A daily regimen of cytisinicline supplemented by behavioral support is an effective treatment for nicotine dependence, according to a study published in JAMA.
The researchers defined cytisinicline, also known as cytisine, as “a naturally occurring plant-based alkaloid” that helps reduce nicotine withdrawal symptoms and nicotine-generated reinforcement when smoking cigarettes. Countries in central and eastern Europe have used this as an OTC smoking cessation product for decades, but others worldwide have not yet authorized it, including the United States.
“No smoking cessation pharmacotherapy has received FDA approval since 2006,” the authors wrote. “New options are needed.”
Because of this, the researchers conducted a multisite, 3-group, double-blind, randomized phase 3 clinical trial to “evaluate the efficacy and tolerability of cytisinicline for smoking cessation when administered in a novel pharmacokinetically based dosing regimen for 6 or 12 weeks vs placebo.”
The researchers conducted the trial at 17 sites nationwide. Eligible participants smoked 10 or more cigarettes per day, wanted to quit smoking, had expired air carbon monoxide (CO) greater than or equal to 10 ppm, and were 18 years or older. Of 1345 individuals screened, 810 were eligible. The researchers randomized the eligible participants into 3 groups, putting 270 in the 12-week cytisinicline group, 269 in the 6-week cytisinicline group, and 271 in the placebo group.
Each participant took tablets orally 3 times daily for 12 weeks; depending on their group, the tablet was either a placebo or contained 3 mg of cytisinicline. They also received 10 minutes of brief smoking cessation behavioral support provided by trained counselors for up to 15 visits through week 12. The researchers followed up with participants for 12 additional weeks post treatment, offering shorter support sessions during weeks 16, 20, and 24.
The researchers utilized primary and secondary outcome measurements throughout the trial. The primary measurement was to verify patients’ continuous smoking abstinence for the last 4 weeks of cytisinicline treatment vs placebo. The secondary measurement was to verify continuous smoking abstinence in both groups from the end of treatment to 24 weeks.
Participants were assessed at in-person visits weekly through week 12. At each visit, the researchers verified the participants’ smoking abstinence, which meant they had not smoked since the past visit and had a breath CO level of less than 10 ppm. The researchers also followed up with participants post treatment during weeks 16, 20, and 24. During this time, they considered participants smoking abstinent if they had not smoked more than 5 cigarettes since the last visit and had a breath CO level of less than 10 ppm.
Of those eligible, 663 (81.9%) completed 12 weeks of treatment (12-week cytisinicline group: 232 [85.9%]; 6-week cytisinicline group: 217 [80.7%]; placebo group: 214 [79.0%]).
For the 6-week course of cytisinicline vs placebo, continuous abstinence rates were 25.3% vs 4.4% during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9-16.3]; P < .001) and 8.9% vs 2.6% during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5-10.2]; P = .002). In comparison, for the 12-week course of cytisinicline vs placebo, continuous abstinence rates were 32.6% vs 7.0% for weeks 9 to 12 (OR, 6.3 [95% CI, 3.7-11.6]; P < .001) and 21.1% vs 4.8% for weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P < .001).
Consequently, both the 6- and 12-week schedules demonstrated efficacy for smoking cessation. The researchers highlighted that those in cytisinicline groups had 6- to 8-fold higher odds of continuous smoking abstinence post treatment than those receiving the placebo.
In terms of safety, 184 participants (68.2%) in the 12-week cytisinicline group reported adverse events, 172 (63.9%) in the 6-week cytisinicline group reported adverse events, and 166 (61.5%) in the placebo group reported adverse events. The researchers noted that most were nonserious, with their severity ranging from mild to moderate. The most common (>5%) adverse events were headaches, nausea, abnormal dreams, and insomnia.
Overall, the researchers found success in both 6- and 12-week cytisinicline schedules supplemented with behavioral support as the participants “demonstrated smoking cessation efficacy and excellent tolerability, offering new nicotine dependence treatment options.”
Despite their findings, researchers cited several study limitations, one being that their population consisted of mostly White participants; this made the results ungeneralizable for other racial and ethnic groups. The study was also ungeneralizable for those excluded from the trial by the researchers, including those diagnosed with serious mental illness and those who currently use marijuana or illicit drugs.
Although it had limitations, the researchers ultimately considered the trial a success as it “demonstrated that a novel regimen of cytisinicline, along with behavioral support, has robust efficacy and excellent tolerability as a treatment for tobacco dependence.”
Rigotti NA, Benowitz NL, Prochaska J, et al. Cytisinicline for smoking cessation: a randomized clinical trial. JAMA. 2023;330(2):152-160. doi:10.1001/jama.2023.10042