Phase 2 Study of Mexiletine for the Treatment of Myotonic Dystrophy

项目摘要 强直性肌营养不良1型（DM 1）是一种常染色体显性多系统疾病， 19号染色体上三核苷酸重复序列[CTG]n的异常扩增。DM 1是最常见的 肌肉萎缩症，在美国的患病率低于10万例。的症状 DM 1是广泛存在的。手臂和腿部远端肌肉无力，沿着面部无力和握力 肌强直可能沿着有肌张力受损，从椅子上站立不稳， 手指运动，吞咽困难，胃肠运动不足，肌肉骨骼疼痛， 健康相关的生活质量。生理性肌强直（或肌肉锁定）被认为是显著有助于 这些临床症状中的许多;尤其是患者相关的安培损伤。 到目前为止，还没有一个大规模的，扩展的，对照治疗试验的肌强直DM 1。两 最近，短期，FDA资助，7周双盲，安慰剂对照，交叉试验的mexilvinine（150毫克 TID对比安慰剂TID; 200 mg TID对比安慰剂TID）已在我们的神经肌肉疾病中心进行。 这些研究表明了令人鼓舞的结果和优选的剂量方案。每项试验都涉及 20例中度DM 1患者。两种剂量的美西律都没有明显的副作用， 证明了握力肌强直的减少。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，具有改善的峰值握力的额外益处。有一个 明确需要对美西律进行长期试验，以确定其作为DM 1治疗的安全性和有效性。在 为了确定美西律是否安全有效，用于长期治疗（6个月）， 我们提出了一项为期6个月的随机、双盲、安慰剂- 美西律对照试验（美西律150 mg TID vs安慰剂TID）。试验的每个组（墨西哥和 安慰剂）将涉及20名中度受影响的DM 1患者。我们的首要目标是确定墨西哥是否 耐受性良好，并且能够在6个月的治疗中改善6分钟步行距离。我们的次要目标 是为了确定是否mexilestrin减少手肌强直，增加肌肉力量（握力，定量 肌测量和手动肌肉测试），改善功能（定时功能测试），和/或改善DM 1特异性 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 使用美沙芬的适应症。

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.