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: 8022616
• 负责人: RICHARD T MOXLEY
• 金额: $ 31.26万
• 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/8022616
• 关键词: Phase; Study; Mexiletine; Treatment; Myotonic

DESCRIPTION (provided by applicant): 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 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 a 6 month, randomized, double-blind, placebo controlled, trial of mexiletine (mexiletine 150 mg TID vs. placebo TID) is proposed. Each arm of the trial (mexiletine and placebo) will involve 20 moderately affected patients with DM1. The primary goal is to determine if mexiletine is well tolerated and able to improve six minute walk distances over 6 months of therapy. The 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.

描述（由申请人提供）： 强直性肌营养不良 1 型 (DM1) 是一种常染色体显性多系统疾病，由 19 号染色体上的三核苷酸重复序列 [CTG]n 不稳定、异常扩增引起。DM1 是最常见的肌营养不良形式，在美国患病率不到 100,000 例。 DM1 的症状很普遍。 手臂和腿部的远端肌肉无力，以及面部无力和握力肌强直可能会发生，同时还会出现行走障碍、从椅子上起身不稳定、手指精细运动困难、吞咽困难、胃肠动力低下、肌肉骨骼疼痛以及与健康相关的生活质量下降。 生理性肌强直（或肌肉锁定）被认为是导致许多这些临床症状的重要原因；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。我们的神经肌肉疾病中心最近进行了两项 FDA 资助的短期、为期 7 周的双盲、安慰剂对照、美西律交叉试验（150 mg TID 与安慰剂 TID；200 mg TID 与安慰剂 TID）。这些研究证明了优先剂量方案。每项试验涉及 20 名中度受影响的 DM1 患者。两种剂量的美西律均未出现明显副作用，并且握力肌强直有所减轻。与 200 mg TID 剂量相比，150 mg TID 剂量产生相似水平的肌强直减少，并具有改善峰值握力的额外好处。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。为了确定美西律对于长期治疗（6 个月）在改善 DM1 的步行能力和减少肌强直方面是否安全有效，建议进行 6 个月的随机、双盲、安慰剂对照美西律试验（美西律 150 mg TID 与安慰剂 TID）。该试验的每个组（美西律和安慰剂）将涉及 20 名中度受影响的 DM1 患者。主要目标是确定美西律是否具有良好的耐受性，并且能够在 6 个月的治疗过程中改善六分钟步行距离。次要目标是确定美西律是否能减少手部肌强直、增加肌肉力量（握力、定量肌力测量和徒手肌肉测试）、改善功能（定时功能测试）和/或改善 DM1 特定的健康相关生活质量。