Proof-of-Concept Trial of an Alpha-7 Nicotinic Agonist for Nicotine Dependence

描述(申请人提供)：戒烟的药物疗法被普遍接受为护理标准，具有很高的成本效益，尽管尝试戒烟的人只有大约20%的人在一次尝试中成功，高达90%的戒烟者在一年内复发，大多数人在戒烟后两周内复发。发现新的治疗方法来帮助那些想要长期戒烟的人，显然是公共卫生的优先事项。人们吸烟是为了尼古丁的有益效果，但也是为了避免出现认知障碍等戒断症状。尼古丁戒断与严重的注意力障碍有关，这是一种与再次吸烟密切相关的症状。与那些没有这些症状的人相比，那些有基线认知障碍的人也更有可能吸烟，更不可能戒烟。在许多情况下，尼古丁可以改善基线认知症状。这项R-01拨款申请是基于这样一个假设，即通过新的生物机制工作以缓解基线和戒断紧急症状(如认知障碍)的药物疗法对持续戒断具有最大的希望。我们建议评估一种新型的选择性口服α-7烟碱型乙酰胆碱受体激动剂EVP 6124的效果，该药处于第二阶段开发，具有活性的IND，已被证明可以改善正常成年人以及精神分裂症和阿尔茨海默病类型的痴呆症患者的认知表现。为此，我们建议进行一项第二阶段的双盲概念验证治疗试验，包括4种积极治疗和安慰剂药物的组合，采用2×2因子设计(EVP 6124+NRT vs安慰剂+NRT vs EVP 6124+安慰剂-NRT vs安慰剂+安慰剂-NRT)。当研究药物开始时，所有参与者都将在研究的第一天尝试戒烟。NRT或安慰剂-NRT(活性或安慰剂贴片)将持续6周，然后停止。在复发预防阶段，随机口服药物将在没有NRT的情况下再继续6周。在口服治疗停止后，参与者将被跟踪2周的复发模式，直到第14周。在每周的访问中将收集关于认知表现、吸烟行为和耐受性的数据。这一设计将使我们能够评估临床试验本身的分析敏感性(通过比较安慰剂+NRT组和安慰剂+安慰剂-NRT组)，并评估选择性α-7尼古丁受体激动剂作为单一疗法(通过比较EVP 6124+安慰剂-NRT组与安慰剂+安慰剂-NRT组)和/或与NRT联合使用(通过比较EVP 6124+NRT组与安慰剂+NRT组)是否有效。在这样做的过程中，我们将发现选择性的α-7 nAChR激动剂是否改善了尼古丁减少期间和早期戒烟的认知表现，以及与安慰剂相比，这种效应是否与更大程度的持续戒烟有关，或者与NRT联合使用。 与公共健康相关：五分之一的美国人吸烟。美国每年有超过43万人和全球500万人死于与吸烟相关的疾病，而且全球的死亡人数还在上升。显然，迫切需要更有效的药物疗法。在这项研究中，我们的目标是发现一种新的治疗方法是否单独有效或与尼古丁替代联合使用，通过最小化尼古丁戒断引起的认知损害来帮助戒烟和减少复发。

DESCRIPTION (provided by applicant): Pharmacotherapy for smoking cessation is universally accepted as standard of care and is highly cost effective, although only approximately 20% who attempt cessation are successful on a given attempt and up to 90% of those who do quit relapse to smoking within one year, and most relapse within two weeks of quitting. Discovery of novel treatments to aid people who want to quit smoking for the long term is a clear public health priority. People smoke for rewarding effects of nicotine, but also to avoid withdrawal-emergent symptoms such as cognitive impairment. Nicotine withdrawal is associated with significant attentional impairment, a symptom that is strongly associated with relapse to smoking. Those with baseline cognitive impairment are also more likely to smoke and less likely to quit than those without such symptoms. In many cases, nicotine ameliorates baseline cognitive symptoms. This R-01 grant application is based on the hypothesis that pharmacotherapies that work through novel biological mechanisms to moderate baseline and withdrawal-emergent symptoms such as cognitive impairment hold the greatest promise for sustained abstinence. We propose to evaluate the effect of a novel, selective, oral, alpha-7 nicotinic acetylcholine receptor agonist, EVP 6124, that is in Phase II development with an active IND, and has been shown to improve cognitive performance in normal adults, and those with schizophrenia and dementia of the Alzheimer's type. To do so, we propose to conduct a Phase II, double-blind, proof of concept treatment trial, comprising 4 combinations of active treatment and placebo arms in a 2 by 2 factorial design (EVP 6124 plus NRT vs placebo plus NRT vs EVP 6124 plus placebo-NRT vs placebo plus placebo-NRT). All participants will attempt to quit smoking on study day 1 when study medications are initiated. NRT or placebo-NRT (active or placebo patch) will be continued for 6 weeks and then discontinued. Randomized oral medication will then be continued without NRT for an additional 6 weeks in a relapse prevention phase. Participants will be followed for relapse patterns for 2 weeks after oral treatment discontinuation, to week 14. Data on cognitive performance, smoking behavior, and tolerability will be collected at each weekly visit. This design will allow us to assess the assay sensitivity of the clinical trial itself (by comparing the placebo plus NRT arm with the placebo plus placebo-NRT arm) and to assess whether the selective alpha-7 nicotinic receptor agonist is effective as monotherapy (by comparing the EVP 6124 plus placebo-NRT arm with the placebo plus placebo-NRT arm) and/or in combination with NRT (by comparing EVP 6124 plus NRT arm with the placebo plus NRT arm). In so doing, we will discover if the selective alpha-7 nAChR agonist improves cognitive performance during nicotine taper and in early abstinence and if this effect is associated, compared to placebo, with greater sustained abstinence from tobacco smoking alone or in combination with NRT. PUBLIC HEALTH RELEVANCE: One in five Americans smoke tobacco. Each year over 430,000 people in the US and 5 million worldwide die from smoking-related illness, and the global mortality toll is rising. Clearly, more effective pharmacotherapies are urgently needed. In this study, we aim to discover whether a novel treatment will work alone or in combination with nicotine replacement to aid cessation and reduce relapse by minimizing nicotine withdrawal- induced cognitive impairment