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

描述（由申请人提供）：药物治疗戒烟被普遍接受为标准护理，具有很高的成本效益，尽管只有大约20%的戒烟尝试成功，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那些想要长期戒烟的人是一个明确的公共卫生优先事项。人们吸烟是为了获得尼古丁的奖励效果，但也是为了避免出现戒断症状，如认知障碍。尼古丁戒断与严重的注意力障碍有关，这种症状与吸烟复发密切相关。与没有这些症状的人相比，有基线认知障碍的人吸烟的可能性更大，戒烟的可能性更小。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的假设：通过新的生物机制来缓解基线和戒断症状（如认知障碍）的药物治疗对持续戒断最有希望。我们建议评估一种新型，选择性，口服，α -7烟碱乙酰胆碱受体激动剂EVP 6124的效果，该药物处于II期开发，具有活性IND，并已被证明可以改善正常成年人，精神分裂症和阿尔茨海默氏型痴呆患者的认知表现。为此，我们建议进行一项II期、双盲、概念验证治疗试验，包括积极治疗组和安慰剂组的4个组合，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）。所有参与者将在研究第一天开始服用研究药物时尝试戒烟。NRT或安慰剂-NRT（活性或安慰剂贴片）将持续6周，然后停止。在预防复发阶段，随机口服药物治疗将在没有NRT的情况下继续进行6周。受试者将在口服治疗停止后随访2周，直至第14周。认知表现、吸烟行为和耐受性的数据将在每周的访问中收集。该设计将使我们能够评估临床试验本身的检测灵敏度（通过比较安慰剂加NRT组与安慰剂加安慰剂-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加安慰剂-NRT组与安慰剂加安慰剂-NRT组）和/或与NRT联合治疗（通过比较EVP 6124加NRT组与安慰剂加NRT组）是否有效。在这样做的过程中，我们将发现选择性α -7 nAChR激动剂是否能改善尼古丁逐渐减少和早期戒烟期间的认知表现，以及与安慰剂相比，这种效果是否与单独或联合NRT更持久的戒烟有关。

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