Non-Invasive Neuromodulation Device for the Treatment of Alcohol Use Disorder

摘要 过量饮酒是美国第三大死亡原因， 100万美国人患有酒精使用障碍（AUD）。澳元在经济上也很昂贵，为2490亿美元 每年花费在医疗保健、工作效率损失和犯罪方面的费用。尽管高流行率， AUD及其严重后果，只有不到20%的AUD患者接受过任何治疗，这主要是由于关键 目前治疗方案的缺点。AUD治疗指南包括药物治疗、行为治疗、 干预，或两者兼而有之。荟萃分析一致表明，一线AUD药物（纳洛酮和 阿坎酸）充其量只是中等有效。AUD药物疗法也有常见的副作用 这限制了患者的可接受性。与药物治疗类似，行为干预，如认知行为干预， CBT疗法仅提供小/中等的治疗益处。此外，项目通常要求禁欲， 这可能是一个障碍，因为许多AUD患者更喜欢非禁欲目标。近期临床前和临床研究 已经表明，针刺外周神经通路可以显着调节渴望，奖励， 药物滥用的戒断反应。因此，我们假设周围神经刺激可以 通过其对渴望，奖励和戒断的直接影响，有效治疗AUD。TheraNova 开发了Empower神经调节系统，这是一种便携式、易于使用的经皮电神经 用于非侵入性神经刺激的电刺激（TENS）设备作为AUD的治疗。的Empower 神经调节系统由一个小型的可穿戴控制器和凝胶电极组成 附着在皮肤上刺激皮下神经我们在AUD患者中进行的I期临床研究表明， Empower治疗显著降低了饮酒量（平均降低= 29%，p=0.026）， 渴望强度（平均降低21%，p=0.001）和焦虑（平均降低= 31%，p<0.001）（与基线相比 周测量）仅治疗两周后。虽然前景光明，但这是一项为期两周的开放标签研究， 因此，需要一个更长的假对照关键试验来严格验证Empower提供了一个全面的 AUD治疗。在本提案的目标1中，我们将首先更新Empower神经调节系统的设计 并进行所有支持FDA申报所需的台架测试。在第二个目标中，我们将进行一个多- 一项临床试验机构、假手术对照的关键临床试验，旨在评价Empower作为 治疗AUD。通过这项工作获得的数据将支持FDA批准， Empower神经调节系统作为AUD综合治疗的商业化。

Abstract Excessive alcohol consumption is the third leading cause of death in the United States, and approximately 15 million Americans suffer from alcohol use disorder (AUD). AUD also economically expensive, with $249 billion spent annually for costs related to healthcare, lost work productivity, and crime. Despite the high prevalence of AUD and its severe consequences, less than 20% of those with AUD receive any treatment, mainly due to key drawbacks of current treatment options. Guidelines for AUD treatment include pharmacotherapy, behavioral intervention, or both. Meta-analyses consistently demonstrate that first-line AUD medications (naltrexone and acamprosate) are only moderately effective, at best. AUD pharmacotherapies also have common side effects that limit acceptability to patients. Similar to medications, behavioral interventions, such as cognitive behavioral therapy (CBT), provide only small/moderate treatment benefits. In addition, programs often require abstinence, which can be a barrier as many AUD patients prefer non-abstinent goals. Recent preclinical and clinical research has shown that acupuncture of a peripheral nerve pathway can significantly modulate craving-, reward-, and withdrawal-related responses for drugs of abuse. We, thus, hypothesize that peripheral nerve stimulation can be an effective treatment for AUD through its direct effects on craving, reward, and withdrawal. Thus, TheraNova has developed the Empower Neuromodulation System, a portable, easy-to-use transcutaneous electrical nerve stimulation (TENS) device for non-invasive nerve stimulation as a treatment for AUD. The Empower Neuromodulation System consists of a small, wearable Controller and gel electrodes that are temporarily adhered to the skin to stimulate the underlying nerve. Our Phase I clinical study with AUD patients demonstrated that the Empower treatment significantly reduced alcohol consumption (mean reduction = 29%, p=0.026), alcohol craving intensity (mean reduction 21%, p=0.001), and anxiety (mean reduction = 31%, p<0.001) (vs. baseline week measurements) after only two weeks of treatment. While promising, this was a two-week, open-label study, so a longer, sham-controlled pivotal trial is needed to rigorously verify that Empower offers a comprehensive AUD treatment. In Aim 1 of this proposal, we will first update the design of the Empower Neuromodulation System and conduct all bench testing required to support an FDA submission. Then, in Aim 2, we will conduct a multi- site, sham-controlled pivotal clinical trial to evaluate the safety, effectiveness, and acceptability of Empower as a treatment for AUD. The data obtained through this work will support FDA clearance, enabling commercialization of the Empower Neuromodulation System as a comprehensive treatment for AUD.