Trigeminal Nerve Stimulation for Epilepsy

描述（由申请人提供）： 该STTR项目的目的是执行三项关键任务，这三项任务对于最终获得FDA批准和将一种新的癫痫微创治疗方法三叉神经刺激商业化至关重要。癫痫是一种以反复发作为特征的慢性疾病，影响着超过三百万美国人。100万人（30%）患有控制不佳的癫痫。癫痫控制不佳是致残的，并导致失业，复发性损伤和死亡的高风险。对癫痫的神经调节的兴趣正在增长，包括迷走神经刺激，深部脑刺激或闭环“响应”神经刺激作为失败的药物治疗的替代方案。这些方法是昂贵的，侵入性的，并且只有适度的功效。三叉神经电刺激（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可以无创、双侧和低成本地输送。它在抗药性癫痫中的应用是在加州大学洛杉矶分校开创的，那里的试点临床试验结果表明它具有强大的效果。三叉神经是最大的颅神经，有三对位于面部的传入皮支。这些分支与已知在癫痫发作抑制和引发中起作用的脑结构（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递送神经刺激的独特载体。来自动物和我们的初步临床试验的数据表明，TNS具有很强的抗癫痫作用，在6个月和12个月时的应答率（癫痫发作减少> 50%）> 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，需要优化用于最大限度地减少皮肤刺激的电极，这是每天使用超过12小时的常见副作用。此外，我们还需要设计和制造一种新的可编程脉冲发生器，以确保在比现有外部刺激器低得多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中测试新的脉冲发生器和电极设计。我们建议进行为期两年的第一阶段短期检讨，以执行以下三项主要工作。完成这些任务对于将TNS推向大型关键试验和最终FDA批准至关重要。1.在符合ISO标准的家兔皮肤刺激模型中评价一系列刺激参数和电极凝胶的影响，以获得系统对患者的最佳耐受性。2.设计并设计一台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：进行人体可行性研究，在健康受试者和癫痫患者中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.