Benefit and Safety of Cytisinicline (cytisine) for Cessation of Nicotine E-cigarette Use

金雀花碱（金雀花碱）用于戒断尼古丁电子烟的益处和安全性

• 批准号: 10630247
• 负责人: Cindy Jacobs
• 金额: $ 58.47万
• 依托单位: ACHIEVE LIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10630247
• 关键词: 18 year old; Abstinence; Accountability; Adolescent and Young Adult; Adult; Agonist; Agreement; Behavioral; Binding; Biochemical; Biological Markers; Biological Sciences; Brain; Budgets; Carbon Monoxide; Cardiovascular Diseases; Case Report Form; Characteristics; Cigarette; Cigarette Smoker; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Consent Forms; Contracts; Cotinine; Counseling; Data Collection; Databases; Development; Devices; Dose; Double-Blind Method; Drug Packaging; Eastern Europe; Electronic Nicotine Delivery Systems; Electronic cigarette; Electronics; Enrollment; Europe; FDA approved; Health; High Prevalence; Immune system; Individual; Infrastructure; Institutional Review Boards; Intervention; Label; Laboratories; Licensing; Logistics; Lung diseases; Lung infections; Marketing; Measurement; Measures; Medical; Monitor; Natural Compound; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Outcome; Pamphlets; Patient Self-Report; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pilot Projects; Placebo Control; Placebos; Probability; Procedures; Professional Organizations; Program Development; Protocols documentation; Public Health; Pulmonary Inflammation; Qualifying; Questionnaires; Randomized; Recommendation; Relapse; Research Design; Research Personnel; Safety; Safety Management; Saliva; Salivary; Schedule; Self Assessment; Severities; Site; Smoking; Smoking History; Statistical Data Interpretation; Subgroup; System; Testing; Treatment Protocols; Vendor; Visit; Withdrawal Symptom; arm; cigarette user; clinical development; clinical research site; commercialization; comparison control; compliance behavior; cytisine; data management; demographics; disorder risk; e-cigarette cessation; efficacy evaluation; efficacy outcomes; electronic cigarette use; electronic cigarette user; group intervention; next generation; nicotine cessation; nicotine exposure; nicotine reward; nicotine use; programs; public health priorities; safety assessment; side effect; smoking cessation; smoking relapse; success; treatment duration; treatment effect; uptake; vaper; vaping; vaping nicotine

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.

抽象的 尼古丁具有高度成瘾性：> 95% 的独立戒烟尝试在 6 个月内失败。 香烟（vaping）是尼古丁输送装置，可能对某些人戒烟有用 但尚未获得 FDA 批准作为戒烟辅助剂，长期使用可能会对健康产生不确定的影响。 有证据表明，吸电子烟尼古丁还可能增加心血管和肺部疾病的风险。 专家和专业协会建议电子烟使用者也应尝试停止使用尼古丁电子烟。 然而，帮助戒烟的治疗方法尚未确定或获得 FDA 批准。 该项目将测试金雀花碱（一种部分 nAChR 激动剂）是否可以减轻尼古丁戒断的严重程度 症状同时抑制尼古丁对大脑的奖赏作用，可以促进电子烟的停止使用。 试验显示金雀花碱具有戒烟功效，并已作为戒烟剂上市销售 几十年来，Achieve Life Sciences 一直在欧洲提供援助，最近（过去 3 年）加快了美国的临床进程。 金雀花碱作为戒烟辅助剂的开发计划，现在提议测试戒烟效果。 这将是第一个针对每日尼古丁电子烟进行的多中心、随机、安慰剂对照试点研究 香烟使用者评估金雀花碱作为戒烟辅助剂的益处和安全性的主要目标是。 评估随机接受每天 3 次 3 mg 金雀花碱 (TID) 治疗 12 周的受试者与安慰剂 TID 相比是否有 从第 9 周到第 12 周，经过生化验证的尼古丁戒烟率较高。 目标包括对金雀花碱与安慰剂的以下方面进行评估： 1. 在第 3 周开始尽早停止吸电子烟 6 或第 6-9 周；2. 通过每周定量可替宁水平测量吸电子烟的减少； 由人口和基线特征定义的亚组疗效结果的影响。 目标将比较金雀花碱与安慰剂服用 12 周时的安全性。 这项研究将在美国 8 个地点招募 150 名成年受试者（≥18 岁），他们每天使用尼古丁电子烟，并且 目前不吸烟（通过唾液可替宁和过期一氧化碳 [CO] 水平确认），打算 戒烟，并愿意在研究治疗开始后 7-14 天设定戒烟日期。 分配 (2:1) 至两个组之一：（金雀花碱 3 mg TID N=100，或相同的安慰剂 TID N=50）进行 12 周的研究 在研究期间，所有受试者将同时接受戒烟/电子烟行为支持。 研究治疗将是双盲的，电子烟状态（戒烟）将在计划后通过自我报告进行评估。 随机化后 7-14 天的戒烟目标，从第 2 周到第 12 周每周进行评估，包括 每周通过测量唾液可替宁水平进行生化验证。 将在治疗第一周以及此后每周对受试者进行安全性评估。 在治疗期间，干预组的戒烟率≥20-30%即为成功，并且 金雀花碱在其他终点方面的益处具有统计学意义（p≤0.1 或 0.05）。