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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dantrolene/Ryanodex | Experimental | Dantrolene/Ryanodex; intravenous administration of dantrolene; 1 mg/ kg IV over 3 minute, one time dose |
|
| Placebo | Placebo Comparator | controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dantrolene/Ryanodex | Drug | muscle relaxant |
|
|
| 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 |
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| William Stevenson, MD | Vanderbilt University Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vanderbilt University Medical Center | Nashville | Tennessee | 37232 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40894163 | Derived | 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. |
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Sixty-eight subjects were enrolled. Fifty-one completed the protocol. 17 participants didn't receive either the drug or the placebo and were withdrawn. Nine due to a prolonged procedure, one developed hypotension, two had tachycardia, one had pulmonary concerns from anesthesia, one participant's eGFR was low, one had a drop in venous oxygen during procedure, one had safety concerns due to several cardioversion's during the procedure and one had a drop in ejection fraction.
A member of the study team identified eligible subjects. Eligible subjects were identified if they were scheduled for a Ventricular Tachycardia (VT) ablation or a Premature Ventricular Contraction (PVC) ablation. The study coordinator then requested permission to contact them about research. If the patient agreed, a member of the study team would approach the patient in person in the Arrhythmia Clinic, Vanderbilt University Hospital, or by phone before ablation.
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| ID | Title | Description |
|---|---|---|
| FG000 | Dantrolene/Ryanodex | Dantrolene/Ryanodex; intravenous administration of dantrolene; 1 mg/ kg IV over 3 minute, one time dose Dantrolene/Ryanodex: muscle relaxant |
| FG001 | Placebo | controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose Placebo: Controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Dantrolene/Ryanodex | Dantrolene/Ryanodex; intravenous administration of dantrolene; 1 mg/ kg IV over 3 minute, one time dose Dantrolene/Ryanodex: muscle relaxant |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Count of Participants | Participants | 10 minutes post drug infusion |
|
24 hours post ablation
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dantrolene/Ryanodex | Dantrolene/Ryanodex; intravenous administration of dantrolene; 1 mg/ kg IV over 3 minute, one time dose Dantrolene/Ryanodex: muscle relaxant |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Intensive Care Unit | Cardiac disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. William Stevenson | Vanderbilt University Medical Center | 615-322-2318 | William.g.stevenson@vumc.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 13, 2023 | Jun 26, 2025 | Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jan 11, 2024 | Jun 26, 2025 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D017180 | Tachycardia, Ventricular |
| ID | Term |
|---|---|
| D013610 | Tachycardia |
| D001145 | Arrhythmias, Cardiac |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D003620 | Dantrolene |
| ID | Term |
|---|---|
| D006827 | Hydantoins |
| D048289 | Imidazolidines |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 |
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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
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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.
| Placebo | Drug | Controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose |
|
| 10 minutes post drug infusion |
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 |
| 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 |
| Arterial Blood Gas - Base Excess | 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 |
| 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 |
controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose
Placebo: Controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Inter-Quartile Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | 17 participants did not receive either the drug or the placebo and were withdrawn from the RCT. Nine due to a prolonged procedure, one developed hypotension, two had tachycardia, one had pulmonary concerns from anesthesia, one participant's eGFR was low, one had a drop in venous oxygen during procedure, one had safety concerns due to several cardioversion's during the procedure and one had a drop in ejection fraction. | Number | participants |
|
controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose
Placebo: Controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | 10 minutes post drug infusion |
|
|
|
| Other Pre-specified | Serial Heart Rate Measurements | Heart rate measurement performed by standard heart rate monitors in the Electrophysiology lab. | Not Posted | pre drug infusion, 1 minute, 5 minute, 10 minute and 20 minutes post infusion | Participants |
| Other Pre-specified | Number of Participants With a Change of Blood Pressure | Change in serial blood pressure at specified time points. | Posted | Count of Participants | Participants | 1 minute, 5 minute,10 minute, 15 minute and 20 minutes post infusion. |
