Benefit and safety of cytisinicline… (R44DA054784) – Project Grant to Achieve Life Sciences, Inc.

Abstract: Nicotine is highly addictive: >95% of unaided attempts at smoking cessation fail by 6 months. Electronic (e)- cigarettes (vaping) are nicotine-delivery devices that may be useful in some individuals for smoking cessation but are not FDA-approved as a smoking cessation aid and long-term use may have uncertain health impacts. Evidence suggests that vaping nicotine may also raise cardiovascular and pulmonary disease risks. Many experts and professional societies recommend that vapers should also attempt to stop using nicotine e- cigarettes. However, treatments to aid e-cigarette cessation have yet to be identified or FDA-approved. This project will test whether cytisine, a partial nachr agonist that reduces the severity of nicotine withdrawal symptoms while inhibiting nicotine reward effects in the brain, can promote cessation of e-cigarette use. Prior trials have shown cytisine's efficacy for smoking cessation, and IT has been marketed as a smoking cessation aid in europe for decades. Achieve life sciences has recently (past 3 years) expedited the US clinical development program for cytisine as a smoking cessation aid and now proposes to test for vaping cessation. This will be the first multicenter, randomized, placebo-controlled pilot study conducted in daily nicotine e- cigarette users to evaluate the benefit and safety of cytisine as a vaping cessation aid. The primary objective is to assess if subjects randomized to 12 weeks of 3 MG cytisine three times a day (TID), VS placebo TID, have a higher prevalence of biochemically- verified nicotine vaping cessation from week 9 to week 12. Secondary objectives include assessment of cytisine VS placebo regarding: 1. Earlier vaping cessation initiated at week 3- 6 or week 6-9; 2. Vaping reduction, measured by weekly quantitative cotinine levels; 3. Testing moderation effects in efficacy outcomes across subgroups defined by demographic and baseline characteristics. The safety objective will compare the safety profile of cytisine VS placebo when administered for 12 weeks. This study will enroll 150 adult subjects (=18 years) at 8 US sites, who are daily nicotine e-cigarette users and not current cigarette smokers (confirmed by saliva cotinine and expired carbon monoxide [CO] levels), intending to quit vaping, and willing to set a quit date 7-14 days from the start of study treatment. Subjects will be randomly assigned (2:1) to one of two arms: (cytisine 3 MG TID n=100, or identical placebo TID n=50) for 12 weeks study treatment. All subjects will receive concurrent behavioral support for nicotine/vaping cessation during the study. Study treatment will be double-blind. Vaping status (abstinence) will be assessed by self-report after the planned quit target of 7-14 days post-randomization and assessed weekly from week 2 through week 12, including weekly biochemical verification via measurement of salivary cotinine levels. Expired CO levels will be monitored for smoking relapse. Subjects will be assessed for safety during week 1 of treatment, and weekly thereafter, during the treatment period. Success will be measured as =20-30% cessation in the intervention group, and statistically significant (p=0.1 or 0.05) cytisine benefit in other endpoints.

Action	Obligated	Date
Amendment	$0	Jun 24, 2024
Amendment	$584,690	Jul 25, 2023
Amendment	$584,690	Jul 25, 2023
Amendment	$1,913,206	May 27, 2022
Original award	$1,913,206	May 27, 2022

Benefit and safety of cytisinicline (cytisine) for cessation of nicotine e-cigarette use

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