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IntroductionCytisinicline (known as cytisine), a nicotinic acetylcholine receptor partial agonist, is a smoking cessation aid currently marketed in Central and Eastern Europe using a 1.5-mg/tablet 25-day downward titration schedule. No prior studies have evaluated other doses or administration schedules. This study evaluated the effects of a higher dosage and simplified dosing schedule on drug efficacy and tolerability.MethodsORCA-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 a 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.ResultsAmong 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 1.5-mg or 3-mg cytisinicline.ConclusionBased on simpler dose scheduling, excellent tolerability, and best-continued abstinence rate, cytisinicline 3-mg TID was selected for future Phase 3 studies.ImplicationsAlthough the 1.5-mg 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.

Introduction Varenicline helps people who smoke quit at rates 2–3 times greater than placebo. Currently, in the United States, varenicline is not available over the counter (OTC). Aims and Methods In this study, we assessed the safety and efficacy of 1 mg and 0.5 mg varenicline as an OTC medication for smoking cessation in comparison to placebo. This randomized, double-blind, placebo-controlled study was performed at two clinical sites in the United States of n  = 313 people. The treatment period was 12 weeks. During the COVID pandemic, the protocol was modified to allow remote participation; verification of smoking status was via breath carbon monoxide levels for in-person visits and mailed urine cotinine kits for the remote participants. Results There was no difference in biologically confirmed continuous abstinence by condition between weeks 8 and 12; however, the odds of biologically confirmed point prevalence abstinence were higher for those in the 1 mg b.i.d. condition than for those in the placebo condition at week 12 (OR 3.39; 95% CI 1.49, 7.71), and were higher for those assigned to the 1.0 mg b.i.d. condition than the 0.5 mg b.i.d. condition at week 12 (OR 2.37; 95% CI 1.11, 5.05). Adverse events were modest, and as expected (vivid dreams and nausea in the medication conditions). Conclusions The results are suggestive that varenicline is safe and effective as an OTC medication. [ABSTRACT FROM AUTHOR]

Background: Greater nicotine delivery is associated with higher nicotine concentrations in electronic nicotine delivery system (ENDS) liquids. However, there is a current debate as to whether this leads to increased dependence and mitigates ENDS public health potential. Methods: Self‐reported dependence among users of myblu ENDS containing different nicotine concentrations was examined with data from a multiwave cross‐sectional survey of US young adults and adults. Questions examined responses related to dependence measures and participants' most often used myblu ENDS nicotine concentration (low: 0%, 1% and 1.2%; medium: 2%, 2.4% and 2.5%; or high: 3.6% and 4%). Results: A global general linear model using nicotine concentration, age and days myblu that was used in the past 30 revealed a significant difference in PROMIS scores among nicotine concentration groups (F = 4.07, p = 0.02). However, pairwise comparisons to examine which specific groups differed significantly from others showed no significant differences. Logistic regression demonstrated that strong past 30‐day cravings to use myblu among participants using high or medium nicotine concentrations were not significantly different from those using a low concentration (ORs 0.66 [0.42, 1.03], p = 0.07 and 0.95 [0.49, 1.82], p = 0.98, respectively). Time to daily first use for high or medium nicotine concentration users was not significantly different from those using a low concentration (ORs 0.89 [0.70, 1.14], p = 0.35 and 0.84 [0.57, 1.25], p = 0.40, respectively). Conclusions: Use of myblu ENDS with different nicotine concentrations is not associated with differing levels of dependence. Our findings contradict the notion that high ENDS e‐liquid nicotine levels generate increased dependence. [ABSTRACT FROM AUTHOR]

Encouraging adult smokers who are uninterested or unwilling to quit, and would otherwise continue to smoke, to transition to potentially less harmful nicotine products such as electronic nicotine delivery systems (ENDS) may positively impact population health. However, counterbalancing this benefit is the societal concern that ENDS may be used by never smokers and youth and serve as a 'gateway' into cigarette smoking. Data were analysed from two independent surveys of the prevalence and perceptions of myblu ENDS use in the United States. Total sample size was 22,232 young adults and 23,264 adults. Being curious to use myblu was 1.6–2.0 times more likely in young adult current smokers than young adult never smokers. This likelihood was 2.8 times greater for adult current smokers compared with adult never smokers in the perceptions survey, while in the prevalence survey, there was no difference between adult current and never smokers. Intentions to use myblu were significantly greater in young adult current smokers compared with young adult never smokers in both surveys and in adults in the prevalence survey. In all surveys and age cohorts, 124 of 45,496 participants (0.1% of the total survey population) reported first using myblu prior to smoking cigarettes and went on to become established smokers. Curiosity and intentions to use myblu were generally higher in current smokers compared with never smokers. There was minimal evidence to suggest the existence of a 'gateway' effect to established cigarette smoking among never‐smoking myblu users. [ABSTRACT FROM AUTHOR]