|
|
|
| Other Pre-specified | 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). | Not Posted | pre drug, post drug 1 minute, 5 minute, 10 minute and 20 minutes | Participants |
| Other Pre-specified | 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). | Not Posted | pre drug infusion, 1 minute , 5 minute, 10 minute and 20 minutes post drug infusion | Participants |
| Other Pre-specified | 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). | Not Posted | pre drug infusion , 1 minute, 5 minute, 10 minute and 20 minutes post drug infusion | Participants |
| Other Pre-specified | Serial Pulmonary Cap. Wedge Pressure Measurements | Measuring the Pulmonary Capillary Wedge pressure by the hemodynamic pulmonary cathether | Not Posted | pre drug infusion, 1 minute, 5 minute, 10 minute and 20 minutes post drug infusion | Participants |
| Other Pre-specified | 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. | Not Posted | 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 | Participants |
| Other Pre-specified | Maximum Observed Plasma Concentration | A pharmacokinetic measure to determine the highest concentration of the drug. | Not Posted | 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 | Participants |
| Other Pre-specified | Time to Reach Maximum Observed Plasma Concentration | Tmax (h) Time to maximum concentration by plasma concentration. | Not Posted | 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 | Participants |
| Other Pre-specified | 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. | Not Posted | 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 | Participants |
| Other Pre-specified | Ventricular Effective Refractory Period Pre/Post Dantrolene | Ventricular effective refractory period measured via electrophysiology catheter. | Not Posted | pre-drug infusion, post drug infusion at 5 minutes, 10 minutes,15 minutes and 20 minute post-drug | Participants |
| Other Pre-specified | Oxygen Saturation | Oxygen saturation measured by pulse oximeter, % | Not Posted | pre-procedure, during procedure | Participants |
| Other Pre-specified | Respiratory Rate | Rate of respiration, respiration per minute | Not Posted | pre-procedure, during procedure | Participants |
| Other Pre-specified | Minute Ventilation | Ventilator measured L/min of ventilation | Not Posted | during procedure | Participants |
| Other Pre-specified | Tidal Volume | Volume of ventilated air, measured as L/breath | Not Posted | during procedure | Participants |
| Other Pre-specified | Arterial Blood Gas - pH | Blood gas, obtained from arterial blood supply, pH measurement | Not Posted | pre-procedure, during procedure, two hours post procedure | Participants |
| Other Pre-specified | Arterial Blood Gas - pO2 | Blood gas, obtained from arterial blood supply, mmHg of O2 concentration | Not Posted | Pre-procedure, during procedure, two hours post procedure | Participants |
| Other Pre-specified | Arterial Blood Gas - pCO2 | Blood gas, obtained from arterial blood supply, mmHg of CO2 concentration | Not Posted | pre-procedure, during procedure, two hours post procedure | Participants |
| Other Pre-specified | Arterial Blood Gas - Base Excess | Blood gas, obtained from arterial blood supply, mmHg of CO2 concentration | Not Posted | pre-procedure, during procedure, two hours post procedure | Participants |
| Other Pre-specified | Muscle Strength | Handgrip strength using a dynamometer; measured in pounds of force | Not Posted | pre-procedure, two hours post procedure | Participants |
| Other Pre-specified | Neuromuscular Twitch Height | Twitch amplitude; measured as a % of the baseline calibration twitch amplitude (unitless, % change) | Not Posted | During procedure, post drug infusion at 0, 5, 10, 15, 20 minutes | Participants |
| Other Pre-specified | Respiratory Support | Bag/mask ventilation, CPAP, BiPAP, LMA, or tracheal intubation | Not Posted | pre-procedure, during procedure, and two hours post procedure | Participants |
| Other Pre-specified | Negative Inspiratory Force | Measured by bedside breathing test. | Not Posted | pre-procedure and two hours post procedure | Participants |
| Other Pre-specified | Neuromuscular Train of Four | Train of four stimulation test measured as a % of the fourth stimulation compared to the first (unitless, % change) | Not Posted | pre-procedure, during procedure, post drug infusion at 0, 5, 10, 15, 20 minutes, and continuous | Participants |
| Other Pre-specified | Blood Chemistry | Arterial blood concentrations of sodium, chloride, potassium, ionized calcium, bicarbonate, glucose, and lactate measured in SI ) international system of units. | Not Posted | pre-procedure, during procedure, two hours post procedure | Participants |
| 0 |
| 29 |
| 0 |
| 29 |
| 5 |
| 29 |
| EG001 | Placebo | controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose Placebo: Controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose | 0 | 22 | 0 | 22 | 2 | 22 |
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| D000075224 |
| Cardiac Conduction System Disease |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| Double extra beats/pre drug/placebo |
|
| Double extra beats/post drug/placebo |
|
| Triple extra beats/pre drug/placebo |
|
| Triple extra beats/post drug/placebo |
|
| 10 minutes |
|
| 15 minutes |
|
| 20 minutes |
|