A Randomized Factorial Trial of Varenicline, Nicotine Lozenges, and Smartphone Medication Adherence Reminders for Smoking Cessation: Protocol for the COMBO II Study

Background: Smoking remains the leading preventable cause of cancer mortality in the United States. Varenicline is the most effective monotherapy for smoking cessation, and combining it with nicotine replacement therapy (NRT) may further improve cessation rates. Smartphone-based medication adherence interventions could enhance pharmacotherapy adherence and cessation outcomes. Objective: This trial will evaluate the efficacy of varenicline plus nicotine lozenges and a smartphone adherence intervention for promoting smoking cessation. Methods: This fully remote, 2 × 2 factorial randomized controlled trial will enroll 496 adults from Oklahoma who smoke cigarettes daily. Participants will be randomized to 1 of 4 conditions: (1) varenicline (VAR) + nicotine lozenges (NRT) versus VAR alone and (2) a smartphone-based smoking cessation app with adherence components (COMBO-A [adherence]) or without adherence components (COMBO-B [basic]). The primary outcomes are biochemically verified 7-day point prevalence abstinence at 26 weeks post quit date and medication adherence during the treatment period. Secondary outcomes include withdrawal symptoms and medication side effects over the 12-week treatment period. Results: Study recruitment began in July 2026. As of the date of this paper's submission, 8 participants have been enrolled. Enrollment is expected to be completed by December 2028, with primary data collection and follow-up completed by June 2029. Primary study results are anticipated later in 2029. Conclusions: If effective, VAR+NRT would offer a new evidence-based cessation treatment option. If the smartphone adherence intervention improves medication adherence and cessation, it could be adapted for other pharmacotherapies and widely implemented. Ultimately, this research aims to enhance cessation efforts and reduce cancer risk among adults who smoke.