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。由于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，因此确定有效的治疗烟草依赖的药物仍然是当务之急。一个有希望的，但相对尚未开发的戒烟药物开发途径是针对压力反应的药物。一些证据表明，压力是吸烟维持和复发的主要中介。临床前研究表明，去甲肾上腺素能通路参与了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，3mg/天的胍法辛（一种α - 2a去肾上腺素能激动剂）耐受性良好，显著提高了抵抗吸烟的能力，减少了对烟草的渴望、随意吸烟和吸烟相关的强化。在fMRI过程中，胍法辛增加了与注意力和自我控制有关的区域的活动。在随后的短暂治疗期间，胍法辛还能减少吸烟和改善滞留。总的来说，我们的结果表明，胍法辛作为一种潜在的药物治疗压力诱发的吸烟复发，在临床环境中是有益的。这个项目的主要目标

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.