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

右美托咪定舌下膜用于门诊治疗家族性自主神经功能异常患者的高肾上腺素能自主神经危象

• 批准号: 10731033
• 负责人: Maria Alejandra Gonzalez-Duarte Briseno
• 金额: $ 34.51万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731033
• 关键词: Dexmedetomidine; Sublingual; Film; Ambulatory; Treatment

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.

抽象的 该提案测试了一种治疗罕见GE-患者的高二烯型自主神经危机的新方法 网络疾病 - 家族性障碍（FD）。 FD是由ELP1中的常染色体隐性突变引起的 基因和表现出发育延迟，肌肉骨骼异常，不稳定血压，慢性肺 感染，吞咽困难和视神经萎缩。没有针对FD的疾病调整疗法。 hy 多肾上腺素能自主神经危机是FD的最频繁和严重症状，经常发生 每天每月一次发生一次，是由身体疾病或情感上的触发的 伴随着血压和心率的急性升高，伴随着连续的呕吐和 退缩。自主犯罪可能是致命的，也可能导致继发并发症（即支气管刺激； tions）。目前在家中解决自主危机的方法涉及非药物治疗 降低交感神经激增，然后是苯二氮卓类和可乐定，这可能会产生镇静 并具有严重的副作用，例如低血压和呼吸抑郁症。有效且安全的疗法 迫切需要在家庭环境中流产或防止自主犯罪。 这项研究将测试在家中解决自主危机的新方法。这种方法的核心是 舌下右美托咪定（Igalmi™; Bioexcel Therapeutics，Inc）的给药。 iv右元 用餐是静脉注射（IV）时流产难治性自主危机的护理标准（iv） 仅在ICU中给药。这种新演讲的创新在于其药物输送方式，一种sublin- gual快速吸收的电影可以规避患者的吞咽困难和呕吐情节，允许 容易在家中治疗药物，并防止住院治疗。这项研究假设 Igalmi™薄膜比安慰剂和非药物治疗更有效 SE在家。同时，与Igalmi™治疗同时，FD患者将接受非药理介入 通过远程医疗进行启动，并有助于管理符号和生命体征监测。这项研究的探索目的是 事件发生前24小时预测自主危机发作的方法的发展以防止 通过早期干预危机。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AI分析的生命体征变化。在该临床试验的AIM 1中，15例FD患者 将被随机分为2：1进入主动治疗（Igalmi™）和安慰剂组，以接受药物/安慰剂 除了通过视频进行非药理援助之外，自主危机的发作。在AIM 2中，我们将 通过在家中使用igalmi™来评估患者的住院时间比上一年少。 分化。在本研究的AIM 3中，将分析通过可穿戴BioBeat®设备收集的数据以识别 每位患者的交流的早期迹象。