Pilot Randomized Trial with Flecainide in ARVC Patients

ARVC 患者使用氟卡尼的随机试验

• 批准号: 9754242
• 负责人: Wojciech Zareba
• 金额: $ 34.98万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754242
• 关键词: 21 year old; Ablation; Adrenergic Agents; Adrenergic beta-Antagonists; Advisory Committees; Amiodarone; Animals; Anti-Arrhythmia Agents; Arrhythmia; Arrhythmogenic Right Ventricular Dysplasia; Atrial Premature Complexes; Calcium; Cardiac; Catecholaminergic Polymorphic Ventricular Tachycardia; Cessation of life; Clinical; Clinical Trials; Cross-Over Trials; Data; Diagnosis; Disease; Double-Blind Method; Electrocardiogram; Enrollment; Event; Exercise; Flecainide; Frequencies; Future; Hour; Implant; Implantable Defibrillators; Individual; Inherited; Italy; Life; Link; Measures; Monitor; Morphology; Mutation; Myocardium; Palliative Care; Patients; Pharmaceutical Preparations; Pilot Projects; Placebos; Preparation; Randomized; Randomized Clinical Trials; Recurrence; Reporting; Research Design; Risk; Running; RyR2; Safety; Sarcoplasmic Reticulum; Sotalol; Sudden Death; Tamoxifen; Ventricular; Ventricular Arrhythmia; Ventricular Fibrillation; Ventricular Premature Complexes; Ventricular Tachycardia; high risk; mortality; mouse model; novel; pilot trial; pre-clinical; prevent; randomized trial; receptor; response; study population; sudden cardiac death; young adult

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited arrhythmia disorder with high risk of ventricular tachycardia or fibrillation, and implantable cardioverter defibrillator remains as palliative therapy of choice. Antiarrhythmic therapy with different agents including beta-blockers, sotalol and amiodarone are usually not effective in reducing risk of arrhythmic events. Recent experimental data using a novel murine model with cardiac-specific tamoxifen induced PKP2 deficiency indicated that enhanced triggered activity and increased sarcoplasmic reticulum (SR) calcium release via RyR2 channels could contribute to adrenergic-induced arrhythmias in the setting of ARVC. This study also reported that flecainide effectively prevented the arrhythmias observed in the experimental animals. Separate preclinical and anecdotal clinical reports also suggest that flecainide, likely through a block of the RyR2 receptor, may be a promising antiarrhythmic approach in ARVC. Furthermore, in a small randomized trial flecainide was effective in reducing ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia, a condition linked to RyR2 mutations causing increased SR release and triggered arrhythmias. These results provide a strong rationale for the implementation of a definitive randomized clinical trial to determine whether flecainide will reduce life-threatening VT/VF episodes in high-risk ARVC patients; however before conducting such a large study a pilot project focused on antiarrhythmic effects of flecainide therapy and its safety in ARVC patients is needed. Therefore, we propose to conduct a pilot study designed as randomized double-blinded placebo-controlled crossover trial with administration of 100 mg bid of Flecainide or matching placebo for 4 weeks each with a washout period. Study population will include 38 ARVC patients diagnosed with the 2010 ARVC Task Force Criteria who are at least 21 years old, have implanted ICD, and show at least 500 VPBs in a 24-hour Holter recording. Primary specific aim of this pilot trial is to determine whether Flecainide administration is associated with a significant reduction of number of ventricular ectopic beats (VEBs) in ARVC patients with ICDs. Secondary specific aims are: 1) to assess safety of flecainide administration with particular emphasis on proarrhythmic response; 2) to assess effects of flecainide on burden of VT runs in 7-day ECG recordings; 3) to assess effects of flecainide on burden of atrial premature beats in 7-day recordings; 4) to demonstrate feasibility of enrollment of rare inherited arrhythmia ARVC patients in a randomized study in the light of planned future large clinical trial with VT/VF/death as endpoint.

心律不齐的右心肌病（ARVC）是一种遗传性心律失常疾病 具有高心脏心动过速或纤颤的高风险，以及植入的心脏扭矩除颤器 仍然是选择的姑息治疗。与不同药物在内的抗心律失常治疗 β受体阻滞剂，Sotalol和amiodarone通常无效地降低心律不齐的风险 事件。最新的实验数据使用具有心脏特异性他莫昔芬的新型鼠模型 诱导的PKP2缺乏表明，增强的触发活性和肌质的增加 通过RYR2通道释放网状（SR）钙可能有助于肾上腺素能诱导的 ARVC环境中的心律不齐。这项研究还报道说氟甲化有效地阻止了 在实验动物中观察到的心律不齐。单独的临床前和轶事 临床报告还表明，氟卡尼可能通过RYR2受体的一个块，可能是 ARVC中有希望的抗心律失常方法。此外，在一项小型随机试验中 氟卡因可有效减少儿茶酚胺能患者的心室心律不齐 多态性心室心动过速，与RYR2突变有关的疾病，导致SR增加 释放并触发心律不齐。这些结果为 实施确定氟卡尼是否会确定的确定随机临床试验 在高危ARVC患者中减少威胁生命的VT/VF发作；但是在进行之前 这样的大型研究，一个试点项目的重点是氟甲化治疗及其其抗心律失常的作用及 需要ARVC患者的安全性。因此，我们建议进行一项设计为 随机双盲安慰剂对照跨试验，给予100 mg竞标 氟甲氧酯或匹配的安慰剂，每4周，并进行冲洗期。研究人群将 包括38名被诊断为2010年ARVC特遣队标准的ARVC患者 21岁，已植入ICD，并在24小时的录音中显示至少500个VPB。 该试验试验的主要特定目的是确定氟卡尼给药是否是 与ARVC中的心室异位拍打（VEB）的大量减少有关 ICD的患者。 次要特定目的是：1）评估氟卡尼给药的安全 强调心律失常的反应； 2）评估氟卡尼对VT运行负担的影响 7天的心电图录音； 3）评估氟卡尼对房屋过早节拍负担的影响 7天录音； 4）证明稀有遗传心律不齐的征收的可行性 在一项随机研究中，患者是根据计划的未来大型临床试验和VT/VF/DEATH的患者 作为终点。