Late Sodium Current Blockade in High-Risk ICD Patients - DCC

高危 ICD 患者的晚期钠电流阻断 - DCC

基本信息

  • 批准号:
    8127814
  • 负责人:
  • 金额:
    $ 75.27万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-08-15 至 2015-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): There are limited treatment options for patients at high risk of ventricular arrhythmic events. Beta- blockers alone do not provide enough protection, sotalol has limited effectiveness, and amiodarone although effective in some groups of patients is used infrequently due to its side effects and limitations of a long-term use. Ischemia and cardiomyopathies are associated with a sodium overload of myocardial cells. Late sodium current plays a pivotal role in this process. Sodium overload leads to calcium overload of myocardial cells with consequent increased vulnerability of myocardium to ventricular tachyarrhythmias as well as increased impairment of diastolic relaxation of myocardium thereby augmenting the risk of ischemia and myocardial damage. Ranolazine is a novel drug with anti-ischemic and anti-arrhythmic properties that uniquely blocks late sodium current, decreases intracellular calcium overload, and improves diastolic relaxation of the ventricles. The anti-ischemic and anti-arrhythmic properties of ranolazine might decrease the likelihood of arrhythmic events and improve the clinical course of patients at the risk for ventricular arrhythmias. We propose a randomized double-blind placebo-controlled clinical trial enrolling 1,200 high-risk ICD patients who will be treated with ranolazine or placebo in addition to optimal medical therapy. Primary aim of the study is to determine whether ranolazine administration in high-risk patients with ICDs contributes to a decrease in the number of patients reaching a composite arrhythmia endpoint consisting of ventricular tachycardia or fibrillation requiring appropriate ICD shocks, or death (whichever occurs first). Secondary aims of the study are: 1) to determine whether ranolazine administration will decrease the likelihood of composite primary endpoints consisting of hospitalization for cardiac causes or death, 2) to determine whether ranolazine administration will decrease the likelihood of a composite secondary endpoint consisting of CHF hospitalization or death, 3) to determine whether ranolazine therapy will decrease the number of repeated hospitalizations for cardiac causes, 4) to assess whether ranolazine administration will decrease the likelihood of repeated ICD therapies, 5) to evaluate whether ranolazine administration will decrease the likelihood of appropriate ICD shocks, 6) to determine whether ranolazine therapy will be associated with improvement in exercise capacity measured by the 6-minute walk test (6MWT) and in the quality of life measured by the Minnesota Leaving with Heart Failure Questionnaire (MLHFQ), and 7) to evaluate the safety of ranolazine therapy utilizing ICD interrogation data documenting all types of ventricular tachyarrhythmias (including torsade de pointes). This proposal consists of two clustered applications covering respective components of the trial: Clinical Core - Leading Application, and Data Coordination Center. (End of Abstract) PUBLIC HEALTH RELEVANCE: The trial with late sodium channel blockade ranolazine in high-risk ICD patients is very much needed since there is no safe and effective treatment for a large number of patients with high risk of ventricular tachyarrhythmias. It is of interest to clinicians, NHLBI, and patients to improve the very low survival of patients at increased risk of ventricular tachyarrhythmias. It is worth stressing that late sodium current blockade represents a new scientifically attractive concept of anti-arrhythmic therapy after two decades of no significant developments in pharmacologic treatment of ventricular arrhythmias. Conducting such a trial might open the door to the development of an entire line of compounds targeting the late sodium current as their main mode of anti-arrhythmic action.
描述(由申请人提供): 对于室性心律失常事件高风险患者,治疗选择有限。单独的β-受体阻滞剂不能提供足够的保护,索他洛尔的有效性有限,胺碘酮虽然在某些患者组中有效,但由于其副作用和长期使用的局限性而很少使用。缺血和心肌病与心肌细胞的钠超载有关。晚钠电流在这一过程中起着关键作用。钠超负荷导致心肌细胞钙超负荷,从而增加心肌对室性快速性心律失常的脆弱性以及增加心肌舒张期舒张的损害,从而增加缺血和心肌损伤的风险。 雷诺嗪是一种具有抗缺血和抗心肌缺血特性的新型药物,其独特地阻断晚期钠电流,降低细胞内钙超载,并改善心室的舒张。雷诺嗪的抗缺血和抗心律失常特性可能降低心律失常事件的可能性,并改善有室性心律失常风险的患者的临床病程。 我们提出了一项随机双盲安慰剂对照临床试验,纳入1,200例高危ICD患者,这些患者除了接受最佳药物治疗外,还将接受雷诺嗪或安慰剂治疗。本研究的主要目的是确定在植入ICD的高风险患者中给予雷诺嗪是否有助于减少达到复合心律失常终点的患者数量,复合心律失常终点包括需要适当ICD电击的室性心动过速或颤动或死亡(以先发生者为准)。本研究的次要目的是:1)确定雷诺嗪给药是否会降低由心脏原因住院或死亡组成的复合主要终点的可能性,2)确定雷诺嗪给药是否会降低由CHF住院或死亡组成的复合次要终点的可能性,3)确定雷诺嗪治疗是否会减少因心脏原因而重复住院的次数,4)评估雷诺嗪给药是否会减少重复ICD治疗的可能性,5)评价雷诺嗪给药是否会降低适当ICD电击的可能性,6)确定雷诺嗪治疗是否与通过6分钟步行试验(6 MWT)测量的运动能力和通过明尼苏达心力衰竭问卷(MLHFQ)测量的生活质量的改善相关,和7)利用记录所有类型室性快速性心律失常(包括尖端扭转型室性心动过速)的ICD询问数据评价雷诺嗪治疗的安全性。 本提案由两个集群应用程序组成,涵盖试验的各个组成部分:临床核心-领先应用程序和数据协调中心。 (End摘要) 公共卫生关系: 非常需要在高危ICD患者中进行晚期钠通道阻滞剂雷诺嗪的试验,因为对于大量室性快速性心律失常高危患者没有安全有效的治疗方法。提高室性快速性心律失常风险增加患者的极低生存率是临床医生、NHLBI和患者的兴趣所在。值得强调的是,在室性心律失常的药物治疗方面没有显著进展的20年后,晚期钠电流阻滞代表了一种新的具有科学吸引力的抗心律失常治疗概念。进行这样的试验可能会为开发一系列针对晚期钠电流的化合物打开大门,这些化合物是其抗癫痫作用的主要模式。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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ARTHUR J. MOSS其他文献

