Evaluation of Cytisine for Cessation of Nicotine-Containing Electronic and Tobacco Cigarette Use: A Randomized, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **effectiveness** of cytisine, in combination with behavioral support, compared to placebo plus behavioral support, for the cessation of single use of electronic cigarettes (EC) containing nicotine or dual use of EC and tobacco cigarettes (TC) in participants motivated to quit. The clinical relevance of this objective lies in its potential to provide an effective intervention for individuals seeking to discontinue nicotine use, thereby reducing the health risks associated with smoking and vaping. The study will measure biochemically verified continuous abstinence rates over a 26-week period preceding a 30-week follow-up from the start of treatment, comparing two groups: one receiving a 12-week course of 1.5 mg cytisine tablets plus behavioral support, and the other receiving placebo tablets with similar appearance plus behavioral support.

Secondary objectives include assessing the effectiveness of cytisine in reducing nicotine consumption and tobacco smoking compared to placebo in participants motivated to quit EC containing nicotine or dual use of EC and TC. Additionally, the study aims to assess the safety of cytisine compared to placebo for cessation of single use of EC or dual use of EC and TC in the same participant group. These objectives are crucial for understanding the broader impact of cytisine on smoking cessation and its safety profile.

The clinical trial focuses on evaluating the effectiveness of cytisine plus behavioral support for **electronic cigarette cessation**. The study population includes both male and female participants, aged 18 and older, who are motivated to quit the use of electronic cigarettes containing nicotine or the dual use of electronic and tobacco cigarettes. Participants are required to be in general good health, with specific lifestyle considerations such as daily or frequent use of electronic cigarettes and, for dual users, tobacco cigarettes. The trial population was selected based on their willingness to make a quit attempt using the study products and their ability to complete all study visits. Participants must have daily access to a mobile phone and be willing to use a mobile application during the treatment period. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the effectiveness of **cytisine** plus behavioral support compared to a placebo plus behavioral support for the cessation of electronic cigarettes (EC) containing nicotine and tobacco cigarettes (TC). This study is a randomized, placebo-controlled trial with a double-blind design, ensuring that neither the participants nor the researchers know which treatment the participants are receiving. The trial is expected to last until June 2027, with recruitment starting in May 2024. Participants will be involved in the study for a total of 30 weeks, with the treatment phase lasting 12 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, willingness to quit EC or TC, and the ability to comply with study procedures. Following the screening, eligible participants will be randomized into either the intervention arm, receiving 1.5 mg cytisine tablets, or the comparator arm, receiving placebo tablets, both accompanied by behavioral support. The primary endpoint is the biochemically verified continuous abstinence from EC and TC for 26 weeks preceding the 30-week follow-up.

Throughout the trial, participants will attend follow-up visits at 2, 4, 12, and 30 weeks post-treatment initiation. These visits will monitor adherence, collect self-reported data on EC and TC use, and conduct biochemical verification of abstinence. The end-of-study visit at 30 weeks will finalize data collection and verify the primary and secondary endpoints. Participants may be terminated early from the study if they fail to adhere to the protocol, experience adverse events, or withdraw consent. The trial aims to provide robust data on the efficacy of cytisine in aiding nicotine cessation, contributing valuable insights into smoking cessation strategies.

The clinical trial involves the administration of **CYTISINE**, an alkaloid used as the experimental medication. CYTISINE is provided in the form of film-coated tablets, with each tablet containing 1.5 mg of the active substance. The route of administration is oral. Participants in the intervention arm will receive a 12-week course of CYTISINE, with a maximum daily dose of 9 mg and a total maximum dose of 424.05 mg over the treatment period. The dosing schedule is designed to ensure participant compliance, with regular monitoring to assess adherence to the prescribed regimen.

The comparator treatment in this study is a **placebo**, which is designed to mimic the appearance of the CYTISINE tablets. The placebo tablets are composed of microcrystalline cellulose, magnesium stearate, and a forcoat green coating. Like the experimental medication, the placebo is administered orally over a 12-week period. Participants in the comparator arm will receive the placebo tablets alongside behavioral support, mirroring the intervention arm's treatment schedule. Compliance with the placebo regimen will be monitored to ensure the integrity of the trial's blinding process.

Efficacy in this clinical trial will be assessed by evaluating the effectiveness of **cytisine** plus behavioral support compared to placebo plus behavioral support for cessation of electronic cigarettes (EC) containing nicotine and tobacco cigarettes (TC). The primary endpoint is the biochemically verified continuous abstinence rate from EC and TC for 26 weeks preceding the 30-week follow-up from the start of treatment. This will be determined through negative urine cotinine and NNAL concentration tests. Continuous EC cessation is defined as self-reporting having remained quit for 26 weeks with no more than five vaping occasions and no slip-ups in the last week, confirmed by a negative biochemical test. Continuous TC cessation is defined as self-reporting having smoked no more than five cigarettes in that time, confirmed by a negative biochemical test. Participants self-reporting continuous abstinence at final follow-up will undergo biochemical verification.

Secondary endpoints include self-reported continuous EC and TC abstinence at various timepoints (2-week, 4-week, 12-week, and 30-week post-treatment start), self-reported 7-day point prevalence abstinence, and biochemically verified 7-day point prevalence abstinence at the 30-week interview. Additionally, self-reported nicotine consumption from EC per day and week will be assessed at 2-week, 4-week, 12-week, and 30-week post-treatment among participants who continue EC use. The proportion of serious adverse events (SAEs) and adverse events (AEs) will also be compared between the cytisine and placebo groups. These efficacy parameters will be collected and analyzed to determine the success of the intervention in achieving smoking cessation.