# Efficacy, Safety, and Economic Impact of Cytisinicline Maintenance Therapy in Patients Who Are Candidates for Smoking Cessation: Protocol for a Phase IV, Multicenter, Randomized, Open-Label, Controlled, Parallel Clinical Trial (CITISILONG Trial)

## TL;DR

This study will test if extending the use of a smoking cessation drug, cytisinicline, improves its effectiveness and cost-efficiency without compromising safety.

## Contribution

The study introduces and evaluates two prolonged cytisinicline regimens to optimize smoking cessation outcomes in clinical practice.

## Key findings

- Efficacy will be measured through sustained abstinence rates at 6 and 12 months.
- Safety will be assessed by tracking adverse events across the three treatment groups.
- Economic impact will be analyzed using cost-effectiveness and cost-utility ratios.

## Abstract

Cytisinicline has proven to be an effective, efficient, and safe molecule in smoking cessation. However, the established 25-day regimen could be insufficient in a high percentage of smokers, so it is necessary to study maintained therapies of this drug.

This study aims to compare the efficacy of the cytisinicline regimen used in routine clinical practice versus 2 maintained regimens of 50 and 75 days, respectively. In addition, the safety and economic impact of each regime will be determined.

A prospective, multicenter, open-label, controlled, parallel, phase IV clinical trial of 402 smoker patients prepared to quit smoking. The study was conducted in 10 hospitals in Spain. A control group is compared to 2 intervention groups in which the duration of the drug is increased without increasing its dose, administering half and all, respectively, of an additional marketed container that includes 100 tablets. Thus, participants will be randomized to three groups in a 1:1:1 ratio to receive cytisinicline: (1) a control group treated with cytisinicline according to the usual clinical guidelines and product information (25 days); (2) a group with a 50-day cytisinicline regimen (an additional 25 days at a dose of 1.5 mg every 12 hours), seeking to increase its efficacy while minimally impacting adherence; and (3) a group with a 75-day regimen (an additional 50 days at a dose of 1.5 mg every 12 hours), attempting to increase its efficacy, although the longer duration of the drug may threaten adherence. Efficacy in the 3 arms will be analyzed through sustained abstinence at 6 and 12 months, point abstinence rate assessed every 7 days, and abstinence rate from Day 25 to Day 50 and from Day 25 to Day 75 in the 3 study arms. (1) The variation in withdrawal and craving symptoms in the 3 groups, (2) safety through the percentage of adverse events in the 3 treatment arms, and (3) economic impact by evaluating the cost-effectiveness and cost-utility ratios of the 2 prolonged regimens versus the usual clinical cytisinicline regimen. To calculate the differences between the 3 groups for each outcome variable, a univariate analysis will be performed. Statistically significant variables will be included in a multivariate model.

Recruitment for the trial and patient enrollment were completed in November 2026. Follow-up of all participants will extend to December 2027.

In conclusion, this study evaluates the optimization of cytisinicline in daily clinical practice, increasing the benefits of its pharmaceutical properties without affecting patient safety. All of this will improve the effectiveness of smoking cessation by reducing the number of smokers, which implies lower morbidity and mortality and lower costs associated with smoking.

European Clinical Trials Register 2024-518936-36-00; https://euclinicaltrials.eu/ctis-public/view/2024-518936-36-00

PRR1-10.2196/76815