will receive additional smartphone-based medication reminders corresponding to the standard nicotine lozenge dosing schedule, in addition to varenicline reminders. Beginning on the quit day, participants will receive reminders to use nicotine lozenges every 1 to 2 hours (6 reminders per day), consistent with recommended dosing guidelines [35], for 6 weeks (days 8‐49). During postquit weeks 7 to 9 (days 50‐70), participants will receive reminders to use nicotine lozenges every 2 to 4 hours (4 reminders per day). Finally, during postquit weeks 10 to 12 (days 71‐91), participants will receive reminders to use nicotine lozenges every 4 to 8 hours (3 reminders per day). After each reminder, participants will be asked when they last used a nicotine lozenge. Participants who report that they have not used a lozenge in more than 8 hours will be asked about the main reason for not using a lozenge and will receive an adherence-promotion message tailored to their response. See Table 3 for example messaging and assessments.

Participants will be prompted to complete an initial baseline assessment, daily and weekly assessments each morning through 12 weeks postquit, interim follow-up assessments at 17, 20, and 23 weeks postquit, and a final follow-up at 26 weeks postquit. All surveys will be completed via smartphone. Participants will be compensated up to US $337 in total via a reloadable study credit card. Compensation includes US $1 per day for completing daily diary assessments during the first 13 weeks (up to US $92), US $50 for completing the baseline 2A and 2B assessments (US $25 each), US $10 per week for completing weekly questionnaires with CO breath sample submissions during the first 13 weeks (up to US $130), US $5 for completing each interim assessment (up to US $15), and US $50 for completing the final follow-up assessment at 26 weeks postquit. A summary of all measures and the assessment schedule is presented in Table 4. Assessments are described in detail below.

Screening assessments will be conducted prior to baseline to determine study eligibility. Initial screening will be completed via a REDCap form or phone screening and will include measures of sociodemographic characteristics, the REALM-SF [31], the CUDIT-SF [28], and tobacco use history.

Following completion of the screening survey, participants will complete the Baseline Part 1 enrollment call, download the Insight Mobile Health Platform app, and complete the baseline survey. Participants will be instructed to complete the full baseline survey via the smartphone app within approximately 1 day of receiving the baseline survey code, although up to 7 days will be allowed for completion before participants are considered ineligible. This survey will assess sociodemographic and background characteristics; financial stress using the Financial Chronic Stress Scale [36]; household food insecurity assessed using the US Household Food Security Survey Module [37]; self-rated health [47]; height and weight; religion and political orientation/stress [38,39]; tobacco use history; nicotine dependence assessed using the Heaviness of Smoking Index [40]; withdrawal symptoms assessed using the Brief Wisconsin Smoking Withdrawal Scale 2-B [41]; depressive symptoms assessed using the Center for Epidemiological Studies Depression Scale-10 (CES-D-10) [44]; alcohol use disorder via the Alcohol Use Disorders Identification Test-Consumption [45] and alcohol use and frequency using a 7-day Timeline Follow-Back approach, capturing daily quantity and frequency of consumption and heavy drinking episodes [46]; marijuana/cannabis use behavior adapted from a statewide study on medical and recreational cannabis use in Oklahoma [60]; motivation/importance/readiness to quit smoking [48]; and smoking self-efficacy via an adapted version of the 9-item Smoking Self-Efficacy/Temptation Short Form [49]. After completing the baseline survey, participants will complete a videoconferencing appointment with study staff (Baseline Part 2A), during which they will submit a CO breath sample to biochemically verify current smoking status. Participants will then complete a medical screening appointment with the study physician via videoconference (Baseline Part 2B). During this visit, participants will complete additional assessments, including the Patient Health Questionnaire-9 (PHQ-9) [42,43] and detailed tobacco use history, and will be evaluated for varenicline eligibility. Only participants who meet all eligibility criteria, including medical clearance for varenicline use, will proceed to randomization.

Participants will complete brief daily diary assessments via the study smartphone app beginning 1 week before their scheduled quit date and continuing through 12 weeks postquit (13 weeks total). Participants will be prompted to complete the daily diary each morning and will be compensated US $1 per day for completion (up to US $92). Daily diaries (≤20 items depending on skip patterns; ≈1‐2 min to complete) will include assessments of tobacco, alcohol, and cannabis use during the previous day (ie, yesterday), medication use (varenicline and nicotine lozenges [for those assigned]), withdrawal symptoms via the Brief Wisconsin Smoking Withdrawal Scale 2-B [41], sleep duration and quality (items adapted from the Pittsburgh Sleep Quality Index) [52], and pain intensity and interference (items adapted from the Patient-Reported Outcomes Measurement Information System questionnaire) [53,54].

Thirteen weekly questionnaires will be administered at 7-day intervals during the 12-week postquit treatment period (beginning 1 week after the scheduled quit date). Weekly survey items will be embedded within the daily survey and presented on prespecified assessment days. Participants will be compensated US $10 for each completed weekly survey and breath sample (up to US $130).

The primary aim of this trial is to evaluate whether the combination of varenicline and oral NRT (VAR+NRT) increases the likelihood of achieving biochemically verified smoking cessation compared with varenicline alone. The primary outcome for the medication treatment factor (VAR+NRT vs VAR) will be CO-confirmed 7-day point prevalence abstinence at 26 weeks (consistent with current recommendations) [61]. Daily smoking behavior will also be monitored via smartphone-based assessments. Secondary analyses for Aim 1 will examine the effect of pharmacological treatment (VAR+NRT vs VAR) on earlier smoking cessation outcomes (eg, 7-day and 30-day point prevalence abstinence at the end of treatment) as well as daily reports of smoking abstinence during the 12-week treatment period.

Aim 2 will evaluate the effect of the smartphone medication adherence app (COMBO-A vs COMBO-B) on 2 primary outcomes: medication adherence during the 12-week treatment period and biochemically verified smoking cessation at 26 weeks postquit. Medication adherence will be measured weekly using an adapted version of the ARMS [50,51] and daily via smartphone-based assessments. Secondary analyses will evaluate the influence of the medication adherence app on earlier smoking cessation follow-up points and daily reports of smoking abstinence and medication adherence during the treatment period. Finally, Aim 3 will compare weekly symptom frequency and severity (including withdrawal symptoms and common medication side effects) between the treatment groups during the intervention period.