cytisine

Assess whether subjects randomized to Arm B (3 mg cytisinicline TID for 12 weeks plus behavioral support) have a higher probability of nicotine vaping cessation from Week 9 to Week 12 post-randomization as compared to subjects randomized to Arm A (placebo TID for 12 weeks plus behavioral support). Successful vaping cessation is defined as weekly vaping abstinence during the last 4 weeks of the 12-week treatment period (Week 9 through Week 12) using quantitative cotinine levels at \<10 ng/mL for biochemical verification and subject's self-report of no vaping using a daily electronic diary

Smoking abstinence as verified by weekly expired carbon monoxide (CO) measurements ≤ 10 parts per million (ppm).

Smoking abstinence as verified by weekly expired CO measurements ≤ 10 ppm.

Vaping abstinence verified weekly using quantitative saliva cotinine levels at \< 10 ng/mL for biochemical verification and participants' self-report of no vaping.

The daily cigarette counts (number of cigarettes smoked in the past 24 hours) were self-reported by participants in the diary. Percentage of expected cigarettes smoked was computed for each participant at the end of treatment (cigarette score), based on daily cigarette counts during treatment vs the screening period. The percentage of expected cigarettes smoked was computed as Y = (100 x N) / (T x R) where N represents total number of cigarettes smoked each day over the treatment period from Day 1 to Day 25; T represents number of post-randomization days where number of cigarettes smoked is recorded; and R represents the average number of cigarettes smoked daily over the 7-day screening period as baseline. T\*R represents the total number of cigarettes that would have been smoked without intervention over the number of recorded days. Separate statistical analyses were performed for the two cytisine administration schedules (commercial and TID).

The daily cigarette counts (number of cigarettes smoked in the past 24 hours) were self-reported by participants in the diary. Percentage of expected cigarettes smoked was computed for each participant at the end of treatment (cigarette score), based on daily cigarette counts during treatment vs the screening period. (See Outcome Measure 1 description for details.) The sensitivity analysis of the primary outcome measure was only performed if results of "Statistical Analysis 5" for Outcome Measure 1 demonstrated the placebo treatment arms (commercial and TID) were not significantly different, and so could be pooled. Separate statistical analyses were performed for the two cytisine administration schedules (commercial and TID).

The daily cigarette counts (number of cigarettes smoked in the past 24 hours) were self-reported by participants in the diary. Percentage of expected cigarettes smoked was computed for each participant at the end of treatment (cigarette score), based on daily cigarette counts during treatment vs the screening period. (See Outcome Measure 1 description for details.) The sensitivity analysis of the primary outcome measure was only performed if results of "Statistical Analysis 5" for Outcome Measure 1 demonstrated the placebo treatment arms (commercial and TID) were not significantly different, and so could be pooled. Separate statistical analyses were performed for the two cytisine administration schedules (commercial and TID).

τ=5 h for Dose 1 and Dose 2 and τ=24 h for Dose 3

τ=5 h for Dose 1 and Dose 2 and τ=24 h for Dose 3

Accumulation of cytisinicline following TID administration will be assessed by estimating R(Cmax), where R is the ratio of the pharmacokinetic parameter following administration of Dose 1 on Day 8 vs. single-dose administration under fasting conditions during Period 1 or 2.

Accumulation of cytisinicline following TID administration will be assessed by estimating R(AUC0-τ), where R is the ratio of the pharmacokinetic parameter following administration of Dose 1 on Day 8 vs. single-dose administration under fasting conditions during Period 1 or 2.

Time invariance will be assessed as R(AUC0-τ/AUC0-∞), where AUC0-τ is estimated on Day 8 Dose 1 and AUC0-∞ is estimated for the single-dose under fasting conditions during Period 1 or 2.

Time to steady state will be assessed by visual inspection of the Ctrough versus time plot.

An adverse event (AE) is defined as any untoward medical occurrence that does not necessarily have to have a causal relationship with the treatment. A serious AE is any untoward medical occurrence or effect, that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; or is an important medical event which requires medical intervention to prevent one of the above. Treatment emergent events are those that occurred after the first dose of study drug.