Cytisinicline for Smoking Cessation: The ORCA Phase 3 Replication Randomized Clinical Trial.

Importance: New smoking cessation medication options are needed. Cytisinicline, a partial agonist at α4β2 nicotinic acetylcholine receptors, has demonstrated smoking cessation efficacy in 1 US trial. Additional evidence is needed.

Objective: To reproduce the findings of the efficacy and tolerability of cytisinicline compared with placebo for smoking cessation and to test its effect on nicotine craving as a mechanism of action.

Design, Settings, And Participants: This was a 3-group double-blind, placebo-controlled phase 3 replication randomized clinical trial (ORCA-3) conducted at 20 clinical trial sites in the US from January 2022 to March 2023. It compared 6 and 12 weeks of a novel cytisinicline regimen to placebo among adults who smoked 10 or more cigarettes daily and sought to quit. Participants were randomized (1:1:1) to 3-mg cytisinicline 3 times daily for 12 weeks; 3-mg cytisinicline 3 times daily for 6 weeks followed by placebo for 6 weeks; or placebo 3 times daily for 12 weeks. The follow-up period was 24 weeks, and all groups received behavioral support. Data analyses were performed from May 3, 2023, to March 20, 2024.

Interventions: Cytisinicline, 3 mg, 3 times daily for 12 weeks; cytisinicline, 3 mg, 3 times daily for 6 weeks followed by placebo for 6 weeks; or placebo 3 times daily for 12 weeks.

Main Outcomes And Measures: Biochemically verified (carbon monoxide <10 ppm) continuous smoking abstinence during the last 4 weeks of 6- and 12-week treatments (primary outcome) and from end of treatment to 24 weeks (secondary outcome); Questionnaire of Smoking Urges; incidence of adverse events.

Results: Of 792 participants randomized (mean [SD] age, 52.0 [11.8] years; 439 [55.4%] female; mean [SD] cigarettes/d, 20.4 [7.5]), 628 (79.3%) completed the trial. Primary and secondary outcomes were significantly higher for both cytisinicline groups vs placebo. For 6-week treatment, 39 cytisinicline participants (14.8%) vs 16 placebo participants (6.0%) were abstinent during weeks 3 to 6 (odds ratio [OR], 2.9; 95% CI, 1.5-5.6; P < .001). For 12-week treatment, 80 cytisinicline participants (30.3%) vs 25 placebo participants (9.4%) were abstinent during weeks 9 to 12 (OR, 4.4; 95% CI, 2.6-7.3; P < .001). Continuous abstinence rates for the 6-week treatment were 6.8% (cytisinicline) vs 1.1% (placebo) from weeks 3 to 24 . Continuous abstinence rates for the 12-week treatment were 20.5% (cytisinicline) vs 4.2% (placebo) for weeks 9 to 24. Reduction in craving at week 6 was greater for cytisinicline than placebo (-15.2 points [95% CI, -16.4 to -14.0] vs -12.0 points [95% CI, -13.5 to -10.5]; P < .001). Cytisinicline was well tolerated with no treatment-related serious adverse events.

Conclusions And Relevance: The findings of the ORCA phase 3 trial reaffirms the efficacy and tolerability of cytisinicline at both 6- and 12-week treatment for smoking cessation, with benefits extending through 24 weeks. As a mechanism of effect, cytisinicline mitigated nicotine craving.

Trial Registration: ClinicalTrials.gov Identifier: NCT05206370.