A Clinical Trial Utilizing Dantrolene in Patients With Ventricular Arrhythmias.

A Randomized Controlled Trial of RyR2 Inhibition With Dantrolene and Susceptibility to Ventricular Arrhythmias in Patients With Structural Heart Disease.

Sponsors

Lead Sponsor: Vanderbilt University Medical Center

Source Vanderbilt University Medical Center
Brief Summary

This is a randomized, placebo controlled trial of Dantrolene (N= 84 participants) to demonstrate the feasibility of using I.V. dantrolene to study the effect of RyR2 inhibition on cardiac electrophysiology, hemodynamics and ventricular arrhythmia inducibility in patients with structural heart disease referred for VT ablation. The investigators will also explore the pharmacokinetic/pharmacodynamic relationship of I.V. dantrolene and it short-term effect on specific cardiac electrophysiologic and hemodynamic parameters.

Detailed 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 VT/VF. Dantrolene, a currently available drug that inhibits RyR2, but has no Na or 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 VT ablation. Aim 2: To explore the pharmacokinetic/pharmacodynamic relationship of I.V. dantrolene and its short-term effect on cardiac electrophysiology, hemodynamics, and muscle and respiratory strength.

Overall Status Recruiting
Start Date 2020-08-21
Completion Date 2023-06-01
Primary Completion Date 2023-06-01
Phase Phase 2/Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Inducibility of sustained VT/VF by standardized ventricular stimulation protocol 10 minutes post drug infusion
Secondary Outcome
Measure Time Frame
Stage of inducibility by standardized ventricular stimulation protocol of the sustained VT/VF 10 minutes post drug infusion
Enrollment 84
Condition
Intervention

Intervention Type: Drug

Intervention Name: Dantrolene/Ryanodex

Description: muscle relaxant

Arm Group Label: Dantrolene/Ryanodex

Other Name: Dantrium, Ryanodex

Intervention Type: Drug

Intervention Name: Placebo

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

Arm Group Label: Placebo

Eligibility

Criteria:

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

Gender:

All

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
William Stevenson, MD Principal Investigator Vanderbilt University Medical Center
Overall Contact

Last Name: William Stevenson, MD

Phone: 615-322-2318

Email: [email protected]

Location
Facility: Status: Contact: Contact Backup: Investigator: Vanderbilt University Medical Center William Stevenson, MD 615-322-2318 [email protected] William Stevenson, MD Principal Investigator Ben Shoemaker, MD Sub-Investigator
Location Countries

United States

Verification Date

2020-11-01

Responsible Party

Type: Principal Investigator

Investigator Affiliation: Vanderbilt University Medical Center

Investigator Full Name: William Stevenson

Investigator Title: Professor of Medicine

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Dantrolene/Ryanodex

Type: Experimental

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

Label: Placebo

Type: Placebo Comparator

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

Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Intervention Model Description: 84 participants will be randomly assigned in a 2:1 ratio to treatment (dantrolene) or control (placebo). A computer-generated randomization list will be prepared by the study statistician using the stratified permuted block randomization, where block size varies randomly from 4 or 6 to ensure overall balance across treatment arms. Randomization will be stratified by 1) documented CAD with prior infarct, 2) amiodarone use within the past 21 days defined as chronic oral use or >5 grams cumulative, 3) LVEF <35%. Enrollment will be evenly distributed across the two study arms by the stratification factors

Primary Purpose: Treatment

Masking: Double (Participant, Investigator)

Masking Description: 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.

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