A Randomized, Double-Blind, Placebo-Controlled Trial Comparing Nicotine-Containing Electronic Cigarettes, Varenicline, and Nicotine-Free Electronic Cigarettes in Smokers

The primary objective of this study is to assess the **efficacy** of electronic cigarettes containing nicotine (ECwN) compared to electronic cigarettes without nicotine (ECwoN) and to varenicline, a licensed smoking cessation medication. This evaluation is clinically relevant as it aims to determine the effectiveness of ECwN as a potential smoking cessation aid, which could provide an alternative to current cessation therapies for individuals smoking at least 10 cigarettes per day.

Secondary objectives include:

• Evaluating the safety profile of ECwN in comparison to electronic cigarettes without nicotine and varenicline.
• Assessing the point prevalence abstinence, defined as self-reported 7-day smoking abstinence at each visit, confirmed by expired air CO levels ≤ 8 ppm.
• Determining the time to relapse to smoking after the predefined target quit day.
• Studying changes in daily cigarette consumption.
• Investigating changes in craving for tobacco.
• Examining changes in withdrawal symptoms.

The clinical trial involves a study population of **smokers** aged between 18 to 70 years, who have been smoking at least 10 cigarettes per day over the past year. Both male and female participants are included, and the trial does not focus on a vulnerable population. Participants are required to be motivated to quit smoking, as indicated by a score greater than 5 on a visual rating scale from 0 to 10. The sponsor has not provided information regarding the total number of participants. The trial aims to assess the efficacy of electronic cigarettes containing nicotine compared to those without nicotine and a reference smoking cessation medication, varenicline. The selection criteria emphasize the participants' smoking habits and motivation to quit, without specific lifestyle considerations such as diet or physical activity being highlighted.

The clinical trial is designed as a **randomized**, **placebo-controlled**, **double-blind**, and **double-dummy** study, conducted across multiple centers. The primary objective is to assess the efficacy of electronic cigarettes containing nicotine compared to electronic cigarettes without nicotine and to a reference smoking cessation medication, **varenicline**. The trial targets individuals who have smoked at least 10 cigarettes per day over the past year, are aged between 18 and 70 years, and are motivated to quit smoking, as defined by a score greater than 5 on a visual rating scale. The trial is expected to run from October 2018 to January 2027, with a treatment period of 3 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the inclusion criteria. During the treatment phase, participants will receive either **varenicline** in the form of 0.5 mg film-coated tablets or a placebo, administered orally. The maximum daily dose of **varenicline** is 2 mg, with a total treatment period of 13 weeks. Follow-up visits will be scheduled to monitor the participants' progress, assess smoking abstinence, and record any adverse events. The primary endpoint is the continuous smoking abstinence rate during the last 4 weeks of the treatment period. Secondary endpoints include the assessment of safety through the comparison of serious and non-serious adverse events, point prevalence abstinence, time to relapse, and changes in cigarette consumption, craving, and withdrawal symptoms.

The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or choose to withdraw consent. The trial's design ensures that all data collected will contribute to understanding the comparative efficacy and safety of the interventions in promoting smoking cessation.

The clinical trial involves the administration of **varenicline**, marketed under the name CHAMPIX, in the form of 0.5 mg **film-coated tablets**. Varenicline is a chemical substance used as a smoking cessation aid. The tablets are administered orally, with a maximum daily dose of 2 mg. The treatment period extends up to 13 weeks. The pharmaceutical form of the medication is designed to ensure proper absorption when taken orally. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

In addition to the experimental medication, a **placebo** is used as a comparator in the study. The placebo is designed to mimic the appearance of the CHAMPIX 0.5 mg film-coated tablets but contains no active substance. The placebo is administered in the same manner as the experimental medication, ensuring that the study remains double-blind. This allows for an unbiased comparison of the efficacy of varenicline against the placebo. Participant compliance with the placebo administration is also monitored to maintain the integrity of the trial results.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the **continuous smoking abstinence rate** during the last four weeks of a treatment period lasting three months. This will be measured to determine the effectiveness of electronic cigarettes containing nicotine compared to electronic cigarettes without nicotine and the reference smoking cessation medication, varenicline.

Secondary endpoints include several parameters: the point prevalence abstinence, which involves self-reported seven-day smoking abstinence at each visit, confirmed by expired air carbon monoxide levels of ≤ 8 ppm; the time to relapse to smoking after the predefined target quit day; changes in the number of cigarettes consumed per day; changes in craving for tobacco; and changes in withdrawal symptoms. These parameters will be collected and analyzed throughout the trial to provide a comprehensive assessment of efficacy.