Cytisinicline shows promise for smoking cessation in industry-funded trial

Smoking cessation treatment with cytisinicline (historically known as cytisine) produced higher continuous smoking abstinence rates than placebo in a recent phase 3 randomized controlled trial.

The industry-funded trial was conducted at 17 U.S. sites from October 2020 to December 2021. Researchers randomized adults who smoked cigarettes daily and wanted to quit to receive cytisinicline (3 mg) three times daily for 12 weeks (n=270), cytisinicline (3 mg) three times daily for six weeks followed by placebo three times daily for six weeks (n=269), or placebo three times daily for 12 weeks (n=271). All participants also received behavioral support. They were followed for 24 weeks. The primary outcome was biochemically verified continuous smoking abstinence for the last four weeks of cytisinicline treatment versus placebo. Continuous abstinence from the end of treatment to 24 weeks was a secondary outcome. Results were published July 11 by JAMA.

Of the 810 randomized participants (mean age, 52.5 years; 54.6% female; mean of 19.4 cigarettes smoked per day), 618 (76.3%) completed the trial. Continuous smoking abstinence during the last four weeks of treatment was significantly higher for cytisinicline compared with placebo at both treatment durations. For the six-week course of cytisinicline versus placebo, continuous abstinence rates were 25.3% versus 4.4% during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9 to 16.3]; P<0.001). For the 12-week course of cytisinicline versus placebo, the rates were 32.6% versus 7.0% during weeks 9 to 12 (OR, 6.3 [95% CI, 3.7 to 11.6]; P<0.001).

Continuous abstinence from the last four weeks of treatment through 24 weeks was also significantly higher with both cytisinicline treatment durations than with placebo. For the six-week course of cytisinicline versus placebo, continuous abstinence rates were 8.9% versus 2.6% during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5 to 10.2]; P=0.002). For the 12-week course of cytisinicline versus placebo, 21.1% versus 4.8% of participants were abstinent during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8 to 11.1]; P<0.001). Treatment-emergent adverse events were reported by 68.2% of the 12-week cytisinicline group, 63.9% of the six-week cytisinicline group, and 61.5% of the placebo group. Most adverse events were nonserious and mild to moderate in severity. While nausea, headache, abnormal dreams, and insomnia were the most common adverse events overall, only the incidences of abnormal dreams and insomnia were higher in the cytisinicline groups compared with placebo.

Limitations of the study include its predominantly White sample and its exclusion of participants with serious mental illness, suicidal ideation, moderate to severe depression symptoms, recent unstable cardiovascular disease, and current marijuana or illicit drug use, which limits generalizability, the authors noted. They added that the trial was not large or long enough to detect uncommon adverse events.

Cytisinicline has been used for smoking cessation in some Eastern European countries for more than 50 years without a serious problem with adverse events, an accompanying editorial noted. The results of the trial provide hope that the drug could become available for smoking cessation in the U.S. soon, after FDA review of clinical trial data, which would make it the first drug approved with an indication for smoking cessation since varenicline in 2006, the editorialists said.

“It is not possible to make direct comparisons between outcomes from the new cytisinicline dosing schedule and the current most effective FDA-approved smoking cessation drug, varenicline, on the basis of this new trial because the trial did not include a varenicline comparison group,” they wrote. “However, the more than 4-fold increase in the smoking cessation rate over placebo at 6 months in this trial is impressive.”