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

描述（由申请人提供）：戒烟药物治疗被普遍接受为标准治疗，具有很高的成本效益，尽管只有大约20%的尝试戒烟者在一次尝试中成功，高达90%的戒烟者在一年内复发，大多数在戒烟后两周内复发。发现新的治疗方法来帮助想要长期戒烟的人是一个明确的公共卫生优先事项。人们吸烟是为了尼古丁的奖励作用，但也是为了避免戒断后出现的症状，如认知障碍。尼古丁戒断与显著的注意力障碍有关，这是一种与复吸密切相关的症状。那些有基线认知障碍的人也更有可能吸烟，而不太可能比那些没有这些症状的人戒烟。在许多情况下，尼古丁改善了基线认知症状。这项R-01资助申请是基于这样一种假设，即通过新的生物学机制来缓解基线和戒断后出现的症状（如认知障碍）的药物疗法最有希望实现持续禁欲。我们建议评估一种新型的、选择性的、口服的α-7烟碱乙酰胆碱受体激动剂EVP 6124的效果，该药物正处于II期开发阶段，具有活性IND，并已被证明可改善正常成人、精神分裂症患者和阿尔茨海默型痴呆患者的认知能力。为此，我们建议进行一项II期、双盲、概念验证治疗试验，包括2 × 2析因设计中的4种活性治疗和安慰剂组组合（EVP 6124 + NRT vs安慰剂+NRT vs EVP 6124+安慰剂-NRT vs安慰剂+安慰剂-NRT）。所有受试者将在研究第1天开始使用研究药物时尝试戒烟。NRT或安慰剂-NRT（活性或安慰剂贴剂）将持续6周，然后停药。然后，在复发预防阶段，将继续随机口服药物治疗，不使用NRT，再持续6周。将在口服治疗停止后2周至第14周对受试者的复发模式进行随访。将在每次每周访视时收集有关认知表现、吸烟行为和耐受性的数据。这种设计将使我们能够评估临床试验本身的检测灵敏度（通过比较安慰剂+NRT组与安慰剂+安慰剂-NRT组），并评估选择性α-7烟碱受体激动剂作为单药治疗是否有效（通过比较EVP 6124+安慰剂-NRT组与安慰剂+安慰剂-NRT组）和/或联合NRT（通过比较EVP 6124加NRT组与安慰剂加NRT组）。通过这样做，我们将发现选择性α-7 nAChR激动剂是否能改善尼古丁减量期间和早期戒烟期间的认知表现，以及与安慰剂相比，这种作用是否与单独或与NRT联合使用时更大的持续戒烟有关。 公共卫生相关性：五分之一的美国人吸烟。每年美国有超过43万人和全世界500万人死于与吸烟有关的疾病，全球死亡人数正在上升。显然，迫切需要更有效的药物治疗。在这项研究中，我们的目标是发现一种新的治疗方法是否会单独或与尼古丁替代品联合使用，以帮助戒烟，并通过最大限度地减少尼古丁戒断引起的认知障碍来减少复发。

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