A Clinical Trial Utilizing Dantrolene in Patients With Ventricular Arrhythmias.

Vanderbilt University Medical Center

Status and phase: Completed; Phase 3; Phase 2

Conditions: Ventricular Tachycardia

Treatments: Drug: Placebo; Drug: Dantrolene/Ryanodex

Study type: Interventional

Funder types: Other

Identifiers

NCT04134845

190797

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 68 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 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

Exclusion criteria

• 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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68 participants in 2 patient groups, including a placebo group

Dantrolene/Ryanodex

Experimental group

Description:

Dantrolene/Ryanodex; intravenous administration of dantrolene; 1 mg/ kg IV over 3 minute, one time dose

Treatment:

Drug: Dantrolene/Ryanodex

Placebo

Placebo Comparator group

Description:

controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose

Treatment:

Drug: Placebo