ORCA-3 (cytisinicline for 12 weeks)
Trial question
What is the role of cytisinicline in adults who smoked cigarettes daily and wanted to quit?
Study design
Multi-center
Double blinded
RCT
Population
Characteristics of study participants
56.0% female
44.0% male
N = 529
529 patients (297 female, 232 male).
Inclusion criteria: adults who smoked ≥ 10 cigarettes daily and wanted to quit.
Key exclusion criteria: previous cytisinicline treatment; receipt of bupropion, varenicline, nortriptyline, or any nicotine replacement product in the past 4 weeks or planned to use these medications during the study; history of acute MI, unstable angina, stroke, cerebrovascular incident, or hospitalization for congestive HF in the past 3 months; current uncontrolled hypertension; hepatic or kidney impairment; moderate-to-severe depression symptoms; current psychosis, suicidal ideation, or suicide risk; positive urinary screen for illicit drugs.
Interventions
N=264 cytisinicline (3 mg TID for 12 weeks plus behavioral support).
N=265 placebo (matching placebo TID for 12 weeks plus behavioral support).
Primary outcome
Rate of biochemically verified continuous smoking abstinence during weeks 9 to 12
30.3%
9.4%
30.3 %
22.7 %
15.2 %
7.6 %
0.0 %
Cytisinicline
Placebo
Significant
increase ▲
NNT = 4
Significant increase in the rate of biochemically verified continuous smoking abstinence during weeks 9 to 12 (30.3% vs. 9.4%; OR 4.4, 95% CI 2.6 to 7.3).
Secondary outcomes
Significant increase in the rate of biochemically verified continuous abstinence rates for weeks 9 to 24 (20.5% vs. 4.2%; OR 5.8, 95% CI 2.9 to 12.5).
Significantly greater reduction in mean serum cotinine levels in participants who did not quit at week 12 (125.87 ng/mL vs. 31.03 ng/mL; MD 94.84, 95% CI 38.57 to 151.11).
Safety outcomes
No significant difference in treatment-emergent adverse events.
Conclusion
In adults who smoked ≥ 10 cigarettes daily and wanted to quit, cytisinicline was superior to placebo with respect to the rate of biochemically verified continuous smoking abstinence during weeks 9 to 12.
Reference
Nancy A Rigotti, Neal L Benowitz, Judith J Prochaska et al. Cytisinicline for Smoking Cessation: The ORCA Phase 3 Replication Randomized Clinical Trial. JAMA Intern Med. 2025 Apr 21:e250628. Online ahead of print.
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