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.

致心律失常性右室心肌病（ARVC）是一种遗传性心律失常疾病 室性心动过速或室颤风险高，植入式心律转复除颤器 仍然是姑息治疗的首选。不同药物的抗肿瘤治疗，包括 β受体阻滞剂、索他洛尔和胺碘酮通常不能有效降低糖尿病的风险。 事件使用心脏特异性他莫昔芬的新型小鼠模型的最新实验数据 诱导的PKP 2缺陷表明，增强触发活动和增加肌浆 通过RyR 2通道的网状（SR）钙释放可能有助于肾上腺素能诱导的 ARVC中的心律失常。这项研究还报告说，氟卡尼有效地防止了 在实验动物中观察到的心律失常。单独的临床前和轶事 临床报告还表明，氟卡尼可能通过阻断RyR 2受体， 在ARVC中有希望的抗肿瘤方法。此外，在一项小型随机试验中， 氟卡尼可有效减少儿茶酚胺能性心律失常患者的室性心律失常， 多态性室性心动过速，一种与RyR 2突变相关的疾病，导致SR增加 释放并引发心律失常。这些结果提供了强有力的理由， 实施确定性随机临床试验，以确定氟卡尼是否 减少高风险ARVC患者中危及生命的VT/VF发作;然而，在进行 这样一项大型研究是一个试点项目，重点是氟卡尼治疗的抗肿瘤作用及其 需要ARVC患者的安全性。因此，我们建议进行一项试验研究， 100 mg bid给药的随机双盲安慰剂对照交叉试验 氟卡尼或匹配的安慰剂治疗4周，各有一个洗脱期。研究人群将 包括38名根据2010年ARVC工作组标准诊断的ARVC患者，他们至少 21岁，植入ICD，24小时霍尔特记录显示至少500个室性早搏。 本试验的主要具体目的是确定氟卡尼给药是否 与ARVC中室性异位搏动（VEB）数量的显著减少相关 ICD患者 次要的具体目的是：1）评估氟卡尼给药的安全性， 强调预防性反应; 2）评估氟卡尼对VT负荷的影响 7-3）评估氟卡尼对房性早搏负荷的影响， 7-日记录; 4）证明入组罕见遗传性心律失常ARVC的可行性 根据计划的未来VT/VF/死亡大型临床试验，随机研究中的患者 作为终点。