THERAPUTIC TRIAL IN PATIENTS WITH LQTS 3 GENE MUTATION

长QT综合征(LQTS)是一种遗传性疾病，在美国约有10,000人，与复极延迟(心电图上出现QTC间期)、阵发性室性心律失常、晕厥和猝死有关。最近，LQTS的四种遗传形式已被发现，包括LQT3，一种钠通道基因突变(SCN5A，deltaKPQ缺失)，钠通道失活受损。这项针对LQT3患者的研究的主要目的是确定：1)小剂量口服钠通道阻滞剂美西律是否能显著缩短QT间期大于或等于40毫秒；2)长期服用美西律是否与QT间期持续缩短和心律失常事件的减少有关。这项研究包括两个相关部分：1)一项短期(7周)、随机、双盲、安慰剂对照的交叉剂量范围研究，口服美西律，以确定小剂量美西律(标准剂量的1/4或1/2)是否与标准剂量美西律一样有效地显著缩短QTC间期；2)一项长期(38个月)的随机、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剂量的美西律，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间期持续缩短和心律失常事件的消失或减少有关。40名基因定义为突变钠通道deltaKPQ缺失的LQT3患者将在I研究的两个部分中登记。这项研究将在三个临床中心(纽约州罗切斯特、亚利桑那州苏城和意大利帕维亚)与设在罗切斯特的协调、数据管理和分析中心一起进行。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，用于定量QTC测量。为了最大限度地检测主要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充当他/她自己的对照。这项试验将为遗传性经络病的分子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与先天性和获得性心脏复极障碍相关的离子通道障碍有关。

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.