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.

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.

Study Overview

• Status: Completed
• Conditions: Ventricular Tachycardia
• Intervention / Treatment: Drug: Dantrolene/Ryanodex; Drug: Placebo

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 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.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dantrolene/Ryanodex; Dantrolene/Ryanodex; intravenous administration of dantrolene; 1 mg/ kg IV over 3 minute, one time dose	Drug: Dantrolene/Ryanodex; muscle relaxant; Other Names: Dantrium, Ryanodex
Placebo Comparator: Placebo; controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose	Drug: Placebo; Controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Inducible Sustained Ventricular Tachycardia/ Ventricular Fibrillation (VT/VF) Utilizing Standardized Stimulation Protocol.	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.	10 minutes post drug infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo.	A standardized induction protocol is performed using programmed ventricular stimulation from the Right Ventricular apex which was done pre-drug/placebo and post drug/placebo. The induction is single, double or triple extra beats of stimulation.	10 minutes post drug infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxygen Saturation	Oxygen saturation measured by pulse oximeter, %	pre-procedure, during procedure
Respiratory Rate	Rate of respiration, respiration per minute	pre-procedure, during procedure
Minute Ventilation	Ventilator measured L/min of ventilation	during procedure
Tidal Volume	Volume of ventilated air, measured as L/breath	during procedure
Arterial Blood Gas - pH	Blood gas, obtained from arterial blood supply, pH measurement	pre-procedure, during procedure, two hours post procedure
Arterial Blood Gas - pO2	Blood gas, obtained from arterial blood supply, mmHg of O2 concentration	Pre-procedure, during procedure, two hours post procedure
Arterial Blood Gas - pCO2	Blood gas, obtained from arterial blood supply, mmHg of CO2 concentration	pre-procedure, during procedure, two hours post procedure
Muscle Strength	Handgrip strength using a dynamometer; measured in pounds of force	pre-procedure, two hours post procedure
Serial Heart Rate Measurements	Heart rate measurement performed by standard heart rate monitors in the Electrophysiology lab.	pre drug infusion, 1 minute, 5 minute, 10 minute and 20 minutes post infusion
Number of Participants With a Change of Blood Pressure	Change in serial blood pressure at specified time points.	1 minute, 5 minute,10 minute, 15 minute and 20 minutes post infusion.
Serial Arterial O2 Sats	Hemodynamic monitoring for O2 sats will be performed during ablation with an arterial line and pulmonary artery (PA) catheter (aka. Swann-Ganz Catheter).	pre drug, post drug 1 minute, 5 minute, 10 minute and 20 minutes
Serial Mixed Venous O2 Sats- Measured From PA Catheter	Hemodynamic monitoring for mixed venous O2 sats will be performed during ablation with an arterial line and pulmonary artery (PA) catheter (aka. Swann-Ganz Catheter).	pre drug infusion, 1 minute , 5 minute, 10 minute and 20 minutes post drug infusion
Serial PA Measurements	PA- mmHg; Hemodynamic monitoring for PA will be performed during ablation with an arterial line and pulmonary artery (PA) catheter (aka. Swann-Ganz Catheter).	pre drug infusion , 1 minute, 5 minute, 10 minute and 20 minutes post drug infusion
Serial Pulmonary Cap. Wedge Pressure Measurements	Measuring the Pulmonary Capillary Wedge pressure by the hemodynamic pulmonary cathether	pre drug infusion, 1 minute, 5 minute, 10 minute and 20 minutes post drug infusion
Per the Pharmacokinetics Measurements That Will be Collected and Measured Offline-drug Half Life	The pharmacokinetic measurement of the time it takes for the concentration of the drug in the body to decrease by half.	post drug infusion at 5 minutes,10 minutes,15 minutes, 20 minutes, 1-4 hours, 6-12 hours,16-24 hours and optional 28-36 hours
Maximum Observed Plasma Concentration	A pharmacokinetic measure to determine the highest concentration of the drug.	Post drug infusion at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 1-4 hours, 6-12 hours,16-24 hours and optional 28-36 hours
Time to Reach Maximum Observed Plasma Concentration	Tmax (h) Time to maximum concentration by plasma concentration.	Post drug infusion at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 1-4 hours, 6-12 hours,16-24 hours and optional 28-36 hours
Area Under the Concentration-time Curve From Zero to Infinity	A measurement of pharmacokinetics which is the area under the curve measured as a function of time.	post drug infusion at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 1-4 hours, 6-12 hours,16-24 hours and optional 28-36 hours
Ventricular Effective Refractory Period Pre/Post Dantrolene	Ventricular effective refractory period measured via electrophysiology catheter.	pre-drug infusion, post drug infusion at 5 minutes, 10 minutes,15 minutes and 20 minute post-drug
Arterial Blood Gas - Base Excess	Blood gas, obtained from arterial blood supply, mmHg of CO2 concentration	pre-procedure, during procedure, two hours post procedure
Neuromuscular Twitch Height	Twitch amplitude; measured as a % of the baseline calibration twitch amplitude (unitless, % change)	During procedure, post drug infusion at 0, 5, 10, 15, 20 minutes
Respiratory Support	Bag/mask ventilation, CPAP, BiPAP, LMA, or tracheal intubation	pre-procedure, during procedure, and two hours post procedure
Negative Inspiratory Force	Measured by bedside breathing test.	pre-procedure and two hours post procedure
Neuromuscular Train of Four	Train of four stimulation test measured as a % of the fourth stimulation compared to the first (unitless, % change)	pre-procedure, during procedure, post drug infusion at 0, 5, 10, 15, 20 minutes, and continuous
Blood Chemistry	Arterial blood concentrations of sodium, chloride, potassium, ionized calcium, bicarbonate, glucose, and lactate measured in SI ) international system of units.	pre-procedure, during procedure, two hours post procedure

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Investigators: Principal Investigator: William Stevenson, MD, Vanderbilt University Medical Center

Publications and helpful links

General Publications

• El-Harasis MA, Yoneda ZT, Varghese B, Grauherr D, Crawford DM, Schmeckpeper J, Williams HL, Ye F, Sun L, Tandri H, Richardson T, Kanagasundram A, Davogustto G, Roden D, Mantinan M, Pretorius M, Billings FT, Siegrist K, Akers WS, Stevenson WG, Knollmann BC, Shoemaker MB. Ryanodine Receptor Inhibition with Dantrolene Prevents Ventricular Tachycardia Induction in Patients with Structural Heart Disease - A Randomized Controlled Trial. medRxiv [Preprint]. 2025 Aug 19:2025.08.17.25333868. doi: 10.1101/2025.08.17.25333868.

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2020
• Primary Completion (Actual): May 29, 2025
• Study Completion (Actual): August 29, 2025

Study Registration Dates

• First Submitted: October 10, 2019
• First Submitted That Met QC Criteria: October 18, 2019
• First Posted (Actual): October 22, 2019

Study Record Updates

• Last Update Posted (Actual): March 10, 2026
• Last Update Submitted That Met QC Criteria: February 17, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Ventricul Tachycardia ablation
• Additional Relevant MeSH Terms: Cardiac Conduction System Disease; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Tachycardia; Pathological Conditions, Signs and Symptoms; Tachycardia, Ventricular; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Imidazoles; Hydantoins; Imidazolidines; Dantrolene
• Other Study ID Numbers: 190797

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No