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.

摘要 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。电子（e）- 香烟（vaping）是尼古丁输送装置，可能对某些人戒烟有用 但是没有FDA批准作为戒烟辅助剂，并且长期使用可能具有不确定的健康影响。 有证据表明，尼古丁也可能增加心血管和肺部疾病的风险。许多 专家和专业协会建议，vapers也应该尝试停止使用尼古丁e- 香烟然而，帮助电子烟戒烟的治疗方法尚未确定或FDA批准。 该项目将测试金雀花碱，一种部分nAChR激动剂，降低尼古丁戒断的严重程度， 症状，同时抑制大脑中的尼古丁奖励效应，可以促进停止使用电子烟。之前 试验表明金雀花碱对戒烟有效，并已作为戒烟药上市。 几十年来，在欧洲的援助。Achieve Life Sciences最近（过去3年）加快了美国临床 金雀花碱作为戒烟辅助剂的开发计划，现在提议测试戒烟。 这将是第一个多中心，随机，安慰剂对照的初步研究，在每日尼古丁e- 吸烟者评估野靛碱作为戒烟辅助剂的益处和安全性。主要目的是 为了评估受试者随机接受12周的3 mg金雀花碱每日三次（TID）与安慰剂TID相比， 从第9周至第12周，经生化验证的尼古丁蒸汽烟戒烟的患病率较高。二次 目的包括评估野靛碱与安慰剂的以下方面：1.在第3周开始的早期vaping停止- 6或第6-9周; 2.通过每周定量可替宁水平测量的Vaping减少; 3.测试适度 根据人口统计学和基线特征定义的亚组中疗效结局的影响。安全 目的是比较金雀花碱与安慰剂给药12周的安全性。 本研究将在8个美国研究中心入组150例成人受试者（≥18岁），他们是每日尼古丁电子烟使用者， 目前不是吸烟者（通过唾液可替宁和呼出的一氧化碳[CO]水平证实）， 放弃vaping，并愿意将戒烟日期设定为研究治疗开始后7-14天。受试者将被随机 分配（2：1）至两组之一：（野靛碱3 mg TID N=100，或相同的安慰剂TID N=50），持续12周研究 治疗所有受试者将在研究期间接受尼古丁/电子烟戒烟的同步行为支持。 研究治疗将是双盲的。Vaping状态（禁欲）将在计划的 随机化后7-14天的戒烟目标，从第2周至第12周每周评估一次，包括 每周通过测量唾液可替宁水平进行生化检查。将监测过期的CO水平 治疗复吸将在治疗第1周评估受试者的安全性，此后每周评估一次， 在治疗期间。成功将被测量为干预组中≥20-30%的戒烟率，并且 在其他终点中，野靛碱获益具有统计学显著性（p≤0.1或0.05）。