Cytisinicline (known as cytisine), a nicotinic acetylcholine receptor partial agonist, is a smoking cessation aid currently marketed in Central and Eastern Europe using a 1.5mg/tablet 25-day downward titration schedule. No prior studies have evaluated other doses or administration schedules. This study evaluated effects of a higher dosage and simplified dosing schedule on drug efficacy and tolerability.
ORCA-1 was a double-blind, randomized, placebo-controlled clinical trial that provided cytisinicline or placebo tablets plus behavioral support for 25 days. Adult smokers (> 10 cigarettes daily) committed to quitting smoking were randomized to compare 2 cytisinicline doses (1.5 mg and 3 mg) versus placebo, and 2 administration schedules [downward titration versus 3 times daily (TID)]. Primary outcome was reduction in expected cigarettes smoked at end of treatment; secondary outcomes were biochemically confirmed 7-day abstinence at Week 4 and continuous abstinence from Weeks 5 to 8.
Among 254 participants, those in cytisinicline arms (regardless of dose or schedule) had greater reductions in cigarettes smoked versus placebo, with differences observed in 3 cytisinicline arms statistically significant versus placebo. All cytisinicline arms had statistically significantly higher abstinence rates at Week 4 versus placebo. Both cytisinicline arms using TID schedules had statistically significantly higher continuous abstinence rates from Weeks 5 to 8 compared with placebo. Participants in the cytisinicline 3-mg TID arm had the highest abstinence rate. There were no safety concerns with either 1.5mg or 3mg cytisinicline.
Based on simpler dose scheduling, excellent tolerability, and best continued abstinence rate, cytisinicline 3mg TID was selected for future Phase 3 studies.
Although the 1.5mg 25-day titration schedule has been marketed in Central and Eastern Europe for decades, this study explored using a higher dosage and a simplified dosing schedule for impact on cytisinicline efficacy and tolerability. Based on these results, a Phase 3 program was initiated using cytisinicline 3 mg tablets on a TID schedule for potential market approval in the United States.
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