Phase-II Clinical Trial Evaluating Guanfacine for Smoking Cessation

描述（由申请人提供）：在美国，烟草使用是可预防的发病率和死亡率的主要原因。确定治疗烟草依赖的有效药物仍然是一个高度优先事项，因为绝大多数吸烟者即使使用FDA批准的药物治疗也无法保持长期戒烟。一个有希望的，但相对未开发的戒烟药物开发途径是针对压力反应的药物。有几条证据表明，压力是维持吸烟和复吸的主要媒介。临床前研究表明，去甲肾上腺素能通路参与应激诱导的尼古丁恢复，以及尼古丁相关的强化和戒断，并且它们的操纵可能对戒烟具有潜在的治疗益处。模拟压力对吸烟行为的影响，我们已经证明，与安慰剂相比，3 mg/天的胍法辛（一种α 2a去甲肾上腺素能激动剂）具有良好的耐受性，显著增加了抵抗吸烟的能力，并减少了烟草渴望，即兴吸烟和吸烟相关的强化。在功能磁共振成像过程中，胍法辛增加了与改善注意力和自我控制相关的区域的活动。胍法辛也减少吸烟和改善保留在随后的短暂治疗期间。总体而言，我们的研究结果表明，胍法辛作为一种潜在的药物治疗的压力沉淀吸烟复发的好处，在临床设置。这个项目的主要目标 是翻译我们的临床前，人体实验室，成像和临床结果的发现与胍法辛和进行第一个单一的网站，概念验证，第二阶段临床试验评估疗效的胍法辛戒烟。使用双盲、安慰剂对照、剂量范围平行组设计，我们计划[将375名每日吸烟的成年人随机分配至胍法辛组（3 mg/天、2 mg/天或安慰剂组，每个细胞n=125）]]，并在8周的治疗期内结合简短的行为支持，以评估哪种剂量的胍法辛在增加延长戒烟时间同时最大限度地减少不良事件方面有效。然后将从治疗结束后对受试者进行为期6个月的随访，以评估治疗效果的持久性。除了标准的戒烟结果外，我们还将评估烟瘾、戒断、感知压力、认知功能和吸烟相关强化作为药物作用的潜在机制。阳性结果将提供必要的数据，以扩大本研究的第三阶段测试。

DESCRIPTION (provided by applicant): Tobacco use is the leading cause of preventable morbidity and mortality in the U.S. Identifying effective medications for the treatment of tobacco dependence remains a high priority as the vast majority of smokers fail to maintain long-term abstinence even with FDA approved pharmacotherapies. One promising, yet relatively unexplored avenue for medication development for smoking cessation, are medications which target stress-reactivity. Several lines of evidence suggest that stress is a primary mediator of smoking maintenance and relapse. Preclinical research demonstrates that noradrenergic pathways are involved in stress-induced reinstatement to nicotine, as well as nicotine-related reinforcement and withdrawal, and that their manipulation may be of potential therapeutic benefit for smoking cessation. Modeling the effect of stress on smoking behavior, we have demonstrated that 3mg/day guanfacine, an alpha2a noradrenergic agonist, compared to placebo was well tolerated, robustly increased the ability to resist smoking, and decreased tobacco craving, ad-lib smoking, and smoking-related reinforcement. During an fMRI session, guanfacine increased activity in regions associated with improved attention and self-control. Guanfacine also reduced smoking and improved retention during a subsequent brief treatment period. Overall, our results point to guanfacine as a potential pharmacotherapy for stress-precipitated smoking relapse with benefit in the clinical setting. The primary goal of this project is to translate our preclinical, human laboratory, imaging, and clinical outcome findings with guanfacine and conduct the first single-site, proof-of-concept, Phase II clinical trial evaluating the efficacy of guanfacine for smoking cessation. Using a double-blind, placebo-controlled, dose- ranging parallel group design, we plan to [[[ randomize 375 adult daily smokers to guanfacine (3mg/day, 2mg/day, or placebo, n=125 per cell) ]]] combined with brief behavioral support for an 8-week treatment period to evaluate which doses of guanfacine are efficacious in increasing prolonging smoking abstinence while minimizing adverse events. Participants will then be followed for a 6-month period from the end of treatment to assess the durability of treatment effects. In addition to standard smoking cessation outcomes, we will evaluate craving, withdrawal, perceived stress, cognitive function, and smoking-related reinforcement as potential mechanisms underlying medication effects. Positive findings will provide the data necessary to expand this investigation to Phase III testing.