Repurposing Melatonin Receptor Agonists as Adjunct Treatments for Smoking Cessation

重新利用褪黑激素受体激动剂作为戒烟的辅助治疗

• 批准号: 9144346
• 负责人: Rebecca Ashare
• 金额: $ 23.76万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144346
• 关键词: Abstinence; Address; Agonist; Attenuated; Carbon Monoxide; Clinical Trials; Constipation; Coupled; Crossover Design; Data; Development; FDA approved; Female; Foundations; Future; Headache; Health; Human; Incentives; Individual; Individual Differences; Intervention; Laboratories; Lead; Marketing; Measures; Melatonin Receptors; Mental Depression; Modeling; Moods; Nicotine Dependence; Nicotine Withdrawal; Outcome; Patient Self-Report; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phase; Physical Dependence; Placebo Control; Placebos; Population; Procedures; Property; Rebound Insomnia; Recording of previous events; Relapse; Research; Research Design; Residual state; Risk; Safety; Sampling; Signal Transduction; Sleep; Sleep Disorders; Sleep disturbances; Sleeplessness; Smoker; Smoking; Staging; Study Subject; Symptoms; Testing; Therapeutic; Withdrawal; Withdrawal Symptom; Withholding Treatment; base; critical period; diaries; drug development; experience; falls; gender difference; improved; indexing; innovation; negative mood; nicotine patch; nicotine replacement; novel; novel strategies; primary outcome; screening; sleep onset; smoking cessation; smoking relapse; success; therapeutic target; treatment effect; varenicline

 DESCRIPTION (provided by applicant): Even with the use of FDA-approved pharmacotherapies for smoking cessation, most smokers relapse within the first few days following a quit attempt. Thus, there is a need to identify novel approaches to optimize treatment to help more smokers maintain abstinence during this critical period. Evidence indicates that sleep disturbance during nicotine withdrawal may be an important, yet overlooked smoking cessation treatment target. This is particularly important since existing treatments do not mitigate withdrawal-related sleep disturbance. Critically, difficulty sleeping is predictive of smoking relapse. In this proof-of-concept study, we hypothesize that the FDA-approved melatonin receptor agonist, ramelteon, in combination with transdermal nicotine replacement therapy (TN), will promote smoking cessation by attenuating sleep disturbance during nicotine withdrawal. Using a well-validated medication screening paradigm, we propose a within-subject, placebo-controlled crossover design with one within-subjects factor of short-term medication (ramelteon vs. placebo). Fifty treatment-seeking smokers will complete this 6-week study, which consists of two 2-week phases separated by a 2-week washout. Each phase includes 1 week of ad libitum smoking (baseline) and 1 week of medication (8mg ramelteon or placebo) plus TN while trying to abstain (quit assessment). Smokers will be provided small monetary incentives for biochemically-confirmed abstinence. Ramelteon's unique properties reduce the likelihood of next-day residual effects, rebound insomnia, and symptoms of physical dependence which render other sleep medications problematic. We have chosen TN because it will be important to address physical nicotine withdrawal symptoms (e.g., headaches, constipation) and it is the most widely used treatment in the U.S. For the duration of the study, subjects will be asked to keep sleep diaries and wear an armband while sleeping which provides objective indices of sleep duration and quality (SensewearPro). All subjects will receive standard TN following completion of the study. The primary outcome will be the total number of days abstinent (out of five), confirmed by carbon monoxide breath sample. This measure is highly predictive of longer-term quit success. Intermediate outcomes will include sleep onset latency (self-report) and sleep efficiency (SensewearPro armband). This innovative line of research will be the first to repurpose a melatonin receptor agonist (ramelteon) to evaluate its effects on withdrawal-related sleep disturbance and short-term quitting success in treatment-seeking smokers. Repurposing medications that have been "de-risked" removes a key barrier to drug development (i.e., safety signals), increasing the likelihood that the drug will be brought to market. Critically, our study design permits exploration of putative mechanisms that underlie the treatment effect. If our hypotheses are supported, these data will lay the foundation for a larger Stage II clinical trial and to extend this adjunct pharmacological treatment to other treatments for smoking cessation.

 描述（由申请人提供）：即使使用 FDA 批准的戒烟药物，大多数吸烟者也会在尝试戒烟后的最初几天内复吸。因此，需要确定新的方法来优化治疗以帮助更多的吸烟者。证据表明，尼古丁戒断期间的睡眠障碍可能是一个重要但被忽视的戒烟治疗目标，因为现有的治疗方法不能减轻与戒断相关的睡眠障碍。在这项概念验证研究中，我们研究了 FDA 批准的褪黑激素受体激动剂雷美替胺与透皮尼古丁替代疗法 (TN) 相结合，将通过减轻尼古丁戒断期间的睡眠障碍来促进戒烟。使用经过充分验证的药物筛选范例，我们提出了一种受试者内安慰剂对照的交叉设计，其中包含短期药物的一个受试者内因素（雷美替胺与雷美替胺）。 50 名寻求治疗的吸烟者将完成这项为期 6 周的研究，该研究由两个为期 2 周的阶段组成，每个阶段包括 1 周的随意吸烟（基线）和 1 周的药物治疗（安慰剂）。 8 毫克雷美替尼或安慰剂）加上 TN，同时尝试戒烟（戒烟评估），将为经生化证实的戒烟者提供小额金钱奖励，雷美替尼的独特特性可降低戒烟的可能性。我们选择 TN 是因为它对于解决身体尼古丁戒断症状（例如头痛、便秘）非常重要，而且它是最广泛使用的。在研究期间，受试者将被要求记睡眠日记并在睡觉时佩戴臂带，以提供睡眠持续时间和质量的客观指标（SensewearPro）。所有受试者在完成后都将接受标准 TN。主要结果是戒烟的总天数（五天），由一氧化碳预测呼吸样本证实，该指标对长期戒烟成功率至关重要，中间结果将包括睡眠潜伏期。报告）和睡眠效率（SensewearPro 臂带），这项创新研究将首次重新利用褪黑激素受体激动剂（雷美替胺）来评估其对戒断相关睡眠障碍和寻求治疗的短期戒烟成功的影响。重新利用已“降低风险”的药物消除了药物开发的关键障碍（即安全信号），增加了药物推向市场的可能性，至关重要的是，我们的研究设计允许探索潜在的机制。如果我们的假设得到支持，这些数据将为更大规模的 II 期临床试验奠定基础，并将这种辅助药物治疗扩展到其他戒烟治疗。