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

Abstract

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.

Figure 1.. CONSORT Flow Diagram

^aRandomization stratified by study site. ^bThere were 228 individuals screened who did not meet inclusion criteria and 380 who met exclusion criteria (could be in both categories). The numbers of potential participants who were ineligible for various reasons are not shown because not every site screened all patients for all potential reasons for ineligibility. ^cIn the 12-week cytisinicline group, 1 participant died of a stab wound, 1 of hemorrhagic stroke, and 1 of a suspected opioid overdose; and in the 6-week cytisinicline group, 1 participant died of postsurgical complications. ^dPhysicians typically withdrew a participant due to habitual noncompliance with study visits and/or diary completion, which made it difficult to adequately assess the participant’s safety to continue with the study.

Figure 2.. Reduction in Craving by Group Over Time per the Brief Questionnaire of Smoking Urges (QSU-brief) Scores

During the first 6 weeks of treatment, mean cigarette craving per QSU-brief scores declined more among participants randomized to the pooled cytisinicline 6- and 12-weeks groups compared to placebo. Mixed-model repeated measures with unstructured covariance and with baseline as a repeated measure were used to estimate the mean at each visit; 95% CIs for the mean estimates are shown for all visits.