Importance: Cigarette smoking is the leading cause of preventable morbidity and mortality in the United States and worldwide, and most tobacco users begin smoking in adolescence. Although advances have yielded efficacious pharmacotherapies to complement smoking cessation counseling in adults, far less progress has been made in addressing tobacco use in adolescence.

Objective: To evaluate the efficacy and safety of varenicline tartrate for smoking cessation in adolescents and young adults.

Design, setting, and participants: This 2-group randomized, placebo-controlled, double-blind intention-to-treat clinical trial enrolled a volunteer sample of treatment-seeking adolescent and young adult cigarette smokers (n = 157) aged 14 to 21 years at an outpatient clinical site in Charleston, South Carolina, from August 15, 2012, to October 20, 2017. Follow-up was completed on January 25, 2018. Data were analyzed from March 19, 2018, to August 11, 2018, with further revisions completed April 10, 2019.

Interventions: Participants were randomized in a 1:1 ratio to a 12-week course of varenicline (n = 77) or placebo (n = 80). All participants received weekly smoking cessation counseling.

Main outcomes and measures: The preselected primary efficacy outcome was urine cotinine level-confirmed 7-day abstinence at the end of treatment. Secondary efficacy outcomes included weekly abstinence throughout active treatment, abstinence at posttreatment follow-up visits, and time to first 7-day abstinence. The primary safety outcome was the frequency of treatment-emergent adverse events.

Results: A total of 157 participants were enrolled (94 male [59.9%]; mean [SD] age, 19.1 [1.5] years). The varenicline and placebo groups did not differ in the primary outcome of cotinine-confirmed self-reported 7-day abstinence at the end of treatment (varenicline group, 4 of 45 [8.9%]; placebo group, 4 of 45 [8.9%]; risk ratio [RR], 0.97; 95% CI, 0.29-2.99; P = .96). However, among secondary outcomes, the varenicline group achieved self-reported earlier abstinence of at least 7 days (hazard ratio, 1.91; 95% CI, 1.12-3.27) and demonstrated higher rates of self-reported weekly abstinence during the full course of treatment (RR, 1.81; 95% CI, 1.09-2.99; P = .02) and at posttreatment follow-up (RR, 1.82; 95% CI, 1.01-3.28; P = .02). Study medication was generally well tolerated, and treatment-emergent adverse events did not differ between groups (any adverse events, 55 [71.4%] in the varenicline group vs 60 [75.0%] in the placebo group; RR, 0.95; 95% CI, 0.79-1.15; P = .61).

Conclusions and relevance: When added to weekly cessation counseling for adolescent cigarette smokers, varenicline, compared with placebo, was well tolerated but did not improve end-of-treatment abstinence. However, varenicline may hasten abstinence and yield improvements in posttreatment abstinence outcomes.

Trial registration: ClinicalTrials.gov identifier:NCT01509547.

Conflict of Interest Disclosures: Dr Gray reported consulting for Pfizer, Inc, and receiving grant support from the National Institutes of Health (NIH). Mr Baker reported receiving grant support from the NIH. Dr McClure reported receiving grant support from the NIH. Dr Tomko reported receiving grant support from the NIH during the conduct of the study and outside the submitted work. Dr Squeglia reported receiving grant support from the NIH. Dr Saladin reported receiving grant support from the NIH. Dr Carpenter reported consulting for Pfizer, Inc, during the conduct of the study. No other disclosures were reported.

• K01 DA036739/DA/NIDA NIH HHS/United States
• K23 AA025399/AA/NIAAA NIH HHS/United States
• K12 DA031794/DA/NIDA NIH HHS/United States
• K12 HD055885/HD/NICHD NIH HHS/United States
• U01 DA031779/DA/NIDA NIH HHS/United States