Trigeminal Nerve Stimulation for Epilepsy

描述(由申请人提供)： 这一STTR项目的目的是执行三项关键任务，这对于FDA最终批准一种治疗癫痫的新的微创疗法--三叉神经刺激--并将其商业化至关重要。癫痫是一种以反复发作为特征的慢性疾病，影响着300多万美国人。100万人(30%)癫痫控制不佳。控制不佳的癫痫是致残的，并导致失业、反复受伤和高死亡风险。人们对癫痫的神经调节越来越感兴趣，包括迷走神经刺激，脑深部刺激，或作为药物治疗失败的替代方案的闭环式“响应性”神经刺激。这些方法费用昂贵，具有侵入性，而且疗效不高。三叉神经刺激(TNS)是一种新兴的神经调节疗法，具有独特的优势。与VNS不同，TNS可以非侵入性、双边和低成本提供。加州大学洛杉矶分校(UCLA)率先将其用于抗药性癫痫，试点临床试验的结果表明，它具有强大的效果。三叉神经是最大的脑神经，面部有三对传入皮支。这些分支与已知在癫痫抑制和启动中起作用的脑结构(蓝斑、丘脑和大脑皮层)有广泛的联系。这些分支的浅表位置使三叉神经成为安全和外部传递神经刺激的独特工具。来自动物的数据和我们的试点临床试验表明，TNS具有强大的抗癫痫作用，在6个月和12个月时的应答率(癫痫发作减少50%)为40%。我们正在开发外部和皮下TNS，外部设备最接近关键试验。在关键试验之前，有必要优化用于将皮肤刺激性降至最低的电极，这是一种每天使用超过12小时的常见副作用。此外，我们需要设计和设计一种新的可编程脉冲发生器，以确保在比现有外部刺激器更低的电流下进行安全刺激。此外，我们需要在健康受试者和癫痫患者身上测试新的脉冲发生器和电极设计。我们建议实施一项为期两年的第一阶段技术转让计划，以执行以下三项主要任务。完成这些任务对于推动TNS走向一项大型关键试验和最终获得FDA的批准至关重要。1.评价一系列刺激参数和电极凝胶在符合ISO标准的兔皮肤刺激模型中的作用，以实现患者对该系统的最佳耐受性。2.设计和设计了一种新的外部脉冲发生器，为关键研究和PMA提交做准备。3.人体可行性研究：在健康人和癫痫患者身上进行人体可行性研究，测试新的脉冲发生器和优化的电极。

DESCRIPTION (provided by applicant): The purpose of this STTR project is to perform three key tasks essential to the ultimate FDA approval and commercialization of a new minimally invasive treatment for epilepsy, Trigeminal Nerve Stimulation. Epilepsy is a chronic condition characterized by recurrent seizures, and affects over three million Americans. One million (30 percent) have poorly controlled epilepsy. Poorly controlled epilepsy is disabling, and leads to unemployment, recurrent injury, and a high risk of death. Interest is growing in neuromodulation for epilepsy, including vagus nerve stimulation, deep brain stimulation, or closed-loop "responsive" neurostimulation as alternatives to failed drug therapy. These approaches are expensive, invasive, and have only modest efficacy. Trigeminal Nerve Stimulation (TNS) is an emerging neuromodulation therapy, which has unique advantages. Unlike VNS, TNS can be delivered non-invasively, bilaterally, and at low cost. Its use in drug resistant epilepsy was pioneered at UCLA, where the results of pilot clinical trials show it to have a robust effect. The trigeminal nerve is the largest cranial nerve, with three pairs of afferent cutaneous branches located over the face. These branches have extensive connections with brain structures known to play a role in seizure inhibition and initiation (locus coeruleus, thalamus, and cerebral cortex). The superficial location of these branches makes the trigeminal nerve a unique vehicle to deliver neurostimulation safely and externally. Data from animals and our pilot clinical trials indicate that TNS has a strong anti-epileptic effect, with a responder rate (> 50 percent reduction in seizures) of > 40 percent at 6 and 12 months. We are developing both external and subcutaneous TNS, and the external device is closest to a pivotal trial. Before the pivotal trial, there is a need to optimize the electrodes used to minimize skin irritation, a common side effect when used for more than 12 hours per day. In addition, we need to design and engineer a new programmable pulse generator to ensure safe stimulation at much lower currents than existing external stimulators. Further we need to test the new pulse generator and electrode design in healthy subjects and people with epilepsy. We propose a two-year, Phase I STTR to perform the following three key tasks. Completing these tasks will be essential in moving TNS toward a large pivotal trial and ultimate FDA approval. 1. Evaluate the effects of a series of stimulation parameters and electrode gels in an ISO compliant skin irritation model in rabbits for optimal tolerability of the system for patients. 2. Design and Engineer a new external pulse generator in preparation for the pivotal study and PMA submission. 3. Human Feasibility Study: Conduct a human feasibility study to test the new pulse generator and optimized electrodes in healthy subjects and people with epilepsy.