Phase 2 Study of Mexiletine for the Treatment of Myotonic Dystrophy

美西律治疗强直性肌营养不良的 2 期研究

• 批准号: 8271228
• 负责人: RICHARD T MOXLEY
• 金额: $ 39.98万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-05 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271228
• 关键词: Phase; Study; Mexiletine; Treatment; Myotonic

PROJECT SUMMARY Myotonic dystrophy type 1 (DM1) is an autosomal dominant, multisystem disease caused by an unstable, abnormal expansion of a trinucleotide repeat [CTG]n on chromosome 19. DM1 is the most common form of muscular dystrophy and has a prevalence of less than 100,000 cases in the United States. The symptoms of DM1 are widespread. Distal muscle weakness in the arms and legs, along with facial weakness and grip myotonia may occur along with impaired ambulation, unsteadiness on arising from a chair, difficulty with fine finger movements, trouble swallowing, gastrointestinal hypomotility, musculoskeletal pain, and a reduction in health-related quality-of-life. Physiological myotonia (or muscle locking) is thought to significantly contribute to many of these clinical symptoms; especially patient relevant impairment of ambulation. To date, there has never been a large scale, extended, controlled treatment trial of myotonia in DM1. Two recent, short-term, FDA funded, 7 week double-blind, placebo-controlled, crossover trials of mexiletine (150 mg TID vs. placebo TID; 200mg TID vs. placebo TID) have been performed in our Neuromuscular Disease Center. These studies demonstrated both encouraging results and a preferential dosage schedule. Each trial involved 20 moderately affected DM1 patients. There were no significant side effects with either dose of mexiletine, and a reduction in grip myotonia was demonstrated. Compared to the 200 mg TID dosage, the 150 mg TID dose produced a similar level of myotonia reduction with an added benefit of improved peak grip force. There is a clear need for a longer-term trial of mexiletine to establish its safety and efficacy as a therapy for DM1. In order to determine if mexiletine is safe and effective for long-term treatment (6 months) in improving ambulation and reducing myotonia in DM1 we propose a 6 month, randomized, double-blind, placebo- controlled, trial of mexiletine (mexiletine 150 mg TID vs. placebo TID). Each arm of the trial (mexiletine and placebo) will involve 20 moderately affected patients with DM1. Our primary goal is to determine if mexiletine is well tolerated and able to improve six minute walk distances over 6 months of therapy. Our secondary goals are to determine if mexiletine reduces hand myotonia, increases muscle strength (grip strength, quantitative myometry and manual muscle testing), improves function (timed function tests), and/or improves DM1-specific health-related quality-of-life. We anticipate that this study has the potential to establish (or discourage) a new indication for the use of mexiletine.

项目概要 强直性肌营养不良 1 型 (DM1) 是一种常染色体显性遗传性多系统疾病，由不稳定的、 19 号染色体上三核苷酸重复序列 [CTG]n 的异常扩增。DM1 是最常见的形式 肌营养不良症在美国的患病率不到 100,000 例。症状 DM1 很普遍。手臂和腿部远端肌肉无力，以及面部和握力无力 肌强直可能伴随行走障碍、从椅子上起身不稳定、精细动作困难而发生 手指运动、吞咽困难、胃肠动力低下、肌肉骨骼疼痛和食欲减退 与健康相关的生活质量。生理性肌强直（或肌肉锁定）被认为对 许多这些临床症状；尤其是患者相关的行走障碍。 迄今为止，还没有针对 DM1 肌强直进行大规模、长期、对照的治疗试验。二 最近的、短期的、FDA 资助的、为期 7 周的双盲、安慰剂对照、美西律（150 mg）交叉试验 TID 与安慰剂 TID； 200 毫克 TID 与安慰剂 TID）已在我们的神经肌肉疾病中心进行。 这些研究证明了令人鼓舞的结果和优惠的剂量方案。每项试验都涉及 20 名中度受影响的 DM1 患者。任一剂量的美西律都没有明显的副作用，并且 已证明握力肌强直减少。与 200 mg TID 剂量相比，150 mg TID 剂量 产生了类似水平的肌强直减少，并具有改善峰值握力的额外好处。有一个 显然需要对美西律进行长期试验，以确定其作为 DM1 疗法的安全性和有效性。在 以确定美西律对于长期治疗（6 个月）改善病情是否安全有效 我们提出了一项为期 6 个月、随机、双盲、安慰剂的研究 美西律对照试验（美西律 150 mg TID 与安慰剂 TID）。试验的每个组（美西律和 安慰剂）将涉及 20 名中度受影响的 DM1 患者。我们的主要目标是确定美西律是否 耐受性良好，并且能够在 6 个月的治疗过程中改善六分钟的步行距离。我们的次要目标 确定美西律是否可以减少手部肌强直、增加肌肉力量（握力、定量 肌力测量和手动肌肉测试），改善功能（定时功能测试），和/或改善 DM1 特异性 与健康相关的生活质量。我们预计这项研究有可能建立（或阻止）一个新的 美西律的使用指征。