Dexmedetomidine Sublingual Film for the Ambulatory Treatment of Hyperadrenergic Autonomic Crisis in Patients with Familial Dysautonomia

摘要 该提案测试了一种新的方法来治疗肾上腺素能自主神经危象患者的罕见ge- 遗传性疾病-家族性自主神经功能障碍（FD）。FD是由ELP 1基因的常染色体隐性突变引起的。 基因，并表现在发育迟缓，肌肉骨骼异常，不稳定的血压，慢性肺 感染、吞咽困难和视神经萎缩。FD无疾病缓解疗法。嗨-- 肾上腺素能自主神经危象是FD最常见和最严重的症状， 每天，平均每月发生一次，是由身体疾病或情绪激动引发的。 引起血压和心率的急性升高，伴有持续呕吐， 干呕自主神经危机可能是致命的或导致继发性并发症（即，支气管吸入 的情况）。目前的方法对自主危机解决在家里涉及非药物治疗 减少苯二氮卓类药物和可乐定引起的交感神经兴奋，这可能会产生镇静作用 并伴有严重的副作用，如低血压和呼吸抑制。有效和安全的治疗 可以中止或防止在家里发生自主神经危机的方法是迫切需要的。 这项研究将测试一种新的方法对自主危机解决在家里。这种方法的核心是 舌下给予右旋美托咪啶（IGALMI™; BioExcel Therapeutics，Inc）。IV右美托咪- 静脉注射（IV）时，Dine是治疗难治性自主神经危象的标准治疗方法， 只能在重症监护室使用这种新的介绍的创新之处在于它的药物输送模式，一种微妙的， 一种快速吸收的薄膜，可以避免病人的吞咽困难和呕吐发作， 在家里就能轻松给药，避免住院。这项研究假设， IGALMI™薄膜在终止自主神经分泌方面比安慰剂和非药物治疗更有效。 在家里。与IGALMI™治疗同时，FD患者将接受非药物干预， 通过远程医疗进行诊断，并帮助管理症状和生命体征监测。本研究的一个探索性目的是 制定一种方法，在事件发生前24小时预测自主神经危象发作，以防止 通过早期干预解决危机。这将通过收集有关患者趋势的连续数据来实现 通过可穿戴设备和人工智能分析来改变生命体征。在该临床试验的目标1中，15名FD患者 将以2：1的比例随机分为活性治疗组（IGALMI™）和安慰剂组， 除了通过视频的非药物援助之外，还可以预防自主神经危象的发作。在目标2中，我们将 通过在家中使用IGALMI™治疗危机患者，评估患者的住院时间是否比前一年减少， - 是的在本研究的目标3中，将分析通过可穿戴Biobeat®设备收集的数据，以确定 每个病人的早期症状。

ABSTRACT This proposal tests a novel approach to treating hyperadrenergic autonomic crises in patients with a rare ge- netic disease – familial dysautonomia (FD). FD is caused by an autosomal recessive mutation in the ELP1 gene and manifests in developmental delay, musculoskeletal abnormalities, labile blood pressure, chronic lung infections, difficulty swallowing, and optic nerve atrophy. There are no disease-modifying therapies for FD. Hy- peradrenergic autonomic crises are the most frequent and severe symptoms of FD, occurring as often as once per day, with a median occurrence of once per month, are triggered by either physical illness or emotional exci- tation, and entail acute elevation in blood pressure and heart rate, accompanied by continuous vomiting and retching. Autonomic crises can be deadly or lead to secondary complications (i.e., bronchoaspiration; infec- tions). Current approaches towards autonomic crisis resolution at home involve non-pharmacologic treatments to decrease the sympathetic surge followed by benzodiazepines and clonidine, which may produce sedation and carry severe side effects, such as hypotension and respiratory depression. Effective and safe therapies that could abort or prevent autonomic crises in the at-home setting are desperately needed. This study will test a novel approach toward autonomic crisis resolution at home. At the core of this approach is the administration of sublingual dexmedetomidine (IGALMI™; BioExcel Therapeutics, Inc). IV dexmedetomi- dine is the standard of care for aborting refractory autonomic crises when delivered intravenously (IV) but can only administered in the ICU. The innovation of this new presentation lies in its mode of drug delivery, a sublin- gual fast-absorbing film that can circumvent a patient’s swallowing difficulties and vomiting episodes, allow for easy administration of the medication at home, and prevent hospitalizations. This study hypothesizes that IGALMI™ film is more effective than placebo and non-pharmacologic treatments in terminating autonomic cri- ses at home. Concurrently with IGALMI™ treatment, FD patients will undergo non-pharmacological interven- tion via telemedicine and help manage symptoms and vital signs monitoring. An exploratory aim of this study is the development of a methodology for predicting autonomic crisis onset 24 hours before the event to prevent the crisis through early intervention. This will be achieved by collecting continuous data on patients’ trend changes in vital signs through wearable device and AI analytics. In Aim 1 of this clinical trial, fifteen FD patients will be randomized 2:1 into active treatment (IGALMI™) and placebo groups to receive medication/placebo at the onset of the autonomic crisis in addition to non-pharmacological assistance through video. In Aim 2, we will evaluate if patients had fewer hospital stays than the previous year by using IGALMI™ at home for crisis man- agement. In Aim 3 of this study, data collected through a wearable Biobeat® device will be analyzed to identify early signs of AC for each patient.