PH III: AZIMILIDE CONTROLLED TRIAL

目的：本研究的目的是评估房颤/房扑和/或阵发性室上性心动过速患者长期使用阿齐利特的安全性。房颤是临床上显著的持续性心动过速的最常见原因，在75岁以上的人群中发生率高达12%。发病率随着年龄的增长而增加。此外，心房颤动是导致多达1/3的血栓栓塞性中风的原因。抗凝、心室反应的药物控制和抗心律失常药物治疗一直是心房颤动治疗的主要手段。然而，可用的抗疟疾药物的选择及其疗效是有限的。具体而言，在现有的抗心律失常药物中，只有索他洛尔和胺碘酮被认为在基础心脏病患者中是安全的。房颤最常与瓣膜性、缺血性或肥厚性心脏病相关，限制了可用的I型抗心律失常药物的使用。此外，III类药物索他洛尔和胺碘酮是强效负性变时剂，这限制了其在与窦房结疾病（心动过缓-心动过速综合征）相关的房颤患者中的有效性，这也是一种常见的临床事件。因此，迫切需要开发具有以下特征的新型抗心律失常药物：1）在患有结构性心脏病的患者中的安全性。2)没有显著的负性变时作用。一种这样的药物是Azimilide，一种III类抗心律失常药，在测试剂量水平下具有非常弱的心动过缓作用，并且在患有结构性心脏病的个体中使用时似乎是安全的。研究方法：这是一项多中心、双盲、安慰剂对照、平行设计的临床试验，研究每日口服剂量为125 mg的盐酸阿齐利特。结果如下：阿齐利特双盲试验的初步结果（n=89）已被报道，与对照组（17天，p（对数秩）为0.002）相比，阿齐利特治疗组（130天; 100 mg/d和125 mg/d）的AF复发平均时间显著缩短。重要性：本临床研究项目的意义在于检验这种有前途的新型抗心律失常药物治疗房颤的安全性和有效性。房颤是临床上显著的持续性心动过速的最常见原因，在75岁以上的人群中发生率高达12%。发病率随着年龄的增长而增加。此外，心房颤动是导致多达1/3的血栓栓塞性中风的原因。未来计划：Azimilide的III期试验正在进行中，预计目前入组的患者将接受总共24个月的前瞻性随访。在Azimilide治疗房颤的III期临床试验完成后，设想进一步研究这种新的抗心律失常药物在特定临床情况下控制阵发性房颤的安全性和有效性。这些研究将根据单独的方案进行。

Purpose: The purpose of this study is to assess the safety of long-term use of azimilide in patients with atrial fibrillation/flutter and/or paroxysmal sypraventricular tachycardia. Atrial fibrillation is the most common cause of clinically significant sustained tachycardia and occurs in up to 12% of individuals over age 75. Incidence increases with each decade of life. Furthermore, atrial fibrillation is responsible for up to 1/3 of thromboembolic strokes. Anticoagulation, pharmacologic control of the ventricular response, and antiarrhythmic pharmacotherapy have been the main stays of treatment for atrial fibrillation. However, the selection of available antiarrhythmic drugs, and their efficacy, are limited. Specifically, of available antiarrhythmic agents, only sotalol and amiodarone are considered safe in patients with underlying heart disease. Atrial fibrillation is most often associated with valvular, ischemic, or hypertrophic heart disease, limiting the use of available type I antiarrhythmic agents. Further, the class III agents sotalol and amiodarone are potent negative chronotropic agents which limits their usefulness in patients with atrial fibrillation in association with sinus node disease (brady-tachy syndrome), also a frequent clinical occurence. Accordingly, there is an important need for the development of new antiarrhythmic drugs with the following characteristics: 1) safety in patients with structural heart disease. 2) absence of significant negative chronotropic effects. One such drug is Azimilide, a class III antiarrhythmic agent with very weak bradycardic effects at test dosing levels, and which appears to be safe when used in individuals with structural heart disease. Methods: This is a multi-center double-blind, placebo-controlled, parallel design clinical trial studying a daily oral dose of 125 mg of azimilide dihydrochloride. Results: Results of the double blind trial of azimilide has been reported in preliminary form (n=89) with demonstration of a significant decreases in mean time to AF recurrence in azimilide treated patients (130 days; 100mg/d and 125mg/d) comparted with control (17 days, p (log rank) of 0.002). Significance: The significance of this clinical research program is to test the safety and efficacy of this promising new antiarrhythmic drug in the treatment of atrial fibrillation. Atrial fibrillation is the most common cause of clinically significant sustained tachycardia and occurs in up to 12% of individuals over age 75. Incidence increases with each decade of life. Furthermore, atrial fibrillation is responsible for up to 1/3 of thromboembolic strokes. Future Plans: Phase III trials of Azimilide are ongoing, and it is anticipated that currently enrolled patients will be followed prospectively for a total of 24 months. After completion of the phase III trials of Azimilide for treatment of atrial fibrillation, further studies of the safety and efficacy of this new antiarrhythmic agent to control paroxysmal atrial fibrillation in specific clinical circumstances are envisioned. These studies will be conducted under separate protocol.