A Multicenter, Double-Blind, Randomized, Placebo-Controlled Phase 2b Trial of Cytisinicline in Adult Smokers (The ORCA-1 Trial)

Abstract

Introduction 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. Methods 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. Results 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. Conclusion Based on simpler dose scheduling, excellent tolerability, and best continued abstinence rate, cytisinicline 3mg TID was selected for future Phase 3 studies. Implications 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.

Cytisinicline for Smoking Cessation

“…Cytisinicline’s mean elimination half-life of 4.8 hours supports a simplified regimen using 3 times daily administration . In a randomized phase 2b trial testing various doses and schedules for 25 days, 3 mg administered 3 times daily produced the highest biochemically confirmed continuous abstinence during 4 consecutive weeks after treatment ended (weeks 4 to 8) and was superior to placebo (30% vs 8%, P = .005) . The 3-mg dose taken 3 times daily was well tolerated, achieved good treatment adherence, and was selected for use in phase 3 clinical trials …”

“…9,14 In a randomized phase 2b trial testing various doses and schedules for 25 days, 3 mg administered 3 times daily produced the highest biochemically confirmed continuous abstinence during 4 consecutive weeks after treatment ended (weeks 4 to 8) and was superior to placebo (30% vs 8%, P = .005). 15 The 3-mg dose taken 3 times daily was well tolerated, achieved good treatment adherence, and was selected for use in phase 3 clinical trials. 15 Because relapse commonly occurs early in a quit attempt, a treatment duration longer than 25 days might improve the effectiveness of the revised cytisinicline regimen.…”

“…15 The 3-mg dose taken 3 times daily was well tolerated, achieved good treatment adherence, and was selected for use in phase 3 clinical trials. 15 Because relapse commonly occurs early in a quit attempt, a treatment duration longer than 25 days might improve the effectiveness of the revised cytisinicline regimen. 9,16 This randomized, double-blind, clinical trial compared the efficacy and tolerability of cytisinicline, 3 mg, administered 3 times daily vs placebo when administered for 6 weeks or 12 weeks.…”

The Effect of Cytisine vs Varenicline on Smoking Cessation—Reply

“…A simplified dosing regimen for cytisine with a more standard extended schedule may lead to enhanced treatment adherence and increased effectiveness but must be balanced against a tolerable adverse event profile. Although the results from a recent placebo-controlled trial and an active comparator trial of cytisine with amended dosing have shown some promise, future studies may provide additional insights about revised treatment dosing of cytisine …”

“…Cytisine is an effective and well-tolerated smoking cessation aid . A relative lack of private investment has stifled production of and wider access to cytisine .…”