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: 2740111
• 负责人: ARTHUR J. MOSS
• 金额: $ 21.57万
• 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: 1999-03-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2740111
• 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10000例患者，与复极延迟（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，LQTS的四种遗传形式已经被确定，包括LQT3，一种钠通道基因突变（SCN5A， deltaKPQ缺失），钠通道失活受损。本研究对LQT3患者的主要目的是确定：1)低剂量口服钠通道阻断药物美西汀是否显著缩短QTc，缩短时间大于或等于40毫秒；2)长期服用美西汀是否与QTc持续缩短和心律失常事件的减少有关。该研究由两个相关部分组成：1)口服美西汀的短期（7周）、随机、双盲、安慰剂对照、交叉、剂量范围研究，以确定低剂量美西汀（标准剂量的1/4或1/2）在显著缩短QTc间隔方面是否与标准剂量美西汀一样有效；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汀剂量，以确定与安慰剂治疗相比，长期服用该剂量美西汀是否与QTc间隔的持续缩短和心律失常事件的消失或减少有关。40名基因定义突变钠通道deltaKPQ缺失的LQT3患者将被纳入两部分研究。该研究将在三个临床中心（纽约州罗切斯特市、印第安纳州苏城和意大利帕维亚）与罗切斯特市的协调、数据管理和分析中心进行。患者的临床随访将包括定期的数字12导联和高分辨率心电图定量测量QTc。为了最大限度地发现主要终点和次要终点的显著差异，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遗传性通道病抗心律失常治疗提供新的见解。这项工作的意义与未来使用分子疗法治疗先天性和获得性心脏复极障碍相关的离子通道障碍有关。