Key Points: Question: Is cytisinicline an effective and safe pharmacotherapy to promote smoking cessation? Findings: In a randomized clinical trial that included 810 adults who smoked, both a 6-week and a 12-week course of a novel cytisinicline dosing regimen were more effective than placebo and were well tolerated, producing significantly higher continuous smoking abstinence rates compared with placebo during the last 4 weeks of drug treatment and from the end of treatment to 24 weeks. Meaning: Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering a new nicotine dependence treatment option. Importance: Cytisinicline (cytisine) is a plant-based alkaloid that, like varenicline, binds selectively to α4β2 nicotinic acetylcholine receptors, which mediate nicotine dependence. Although not licensed in the US, cytisinicline is used in some European countries to aid smoking cessation, but its traditional dosing regimen and treatment duration may not be optimal. Objective: 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. Design, Setting, and Participants: A 3-group, double-blind, placebo-controlled, randomized trial (ORCA-2) compared 2 durations of cytisinicline treatment (6 or 12 weeks) vs placebo, with follow-up to 24 weeks, among 810 adults who smoked cigarettes daily and wanted to quit. It was conducted at 17 US sites from October 2020 to December 2021. Interventions: Participants were randomized (1:1:1) to cytisinicline, 3 mg, 3 times daily for 12 weeks (n = 270); cytisinicline, 3 mg, 3 times daily for 6 weeks then placebo 3 times daily for 6 weeks (n = 269); or placebo 3 times daily for 12 weeks (n = 271). All participants received behavioral support. Main Outcomes and Measures: Biochemically verified continuous smoking abstinence for the last 4 weeks of cytisinicline treatment vs placebo (primary) and from end of treatment to 24 weeks (secondary). Results: Of 810 randomized participants (mean age, 52.5 years; 54.6% female; mean of 19.4 cigarettes smoked daily), 618 (76.3%) completed the trial. 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). 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% during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P <.001). Nausea, abnormal dreams, and insomnia occurred in less than 10% of each group. Sixteen participants (2.9%) discontinued cytisinicline due to an adverse event. No drug-related serious adverse events occurred. Conclusions and Relevance: Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering new nicotine dependence treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT04576949 This randomized trial compares the efficacy and tolerability of 2 durations of cytisinicline treatment (6 or 12 weeks) vs placebo for smoking cessation in adults who smoked cigarettes daily. [ABSTRACT FROM AUTHOR]

A study was conducted to assess efficacy and safety of varenicline for smoking cessation compared with sustained-release bupropion (bupropion SR) and placebo. It was found that varenicline was significantly more efficient than placebo for smoking cessation at all time points and significantly more effective than bupropion SR at the end of 12 weeks of drug treatment and at 24 weeks.

The antidepressant drug bupropion appears to be more effective than a nicotine patch for smokers who want to quit. Researchers randomly assigned 893 smokers to take bupropion, use a nicotine patch, use both bupropion and a nicotine patch, or take a placebo. Treatments lasted 8 to 9 weeks. One year later, 35% of those who used bupropion and a nicotine patch had quit smoking compared to 30% of those taking bupropion alone, 16% of those using a nicotine patch and 15% of those taking a placebo. Bupropion alone was almost as effective as bupropion plus a nicotine patch.

The magnitude of nicotine replacement among previous smokers was examined among the special intervention group in the Lung Health Study by measuring the ad-libitum levels of nicotine polacrilex gum (NG) usage over a span of five-years of free access. Approximately two-thirds of the subjects initially quit smoking using NG during the first four months. The results revealed that successful quitters used an average of eight NG per day and that those using NG while still smoking consumed an average of six to seven pieces per day.

The smoking cessation programs of the Lung Health Study are evaluated. It was found that 47% of the males who participated in the Restart programs have stopped smoking after the fifth year, compared to 28% who continued smoking. Forty-two percent of the women participants also stopped smoking while 33% failed to quit. It is concluded that the programs must be studied further to make them more effective in preventing relapse.