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: 9014081
• 负责人: Rebecca Ashare
• 金额: $ 20万
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014081
• 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; Sex Characteristics; 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; 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（由适用提供）：即使使用FDA批准的药物疗法进行戒烟，大多数吸烟者都会在戒烟尝试后的头几天内传递。这是有必要确定新颖的方法来优化治疗方法，以帮助更多的吸烟者在这个关键时期保持戒酒。证据表明，戒断尼古丁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。这尤其重要，因为现有治疗方法不能减轻与戒断相关的睡眠灾难。至关重要的是，困难的睡眠可以预测吸烟。在这项概念验证的研究中，我们假设由FDA批准的褪黑激素受体激动剂Ramelteon与变压器尼古丁替代疗法（TN）结合使用，将通过尼古丁戒断期间减轻睡眠障碍来促进吸烟。使用验证良好的药物筛查范式，我们提出了一个受试者内，安慰剂对照的跨界设计，其中一种受试者内部的短期药物因子（Ramelteon vs.安慰剂）。五十名寻求治疗的吸烟者将完成这项为期6周的研究，该研究包括两个2周的2周阶段，分别是2周的冲洗。每个阶段都包括自意吸烟（基线）和1周的药物（8mg ramelteon或安慰剂）加上TN的1周（退出评估）。吸烟者将获得少量的货币激励措施，以避免生化确认。 Ramelteon的独特特性减少了第二天残留影响，反弹失眠和身体依赖症状的可能性，这使其他睡眠药物有问题。我们之所以选择TN，是因为解决物理尼古丁戒断症状（例如，标头，便秘）非常重要，并且在研究期间，它是美国最广泛使用的治疗方法，受试者将被要求保留睡眠日记并佩戴臂铃，而在提供睡眠时间和质量的客观索引时（Sensewearpro）。研究完成后，所有受试者都将获得标准TN。主要结果将是一氧化碳呼吸样品证实的节制天数（五个）。该措施高度预测了长期退出成功。中级结果将包括睡眠发作潜伏期（自我报告）和睡眠效率（Sensewearpro臂章）。这项创新的研究线将是第一个重新使用褪黑激素受体激动剂（Ramelteon）来评估其对戒断相关睡眠障碍的影响和短期退出寻求治疗吸烟者的成功。重新利用已经“脱离风险”的药物消除了药物开发的关键障碍（即安全信号），从而增加了将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基于治疗效果的假定机制。如果支持我们的假设，这些数据将为更大的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的治疗方法。