THERAPUTIC TRIAL IN PATIENTS WITH LQTS 3 GENE MUTATION

LQTS 3 基因突变患者的治疗试验

• 批准号: 6498946
• 负责人: ARTHUR J. MOSS
• 金额: $ 21.2万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6498946
• 关键词: clinical research; drug screening /evaluation; electrocardiography; gene deletion mutation; genetic disorder; heart disorder chemotherapy; human subject; long QT syndrome; mexiletine; sodium channel

The Long QT Syndrome (LQTS), an hereditary disorder involving about 10,000 persons in the U.S., is associated with delayed repolarization (yields QTc interval on ECG), paroxysmal ventricular arrhythmias, syncope, and sudden death. Recently, four genetic forms of LQTS have been identified including LQT3, a sodium-channel gene mutation (SCN5A, deltaKPQ deletion) with impairment of sodium-channel inactivation. The primary aims of this study of LQT3 patients are to determine: 1) if a low dose of the oral sodium-channel blocking drug mexiletine significantly shortens QTc by greater than or equal to 40 msec; and 2) if chronic administration of mexiletine is associated with sustained QTc shortening and a reduction in arrhythmic cardiac events. The study consists of two related parts: 1) a short-term (7-week), randomized, double-blind, placebo-controlled, crossover, dose-ranging study with oral mexiletine to determine if a low dose of mexiletine (1/4 or 1/2 of the standard dose) is as effective as a standard dose of mexiletine in significantly shortening the QTc interval; and 2) a long-term (38-month), randomized, double-blind, placebo-controlled, crossover, safety and efficacy study using the lowest effective mexiletine dose identified in part 1 to determine if chronic administration of this dose of mexiletine is associated with sustained shortening of the QTc interval and absence or a reduction of arrhythmic cardiac events when compared to placebo therapy. Forty LQT3 patients with genetically defined deltaKPQ deletion of the mutant sodium channel will be enrolled in the two parts of the i study. The study will be conducted in three clinical centers (Rochester, NY; Sioux City, IA; and Pavia, Italy) with the coordination, data management, and analysis center in Rochester. Clinical follow-up of the patients will include periodic digital 12-lead and high-resolution ECGs for quantitative QTc measurements. To maximize the power to detect significant differences in the primary and secondary end points, the crossover design will allow each patient to serve as his/her own control in the analysis. The trial should provide new insight into molecular-based, antiarrhythmic therapy for an inherited channelopathy. The significance of this work relates to the future use of molecular therapeutics to treat ion-channel disorders associated with congenital and acquired cardiac repolarization disorders.

长 QT 综合征 (LQTS) 是一种遗传性疾病，在美国约有 10,000 人患病，与延迟复极（心电图显示 QTc 间期）、阵发性室性心律失常、晕厥和猝死有关。 最近，已鉴定出 LQTS 的四种遗传形式，包括 LQT3，一种钠通道基因突变（SCN5A，deltaKPQ 缺失），会损害钠通道失活。 这项针对 LQT3 患者的研究的主要目的是确定： 1) 低剂量的口服钠通道阻断药物美西律是否会显着缩短 QTc 大于或等于 40 毫秒； 2) 长期服用美西律是否与持续 QTc 缩短和心律失常心脏事件减少有关。该研究由两个相关部分组成：1）一项口服美西律的短期（7周）、随机、双盲、安慰剂对照、交叉、剂量范围研究，以确定低剂量美西律（标准剂量的1/4或1/2）在显着缩短QTc间期方面是否与标准剂量美西律一样有效； 2) 一项长期（38 个月）、随机、双盲、安慰剂对照、交叉、安全性和有效性研究，使用第 1 部分中确定的最低有效美西律剂量，以确定与安慰剂治疗相比，长期服用该剂量的美西律是否与 QTc 间期持续缩短以及心律失常心脏事件的消失或减少有关。 40 名具有基因定义的 deltaKPQ 突变钠通道缺失的 LQT3 患者将被纳入 i 研究的两个部分。该研究将在三个临床中心（纽约州罗切斯特、爱荷华州苏城和意大利帕维亚）进行，协调、数据管理和分析中心位于罗切斯特。 患者的临床随访将包括定期数字 12 导联和高分辨率心电图，以进行定量 QTc 测量。 为了最大限度地提高检测主要和次要终点显着差异的能力，交叉设计将允许每个患者在分析中作为他/她自己的对照。该试验将为基于分子的抗心律失常治疗遗传性离子通道病提供新的见解。 这项工作的意义在于未来使用分子疗法来治疗与先天性和获得性心脏复极疾病相关的离子通道疾病。