Phase 2 Study of Mexiletine for the Treatment of Myotonic Dystrophy

项目总结 强直性肌营养不良1型(DM1)是一种常染色体显性遗传的多系统疾病，由一种不稳定的， 19号染色体上三核苷酸重复序列[CTG]n的异常扩张。DM1是最常见的形式 肌营养不良症，在美国的流行率不到10万例。的症状 DM1广泛存在。手臂和腿的远端肌肉无力，以及面部无力和握力 肌强直可能伴随着行走障碍、从椅子上站立不稳、精细困难而发生。 手指运动，吞咽困难，胃肠动力减退，肌肉骨骼疼痛，以及 与健康相关的生活质量。生理性肌强直(或肌肉锁定)被认为是导致 这些临床症状很多，尤其是与患者相关的行走障碍。 到目前为止，还没有大规模的、延长的、对照的DM1肌强直治疗试验。二 近期美西律(150 Mg)的短期、FDA资助的7周双盲安慰剂对照交叉试验 TID与安慰剂TID；200 mg TID与安慰剂TID)在我们的神经肌肉疾病中心进行了试验。 这些研究既显示了令人鼓舞的结果，也显示了优惠的剂量时间表。涉及的每一项试验 20例中度感染的DM1患者。两种剂量的美西律都没有明显的副作用， 表现为握力肌强直的减少。与200毫克TID剂量相比，150毫克TID剂量 产生了类似水平的肌强直减少，并增加了改善峰值握力的好处。有一个 显然有必要对美西律进行长期试验，以确定其作为DM1治疗方法的安全性和有效性。在……里面 以确定美西律在长期治疗(6个月)中是否安全有效 在DM1中行走和减少肌张力我们建议一个6个月的随机、双盲、安慰剂。 美西律对照试验(美西律150 mg，tid与安慰剂tid比较)。试验的每一支手臂(美西律和 安慰剂)将涉及20名患有DM1的中度影响患者。我们的主要目标是确定美西律 耐受性良好，在6个月的治疗中能够提高6分钟的步行距离。我们的次要目标 是为了确定美西律是否减少手部肌张力，增加肌肉力量(握力，定量 肌肉测量和手动肌肉测试)、改善功能(定时功能测试)和/或提高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.