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（DM 1）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。 DM 1是肌营养不良症最常见的形式，在美国的患病率不到10万例。DM 1的症状很普遍。 手臂和腿部远端肌无力、沿着面部无力和握力肌强直可能伴随沿着上肢功能受损、从椅子上站立不稳、手指精细运动困难、吞咽困难、胃肠道运动功能减退、肌肉骨骼疼痛和健康相关生活质量降低。 生理性肌强直（或肌肉闭锁）被认为是许多这些临床症状的重要原因;尤其是患者相关的肌萎缩障碍。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。最近在我们的神经肌肉疾病中心进行了两项FDA资助的短期、7周双盲、安慰剂对照、交叉试验（150 mg TID vs.安慰剂TID; 200 mg TID vs.安慰剂TID）。这些研究证明了优先给药方案。每项试验涉及20名中度受累的DM 1患者。两种剂量的美西律都没有明显的副作用，并且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轻，并增加了改善峰值握力的益处。显然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。为了确定美西律在改善DM 1患者的肌张力和减轻肌强直方面的长期治疗（6个月）是否安全有效，提出了美西律的随机、双盲、安慰剂对照试验（美西律150 mg TID vs.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DM 1患者。主要目标是确定美西律是否耐受良好，并能够在6个月的治疗中改善6分钟步行距离。次要目标是确定美西律是否减少手部肌强直，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。