ARTHUR J. MOSS的其他文献

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{{ truncateString('ARTHUR J. MOSS', 18)}}的其他基金

Late Sodium Current Blockade in High-Risk ICD Patients - DCC
高危 ICD 患者的晚期钠电流阻断 - DCC
  • 批准号:
    7885048
  • 财政年份:
    2010
  • 资助金额:
    $ 75.27万
  • 项目类别:
Late Sodium Current Blockade in High-Risk ICD Patients - DCC
高危 ICD 患者的晚期钠电流阻断 - DCC
  • 批准号:
    8392239
  • 财政年份:
    2010
  • 资助金额:
    $ 75.27万
  • 项目类别:
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
  • 财政年份:
    1999
  • 资助金额:
    $ 75.27万
  • 项目类别:
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:
    6351509
  • 财政年份:
    1999
  • 资助金额:
    $ 75.27万
  • 项目类别:
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
  • 财政年份:
    1999
  • 资助金额:
    $ 75.27万
  • 项目类别:
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:
    6294429
  • 财政年份:
    1999
  • 资助金额:
    $ 75.27万
  • 项目类别:
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:
    6151352
  • 财政年份:
    1999
  • 资助金额:
    $ 75.27万
  • 项目类别:
THERAPEUTIC TRIAL IN PATIENTS W/ LQTS 3 GENE MUTATION
LQTS 3 基因突变患者的治疗试验
  • 批准号:
    6263800
  • 财政年份:
    1998
  • 资助金额:
    $ 75.27万
  • 项目类别:
CLINICAL PHARMACOLOGIC TARGETING W/ FLECAINIDE OF SCN5A GENE MUTATION
氟卡尼针对 SCN5A 基因突变的临床药理学靶向
  • 批准号:
    6263833
  • 财政年份:
    1998
  • 资助金额:
    $ 75.27万
  • 项目类别:
LONG QT SYNDROME--THERAPEUTIC STUDIES
长 QT 综合征——治疗研究
  • 批准号:
    6244892
  • 财政年份:
    1997
  • 资助金额:
    $ 75.27万
  • 项目类别:
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