A Randomized Controlled Trial of RyR2 Inhibition With Dantrolene and Susceptibility to Ventricular Arrhythmias in Patients With Structural Heart Disease.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 68
- 试验地点
- 1
- 主要终点
- Number of Participants With Inducible Sustained Ventricular Tachycardia/ Ventricular Fibrillation (VT/VF) Utilizing Standardized Stimulation Protocol.
研究概览
简要总结
This is a randomized, placebo-controlled trial of Dantrolene (N= 84 participants) to demonstrate the feasibility of using intravenous (IV) dantrolene to study the effect of RyR2 inhibition on cardiac electrophysiology, hemodynamics, and ventricular arrhythmia inducibility in patients with structural heart disease referred for Ventricular Tachycardia (VT) ablation. The investigators will also explore the pharmacokinetic/pharmacodynamic relationship of IV dantrolene and its short-term effect on specific cardiac electrophysiologic and hemodynamic parameters.
详细描述
The hypothesis to be tested is that RyR2 hyperactivity in patients with structural heart disease drives proarrhythmic changes in refractoriness and conduction, and decreases cardiac contractility, which promotes Ventricular Tachycardia/Ventricular Fibrillation (VT/VF). Dantrolene, a currently available drug that inhibits RyR2, but has no Sodium (Na) or potassium (K) channel activity, will be used as a tool to study RyR2 modulation. The investigators propose a randomized controlled trial of dantrolene versus placebo in patients with structural heart disease referred for VT ablation to evaluate electrophysiologic, hemodynamic, and arrhythmia prevention endpoints. Dantrolene's inhibition of RyR1 will also be studied to define its effect on muscle and respiratory strength in this clinical population, which will be important if dantrolene is to be considered for repurposing as an antiarrhythmic drug.
The two aims are:
Aim 1: To conduct a randomized, placebo-controlled trial of dantrolene to study the effect of RyR inhibition on cardiac electrophysiology, hemodynamics, arrhythmia inducibility, muscle strength, and respiratory mechanics in patients with structural heart disease referred for Ventricular Tachycardia (VT) ablation.
Aim 2: To explore the pharmacokinetic/pharmacodynamic relationship of IV dantrolene and its short-term effect on cardiac electrophysiology, hemodynamics, and muscle and respiratory strength.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
The study statistician will generate the allocation schedule but will remain blinded to the treatment assignment as well as the study staff physician's. The research clinician will not be blinded.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Greater than or equal to 18 years of age
- •Able to give written informed consent
- •Referred for catheter-based VT ablation
- •Structural heart disease (cardiomyopathy or RV/LV scar)
- •Permanent pacemaker or implantable cardioverter defibrillator
排除标准
- •Mechanical ventricular support (e.g. LVAD, ECMO)
- •NYHA class IV heart failure
- •LVEF < 20%
- •Morbid obesity (BMI > 40 kg/m2)
- •Severe renal insufficiency (GFR<30 mL/min)
- •Chronic liver disease (Child Pugh class A-C)
- •Current use of calcium channel blockers
- •Neuromuscular disorder (e.g. muscular dystrophy)
- •Chronic obstructive pulmonary disease or restrictive lung disease requiring oxygen
- •Therapy or history of intubation
- •Pregnant or nursing
- •History of dysphagia
研究组 & 干预措施
Dantrolene/Ryanodex
Dantrolene/Ryanodex; intravenous administration of dantrolene; 1 mg/ kg IV over 3 minute, one time dose
干预措施: Dantrolene/Ryanodex (Drug)
Placebo
controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participants With Inducible Sustained Ventricular Tachycardia/ Ventricular Fibrillation (VT/VF) Utilizing Standardized Stimulation Protocol.
时间窗: 10 minutes post drug infusion
Post drug ventricular stimulation with Right Ventricle (RV) ventricular catheter in the Right Ventricle( RV) apex with increasing extra stimuli with planned decrement stimuli by 10 milliseconds (ms) to effective refractory period (ERP). Outcome is measured as Ventricular inducibility yes/no.
次要结局
- Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo.(10 minutes post drug infusion)
研究者
William Stevenson
Professor of Medicine
Vanderbilt University Medical Center