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Completed

NCT Number: NCT04134845

A Clinical Trial Utilizing Dantrolene in Patients With Ventricular Arrhythmias.

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.

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Key information

Conditions

Ventricular Tachycardia Arrhythmias, Cardiac Cardiac Conduction System Disease Cardiovascular Diseases Heart Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Tachycardia Tachycardia, Ventricular

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Dantrolene/Ryanodex

Drug

muscle relaxant

Other names: Dantrium, Ryanodex

Placebo

Drug

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

Primary outcomes

  1. Number of Participants With Inducible Sustained Ventricular Tachycardia/ Ventricular Fibrillation (VT/VF) Utilizing Standardized Stimulation Protocol.

    Time frame: 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.

Secondary outcomes

  1. Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo.

    Time frame: 10 minutes post drug infusion

    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.

Other outcomes

  1. Serial Heart Rate Measurements

    Time frame: pre drug infusion, 1 minute, 5 minute, 10 minute and 20 minutes post infusion

    Heart rate measurement performed by standard heart rate monitors in the Electrophysiology lab.

  2. Number of Participants With a Change of Blood Pressure

    Time frame: 1 minute, 5 minute,10 minute, 15 minute and 20 minutes post infusion.

    Change in serial blood pressure at specified time points.

  3. Serial Arterial O2 Sats

    Time frame: pre drug, post drug 1 minute, 5 minute, 10 minute and 20 minutes

    Hemodynamic monitoring for O2 sats will be performed during ablation with an arterial line and pulmonary artery (PA) catheter (aka. Swann-Ganz Catheter).

  4. Serial Mixed Venous O2 Sats- Measured From PA Catheter

    Time frame: pre drug infusion, 1 minute , 5 minute, 10 minute and 20 minutes post drug infusion

    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).

  5. Serial PA Measurements

    Time frame: pre drug infusion , 1 minute, 5 minute, 10 minute and 20 minutes post drug infusion

    PA- mmHg; Hemodynamic monitoring for PA will be performed during ablation with an arterial line and pulmonary artery (PA) catheter (aka. Swann-Ganz Catheter).

  6. Serial Pulmonary Cap. Wedge Pressure Measurements

    Time frame: pre drug infusion, 1 minute, 5 minute, 10 minute and 20 minutes post drug infusion

    Measuring the Pulmonary Capillary Wedge pressure by the hemodynamic pulmonary cathether

  7. Per the Pharmacokinetics Measurements That Will be Collected and Measured Offline-drug Half Life

    Time frame: 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

    The pharmacokinetic measurement of the time it takes for the concentration of the drug in the body to decrease by half.

  8. Maximum Observed Plasma Concentration

    Time frame: 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

    A pharmacokinetic measure to determine the highest concentration of the drug.

  9. Time to Reach Maximum Observed Plasma Concentration

    Time frame: 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

    Tmax (h) Time to maximum concentration by plasma concentration.

  10. Area Under the Concentration-time Curve From Zero to Infinity

    Time frame: 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

    A measurement of pharmacokinetics which is the area under the curve measured as a function of time.

  11. Ventricular Effective Refractory Period Pre/Post Dantrolene

    Time frame: pre-drug infusion, post drug infusion at 5 minutes, 10 minutes,15 minutes and 20 minute post-drug

    Ventricular effective refractory period measured via electrophysiology catheter.

  12. Oxygen Saturation

    Time frame: pre-procedure, during procedure

    Oxygen saturation measured by pulse oximeter, %

  13. Respiratory Rate

    Time frame: pre-procedure, during procedure

    Rate of respiration, respiration per minute

  14. Minute Ventilation

    Time frame: during procedure

    Ventilator measured L/min of ventilation

  15. Tidal Volume

    Time frame: during procedure

    Volume of ventilated air, measured as L/breath

  16. Arterial Blood Gas - pH

    Time frame: pre-procedure, during procedure, two hours post procedure

    Blood gas, obtained from arterial blood supply, pH measurement

  17. Arterial Blood Gas - pO2

    Time frame: Pre-procedure, during procedure, two hours post procedure

    Blood gas, obtained from arterial blood supply, mmHg of O2 concentration

  18. Arterial Blood Gas - pCO2

    Time frame: pre-procedure, during procedure, two hours post procedure

    Blood gas, obtained from arterial blood supply, mmHg of CO2 concentration

  19. Arterial Blood Gas - Base Excess

    Time frame: pre-procedure, during procedure, two hours post procedure

    Blood gas, obtained from arterial blood supply, mmHg of CO2 concentration

  20. Muscle Strength

    Time frame: pre-procedure, two hours post procedure

    Handgrip strength using a dynamometer; measured in pounds of force

  21. Neuromuscular Twitch Height

    Time frame: During procedure, post drug infusion at 0, 5, 10, 15, 20 minutes

    Twitch amplitude; measured as a % of the baseline calibration twitch amplitude (unitless, % change)

  22. Respiratory Support

    Time frame: pre-procedure, during procedure, and two hours post procedure

    Bag/mask ventilation, CPAP, BiPAP, LMA, or tracheal intubation

  23. Negative Inspiratory Force

    Time frame: pre-procedure and two hours post procedure

    Measured by bedside breathing test.

  24. Neuromuscular Train of Four

    Time frame: pre-procedure, during procedure, post drug infusion at 0, 5, 10, 15, 20 minutes, and continuous

    Train of four stimulation test measured as a % of the fourth stimulation compared to the first (unitless, % change)

  25. Blood Chemistry

    Time frame: pre-procedure, during procedure, two hours post procedure

    Arterial blood concentrations of sodium, chloride, potassium, ionized calcium, bicarbonate, glucose, and lactate measured in SI ) international system of units.

Sponsors and collaborators

Lead sponsor

Vanderbilt University Medical Center

Other

Registry information

Official study title

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

Important dates

Study start
2020
Primary completion
2025
Study completion
2025
First posted
Oct 22, 2019
Registry last updated
Mar 10, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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