Pilot Randomized Trial with Flecainide in ARVC Patients

ARVC 患者使用氟卡尼的随机试验

基本信息

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
项目类别：
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

项目摘要

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有室性心动过速或颤动的高风险，以及植入式心脏复律除颤器仍然作为姑息治疗的选择。使用不同药物的抗心律失常治疗，包括 β-受体阻滞剂、索他洛尔和胺碘酮通常不能有效降低心律失常的风险事件。使用具有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 PKP2 缺乏表明触发活性增强并增加肌质通过 RyR2 通道的网状 (SR) 钙释放可能有助于肾上腺素能诱导 ARVC 情况下的心律失常。这项研究还报告说，氟卡尼可以有效预防在实验动物中观察到的心律失常。分开临床前和轶事临床报告还表明，氟卡尼可能通过阻断 RyR2 受体， ARVC 中一种有前途的抗心律失常方法。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患者的室性心律失常多形性室性心动过速，一种与 RyR2 突变相关的疾病，导致 SR 增加释放并引发心律失常。这些结果为以下结论提供了强有力的理由：实施一项明确的随机临床试验以确定氟卡尼是否会减少高危 ARVC 患者危及生命的 VT/VF 发作；然而在进行之前如此大规模的研究是一个试点项目，重点关注氟卡尼疗法及其抗心律失常作用 ARVC 患者的安全性是必要的。因此，我们建议进行一项试点研究，旨在每日两次服用 100 毫克的随机双盲安慰剂对照交叉试验氟卡尼或匹配的安慰剂，每次 4 周，并有一个清除期。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，已植入ICD，24小时动态心电图显示至少500个VPB。该试点试验的主要具体目的是确定氟卡尼给药是否有效与 ARVC 中室性异位心搏 (VEB) 数量显着减少相关装有 ICD 的患者。次要具体目标是：1) 评估氟卡尼给药的安全性，特别是强调促心律失常反应； 2) 评估氟卡尼对跑步时VT负担的影响 7天心电图记录； 3) 评估氟卡尼对房性早搏负担的影响 7天的录音； 4）证明罕见遗传性心律失常ARVC入组的可行性根据计划的未来大型 VT/VF/死亡临床试验进行随机研究的患者作为端点。